DK - PhD Thesis (FINAL)

PRACTICAL NAZAROV CHEMISTRY

FOR ORGANIC SYNTHESIS:

Concise Synthesis of Roseophilin and

Auxiliary Mediated Asymmetric Nazarov Reaction

A Thesis Presented for the Degree of

Doctor of Philosophy

Daniel J. Kerr

Department of Medicinal Chemistry

Victorian College of Pharmacy

Monash University

2009

- i -

DECLARATION

The work described in this thesis is my own and has not been submitted for a degree or diploma at

any other university or college, except where otherwise stated. To the best of my knowledge, it

does not contain material previously published or presented by any other person except where due

reference has been made in the text.

Daniel Jarrah Kerr

- ii -

ACKNOWLEDGEMENTS

I would like to take this opportunity to thank and recognise the people who have helped make the

years undertaking my PhD research years a valuable and rewarding experience.

First and foremost I would like to thank my supervisor Dr. Bernard Flynn, whose knowledge and

enthusiasm have proved inspirational in keeping the projects progressing.

I would like to thank Professor Peter Scammells and the VCP Medicinal Chemistry Department

for the opportunity to undertake this research.

I would like to thank the staff and student body of the Victorian College of Pharmacy (particularly

members of the Flynn and Scammells groups) for creating a stimulating and enjoyable

environment in both the lab and office.

I would also like to thank Professor Jonathan White at the Bio21 Institute (Melbourne University)

for obtaining the X-ray crystal structure of compound 364.

Finally, I would like to thank my family who have always supported me.

Cheers.

- iii -

ABSTRACT

The work described herein is all based on methodology developed previously within our

group (Scheme A).9 Carbonyl-alkynes 150 are hydrostannylated under palladium catalysis and

coupled in one-pot with α,β-unsaturated acid chlorides 142 to give dienones 33. Nazarov

cyclisation of 33 then allows concise access to cyclopentenones 37.

R2

O R1

R1

O

R2

Bu3SnR1

O

R2

R3

R4

O

150 151

ClR3

R4

O

Bu3SnH

Pd0 CuI

33

142

O

R3

R4 R2

R1

OACID

Nazarov

37 Scheme A; Cyclopentenoids by hydrostannylation-coupling and Nazarov reaction.

Two approaches towards the natural product roseophilin 156 were attempted (Schemes C

and D). The unique macrocyclic deep red pigment roseophilin 156 (Scheme B) was isolated from

the culture broth of Streptomyces griseoviridis and exhibits potent cytotoxicity towards several

human cancer cell lines, though the exact mechanism of its action is unknown.44 Unfortunately, the

inherent toxicity of 156 is too high for its development as a drug. It was our aim to develop a

strategy for the synthesis of roseophilin that is very concise, inexpensive and amenable to

adaptation to generate the multitude of analogs required for detailed SAR and medicinal chemistry

studies.

Both strategies were directed towards the concise construction of the macrocyclic

ketopyrrole fragment 157 (Scheme B). Condensation of this fragment with the pyrrolylfuran 158

has been achieved previously and the synthesis of this ketopyrrole fragment 157 constitutes a

formal synthesis of roseophilin.

PgN

O

O

N

OMe

Cl

Pg'

O

HN

OMe

Cl

N

157156 158 Scheme B; Common retrosynthetic strategic disconnection of roseophilin (156).

- iv -

The first strategy was based around the production of the cyclopenta[b]pyrrole core with

our previously described methodology (Scheme C, Chapter 2). The pyrrole-containing Nazarov

precursor 176 was accessed by our hydrostannylation-coupling reaction, Nazarov reaction of this

substrate gave 177 which was then elaborated to the diene 178. Unfortunately, the ring-closing

metathesis (RCM) of this class of substrate was not achievable.

Pg

NO Pg

N

O

Pg

N

O

Y

OO

Y

Pg

NO

Cl

YO

Pg

N

OY = OEt, O

N O

Ph

174

( )n

( )6-n

( )n( )n

( )n

Bu3SnH

Pd0/CuI

Nazarov

i) RCM

ii) H2/Pd

175 176 177

178 157

Steps

Scheme C; Attempted synthesis of ketopyrrole fragment 157 by Nazarov reaction of a pyrrole-based precursor.

An alternative route to fragment 157 (as the unprotected 167) was pursued and a concise

racemic formal synthesis of roseophilin was developed based on a homologated variant of our

standard hydrostannylation-coupling reaction (Scheme D, Chapter 3). Hydrostannylation of

homologated keto-alkynes such as 286 has not yet been reported and the adaptation of our standard

reaction to allow the coupling of 286 with 264 involved significant optimisation. The coupling

product 297 was cyclised under hydrolytic conditions to give racemic 300 which was then

successfully elaborated to the ketopyrrole fragment 167 in three steps.

O

( )4

286

MeOCl

O

264 297

OH

OO

((((±±±±))))-309

HN

O

((((±±±±))))-167

OH

OO

((((±±±±))))-300

OO

MeO

( )4

Bu3SnH

Pd0/CuI

Nazarov

i) RCM

ii) H2/Pd

Paal-

Knorr

Scheme D; Concise synthesis of ketopyrrole fragment 167 based on a homologated variant of our coupling reaction.

- v -

We also investigated the oxazolidinone auxiliary mediated asymmetric Nazarov reaction

(Scheme E, Chapter 4). Auxiliary-bearing substrates S-SM were synthesised using our

hydrostannylation-coupling reaction. In most cases we were able to isolate good yields of a single

diastereomeric product. Significantly, we found the particular major product for a specific

substrate was primarily determined by the aliphatic or aromatic nature of the β-substituents.

O

R2

R1

Alkyl

N

O

O

O

R2

R1

Alkyl

O

O

N

OO

S-SM-Ak S-αααα-trans

O

R2

R1

Aryl

N

O

O

O

S-SM-Ar

R2

R1

Aryl

O

O

N

OO

S-ββββ-tr ans

Protic Acid Lewis Acid

Scheme E; The oxazolidinone-auxiliary mediated asymmetric Nazarov reaction.

Some other aspects of Nazarov chemistry were also investigated, along with a related

cyclopentenylation reaction (Scheme F, Chapter 5).

O

NMe2

O

OMe

OMe

OMe

MeO

Nu

OMe

MeO

MeO

O

NMe2

OMe

417

MeSO3H

Nu-

411 Nu

OMe

MeO

MeO

O

NMe2

OMe

418

SiO2

Scheme F; Indenes by tandem Friedel-Crafts / Nucleophilic substitution (Nu = Cl, OR, SR, heteroaryl).

- vi -

GLOSSARY OF ABBREVIATIONS (±)- racemic

Ac acetyl

AlCl3 aluminium chloride

app. apparent (NMR, Japp = apparent coupling constant)

aq. aqueous

Aux auxiliary

Bn benzyl

BOC tert-butoxycarbonyl

BOX bisoxazoline ligands

br s broad singlet

Bu / n-Bu n-Butyl

BuLi butyllithium

Bu3SnH tributyltin hydride

calcd calculated

cat. catalyst / catalytic

cm-1 wave number

conc. concentrated

Cu(OTf)2 cupric triflate

CuTC copper(I) thiophene-2-carboxylate

d day/s (or doublet for NMR data)

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE 1,2-dichloroethane

DCM dichloromethane

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

δ chemical shift (ppm)

∆ thermal conditions / heated

DMAP 4-(N,N-dimethylamino)pyridine

DMF N,N-dimethyformamide

DMSO dimethyl sulfoxide

dr diastereoisomeric ratio

ee enantiomeric excess

- vii -

ESI electrospray ionisation

Et ethyl

Et2O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

eV electron volt/s

FeCl3 ferric chloride

FMO frontier molecular orbital (theory)

g grams, gas

h hours

HCl hydrochloric acid

HFIP 1,1,1,3,3,3-hexafluoroisopropanol

HOMO highest occupied molecular orbital

HRMS high resolution mass spectrometry

Hz hertz

IC50 50% inhibitory concentration

i-Pr isopropyl

IR infrared (spectrum)

J coupling constant (Hz)

JMOD J-modulated spin echo

L.A. Lewis acid

LDA lithium diisopropylamide

LiHMDS lithium hexamethyldisilazide

LRMS low resolution mass spectrometry

LUMO lowest unoccupied molecular orbital

mc centred multiplet

Me methyl

MeCN acetonitrile

MeOH methanol

MeSO3H methanesulfonic acid

min minute/s

MOM methoxymethyl

MP melting point

- viii -

m/z mass-to-charge ratio

NBS N-bromosuccinimide

NMR nuclear magnetic resonance

n-Pr n-propyl

Nu nucleophile

ORTEP Oak Ridge thermal ellipsoid plot

Pg protecting group

Ph phenyl

ppm parts per million

pyBOX pyridyl-bisoxazoline ligands

q quartet

quin quintet

Rac racemic

RCM ring closing metathesis

Rf retardation factor (chromatography)

rt room temperature

s singlet

SAR structure-activity relationship

s-Bu sec-butyl

SEM (2-(trimethylsilyl)ethoxy)methyl

sept septet

sext sextet

t triplet

TBS tert-butyldimethylsilyl

t-Bu tert-butyl

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

TFE 2,2,2-trifluoroethanol

THF tetrahydrofuran

TIPS triisopropylsilyl

TLC thin layer chromatography

TMS trimethylsilyl

Ts p-toluenesulfonyl

- ix -

TABLE OF CONTENTS

DECLARATION I

ACKNOWLEDGEMENTS II

ABSTRACT III

GLOSSARY OF ABBREVIATIONS VI

CHAPTER 1: INTRODUCTION 1

1.1 THE NAZAROV REACTION 2

1.1.1 MECHANISM AND BACKGROUND 2

1.1.2 RECENT DEVELOPMENTS 4

1.1.3 INTERRUPTED NAZAROV REACTIONS 8

1.1.4 ASYMMETRIC NAZAROV REACTIONS 12

1.1.5 SYNTHESIS OF NAZAROV SUBSTRATES 20

1.2 ROSEOPHILIN 23

1.2.1 OCCURRENCE AND BIOLOGICAL ACTIVITY 23

1.2.2 PREVIOUS SYNTHETIC EFFORTS 24

CHAPTER 2: ROSEOPHILIN SYNTHESIS; PYRROLE APPROACH 28

2.1 OUR SYNTHETIC STRATEGY 28

2.2 RACEMIC MODEL STUDY 29

2.3 ASYMMETRIC MODEL STUDY 31

2.4 THE REAL SYSTEM; ASYMMETRIC EFFORTS 33

2.5 THE REAL SYSTEM; RACEMIC EFFORTS 36

2.6 RCM FAILURE AND ITS IMPLICATIONS 37

- x -

CHAPTER 3: ROSEOPHILIN SYNTHESIS; Α-ALKOXY APPROACH 40

3.1 A NEW SYNTHETIC STRATEGY 40

3.2 SYNTHETIC EFFORTS BASED ON OUR STANDARD PROTOCOL 41

3.3 HYDROSTANNYLATION STUDIES OF REMOTELY ACTIVATED ALKYNES 44

3.4 HYDROSTANNYLATION-COUPLING AND NAZAROV REACTION 48

3.5 COMPLETING THE CONCISE SYNTHESIS OF ROSEOPHILIN 52

3.6 CONCLUSION; ANALOGING AND ASYMMETRY 56

CHAPTER 4: THE ASYMMETRIC NAZAROV REACTION 59

4.1 SYNTHESIS OF AUXILIARY-BEARING NAZAROV PRECURSORS 60

4.2 STUDY GOALS 62

4.3 AUXILIARY EVALUATION 63

4.4 SUBSTRATE STUDY 66

4.5 PRODUCT DISTRIBUTION 71

4.6 STEREOCHEMISTRY AND SPECTROSCOPY 75

4.7 SUMMARY 82

CHAPTER 5: MISCELLANEOUS DEVELOPMENTS 83

5.1 INDENES BY TANDEM FRIEDEL-CRAFTS / NUCLEOPHILIC SUBSTITUTION 83

5.2 ONE-POT HYDROSTANNYLATION-COUPLING / NAZAROV 85

CHAPTER 6: EXPERIMENTAL 86

CHAPTER 7: REFERENCES 147

APPENDICES 150

Chapter 1: Introduction

- 1 -

CHAPTER 1: INTRODUCTION

Providing meaningful access to structurally complex bioactive natural products and gaining

diversity-orientated synthetic access to natural product-like and drug-like compounds represent

fascinating challenges to methodology development within organic synthesis. Both require

protocols that are concise and selective (chemoselective, regioselective, diastereoselective and

enantioselective). There is an increasing demand for the development of synthetic methodologies

that allow efficient access to complex natural products, natural product-like molecules and simpler

analogs of natural products. Such methods have applications in both target-oriented and diversity-

oriented synthesis and in drug discovery. Rigid polycyclic molecules are recognised as being

particularly important scaffolds because of their potential to bind more tightly and selectively to

biomolecular targets than more linear or acyclic molecules.

The most prevalent carbocycle in natural products and pharmaceuticals is the six-

membered ring. Synthetically it is most commonly assembled by the [4+2]-cycloaddition or Diels-

Alder reaction. The versatility and selectivity (chemo, regio, diastereo and enantioselectivity)

possible with the Diels-Alder reaction has prompted its use as the key step in the synthesis of many

complex polycyclic cores. Second only to the six-membered ring in terms of prevalence, the five-

membered ring is found in many natural products and pharmaceuticals. Unfortunately, a suitably

versatile [3+2]-cycloaddition equivalent of the Diels-Alder reaction does not exist.

Recent investigations and developments of the Nazarov reaction have revealed it to be a

versatile and selective method of producing cyclopentanoids 4 (Scheme 1.1).1 The recognition that

the requisite dienone substrates 3 can be efficiently constructed by the coupling of vinyl-metals 1

to α,β-unsaturated carbonyl compounds 2 means this combined strategy (coupling and Nazarov)

can potentially be developed into an appropriately versatile two-step protocol for the formal [3+2]-

cycloadditive synthesis of five-membered rings. Both steps need development if this strategy is to

be of comparable utility in constructing 5-membered rings as the Diels-Alder cycloaddition is in

constructing 6-membered rings. It is the objective of this study to undertake such developments

and apply them to the synthesis of a complex natural product.


- 2 -

O

3

O

Y

2

M

1

O

4

Nazarov

Cyclisation

Coupling

Reaction+

Scheme 1.1; A Nazarov-based approach to cyclopentanoids (M = metal, Y = Cl, NR2, H with subsequent oxidation).

1.1 The Nazarov Reaction

1.1.1 Mechanism and background

The origins of what is now known as the Nazarov reaction can be traced back to the work

of I.N. Nazarov.2 In his extensive study of the chemistry of vinyl-acetylenes, Nazarov disclosed

the transformation of diene-ynes 5 to cyclopentenones 8 by heating in mineral acids (Scheme 1.2).

With further analysis and development the transformation was determined to proceed through

intermediates 6 and 7. The final step in this process is now what is classified as a Nazarov reaction.

R1O

R1

O

R1

O

R1Conc. Mineral Acid

∆

5 6 7 8

R2

R2 R2R2

Scheme 1.2; Reaction cascade reported by I.N. Nazarov in the early 1940’s.

The Nazarov reaction is now most often defined as the acid promoted transformation of

divinyl-ketones 9 to cyclopentenones 12-19 and is understood to proceed as outlined below

(Scheme 1.3). Treatment of 9 with either a Brønsted or Lewis acid promotes formation of the

delocalised cation 10, which undergoes a 4π-electrocyclisation to form oxallyl cation 11, hydrogen

migration then produces products 12-19. Hydrogen migration occurs through proton elimination

followed by tautomerisation of the resultant enol to the corresponding ketone. Enol protonation

occurs initially from the less-hindered face producing cis-products 12-15, these may or may not

isomerise to trans-products 16-19.


- 3 -

O

R1 R3

R4R2

R1 R3

R4R2

O-Acid O-Acid

R1

R2 R4

R3

O

R1

R2 R4

R3

O

R1

R2 R4

R3

O

R1

R2 R4

R3

O

R1

R2 R4

R3

O

R1

R2 R4

R3

O

R1

R2 R4

R3

O

R1

R2 R4

R3

O

R1

R2 R4

R3

Acid 4π

9 10 11

12 16

13 17

14 18

15 19

R2 R4

R2

R4

R1 R3 R1 R3O-Acid O-Acid

4π

∆

Ψ2

Scheme 1.3; The Nazarov reaction (normal / thermal conditions).

The pericyclic nature of the Nazarov reaction dictates that the 4π-electrocyclisation occurs

in a conrotatory fashion under normal (thermal) conditions as a result of the anti-symmetric nature

of the 4π HOMO (Ψ2), as predicted by frontier molecular orbital (FMO) theory. The pericyclic

nature is best demonstrated by the complementary rotatory pathways observed by Woodward et.al.

in the cyclisation of 20 under either thermal or photochemical conditions (Scheme 1.4).3 Under

thermal conditions the HOMO is Ψ2 and a conrotation of the two ends of the pentadienyl cation is

required to achieve bond formation (ring closure) between orbital nodes of the same phase. Under

photochemical conditions the HOMO is Ψ3 (singularly occupied) and bears opposite symmetry to

Ψ2, thus a disrotation is required to achieve bond formation between orbital nodes of the same

phase. As with all pericyclic processes, orbital symmetry and stereochemistry are inexorably

linked.

R2 R4

R2

R4

R1 R3 R1 R3O-Acid O-Acid

4π

∆

Ψ2

R2 R4

R2 R4

R1 R3 R1 R34π

hν

Ψ3

O O

O

R R

O

R R

H

O

R R

H

20

21

22

H 3PO4

, AcOH

50°C

254 nm

conrotatory

disr otator y

Photochemical Conditions (disrotatory)

Thermal Conditions (conrotatory)

Scheme 1.4; Complementary rotatory pathways for thermal and photochemical Nazarov reactions (R = H, Me).


- 4 -

1.1.2 Recent developments

Since its origins, the Nazarov reaction had until very recently received limited attention

from the synthetic community. Major reasons for this lack of attention were the harsh conditions

originally needed (concentrated strong mineral acids and heating) and the sometimes poor control

over the regio- and stereochemistry of products formed (see Scheme 1.3). In the last 5-10 years,

however, efforts towards addressing these shortcomings have allowed the reaction to be

significantly developed. Major advancements have been the recognition that Lewis acids are

effective in promoting the reaction and that the reaction works in aprotic solvents, with chlorinated

solvents being particularly useful. The current interest in the reaction has produced some

fascinating and useful chemistry, this is well illustrated by the number of recent reviews of the

Nazarov reaction.1 Some key developments are outlined below.

A greater understanding of the reactivity profile of the reaction has been developed.

Because the reaction proceeds via a cationic mechanism, substituents that can stabilise the cationic

intermediates increase the reactivity of substrates. Aromatic substituents are observed to be more

promoting of reactivity than are aliphatic groups and electron-donating groups on aromatic

substituents further add to substrate reactivity.

Substituent effects on substrate conformation are also important considerations (Scheme

1.5). Ideally, substrates should be substituted at both α-positions as this allows the greatest

population of the reactive U-conformer. The absence of substituents at the α-positions is observed

to lead to a significant reduction in substrate reactivity. This can be explained by considering the

expected relative population of the reactive U-conformer. When R1 and R2 = Hydrogen it is

expected that the unreactive S and W-conformers will predominate as a result of their lower steric

congestion relative to the U-conformer. Substrates bearing internal substituents are also observed

to suffer reduced reactivity on a similar basis. The population of the reactive U-conformer is

significantly reduced as a result of its great steric congestion. Despite the observed lower reactivity

of substrates either lacking α-substitution or bearing internal substituents, numerous examples of

successful Nazarov cyclisation of both classes of substrates do exist.


- 5 -

R1

R2 R4

R3

OO

R3

R4

R1

R2

O

R1

R2 R3

R4

O

R1

R2 R4

R3

S UW P

H

R2 R4

R3

OO

R3

R4

H

R2

O

H

R2 R3

R4

O

H

R2 R4

R3

S UW P

O

R1

R2R4

R3

R5

P

R1

R2R4

R3

O

R5

U

R1

R2

O

R3

R4

R5

S

O

R3

R4

R1

R2

R5

W

Acid

Acid

Acid

Ideal Substitution (R1, R3 ≠ H)

Lowered Reactivity With Substrates Lacking α-Substitution

Lowered Reactivity With Substrates Bearing Internal Substituents

Scheme 1.5; Substitution effects on conformation and substrate reactivity.

An important regioselectivity consideration is the placement of the double bond in the

product resulting from proton elimination from the allyl cation 11 to give 12-19 (Scheme 1.3). The

regiochemistry of this double-bond placement can be controlled by the incorporation of

electrofugal leaving groups.4,5 Treatment of either β-silyl or β-stannyl Nazarov substrates of type

23 with acid produces products 26 or 27 in a regiocontrolled manner with elimination of the metal

(Scheme 1.6). Products 26 and 27 would normally be disfavoured on both kinetic and

thermodynamic grounds.

O

R1

MR2

R1

MR2

O-Acid O-Acid

R1

R2 M

O

R1

R2

Acid 4π

23 24 25 26

O

R1

R2

27 Scheme 1.6; TMS (and tin) directed Nazarov reaction (M = Me3Si or Bu3Sn).

Similarly if substrates bear a silyl group on an α-substituent, as in 28 (Scheme 1.7), the

Nazarov reaction will proceed with elimination of the silyl group producing products 31 or 32 with

an exocyclic double-bond.6


- 6 -

O

R3

R4R2

R3

R4R2

O-Acid O-Acid

R2 R4

R3

O

R2 R4

R3

O

R2 R4

R3Acid 4π

28 29 30 31 32

TMS TMS TMS

R1 R1R1R1R1

Scheme 1.7; TMS directed Nazarov reaction.

Substrates bearing a carbonyl functionality in an α-position 33 have been demonstrated to

produce products 37 with the double-bond on the opposite side to the carbonyl (Scheme 1.8).7,8,9

This regiocontrol is most likely a result of the charge localisation in the oxallyl cation being such

that the positive charge is on the far side of the carbonyl, allowing for a donor-acceptor

relationship to exist between the enol and carbonyl in 35. Elimination of the hydrogen from the

carbon adjacent to the cation generates the double bond. Additionally, the ease of epimerisation of

1,3-dicarbonyls means trans-configured 37 is most often the sole product.

O

R3

R4R2

R3

R4R2

O-Acid O-Acid

R2 R4

R3

O

R2 R4

R3

O

R2 R4

R3Acid 4π

33 34 35 36 37 (sole product)

R1

O O

R1

O

R1

O O

R1 R1

Scheme 1.8; The Nazarov reaction of carbonyl-bearing substrates.

Substrates with a heteroatom (oxygen,10 nitrogen11 or fluorine12) in an α-position 38 have

also been well studied (Scheme 1.9). With these systems the double-bond in the products (41 or

42) is located on the side of the molecule containing the heteroatom. This regiocontrol is most

likely a result of charge localisation in the oxallyl cation being such that the positive charge is

stabilised by the heteroatom (as in 40). Proton elimination from the adjacent carbon results in

products 41 and/or 42. Additionally, Nazarov reactions of these substrates have been shown to be

quite facile (oxygen and nitrogen variants) presumably as a result of the stabilisation of cationic

intermediates 39 and 40 by the electron-donating heteroatom. These reactions can quite commonly

be achieved with only catalytic quantities of Lewis acid.

O

Y R3

R4R2

Y R3

R4R2

O-Acid O-Acid

Y

R2 R4

R3

O

Y

R2 R4

R3

O

Y

R2 R4

R3Acid 4π

38 39 40 41 42 Scheme 1.9; The Nazarov reaction of heteroatom-bearing substrates (Y = OR, NR2 or F).

Substrates possessing both carbonyl and heteroatom functionalities 43 have been shown to

be exceptionally facile Nazarov substrates (Scheme 1.10).13 Complete reaction is observed with


- 7 -

only 2 mol% of cupric triflate at room temperature, often within minutes. The donor-acceptor

relationship that exists in these substrates has been used to explain their reactivity (vinyl

nucleophile / vinyl electrophile).

O

O

R

O

OMe

δ+δ-

OO

R

OMe

OCu(OTf)2, (2 mol%)

DCE, 25°C

43 44 Scheme 1.10; The polarised Nazarov reaction.

Allenyl ethers can also be incorporated into Nazarov substrates (Scheme 1.11). Allene

ether substrates 47 (generated in situ from amides 45 and lithioallenyl ethers 46) react to form

products 49 after hydrolysis of intermediates 48.14

O

ORR1

R2

Li ORO

NR2R1

R2•

•

OH

R2

R1 OR

OH

R2

R1 OAcid H2O

45 46 47 48 49 Scheme 1.11; Allene ether variant of the Nazarov reaction.

Treatment of Nazarov substrates bearing an aromatic ring 50 with acid produces indanones

51 (Scheme 1.12).15,9,16 The disruption of aromaticity by the Nazarov reaction on these substrates

does mean they are somewhat less reactive than regular substrates; however electron-donating

groups on the aromatic ring significantly activate them.

O

R1

R2

R3

R2

R1

O

R3Acid

50 51 Scheme 1.12; Synthesis of indanones.

Typically it is observed that one or more equivalents of acid promoter are required to

achieve complete reaction, probably a result of association of the acid promoter with the

cyclopentenone product. A significant amount of attention has been devoted to developing truly

catalytic variants of the Nazarov reaction. Typically this involves the use of substrates that have

activating substituents (such as systems 38 and 43), reducing the generality of this approach.

Catalytic variants of the Nazarov reaction have been described with promotion by complexes of


- 8 -

copper13, palladium17, scandium11,18 and iridium19 as well as aluminium chloride.10 Nazarov

reactions have also been achieved under thermal conditions without acid promoters (refluxing in

DMF or microwave irradiation of ionic liquid solutions).20

1.1.3 Interrupted Nazarov reactions

The Nazarov reaction is an excellent candidate for inclusion in tandem processes. The

initial electrocyclisation results in a valuable cyclopentanoid ring, while also producing a reactive

oxallyl cation intermediate. The capture of this oxallyl cation prevents the stereochemistry

destroying elimination event and also allows concise access to complex polycyclic cores, often

with excellent regio and stereocontrol. These types of Nazarovs have been labelled “interrupted” in

reference to their mechanistic diversion from the more common elimination pathway, and have

been almost exclusively the work of F.G. West and co-workers.

The simplest version of this type of process is the reductive Nazarov (Scheme 1.13).21,22 In

this case the oxallyl cation intermediate is captured by hydride from a source such as triethysilane.

This reaction preserves both stereocentres formed on initial electrocyclisation.

R1 R3

O

R4R2

9

O

R1

R2 R4

R3

OSiEt3

R1

R2 R4

R3

+

52 53

L.A.

Et3SiH

Scheme 1.13; The reductive Nazarov.

More exciting are interrupted processes where the nucleophilic trapping species is either an

intra or intermolecular π-system, resulting in the formation of polycyclic cores. The first example

of this type of process involved the 5-exo trapping of oxallyl cations like 55 with a tethered alkene

(Scheme 1.14).23 The intermediate [3.3.0]-bicyclic ring system 56 is further closed by trapping of

the carbocation with the enolate, hydration on work-up gives 58 in good yield and complete

diastereoselectivity. This process was found to be limited to substrates with a two-carbon tether

and a terminally disubstituted olefin.


- 9 -

R1

O

R2

O-BF3

R1

R2

58

F3B-O

HR2

R1

R2

R1

H

O

R2

R1

H

OHHO

54 55 56

57

H2O

BF3.OEt2

Scheme 1.14; 5-Exo capture of the intermediate oxallyl cation with tethered olefins.

The dominant interrupted Nazarov pathway for substrates bearing a terminal olefin on a

two-carbon tether is the 6-endo ring closure onto the oxallyl cation, producing intermediate 61

(Scheme 1.15).24 The fate of this cation has been observed to lie in four different directions: (1)

elimination of a proton α to the cation leads to 62; (2) capture with chloride leads to 63 (only with

TiCl4 as catalyst); (3) hydride shift from a nearby carbon leads to 64; (4) enolate attack on the

cation leads to 65 (a formal [3+2]-cycloaddition from 60). Most experiments give a multi-

component mixture of products but moderate to high chemoselectivity can be achieved under

optimised conditions. Substrate substitution is the dominant factor in determining product

distribution.

R1

O

R2

O-L.A.

R1

R2

O-L.A.

HR2

R1L.A.

59 60 61

O

HR2

R1

O

HR2

R1

Cl

O

HR2

R1

O-L.A.R2

R1OR1 R2

O-L.A.R2

R1

H+-Elimination

Cl--Trapping

H--Migration

[3+2]

H

≡≡

62

63

64

65

Scheme 1.15; 6-Endo capture of the intermediate oxallyl cation with tethered olefins.


- 10 -

Tethered electron rich arenes are also observed to capture the intermediate oxallyl cation

via a 6-endo (Scheme 1.16).25 In these systems cation 68 is exclusively driven down the

elimination pathway to give 69.

R1

O

R2

O-TiCln

R1

R2

6867

R3TiCl4

ClnTi-O

H

H R3

R2

R1

O

H

R3

R2

R1

69

R3

66

Scheme 1.16; Capture of the intermediate oxallyl cation with tethered arenes.

A spectacular cationic cascade sequence triggered by Nazarov has been realised for aryl-

trienones of type 70 (Scheme 1.17).26 Steroid-like molecules of type 74 are produced in excellent

yield and complete diastereoselectivity. The reaction sequence involves an initial Nazarov

cyclisation followed by two successive 6-endo cyclisations.

R1

O

R2

O-TiCln

R1

R2

ClnTi-O

HR2

R1

ClnTi-O

HR2

R1 HH

O

HR2

R1H

TiCl4

74

70 71 72

73 Scheme 1.17; Synthesis of steroid-like molecules via a Nazarov initiated cascade.

When a 1,3-diene is tethered to a Nazarov substrate as in 75, the oxallyl cation can be

captured by a [4+3]-cycloaddition to give 77 or 78 (Scheme 1.18).27 Dienones with β-substituents

(R2 ≠ H) cycloadd with complete facial selectivity. Substrates with dienes on a four-carbon tether

produce exo-products, whilst a mixture of exo and endo-products are obtained when a three-carbon

tether is used.


- 11 -

R3

R275

L.A.O

R3

( )1,2

O-L.A.

R1 R2

R3 ( )1,2

R1 R2

76

( )1,2

R1

O

L.A.

R2R1

OR3 ( )1,2

R2R1

OR3 ( )1,2

[4+3]-exo

[4+3]-endo

77

78

Scheme 1.18; Nazarov reaction with intramolecular trapping of the oxallyl cation by [4+3] cycloaddition.

The corresponding intermolecular variant has also been developed (Scheme 1.19).28

Intermolecular [4+3]-cycloadditions using cyclic dienes proceed via the endo transition state and

facial selectivity is controlled by substituents on the oxallyl cation.

O

R2R1

O-L.A.

R1 R279 80

L.A.

Y

81

R1

YR2

O

[4+3]

82 Scheme 1.19; Intermolecular trapping of the oxallyl cation by [4+3] cycloaddition (Y = CH2, O).

The oxallyl cation can also be trapped with nucleophilic allylic silanes (Scheme 1.20).29

Treatment of substrate 9 with Lewis acid in the presence of allyl-silane 83 leads to [3+2]-

cycloaddition of the oxallyl cation 11 with the olefin of the allyl-silane. The nucleophilicity of the

allylic silane is sufficient to attack the oxallyl cation intermediate, producing secondary cation 84.

This cation is then attacked by the enolate to give the observed [2.2.1]-bicyclic product 85.

R1 R3

O

R4R2

O-L.A.

R1

R2 R4

R3

9 11

Si(i-Pr)3

O-L.A.

R2 R4

R3

R1

Si(i-Pr)3

O

R2

R3R1

R4

(i-Pr)3Si

L.A.

84 85

83

Scheme 1.20; Nazarov reaction with intermolecular trapping of the oxallyl cation by [3+2] cycloaddition.


- 12 -

1.1.4 Asymmetric Nazarov reactions

In the Nazarov reaction conrotatory ring closure can occur in either a ‘clockwise’ or

‘counter-clockwise’ sense (Scheme 1.21). If the reaction is controlled such that only one direction

of conrotation occurs, is described as torquoselective. Controlling the torquoselectivity is the key

factor in the development of asymmetric variants of the reaction as this directly controls the

absolute stereochemistry at the non-epimerisable β-centres. In general, there are three ways to

control absolute stereochemistry: (1) through asymmetry transfer; (2) through the use of chiral

auxiliaries; (3) through the use of chiral catalysts. All of these strategies have shown promise with

the Nazarov reaction.

OAcid

R3R1

R2 R4

OAcid

R1 R3

R4R2

OAcid

R3R1

R2 R4

αααα-17

O

R2 R4

R1 R3

O

R3R1

R2 R4

O

R3R1

R2 R4

αααα-11

109

ββββ-17ββββ-11

Clockwise

Counter-Clockwise

Acid

Scheme 1.21; Enantiodivergence as a result of torquoselectivity with the Nazarov reaction.

Asymmetry transfer refers to cases where chirality already present in substrates directly

influences the formation of new stereocentres (diastereoselectivity). In the Nazarov reactions

employing this strategy, torquoselectivity is most commonly controlled by stereocentres present on

rings directly fused to the reacting dienone. Various ring sizes (with and without heteroatoms)

have been studied, with stereocentres at various positions in these rings effectively controlling

torquoselectivity.

In 1983 Denmark and co-workers demonstrated diastereoselectivity for silicon directed

Nazarov reactions (Scheme 1.22).30 Although not asymmetric on account of the use of racemic

substrates, the observed diastereoselectivity indicates effective induction of torquoselectivity. As

one might expect, larger R and silyl groups give better selectivity at the cost of chemical yield.


- 13 -

O

R

[Si]

R

OH

HR

OH

H

FeCl3

DCM, 0°C+

86 87 88 R [Si] Yield (%) Product Ratio (88/89)

Ph SiMe3 76 94/6

t-Bu SiMe3 63 94/6

Me SiMe3 99 78/22

Me SiPh2Me 83 86/14

Me Si(i-Pr)3 70 90/10

Scheme 1.22; Diastereoselective silicon-directed Nazarov reactions.

In 1990, Denmark and co-workers reported the use of a stereogenic TMS-bearing carbon

atom to control the sense of conrotation in the cyclisation of 89 (Scheme 1.23).31 Complete transfer

of asymmetry is observed, with the TMS group being lost as an electrofugal leaving group.

OMe3SiO

H H

HO

H H

Me3SiFeCl3

DCM, -50°C

89, (86% ee) 90 91, 72%, (86% ee) Scheme 1.23; A torquoselective silicon-directed Nazarov reaction.

More remote stereogenic centres can also significantly influence torquoselectivity. In 2003

Trauner and co-workers reported the Nazarov reaction of the perillaldehyde derived substrate 92

(Scheme 1.24).10 The observed 4:1 mixture of products 93 and 94 indicates that the remotely

located isopropenyl-bearing stereogenic centre still significantly influences torquoselectivity.

O

OO

OAlCl3, (cat.)

DCM

85%, dr = 4:1

O

OH

H H

H

+

92 93 94 Scheme 1.24; Asymmetry transfer from a remote stereocentre.

Occhiato and co-workers have reported the torquoselective cyclisation of chiral

dihydropyrrole containing substrates 95 (Scheme 1.25).32 This particular reaction is the key step in

Occhiato’s asymmetric synthesis of roseophilin.


- 14 -

OTsN

R2

R1

TsN

O

R2

R1neat TFA

R1 = Me, R2 = Me, 50%

R1 = Me, R2 = i -Pr, 40%

R1 = CH2OH, R2 = i-Pr, 27%

R1 = 3-Butenyl, R2 = i -Pr, 43%95 96

Scheme 1.25; Asymmetry transfer from chiral dihydropyrroles.

The stereogenic centres inducing torquoselectivity need not be sp3 hybridised. This was

demonstrated by Tius and co-workers with the transmission of chirality from the stereogenic

allenyl ether functionality (containing axial chirality) in 99 through control of torquoselectivity to

produce 101 in high enantiopurity (Scheme 1.26).33

H

OH

•

O

TBSO

OMeO

O

OTBS

•

OMeO

NO

•

OMe

O

Li

OTBS

OH

O

OTBS

THF

-78°C

KH2PO4

98, (98% ee) 99 10097 101, 64%, (95% ee)

Scheme 1.26; Asymmetry transfer from chiral allene-ethers.

The second way to control absolute stereochemistry is through the use of chiral auxiliaries.

This strategy is a variant of asymmetry transfer where the stereogenic diastereocontrolling element

is attached to, but not integral to the core chemical structure. In these cases the auxiliary controls

the torquoselectivity of the Nazarov reaction and can subsequently be removed. After the auxiliary

is removed, an essentially achiral substrate has effectively been converted to an enantiopure (or at

least enantioenriched) chiral product.

In 1999 Pridgen and co-workers reported the chiral auxiliary controlled asymmetric

cyclisation of 102 (Scheme 1.27).15 The fact that Brønsted acids seem to be as effective as Lewis

acids and the success of the carbonyl-lacking phenylmenthol auxiliary c seem to suggest metal-

carbonyl complexation is not a prerequisite for establishing stereoselective cyclisation. In all cases

the products were isolated as crude mixtures, 103a was readily purified by crystallisation and its

stereochemistry was assigned by X-ray crystallography.


- 15 -

O

PrO

O

O

O

Aux PrOO

Aux

O

PrOO

Aux

O

NO

O

Ph

O

O

O

O

NO

O

O

Ph

Aux =

102a-c 103a-c 104a-c

a b c

Acid

Auxiliary Acid Yield (%) Isomer Ratio: 103 / 104 / other

a SnCl4 85 88 : 12 : 0

a MeSO3H 88 85 : 15 : 0

b SnCl4 74 71 : 16 : 14

c SnCl4 90 92 : 4 : 4

Scheme 1.27; Asymmetric Nazarov reaction performed by Pridgen and co-workers.

Our group also demonstrated the effective use of the phenyloxazolidinone auxiliary on the

more conventional Nazarov substrate 105 (Scheme 1.28).9 In this case the torquoselectivity

exhibited the same directionality as observed by Pridgen, but here the subsequent protonation step

could be controlled. Production of either the kinetic cis-isomer 107 or the thermodynamic trans-

isomer 106 can be controlled through use of either a Brønsted or Lewis acid respectively.

O

Ph

O

N

O

O Ph

O

Ph

O

N

O

O

Ph

O

Ph

O

N

O

O

Ph

106, 76%

107, 73%

105

Cu(OTf)2

MeSO3H

Scheme 1:28; Diastereodivergent asymmetric Nazarov reaction with an oxazolidinone auxiliary.

Our group has also used the phenyloxazolidinone auxiliary to mediate asymmetric

interrupted Nazarov reaction of 108 (Scheme 1.29, see Scheme 1.16 for West’s racemic variant).34

In this reaction four contiguous chiral centres are formed in a controlled manner to give 109 in

good yield. The major by-product is the readily separable diastereoisomer 110, the ratio of

products 109 and 110 indicate the torquoselectivity of the reaction was approximately 4:1.


- 16 -

O

Ph

O

N

O

O Ph

108

Cu(OTf)2

O

MeO

O

Ph

O

N

O

O

Ph

109, 61%O

MeOO

Ph

O

N

O

O

Ph

110, 15%O

MeO

Scheme 1.29; Asymmetric interrupted Nazarov reaction.

Tius’ cyclopentenylation reaction is based on the auxiliary mediated asymmetric Nazarov

reaction of allenyl ether substrates 114 (Scheme 1.30).35 The Nazarov precursor is apparently too

reactive to be isolated and is instead cyclised under optimised work-up conditions. This process is

effectively an asymmetric [3+2]-cycloaddition with all processes carried out in a “single

operation”. The reaction seems to have a broad scope, with substrates bearing alkyl, aryl, silyl and

even halides producing good yields of products 115 with good to excellent enantioselectivity.

AuxO AuxO LiR1

R2

O

AuxO

OH

O R1

R1

R2

O

N

O

111 112

113

114 115

OTBSO

TBSO H

OTBS

O

Aux =

A B

BuLi

THF

HCl

HFIP/TFER3

R3R2

R3

LiCl

R1 R2 R3 Aux A Aux B

3-Butenyl Isopropyl H 78%, 86% ee

Me Ph H 71%, 77% ee 84%, 86% ee

Br Ph H 53%, 78% ee 78%, 93% ee

Ph Ph H 74%, 55% ee 60%, 89% ee

Me Et H 69%, 74% ee 66%, 90% ee

Me t-Bu H 84%, 87% ee 85%, 88% ee

TMS cyclohexyl H 60%, 85% ee

Me Ph Me 64%, 69% ee

Me Me Ph 42%, 77% ee

R1, R2 = -(CH2)4- H 62%, 69% ee 75%, 91% ee

Scheme 1.30; Tius’ cyclopentenylation reaction.

Inducing torquoselectivity through use of chiral catalysts has proven challenging. This

approach is complicated by many factors; firstly the carbonyl bound to the chiral promoter is

remote from the bond-forming event; secondly low catalyst turnover is a well documented issue

associated with the Nazarov reaction (reaction generally requires at least stoichiometric quantities

of promoter); thirdly the complex Nazarov mechanism involves de-protonation and re-protonation


- 17 -

steps, non-torquoselective cyclisation may be promoted by ‘liberated’ protons; lastly coordinating

chiral ligands to Lewis acids significantly reduces their acidity, limiting the applicability of these

chiral complexes to use on only the more reactive substrates. To date no examples of high

torquoselectivity induced by truly catalytic quantities of chiral Lewis acid promoter has been

reported for the Nazarov reaction. Significant steps towards this goal have been taken, the majority

of work in this area focusing on the use of BOX and pyBOX complexes of transition metals.

In 2003 Aggarwal and Belfield reported successful induction of torquoselectivity in the

Nazarov reaction of ester and amide bearing substrates with pyBOX and BOX complexes of

copper (Schemes 1.31 and 1.32 respectively).36 In the case of reacting esters 116 the best promoter

identified was the pyBOX complex 118, using a stoichiometric amount of this catalyst gave good

yields of product 117 (Scheme 1.31). An aromatic β-substituent (R2) in 116 seems necessary for

good induction and low catalyst turnover is an obvious limitation.

O

R1

R2Ph

OEt

O O

Ph

R1

R2

OEt

O118

DCM, rt

116 117

NO

N N

O

Cu(SbF6)2

118

R1 R2 Catalyst equiv. Yield (%) ee (%)

1.0 73 76 Me Ph

0.5 42 78

1.0 98 86 Ph Ph

0.5 96 86

1.0 35 3 Me Me

0.5 27 1

1.0 86 42 Ph Me

0.5 86 35

Scheme 1.31; Asymmetric Nazarov reaction of ester-bearing substrates.

Catalyst 118 was unable to induce the Nazarov cyclisation of the amides 119, but it was

found that the BOX complex 121 was more successful (Scheme 1.32). As in the ester case, good

yields and enantioselectivities were obtained with stoichiometric quantities of catalyst. The

potential for the amide and ester groups to participate in bidentate complexation with the Lewis

acid complex is thought to be critical to asymmetric induction in these systems.


- 18 -

O

R1

PhPh

NEt2

O O

Ph

R1

Ph

NEt2

O121

DCM, rt

119 120

(SbF6)2

N N

OO

Cu

121

R1 Catalyst equiv. Yield (%) ee (%)

1.0 72 84 Me

0.5 56 85

1.0 92 86 Ph

0.5 56 87

Scheme 1.32; Asymmetric Nazarov reaction of amide-bearing substrates.

In the reaction of the related reactive polarised substrate 122 recently disclosed by Frontier

and He, low catalyst loading compromises enantioselectivity and not yield (Scheme 1.33).37

O

O OO

TMPTMP

Cu(OTf)2 (10 mol%),124 (20 mol%)

123, 99%, 50% ee

OMe

O

O

OMe

OMe

MeO

MeO

TMP =122

N N

OO H

H

H

H

124

Scheme 1.33; Asymmetric Nazarov reaction of a polarised substrate.

α-Alkoxy-substrates have been the focus for most studies towards asymmetric catalysis of

the Nazarov reaction because of their high reactivity and potential bidentate binding to metal

centres. In 2003 Trauner and co-workers reported cyclisation of 125 in moderate yield and

asymmetric induction with the scandium pyBOX complex 127 (Scheme 1.34).10

O

OO

O

H

H

126, 53%, 61% ee

127 (20 mol%)

THF, rt

125

NO

N N

O

Sc(OTf)3

127

Scheme 1.34; Asymmetric Nazarov reaction of an α-alkoxy substrate.

Moderate enantioselectivity for a hydrolytic variant of the Nazarov reaction was recently

disclosed by Tius and Leclerc (Scheme 1.35).38 Treatment of MOM-enol-ether 128 with 20 mol%

ytterbium triflate in the presence of 30 mol% of pyBOX ligand 130 gave 129 in good yield after

hydrolysis of the intermediate MOM-ether cation.


- 19 -

O

O

Ph

MeO

OH

O

Ph129, 80%, 47% ee

Yb(OTf)3 (20 mol%),130 (30 mol%)

128

NN

OO

N

130

Scheme 1.35; Hydrolytic asymmetric Nazarov reaction of an α-alkoxy substrate.

The situation is more complex when diastereoisomers are possible for products. In 2004

Trauner and co-workers reported that treatment of 131 with catalytic scandium pyBOX complex

134 gave rise to the diastereoisomeric products 132 and 133 in good overall yield (Scheme 1.36).39

Significantly it was noted that the two diastereoisomers exhibited markedly different ee’s. This

result showed that although the Lewis acid complex had promoted moderately torquoselective

electrocyclisation, it had also significantly influenced the subsequent protonation step.

O

OO

OO

O

132, 62%, 40% ee 133, 18%, 79% ee

134 (10 mol%)

MeCN, rt

131

NO

N N

O

Sc(OTf)3H

H

H

H

134

Scheme 1.36; Complicated asymmetric Nazarov reaction of an α-alkoxy substrate.

This observation prompted Trauner and co-workers to study the equivalent reaction on

substrates lacking β-substitution (Scheme 1.37).39 The scandium pyBOX complex 134 proved to

be an excellent mediator of asymmetric protonation and in this capacity catalysed the conversion

of 135 to 136 in excellent yield and enantioselectivity.

NO

N N

O

Sc(OTf)3

H

H

H

H

134

O

O

X

R

X

OO

R

136, 65-94%, 76-97% ee

134 (10 mol%)

MeCN

135 Scheme 1.37; Catalytic asymmetric proton transfer in Nazarov reactions (X = CH2, O).

A very recent and quite significant discovery is the apparent superiority of chiral Brønsted

acids (such as 140) in mediating asymmetric cyclisation of these activated systems (Scheme

1.38).40 Rueping and co-workers achieved the first highly selective truly catalytic asymmetric

induction of the Nazarov reaction (based on control of torquoselectivity) through the use of the

binol phosphoramide 140. Moderate to excellent yields of 138 and 139 were obtained on treating

dihydropyran-derived substrate 137 with low loadings of this chiral Brønsted acid in chloroform.


- 20 -

Moderate to excellent diastereoselectivity was observed, with cis-products dominating, while

enantioselectivity was good to excellent (86-98% ee). This reaction is an excellent example of the

emerging field of chiral ion pair catalysis. Although the exact mechanistic underpinnings of the

torquoselectivity observed for this reaction are unclear, it would seem that protonation of 137

produces cationic intermediates that exhibit sufficient interaction with the chiral anion of 140 to

direct the stereochemical outcome of the reaction.

O

O R1

R2

OO

R1

R2

OO

R1

R2

13886-93% ee

13990-98% ee

140 (2 mol%)

CHCl3, 0°C

45-92%

(138/139 1.5:1 - 9.3:1)137140

POO

TfN O

H

Scheme 1.38; Catalytic asymmetric Nazarov reactions with a chiral Brønsted acid (R1 = Alkyl, R2 = Aryl, Alkyl).

1.1.5 Synthesis of Nazarov substrates

As with all reactions, the synthetic utility of the Nazarov reaction is determined not only by

its own intrinsic versatility, but also by the accessibility of its precursors. Developing protocols for

the concise regio- and stereocontrolled access to appropriately configured Nazarov substrates 9

with good general applicability is the most important factor in developing the Nazarov reaction as

a broadly useful synthetic strategy. Most protocols developed so far are based on the strategy of

coupling a vinyl metal component 141 to a reactive α,β-unsaturated carbonyl component 142

(Scheme 1.39). Accessing substituted vinyl metals is not trivial, thus developing methods for their

formation is the basis of developing strategies for the synthesis of Nazarov precursors.

R4

R3

O

Y

MR1

R2

R4

R3

O

R1

R2141 142 9

Scheme 1.39; General access to Nazarov substrates 9 (M = metal, Y = Cl, NR2, H with subsequent oxidation).

The synthesis of α-alkoxy-substrates 145 is most commonly achieved by lithiation of enol

ethers 143 followed by reaction of the intermediate vinyl-lithium 144 with an α,β-unsaturated

amide or aldehyde 142 (Scheme 1.40).10,17 A major drawback to this strategy is the limited range

of enol ethers available either commercially or through synthesis in a stereoselective manner. To

date, this strategy has been almost exclusively limited to dihydropyran and ethyl vinyl ether.


- 21 -

R4

R3

Y

O

R4

R3

O

R1O

R2

HR1O

R2

LiR1O

R2

143 144 145

142t-BuLi

Scheme 1.40; Synthesis of Nazarov substrates by lithiation of enol-ethers.

A multi-component coupling approach based on conjugate addition of organo-cuprates 147

to terminal carbonyl-acetylenes 146, followed by reacting the intermediate vinyl-cuprate 149 with

an α,β-unsaturated acid chloride 142 was reported by Marino and Linderman in 1981 (Scheme

1.41).7 The difficulty of this reaction along with precursor availability issues and low yields mean

it has been little used for the synthesis of substrates of type 33.

R1

33

R4

R3O

Cl

R4

R3

O

R1

OOR1

CuR

O

R2R2R2

R1 OCuRR2 CuR

149148146

142147

Scheme 1.41; Copper mediated conjugate addition / coupling approach to Nazarov substrates.

Our group has developed a one-pot hydrostannylation-coupling reaction for the synthesis of

Nazarov precursors (Scheme 1.42).9 Readily available carbonyl-alkynes 150 are hydrostannylated

with tributyltin hydride under palladium catalysis to give the intermediate vinyl-stannanes 151

which can then be coupled to an organo-halide. Two classes of Nazarov precursors are available by

this methodology; if the organo-halide is an α,β-unsaturated acid chloride 142, coupling gives α-

carbonylated Nazarov precursors 33; if the starting alkyne 150 contains appropriate unsaturation,

coupling of 151 to any organo-halide gives the more conventional Nazarov precursors 152.

R2

OR1

R1

O

R2

SnBu3

O

R2

R3R1''

R1'

R1

O

R2

R3

R4

O

150 151

152

ClR3

R4

O

Bu3SnH

Pd0, THF

CuCl

R3X

CuCl

33

142

R1 = alkene

Scheme 1.42; Our hydrostannylation-coupling route to Nazarov substrates.


- 22 -

An alternate route to α-carbonylated Nazarov precursors 33 not based on vinyl-metal

chemistry was initially developed by Regan and Andrews (Scheme 1.43).8 Here an α,β-unsaturated

acid chloride 142 is coupled via enolate chemistry to an acetate 153. A Knoevenagel condensation

reaction is then used to couple the 1,3-dicarbonyl 154 to an aldehyde 155 to give the desired α-

carbonylated Nazarov precursor 33.

O

R1OR4

R3

Cl

O

R4

R3

O

R1O

O

R4

R3

O

R1O

O

R2

O

HR2

153 142 154 33

155

Scheme 1.43; Knoevenagel route to Nazarov substrates.


- 23 -

1.2 Roseophilin

1.2.1 Occurrence and biological activity

The unique macrocyclic deep red pigment roseophilin 156 (Figure 1.1) was isolated from

the culture broth of Streptomyces griseoviridis by Seto and co-workers.41 Roseophilin exhibits

potent cytotoxicity towards several human cancer cell lines including K562 erythroid leukaemia

cells (IC50, 0.34 µM) and KB nasopharyngeal carcinoma cells (IC50, 0.88 µM) though the exact

mechanism of its action is unknown. Furthermore, roseophilin is a rare case in which the non-

natural enantiomer exhibits higher cytotoxicity against several cancer cell lines than does the

naturally occurring form.42,43 Unfortunately, the inherent toxicity of 156 is too high for its

development as a drug.

O

HN

OMe

Cl

N

Figure 1.1; Roseophilin 156.

Roseophilin is related to the prodigiosin alkaloids (Figure 1.2) which are produced by a

restricted group of eubacteria and actinomycetes of the Serratia and Streptomyces genera.44 These

compounds are of interest as they exhibit a broad range of activity against bacteria, protozoa,

pathogenic fungi, the human malaria parasite Plasmodium falciparum and various human cancer

cell lines, as well as displaying promising immunosuppressive activity. More recently, it has been

discovered that certain roseophilin and prodigiosin-type compounds define a new class of potent

protein tyrosine phosphatase inhibitors.45 The mechanistic underpinnings of these observed

biological effects and the relationships between them are not well understood despite significant

investigation.


- 24 -

N

NHHN

OMe

N

NH HN

OMe

N

NH HN

OMe

N

NH HN

OMe

N

NH HN

OMe

N

NH HN

OMe

UndecylprodigiosinProdigiosin Metacycloprodigiosin

Streptorubin B Butylcycloheptylprodiginine Nonylprodigiosin Figure 1.2; Some representative prodigiosins.

1.2.2 Previous synthetic efforts

The promising cytotoxicity and intricate topology of roseophilin 156 has made it a popular

target for synthesis.44 All synthetic approaches published to date rely on the same strategic

disconnection at the azafulvene site, envisioning a condensation of the macrocyclic ketopyrrole

157 with pyrrolylfuran 158 (Scheme 1.44).

PgN

O

O

N

OMe

Cl

Pg'

O

HN

OMe

Cl

N

157156 158 Scheme 1.44; Retrosynthetic disconnection of roseophilin.

Of the two fragments the macrocyclic ketopyrrole 157 provides the greater synthetic

challenge and as such is the major focus of synthetic efforts towards the natural product. To date

nine groups have published total or partial syntheses of 157 and synthesis has been accomplished

for both enantiomers as well as for the racemate (Scheme 1.45).32,46-53 Unfortunately, all routes

developed to date are too long and low yielding to provide meaningful quantities of roseophilin, or

practical enough for adaptation to generate the numerous analogs required for detailed structure-

activity relationship (SAR) studies.46,47,48,49,50,51,52,53,32


- 25 -

NH

O

O

OH

Cl

HO Cl

ON

Ac

Oi -Pr

Cl Cl

OH

Terashima et.al., 199852

15 steps, 2%

racemic

Boger et.al., 200150

26 steps, <3%

(22S, 23S)

Fuchs et.al., 199747

20 steps, 5%

racemic

Robertson et.al., 199953

13 steps, <1%racemic

Trost et.al., 200051

20 steps, <2%

(22R, 23R)

Hiemstra et.al., 200048

21 steps, 1%

(22S, 23S)

Fürstner et.al., 199746

11 steps, 5%

racemic

Tius et.al., 199949

13 steps, 12%(22R, 23R)

Pg = H, Bn, BOC, Ts, SEM

NH

O

HOOcchiato et.al., 200532

15 steps, <1%(22R, 23R)

PgN

O

Scheme 1.45; Synthesis of ketopyrrole fragment 157.

The Nazarov reaction has already been successfully used as the key transformation in two

of these previous synthetic efforts. Tius and Harrington developed a synthesis based on Tius’

cyclopentenylation reaction (Scheme 1.46, refer to Scheme 1.30).49 Allene 160 and amide 162 are

coupled and cyclised to give cyclopentenone 164 in one operation. Cyclopentenone 164 is then

elaborated to diene 165 through a Stetter reaction and the macrocycle is formed using ring-closing

metathesis (RCM) promoted by Grubbs’ catalyst, subsequent hydrogenation then gives 166. A

Knorr reaction is used to install the pyrrole and thus complete the synthesis of the ketopyrrole

fragment 167. This fragment was successfully elaborated to the natural product 156 in three steps.


- 26 -

N

O OMe

HN

Cl

Roseophilin (156)

58%O

OBz

O

HN

OO

OBz

O

O

OH

O

N

O

O

O

O

O

O

HO

CO2H

CO2H4 Steps

47%

7 Steps

51%

HCl

164, 78%, 86% ee

2 Steps

69%

1) RCM

2) H2/Pd

Knorr

Reaction

167, 54%166, 81%165

162

160159

161

163

BuLi

Scheme 1.46; Total synthesis of roseophilin by Tius and Harrington.

A formal synthesis of roseophilin based on a more conventional Nazarov reaction was

recently reported by Occhiato and co-workers (Scheme 1.47).32 Pyrrolidinone 168 is elaborated to

the monochiral Nazarov precursor 169. Treatment of 169 with neat TFA promotes a

diastereoselective Nazarov reaction to give 170 which is subsequently oxidised to give pyrrole 171

as a single enantiomer. At this point the strategy overlaps with Fuchs’ synthesis.47 Fuchs and co-

workers elaborated racemic 171 to diene 172 which was subjected to RCM with Grubbs’ catalyst

to give 173. The ketopyrrole fragment 167 was then produced from 173 in four steps.

OTsN

TsN

O

169 170, 43%

OHNHO

TsN

O

TsN

O

OTIPSH

173, 60% 167

4 steps

59%

2 steps

92%

171, 48%

RCM

168

DDQ

HN

OTsN

O

H

OTIPS

TFA6 steps

13%

172 Scheme 1.47; Formal synthesis of roseophilin by Occhiato and co-workers.

Both of these successful strategies show the Nazarov reaction can be used effectively in the

synthesis of roseophilin. However, the practicality of both these syntheses is limited by the long

and inefficient production of the relevant Nazarov substrates, as well as by the use of expensive /


- 27 -

low-availability starting materials, reagents and catalysts. It is our aim to develop a strategy for the

synthesis of roseophilin that is very concise, inexpensive and amenable to adaptation to generate

the multitude of analogs required for detailed SAR and medicinal chemistry studies. We also

believe this work should allow valuable development of the Nazarov reaction, a reaction that

despite current interest has yet to be developed to its full potential in synthetic chemistry. Much of

the work described in this thesis was developed contemporaneously with that described in the

introduction.

Chapter 2: Roseophilin Synthesis; Pyrrole Approach

- 28 -

CHAPTER 2: ROSEOPHILIN SYNTHESIS; Pyrrole Approach

2.1 Our Synthetic Strategy

Our initial strategy towards the synthesis of roseophilin was based on the Nazarov reaction

of a pyrrole-containing substrate like 176 (Scheme 2.1). This substrate should be readily produced

using our previously described hydrostannylation-coupling protocol of an acid chloride 174 and

alkyne 175 (see Scheme 1.42).9 Treatment of 176 with acid should give racemic 177 in the ester

case and enantiopure 177 in the case where Y is a chiral auxiliary. Nazarov product 177 should be

readily elaborated to the diene 178, which should then be converted to the known fragment 157 by

RCM with subsequent hydrogenation. Production of 157 with a number of protecting groups

constitutes a formal total synthesis of roseophilin.

Pg

NO Pg

N

O

Pg

N

OO N

MeOCl

Pg'

O

HN

OMe

Cl

N

Y

OO

Y

Pg

NO

Cl

YO

Pg

N

OY = OR, O

N O

Ph

174

( )n

( )6-n

( )n( )n

( )n

Bu3SnH

Pd0/CuI

Nazarov Steps

i) RCM

ii) H2/Pd 3 Steps, 58%

175 176 177

178 157

158

156

Scheme 2.1; Our initial plan for the synthesis of roseophilin.

Since the synthesis of acid chloride 174 bearing a tethered olefin is not entirely trivial, we

initially sought to perform a model study on the known substrates 175 and 179 (Scheme 2.2). A

number of key transformations in our proposed strategy were in need of validation, not least of

which was the Nazarov reaction of pyrrole-based substrates, which (at the time) was

unprecedented.54,18 The processes of decarboxylation and alkylation in the elaboration of 177 to

178 was also to be evaluated with the equivalent transformation of 181 to 182.

N

Ph

Cl

O

YO O

Y

O

N

Ph

N

Ph O

Y

OBu3SnH

Pd0/CuI

NazarovN

Ph O

( )6-nSteps

179 175 180 181 182

Y = OEt,

NO

O

Ph

Scheme 2.2; Proposed racemic model study.


- 29 -

Conducting these model studies would give us the information on how to proceed with the

synthesis of the natural product and, in addition, we would also produce fragments of roseophilin

lacking the macrocycle which may be useful in analoging studies.

2.2 Racemic Model Study

Ester 186 (a version of 175), which was to be used for both the racemic model studies as

well as for the real system, was prepared by the Corey-Fuchs protocol as previously reported

(Scheme 2.3).55 Isobutyrylaldehyde 183 was converted to the gem-dibromo-olefin 184, which was

converted to the lithium acetylide 185 and reacted with ethyl chloroformate to give the ester 186.

O Br BrOEtO

H

O

OEtCl

186, 96%

Li

185184, 84%

2 x BuLi

THF

Ph3P=CBr2

DCM

183 Scheme 2.3; Synthesis of ester 186.

Our model acid chloride 179 was produced efficiently from N-benzylpyrrole through a

modification of the one-pot synthesis of the acid 189 by Parker and Ku (Scheme 2.4).56 Acylation

of benzylpyrrole with trichloroacetyl chloride occurs without catalysis in diethyl ether to give 188.

The trichloromethyl ketone is hydrolysed by refluxing in ethanol/water with sodium hydroxide and

after protonation with HCl the acid 189 is obtained. Conversion to acid chloride 179 was achieved

with thionyl chloride in diethyl ether at room temperature.

N

Ph

O

CCl3

N

Ph

O

OH

N

Ph

N

Ph

Cl

Oi) NaOH

EtOH/H2O

ii) HCl

SOCl2

Et2O

O

CCl3Cl

179, 90%187 188 189

Et2O

Scheme 2.4; Synthesis of model acid chloride 179.

These substrates (186 and 179) were coupled with our one-pot protocol (see Scheme 1.42)

to give our model Nazarov substrate 190 as a mixture of stereoisomers (Scheme 2.5). The Nazarov

reaction of 190 was found to be quite sluggish. No reaction occurred with one equivalent of either

methanesulfonic acid or cupric triflate at room temperature, however, an excellent yield of 191

was obtained with a ten-fold excess of methanesulfonic acid.


- 30 -

N

Ph

Cl

O

OEtO O

OEt

O

N

Ph

N

Ph O

OEt

OBu3SnH, THF

Pd0/CuI

MeSO3H (10 eq.)

DCM

179 186 190, 82% (±±±±)-191, 99%

Scheme 2.5; Hydrostannylation-coupling / Nazarov synthesis of model ester 191.

With 191 in hand, we now had to evaluate its conversion to 182. Accordingly, the steps of

hydrolysis, decarboxylation and alkylation were examined (Schemes 2.6-2.8). Our first attempts at

the hydrolysis of 191 were under basic conditions (Scheme 2.6). Heating was required to

accomplish the hydrolysis with lithium hydroxide in THF/water. After protonation with HCl,

decarboxylation of acid 193 was achieved by refluxing in ethyl acetate, giving 194 in moderate

yield.

N

OPh

N

OPh

OLi

O

O

OEt

N

Ph O

O

O

H

193

N

OPh

(±±±±)-194, 55%192(±±±±)-191

LiOH, ∆

THF/H2O

HCl EtOAc, ∆

Scheme 2.6; Hydrolysis / decarboxylation of ester 191 (basic conditions).

Acidic conditions were found to be much more practical and high yielding for the

conversion of 191 to 194 (Scheme 2.7). Refluxing 191 with sulfuric acid in ethanol/water led to

clean conversion to 194 in the one pot.

N

OPh

OEt

O N

OPh

(±±±±)-194, 93%

N

Ph O

O

O

H

193(±±±±)-191

H2SO4, ∆

EtOH/H2O

CO2

Scheme 2.7; Hydrolysis / decarboxylation of ester 191 (acid conditions).

Alkylation of 194 was readily achieved with LDA in tetrahydrofuran (Scheme 2.8).

Lithiation of 194 followed by addition of either allyl bromide 196 or iodopentene 198 gave 197

and 199 in excellent yield and complete stereoselectivity for the desired trans configuration.

Reaction of enolate 195 with primary alkyl bromides was only modestly successful. With these

encouraging results in the racemic model study we then turned our attention to the asymmetric

model.


- 31 -

N

Ph O

N

Ph OLi

N

Ph O

N

Ph O

I

Br

LDA, THF(±±±±)-197, 82%

(±±±±)-199, 95%

(±±±±)-194 195 198

196

Scheme 2.8; Model alkylation studies.

2.3 Asymmetric Model Study

Our auxiliary-bearing alkyne 204 was synthesised in one pot from gem-dibromo olefin 184

by a protocol developed previously within our group (Scheme 2.9).34 Double lithiation of 184

followed by reaction with gaseous carbon dioxide gives lithium carboxylate 200 which reacts with

pivaloyl chloride to form the mixed anhydride 201. The addition of lithiated oxazolidinone 203

then gives alkyne 204 in good yield. Although we anticipated we would require the S-configured

oxazolidinone to synthesise the natural enantiomer of roseophilin, the R-configured version was

used in the model study only because it was on hand.

Br Br NO

O

Ph

O

Li OLiO

OO Li N O

OO

O

Cl2 x BuLi

THF

CO2 Ph

HN O

O

Ph

BuLi, THF

201 R-204, 69%200185184

R-202

R-203

Scheme 2.9; One-pot synthesis of alkyne R-204.

The coupling of R-204 to 179 by our one-pot protocol gave R-206 in excellent yield as a

single stereoisomer (Scheme 2.10). We were now ready to study the asymmetric Nazarov reaction.


- 32 -

N

Ph

Cl

O

NO

OO

PhBu3Sn

N

O

O

PhO N

O

O

PhO

N

Ph O

R-206, 91%

Bu3SnH, THF

Pd(PPh3)4 CuCl

179

R-205R-204 Scheme 2.10; Synthesis of auxiliary-bearing model Nazarov substrate R-206.

The Nazarov reaction of R-206 like the ester 190 was found to be quite sluggish (Scheme

2.11). A number of acids were tried with this reaction, significantly it was found that Brønsted and

Lewis acids give opposite torquoselectivities. A good yield of a single diastereoisomer was

realised by refluxing R-206 in dichloromethane with an equivalent of ferric chloride (Entry 3). A

more detailed study of the oxazolidinone mediated asymmetric Nazarov reaction is described in

Chapter 4, along with a description of NMR based stereochemical assignments. Crude NMR

spectra of Entries 1-3 are included in Appendix A1.

N

OPh

O

N

O

Ph

O

N

OPh

O

N

O

Ph

O

N

O

O

PhO

N

Ph O

R-206 207 208

ACID

ENTRY ACID CONDITIONS 207 208

1 MeSO3H (10 eq.) -78 ºC → rt, 48h 32%* 68%*

2 Cu(OTf)2 (1 eq.) reflux, 24h 66% 24%

3 FeCl3 (1 eq.) reflux, 18h 75% 21%

Scheme 2.11; Nazarov reaction of model pyrrole system 206 (* NMR Ratios).

With a good yield of an asymmetric product now obtained, we then investigated its

elaboration to R-194. It was found that hydrolysis of 207 with lithium hydroxide was more facile

than with ester 191 in that heating was not required (Scheme 2.12). Even so, the yield of 194 after

protonation and decarboxylation was still only moderate.

N

OPh

OLi

O

N

Ph O

O

O

H

193

N

OPh

R-194, 61%192207

LiOH

THF/H2O

HCl EtOAc, ∆N

OPh

O

N

O

Ph

O

O

HN O

Ph 202

extractwith EtOAc

Scheme 2.12; Hydrolysis / decarboxylation of 207 (basic conditions).


- 33 -

As with the racemic ester case (see Scheme 2.7), hydrolysis and decarboxylation of 207

was best achieved by heating in ethanol/water with sulfuric acid (Scheme 2.13). This one-pot

procedure allowed formation of R-194 in excellent yield as a single enantiomer.

N

OPh

R-194, 99%

N

Ph O

O

O

H

193

H2SO4, ∆

EtOH/H2O

CO2

N

OPh

O

N

O

Ph

O

207

O

HN O

Ph202, 71%

(recovered) Scheme 2.13; Hydrolysis / decarboxylation of 207 (acid conditions).

Having had significant success with our model studies we were encouraged to apply these

chemistries to the synthesis of the natural product. All this required was replacing the model acid

chloride 179 with one bearing a tethered olefin such as 174 (see Scheme 2.1).

2.4 The Real System; Asymmetric Efforts

After a few unsuccessful attempts at direct alkylation of pyrroles at the 2-position, we

decided to utilise the more common approach of reducing 2-acylpyrroles. In fact 2-(4-pentenyl)-

1H-pyrrole 214 and 2-(5-hexenyl)-1H-pyrrole 215 have both been synthesised by Fürstner using

this approach (Scheme 2.14).57 Conversion of acids 209 and 210 to their pyridyl thioesters

followed by addition of pyrrolyl magnesium chloride 211 produces 2-acylpyrroles 212 and 213.

These are then reduced to 2-alkylpyrroles 214 and 215 by refluxing with sodium borohydride in

isopropanol.

MgClNOH

O

( )1,2

HN

O

( )1,2

HN

( )1,2

211

n = 1, 209n = 2, 210

n = 1, 212, 95%n = 2, 213, 98%

NaBH4

i-PrOH, ∆

NSSN

n = 1, 214, 63%n = 2, 215, 65%

PPh3

Scheme 2.14; Fürstner et.al.’s synthesis of 214 and 215.

Since we did not have some of the reagents used by Fürstner on hand, a Vilsmeier-Haack

route to 214 was used instead (Scheme 2.15). Amide 217 was synthesised by allylation of dimethyl

acetamide. Addition of phosphorus oxychloride to amide 217 followed by pyrrole allowed access


- 34 -

to 212 (with the 3-acyl regioisomer being the major by-product). Reduction of 212 gave us

significant quantities of our requisite pentenyl-pyrrole 214.

HN

NMe2

O HN

O HN218 NaBH4

i-PrOH, ∆

214, 86%

NMe2

O

Br

POCl3DCE

LDA

THF

212, 72%217, 54%

216

196Scheme 2.15; Vilsmeier-Haack route to 214.

Our desired acid chloride component 220 was readily produced from 214 (Scheme 2.16).

The pyrrole nitrogen was protected by benzylation with sodium hydride and benzyl chloride to

give 219, this was then converted to acid chloride 220 in an analogous manner to the synthesis of

the model system 179 (see Scheme 2.4).

N

Ph

N

Ph

Cl

OO

CCl3Cl

220, 93%

HN

214 219, 96%

NaH, BnCl

DMF ii) NaOH, EtOH/H2Oiii) SOCl2, Et2O

i) , Et2O

Scheme 2.16; Synthesis of acid chloride 220.

The requisite alkyne bearing the S-configured oxazolidinone S-204 was synthesised in an

analogous manner to its enantiomer (Scheme 2.17). We thus had both substrates in hand for the

synthesis of the natural enantiomer of roseophilin.

Br Br NO

O

Ph

O

Li OLiO

OO Li N O

OO

O

Cl2 x BuLi

THF

CO2 Ph

HN O

O

Ph

BuLi, THF

201 S-204, 40%200185184

S-202

S-203

Scheme 2.17; One-pot synthesis of alkyne S-204.

Substrates 220 and S-204 were successfully coupled by our one-pot protocol to give our

desired Nazarov precursor S-221 in good yield (Scheme 2.18).


- 35 -

N

Ph

Cl

O

NO

OO

PhBu3Sn

N

O

O

PhO N

O

O

PhO

N

Ph O

S-221, 78%

Bu3SnH, THF

Pd(PPh3)4 CuCl

220

205S-204 Scheme 2.18; Synthesis of auxiliary-bearing Nazarov substrate S-221.

When we came to attempt the Nazarov reaction of 221 we were disappointed to find that its

cyclisation was complicated by the migration of the terminal olefin (Scheme 2.19). This problem

was further compounded by the low rate of conversion of cis-configured 223 to trans-configured

222. Treatment of 221 with various acids in dichloromethane led to mixtures of 222, 223, and 224

that were contaminated with inseparable regioisomers 225, 226 and 227. Ultimately it was

revealed that the double-bond migration is concentration dependent, performing the reaction with

ferric chloride at relatively high dilution was sufficient to suppress double-bond migration,

allowing a good yield of 222 to be obtained (Entry 4, some epimerisation of 223 apparently occurs

during chromatography). The crude NMR spectra of Entry 4 is included as Appendix A1.3, for the

NMR spectra of compounds 222 and 224 see Appendices C13 and C14.

Acid

DCM

N

OPh

O

N

O

Ph

O

N

OPh

O

N

O

Ph

O

N

O

O

PhO

N

Ph O

S-221222 (4-pentenyl)225 (3-pentenyl)

224 (4-pentenyl)227 (3-pentenyl)

N

OPh

O

N

O

Ph

O

223 (4-pentenyl)226 (3-pentenyl)

ENTRY CONDITIONS 222 + 225 (%) 223 + 226 (%) 224 + 227 (%) Olefin Purity

1 Cu(OTf)2, DCM, Reflux, 8h 58% 15% 27% 21% terminal

2 FeCl3, DCM, Reflux, 8h 71%, 8% 21% 78% terminal

3 10 eq. MeSO3H, DCM, rt, 8h 20% 22% 58% 87% terminal

4 FeCl3, DCM, Reflux, 24h, (dilute) 67% (70%) 10% 23% (22%) ≥92% terminal

Scheme 2.19; Asymmetric Nazarov reaction of substrate S-221 (NMR study, yields in parenthesis isolated).

The migration of the double-bond from the 4-position to the 3-position of the pentenyl

group is evident in the proton NMR spectra of the products 225 and 227 (Figure 2.1). Here the

typical terminal olefin resonances at 5.7 and 5.0 ppm (positions 1 and 2 in 222 and 224) are

replaced with a methyl doublet and two overlapping olefinic resonances at around 5.4 ppm

(positions 1, 2 and 3 of the pentenyl group in 225 and 227). The preservation of the pyrrole

resonances at 5.95 (position 6) in 225 and 227 rules out cyclisation of the double-bond onto the

pyrrole ring. [for 1H NMR spectra of compounds 225 and 227 see Appendix C92].


- 36 -

N

OPh

O

Aux N

OPh

O

Aux

(1) (2)

(3)

(4)

(5)

(6)

(1) (2)

(3)

(4)

(5)

(6)

222 and 224 225 and 227 POSITION 222 and 224 (1H NMR) 225 and 227 (1H NMR)

1 5.00-4.92 (m, 2H) 1.61 (d, J = 4.8 Hz, 3H)

2 ~5.71 (mc, 1H)

3 ~2.04 (q, 2H) }5.50-5.30 (m, 2H)

4 ~1.60 (quin., 2H) ~2.19 (q, 2H)

5 ~2.45 (mc, 2H) ~2.50 (mc, 2H)

6 ~5.95 (s, 1H) ~5.95 (s, 1H)

Figure 2.1; NMR evidence for migration of the double-bond in 225 and 227.

Whilst the optimisation of the asymmetric reaction was being studied, we decided to

explore the remaining steps of the synthesis utilising the less complicated racemic series.

2.5 The Real System; Racemic Efforts

Substrates 220 and 186 were coupled in an analogous manner to the model system 190

giving the Nazarov precursor 228 in modest yield (Scheme 2.20, no attempt was made to optimise

this reaction). The Nazarov reaction of 228 was accomplished without significant migration of the

double-bond and 229 was isolated in excellent yield. Double-bond migration was negated by

achieving the Nazarov reaction in a rapid manner with a large excess of Brønsted acid. Also, as

expected, no other diastereoisomers were detected in contrast to the asymmetric system 221 (see

Scheme 2.19).

N

Ph

Cl

OOEtO O

OEt

O

N

Ph

N

Ph O

OEt

OBu3SnH, THF

Pd0/CuI

MeSO3H

DCM

220 186 228, 55% (±±±±)-229, 99%Scheme 2.20; Hydrostannylation-coupling / Nazarov synthesis of ester 229.

The elaboration of Nazarov product 229 to our desired racemic diene 231 was also

achieved in an analogous manner to the model system (Scheme 2.21). One-pot hydrolysis-

decarboxylation of 229 was accomplished in good yield under acidic conditions to give 230. This

ketone was readily alkylated with LDA and iodopentene to give diene 231 in good yield.


- 37 -

N

OPh

OEt

O N

OPh

(±±±±)-230, 89%(±±±±)-229

H2SO4, ∆

EtOH/H2O

N

Ph O

I

LDA, THF

(±±±±)-231, 79%

198

Scheme 2.21; Hydrolysis-decarboxylation / alkylation synthesis of racemic diene 231.

Unfortunately, we were unable to achieve a ring closing metathesis (RCM) reaction on our

diene 231 (Scheme 2.22). Refluxing 231 in dichloromethane in the presence of either the first or

second generation Grubbs’ catalysts produced only polymeric mess, even at high dilution of the

substrate (0.0005 M).

Grubbs' Catalyst233

RuPh

PCy3

PCy3

Cl

Cl

Grubbs' Catalyst(Second Generation)

234

RuPh

PCy3

Cl

Cl

NNMes MesN

Ph O

(±)-231

N

OPhGrubbs' Catalyst

(233 or 234)

232

DCM, 0.0005 M

Scheme 2.22; Attempted synthesis of racemic 232 by ring-closing olefin metathesis (RCM) of diene 231.

The olefin-metathesis reaction is principally driven by the entropy gain associated with the

release of gaseous by-product (typically ethylene). The selectivity of the process towards ring-

closure over cross-metathesis is primarily a result of greater entropy gain. As such, olefin-

metathesis does not allow ring-closure if significant enthalpy barriers are present, here cross-

metathesis pathways will dominate. The application of RCM to the synthesis of strained products

thus requires preorganisation of the substrates into conformations that favour cyclisation.

2.6 RCM Failure and Its Implications

The same problem was also encountered by Fuchs and co-workers who reported the failure

of the related substrate 236 to undergo RCM (Scheme 2.23).47 To circumvent this problem Fuchs

instead performed the reaction on the conformationally biased diene 172. Conformational control

was achieved by the use of a strategically placed triisopropylsilyloxy (OTIPS) group that, in the

major diastereoisomer of 172, favoured a conformation placing both olefins in close proximity,

facilitating ring closure. The silyloxy fragment 173 was then deoxygenated in four steps to give the


- 38 -

desired ketopyrrole 167. The use of the more active second generation Grubbs’ catalyst 234 was

not investigated by Fuchs as his studies (1997) preceded its development.

N

Ts O

236

Ts

N

O

237N

Ts O

171

N

Ts O

OR

Ts

N

O

173

OTIPSH

H

HN

O

167

4 steps

59%

R = H, 235, 95%

R = TIPS, 172, 97%

RCM233

60%

RCM

LiHMDS

5-Hexenal

Scheme 2.23; Synthesis of ketopyrrole 167 from 171 via a RCM strategy by Fuchs and co-workers.

Although this strategy is feasible for our system, the extra steps required and

accompanying reduced yield would render our approach no more concise or efficient than other

published approaches (Scheme 2.24, ~14 steps, ~12%, refer to Scheme 1.45). In this scenario, half

the reaction sequence is spent on the seemingly trivial elaboration of 239 to 167. Since we were

looking for a very concise approach to roseophilin to aid SAR studies, we decided to devise an

alternative route.

N

Pg O

239

HN

O

167

7 steps( )n

Pg

NO

Cl

YO

174

( )n

175

3 steps4 steps

OH

O

( )n-1

238

33%(n=2, Pg=Ts)

48% (rac, Y=OEt)~50% (Y=Aux)*(n=3, Pg=Bn)

73%(n=3, Pg=Bn)

Scheme 2.24; Hypothetical incorporation of Fuchs’ RCM strategy into our synthetic plan. (* hydrolysis / decarboxylation not attempted)

It is possible that sufficient conformational bias to allow RCM may be present in variants

of the diene 241 (particularly where R is bulky). Systems such as 240 are readily accessed by the

chemistries developed in this work, alkylation to give 241 would hopefully be routine. The bulky

isopropyl and R groups should substantially restrict the space available for the nearby tethered

olefin in a manner that should direct it towards the opposite end of the molecule as required to

facilitate ring-closure. The RCM product 242 would then need to be elaborated to the ketopyrrole

fragment 157. This strategy was not investigated further as successes in the alternative approach

detailed in the following section took precedence.


- 39 -

Pg Pg

N

O

R

O

N

O

R

O

N

O R

ORCM

233

?

N

O

240 241 242 157

Pg Pg

Scheme 2.25; A possible conformational restriction strategy to facilitate ring-closure (R = bulky auxiliary)?

Chapter 3: Roseophilin Synthesis; α-Alkoxy Approach

- 40 -

CHAPTER 3: ROSEOPHILIN SYNTHESIS; α-Alkoxy Approach

3.1 A New Synthetic Strategy

The alternative to starting with an intact pyrrole in the synthesis of the ketopyrrole

fragment is to form it later via a Paal-Knorr reaction. This strategy was successfully employed by

Tius and Harrington who concisely elaborated cyclopentenoid 165 to the unprotected ketopyrrole

fragment 167 (Scheme 3.1, see also Scheme 1.46).49 However, we believed the hydrostannylation-

coupling and Nazarov reaction sequence could significantly reduce the number of steps required to

access 165 (or close analogues).

OO

BzO

2

4

165

10 Steps

28%

OH

161

O

BzOO

243, 91%

O

BzOO

166, 89%

HN

O

167, 54%

i) ii) iii)

Scheme 3.1; Elaboration of cyclopentenoid 165 to ketopyrrole 167 by Tius and Harrington. i) RCM, Grubbs’ catalyst; ii) Hydrogenation, H2 / Pd, THF; c) Paal-Knorr reaction, NH4OAc / Ti(OiPr)4 / propionic acid, 140ºC.

Our first strategy was to couple alkyne 175 (variants of which we already had) with an α-

alkoxy acid chloride 244 to give the α-alkoxy Nazarov substrate 245 (Scheme 3.2). Nazarov

reaction of 245 gives cyclopentenone 246, which should be readily hydrolysed with

decarboxylation to give 247. It should then be possible to alkylate 247 to give our desired RCM

precursor 248. This approach should allow us access to roseophilin in racemic form through

incorporation of alkyne 175 as the ester 186, or in both enantiomeric series through incorporation

of the alkyne as the auxiliary-bearing S-204 and R-204.

O

RO

6-n

245

O

Y

Cl

O

RO

6-n

244

O

RO/HO

6-n

247

O

RO/HO

6-n

246

O

YYO

175

OO

RO/HO

6-n

n

248

i) ii) iii) iv)

Scheme 3.2; Proposed access to 248 using our standard methodology. i) Hydrostannylation-coupling; ii) Nazarov reaction; iii) Hydrolysis-decarboxylation iv) Alkylation.

A more concise but considerably more speculative strategy would be to produce 248

directly through a homologated variant of our standard hydrostannylation-coupling reaction

(Scheme 3.3). We thought it might be feasible to hydrostannylate homologated keto-alkyne 249

under palladium catalysis to give 250. The regiochemistry of 250 should be preferred based on the


- 41 -

steric and electronic bias present in 249 and the stereochemistry should be determined by the

preference for syn-hydrostannylation under palladium catalysis. Coupling of acid chloride 244 to

vinylstannane 250 (either isolated or in one-pot) should then give the fully substituted Nazarov

precursor 251 in a very concise manner. Nazarov reaction of 251 should then provide our desired

cyclopentenoid 248.

O

n

On

Bu3SnCl

ORO

6-n244

250249

O

RO

O

6-n

n

251

OO

RO/HO

6-n

n

248

Bu3SnH

Pd0

Nazarov

Scheme 3.3; Alternate route to 248 based on hydrostannylation of remotely activated alkyne 249.

3.2 Synthetic Efforts Based On Our Standard Protocol

Common to our two proposed strategies is the use of an α-alkoxy acid chloride 244 (see

Schemes 3.2 and 3.3). We believed the best way to produce 244 was to utilise Wittig chemistry. In

1997 Senici and co-workers reported a detailed study on the reaction of various alkoxy and

aryloxy-acetate derived phosphorus compounds 253 with aldehydes 252, giving alkoxy and

aryloxy-alkenoates 254, typically as mixtures of stereoisomers (Scheme 3.4).58

O

R H

252

R1OOMe

O

RZ-254

R1OOMe

O

E-254R

Base

Solvent

O

OMeR1O

H [P]

253 Scheme 3.4; Preparation of E- and Z-2-alkoxy and 2-aryloxy-alkenoates (R = alkyl, vinyl, aryl).

The best result obtained by Senici for production of Z-configured products in reactions with

alkyl aldehydes was realised with phosphonium salt 256 in tetrahydrofuran with DBU as the base

(Scheme 3.5). Treatment of butyrylaldehyde with phosphonium salt 256 and DBU in

tetrahydrofuran gave 257 in 63% yield and 92% Z-selectivity when allowed to react for 24 hours

(longer times were not tried). A comparable result was obtained with dichloromethane as solvent

with 257 isolated in 60% yield and 88% Z-selectivity.


- 42 -

H

OO

OMeMeO

PPh3 Br

256

MeOOMe

O

Z-257, 58%

MeOOMe

O

E-257, 5%255

DBU, rt

THF, 24h

Scheme 3.5; Synthesis of Z-methyl 2-methoxyhex-2-enoate.

Phosphonium salt 256 is readily produced in excellent yield from methyl methoxyacetate

258 (Scheme 3.6).59 Benzoyl peroxide catalysed α-bromination of 258 with NBS followed by

removal of the precipitated succinamide gave bromide 259. Reaction of this crude material with

triphenylphosphine in toluene gave the desired salt 256.

O

OMeMeO

O

OMeMeO

Br

O

OMeMeO

PPh3 Br

NBS, CCl4

(BzO)2 (cat.)

PPh3, PhMe

258 256, 86%259 Scheme 3.6; Preparation of Wittig reagent 256.

With the phosphonium salt 256 in hand we were ready to try the Wittig chemistry (Scheme

3.7). A good yield of the desired Z-configured ester 261 was obtained after treating 256 with DBU

and our requisite aldehyde, 4-pentenal (260). A minor amount of the E-isomer was observed but

was not isolated.

O

H

O

OMeMeO

PPh3 Br

MeOOMe

ODBU

THF

5 daysZ-261, 80%260 256

Scheme 3.7; Synthesis of ester 261 from 4-pentenal.

Since 4-pentenol 262 is significantly cheaper and available in larger quantities than 260, we

also attempted to synthesise 261 from it (Scheme 3.8). The alcohol 262 can be oxidised in DCM

under Swern conditions. After aqueous quenching and washing, the crude organic phase can be

dried with magnesium sulfate and treated with 256 and DBU without necessitating the isolation of

the volatile aldehyde 260. This procedure, although only modest in yield, allowed us access to

large quantities of 261. In this case, the use of dichloromethane as solvent meant the production of

a significant amount of the E-isomer was unavoidable, however, these isomers were readily

separated by chromatography.


- 43 -

O

H260

OH

262

O

OMeMeO

PPh3 Br256 MeOOMe

O

Z-261, 58%

MeOOMe

O

E -261, 9%

DBU, THF/DCM

Swern

DCM

Scheme 3.8; Synthesis of ester 261 from 4-penten-1-ol.

Ester Z-261 was readily elaborated to our desired acid chloride 264 (Scheme 3.9).

Treatment of the ester with lithium hydroxide in THF/water gave crude acid 263 after acidic work-

up. This material could then be converted cleanly to the acid chloride 264 by treatment with either

thionyl chloride or oxalyl chloride. Scale-up of the thionyl chloride reaction was problematic

possibly due to reaction rate / HCl liberation issues, oxalyl chloride is thus the superior reagent in

this case.

MeOCl

O(CO)2Cl2, DCM

DMF (cat.)

MeOOH

O

MeOOMe

O

Z-261

LiOH

H2O/THF

264, 97%263 Scheme 3.9; Synthesis of acid chloride 264 from ester 261.

With our α-alkoxy acid chloride 264 and the alkynes 186 and 204 from our pyrrole-based

roseophilin work in hand, we were ready to attempt their coupling (Scheme 3.10). The coupling of

ester 186 to acid chloride 264 produced only a low yield of impure 265 as a mixture of

stereoisomers. Furthermore, 265 was unstable and as such was not elaborated further.

OEtO

MeOCl

OMeO

O O

265, low yield, impure

Bu3SnH

Pd0, CuIOEt

264 186 Scheme 3.10; Synthesis of Nazarov substrate 265.

The coupling of the auxiliary-bearing alkyne 204 to acid chloride 264 was more promising

(Scheme 3.11). Although the crude NMR revealed the reaction proceeded quite well, 266 was only

isolated in moderate yield, probably as a result of the instability of this material. Decomposition of

this material was observed even when stored in the freezer (-20°C).


- 44 -

NO

O

Ph

O

MeOCl

O

MeO

O N

O

O

O Ph

S-266, 57%

Bu3SnH

Pd0, CuI

264 S-204 Scheme 3.11; Synthesis of auxiliary-bearing Nazarov substrate 266.

Despite these difficulties we did manage to attempt some Nazarov reactions on 266

(Scheme 3.12). Unfortunately the Nazarov reaction was complicated by seemingly unavoidable

hydrolysis. Both of the diastereoisomeric products 267 and 268 were highly polar and inseparable

by column chromatography. Slightly greater selectivity was observed with methanesulfonic acid

(dr = 7:3) than with cupric triflate (dr = 6:4). The low yields and instability of compounds 265 and

266 prompted us to abandon this approach in favour of investigating our other strategy (see

Scheme 3.3).

MeO

O N

O

O

O Ph OH

O

O

N

O

Ph

OOH

O

O

N

O

Ph

O

S-266267 268

MeSO3H or

Cu(OTf)2

Inseparable diastereomers Scheme 3.12; Nazarov reaction of 266.

3.3 Hydrostannylation Studies of Remotely Activated Alkynes

Our second strategy requires an extension of our hydrostannylation-coupling protocol to

homologated keto-alkynes like 249 (Scheme 3.3). Initially, we were doubtful of the feasibility of

this strategy on the basis that dialkyl-substituted internal alkynes are known to be very resistant to

hydrostannylation under palladium catalysis. Radical mediated hydrostannylation would not be

appropriate on account of the probable low degree of regio- and stereocontrol. However, we were

encouraged by a recent report by Marshall and Bourbeau in which they reported the successful

palladium mediated hydrostannylation of internal propargylic alcohols and acetates 269 (Scheme

3.13).60 Here the weak polarisation of the alkyne and/or the presence of a ligating functionality is

sufficient to promote the palladium mediated process, moderate regioselectivity is observed in the

absence of steric bias (Entries 2,3,5) and excellent selectivity is observed with synergistic steric

bias (Entries 1 and 4).


- 45 -

R1

OR

R1

Bu3Sn

OR

R1

OR

Bu3Sn

Bu3SnH, THF

Pd(PPh3)2Cl2

270269 271 ENTRY R R

1 Yield (%) 270 : 271

1 H s-Bu 75 >20 : 1

2 H n-Bu 73 7 : 1

3 H Me 58 3 : 1

4 Ac s-Bu 79 >20 : 1

5 Ac n-Bu 73 7 : 1

Scheme 3.13; Hydrostannylation of weakly polarised internal alkynes.

The most rational way to access homologated keto-alkynes 277 is through oxidation of a

Yamaguchi-Hirao product 276 (Scheme 3.14). The Yamaguchi-Hirao reaction is the coupling of

the BF3.OEt2 adducts (274) of lithium-acetylides to epoxides 275, producing homopropargylic

alcohols 276.61 This two-step strategy should allow concise general access to homologated keto-

alkynes including 249 (see Scheme 3.3).

R1

R1

Li

R1

BF3.Li

R1

OH

R2

OR2

274273 276272

275BF3.OEt2BuLi

R1

O

R2

277

[O]

Scheme 3.14; Synthesis of homologated keto-alkynes by Yamaguchi-Hirao coupling and oxidation.

The alcohol precursor 280 for our desired homologated keto-alkyne was readily produced

by coupling methylbutyne 278 to epoxyoctene 279 (Scheme 3.15). To examine the intrinsic

regioselectivity of hydrostannylation, we also sought to examine the proposed chemistry on

substrates lacking steric bias (this being important for future analoging studies). To this end, we

also produced the regioisomeric alcohol 282 from pentyne 281 and epoxyoctene 279.

OH

( )4

280, 80%

O

OH

( )4

( )4BuLi, BF3.OEt2

THF279

281 282, 93%

O( )4

BuLi, BF3.OEt2

THF279

278

Scheme 3.15; Synthesis of homopropargylic alcohols 280 and 282.

Since 280 (and 282) is chiral and both enantiomers of precursor epoxide 279 are known,62

we considered the possibility that if the stereocentre was carried into the Nazarov precursor,

Nazarov cyclisation may occur with diastereoselectivity allowing access to enantiopure


- 46 -

roseophilin. Elaboration of monochiral (albeit racemic) alcohol 280 to an appropriate monochiral

Nazarov precursor would require selective hydrostannylation of the protected alkyne. The

feasibility of this reaction was tested with the model system 282 (Scheme 3.16). Alcohol 282 was

readily protected as the acetate 283. Unfortunately, treatment of 283 with tributyltin hydride in the

presence of palladium resulted in very little reaction; consequently this strategy was not pursued

further.

OH

( )4

282

OAc

( )4

283, 70%

Bu3Sn

AcO ( )4 AcO ( )4

Bu3Sn

284 285

Ac2O, Et3N

DCM, DMAP

Bu3SnH

Pd0, THF

Scheme 3.16; Attempted hydrostannylation of homopropargylic acetate 283.

Alcohols 280 and 282 were readily oxidised to homologated keto-alkynes 286 and 287 with

the Dess-Martin periodinane (Scheme 3.17). The ketone products were best isolated as crudes,

with some decomposition observed during chromatography. Attempts to oxidise alcohols 280 and

282 with Swern variants were unsuccessful, returning only starting material and decomposition

products.

OOH

( )4 ( )4Dess-Martin

DMSO

280 286, 99%

OOH

( )4 ( )4Dess-Martin

DMSO

282 287, 99% Scheme 3.17; Oxidation of alcohols 280 and 282 to keto-alkynes 286 and 287 with Dess-Martin periodinane.

The hydrostannylation of alkynes 286 and 287 proved to be quite problematic (Scheme

3.18). Application of the conditions reported by Marshall and Bourbeau in their hydrostannylation

of propargyl alcohols and acetates 269 was only moderately successful (Entries 1 and 2). Dropwise

addition of 1.5 equivalents of tributyltin hydride to tetrahydrofuran solutions of 286 or 287 in the

presence of 10 mol% of Pd(PPh3)2Cl2 led to 50% conversion to vinyl-stannane products B and C

(as determined by 1H NMR, see Figure 3.1 for key NMR-resonance assignments). Reducing the

catalyst loading led to lower conversion (Entry 3) whilst changing the solvent or catalyst had

minimal effect (Entries 4-6). Longer reaction times did not improve results.


- 47 -

R1

O

( )4

AR1

Bu3Sn

O ( )4

R1

O ( )4

Bu3SnB C

Bu3SnH

Pd, Solvent

Entry Alkyne A

R1 = Pd Catalyst Catalyst

Loading

Equiv.

Bu3SnH

Solvent Conversion

(%)

Ratio

B : C

Stannane B

R1 =

1 i-Pr, 286 Pd(PPh3)2Cl2 10 mol% 1.5a THF ~50 >20 : 1 i-Pr, 288

2 n-Pr, 287 Pd(PPh3)2Cl2 10 mol% 1.5a THF ~50 3 : 1 n-Pr, 289

3 n-Pr, 287 Pd(PPh3)2Cl2 3 mol% 1.5a THF ~30 3 : 1 n-Pr, 289

4 n-Pr, 287 Pd(PPh3)2Cl2 10 mol% 1.5a DMF ~50 3 : 1 n-Pr, 289

5 n-Pr, 287 Pd(PPh3)2Cl2 10 mol% 1.5a DCM ~50 4 : 1 n-Pr, 289

6 n-Pr, 287 Pd(PPh3)4 10 mol% 1.5a THF ~50 3 : 1 n-Pr, 289

7 n-Pr, 287 Pd(PPh3)4 10 mol% 1.5a CDCl3 ~50 5 : 1 n-Pr, 289

8 n-Pr, 287 Pd(PPh3)4 10 mol% 3b CDCl3 100 5 : 1 n-Pr, 289

9 n-Pr, 287 Pd(PPh3)4 5 mol% 1.3c THF 100 3 : 1 n-Pr, 289

10 n-Pr, 287 Pd(PPh3)4 5 mol% 1.3c DCM 100 4 : 1 n-Pr, 289

11 i-Pr, 286 Pd(PPh3)4 5 mol% 1.3c THF 100 >20 : 1 i-Pr, 288

12 i-Pr, 286 Pd(PPh3)4 5 mol% 1.3c DCM 100 >20 : 1 i-Pr, 288 adropwise addition, bportionwise addition (1.5 equiv. + 1 equiv. + 0.5 equiv.), cdropwise addition of a solution over the course of one hour

Scheme 3.18; Optimizing hydrostannylation of keto-alkynes 286 and 287 (NMR study).

Up to this stage we were directly concentrating the crude reaction mixture to obtain

samples for NMR analysis and were not observing the starting materials A in any of these trials.

We interpreted these results as indicating the reaction was complete and that decomposition

processes accounted for the apparent missing starting material (integration of the terminal olefin

peaks at ~5.8 and ~5.0 ppm allowed the absolute amount of stannanes B and C to be calculated

with respect to the starting amount of alkyne A used). However, when we carried out the reaction

in (D)chloroform we circumvented the requirement for evaporation and were surprised to see half

the starting material A (287) still present, along with a minor improvement in product ratio (Entry

7). After the addition of two more portions of tributyltin hydride we successfully achieved

complete conversion of the alkyne to vinyl-stannanes B and C in a 5:1 ratio, respectively (Entry 8).

A common observation in the preceding tests was gas evolution (bubbling) at

approximately the halfway-point of tin hydride addition. We attributed this to hydrogen gas

formation as a result of a palladium mediated disproportionation of the tin hydride ii into hydrogen

and bis-tributyltin v (Scheme 3.19). According to our proposed mechanism, the disproportionation

reaction competes with the desired hydrostannylation reaction of iii (Paths 2 and 1, respectively).

We rationalised that lowering the rate of addition of tin hydride to a rate commensurate or lower

than its rate of consumption (avoiding accumulation) would minimise the concentration of tin

hydride during the course of the reaction and should favour reaction of iii with A (Path 1) over its


- 48 -

reaction with tin hydride ii (Path 2). Pursuing this line of reasoning lead to optimised conditions

whereby complete hydrostannylation was achieved with 5 mol% of catalyst and only a slight

excess of tin hydride (Figure 3.18, Entries 9-12).

O

( )4

287

Bu3Sn

O ( )4

O ( )4

Bu3Sn

289 290

δ 3.24(d, J = 6.9 Hz)

δ 3.21(t, J = 2.4 Hz)O

( )4

286

Bu3Sn

O ( )4

288

δ 3.37 (s)

δ 3.19(d, J = 2.1 Hz)

δ 5.48(d, J = 9.0 Hz)

δ 5.69(t, J = 6.9 Hz)

δ 3.37 (s)

Figure 3.1; Key NMR resonances of 286-290.

R1

O

R2

Bu3Sn

R1

O R2

Pd

R1

H Pd

PPh3

PPh3

HH

Bu3Sn

Ph3P

PPh3

H

R2

O

Bu3Sn Pd

PPh3

PPh3

H

Bu3Sn H

SnBu3H

H2

(Ph3P)2Pd0

(Bu3Sn)2

Path 2

Path 1

iv A

B

iii

vi

i

v ii

ii

Scheme 3.19; Proposed mechanism for hydrostannylation of A with competitive disproportionation (R2 = hexenyl).

During these trials it became apparent that purification of stannanes 288 and 289 by

chromatographic means may not be possible. Chromatography was attempted on silica, base-

washed silica, neutral alumina and basic alumina; in all cases only small amounts of 288 or 289

were isolated off the column and this material was contaminated with protodestannylated material

and other uncharacterised decomposition products. This meant that hydrostannylation and

subsequent coupling of 286 (and congeners, such as 287) almost certainly must be accomplished in

one pot.

3.4 Hydrostannylation-Coupling and Nazarov Reaction

Concurrent with our hydrostannylation optimisation studies, we attempted the coupling of

model alkyne 287 to acid chloride 264 by our standard hydrostannylation-coupling procedure

(Scheme 3.20). This reaction was quite messy and 291 was isolated in low yield along with a


- 49 -

vinylstannane homocoupling product 292 that has apparently been formed with an accompanying

carbonyl transfer (presumably from 264). Model Nazarov substrate 291 is reasonably stable and

we obtained a sufficient quantity to investigate its Nazarov cyclisation.

MeO

O

Cl

OO

O

OO

MeOO

( )4

287

Bu3Sn

O ( )4

289

Bu3SnH

Pd(PPh3)4, THF CuCl

( )4

291, 29%

292, 10%

( )4( )4

264

Scheme 3.20; Hydrostannylation-coupling synthesis of model Nazarov substrate 291.

Treatment of 291 with methanesulfonic acid in dichloromethane promoted clean hydrolytic

Nazarov reaction to give the enol product 294, no proton-elimination product 295 was observed

(Scheme 3.21). Significantly, the enol placement in 294 is different to what was observed with the

closely related product 296, which is produced by hydrolysis of regiodefined benzoate 165

(Scheme 3.22).49b This result indicates that the regiochemistry of enol placement in such systems is

determined by the reaction pathways producing them and not by the relative energies of the two

tautomeric forms, that is, there is not thermodynamic equilibration of the tautomers under standard

conditions (Scheme 3.23). The impact of this factor on the potential success of our strategy was

unknown.

OHO

O

(±±±±)-294, 99%MeSO3H

DCM

( )4

OO

MeO

( )4

291

OHO

MeO

293

( )4

OO

MeO

(±±±±)-295, not observed

( )4

Hydrolysis

H +Elimination

Scheme 3.21; Nazarov reaction of model substrate 291.


- 50 -

OO

HO

296

( )4OO

BzO

165

( )4

Hydrolysis

Scheme 3.22; Hydrolysis of 165 by Tius and Harrington.

OH

Alkyl2O

Alkyl1 R

O

Alkyl2HO

Alkyl1 R Scheme 3.23; Lack of tautomeric interconversion of 2-hydroxy-3,5-dialkylcyclopent-2-enones.

Having proven the viability of both the hydrostannylation-coupling and Nazarov reactions

on our model system, we then turned to the real system (Scheme 3.24). Preliminary tests revealed

hydrostannylation of alkyne 286 occurred with high regioselectivity (>20:1) independent of the

solvent used (see Scheme 3.18), as expected due to the steric bias present. Our initial

hydrostannylation-coupling attempts produced only low yields of the desired Nazarov precursor

297 (Scheme 3.24, Entry 1). These were conducted in tetrahydrofuran with the slow tin hydride

addition approach developed in the model study (see Scheme 3.18, Entry 11). In this reaction the

major product isolated was not 297 but the product of vinylstannane homocoupling with carbonyl

transfer 298. Inconsistent results were obtained on repetition of this reaction with considerable

variation in the ratio of products 297 and 298. Attempts to improve the yield of 297 by changing

catalysts and using a carbon monoxide atmosphere (to suppress decarbonylation of 264) proved

unsuccessful.

MeO

O

Cl

OO

O

OO

MeOO

( )4

286

Bu3Sn

O ( )4

288

Bu3SnH

Pd(PPh3)4

Solvent

CuI

( )4

297

298

( )4( )4

264

Entry Solvent CuI Yield 297 (%) Yield 298 (%)

1 THF CuCl (1 equiv.) 5-20 10-40

2 DCM Cu(I) thiophenecarboxylate (10 mol%) 58-65 <5 (by NMR)

Scheme 3.24; Hydrostannylation-coupling synthesis of Nazarov substrate 297.


- 51 -

Fortuitously, it was discovered that performing the reaction in dichloromethane with a

soluble copper co-catalyst produced better and more consistent results (Entry 2). This allowed

synthesis of our desired fully-substituted Nazarov precursor 297 in good, reproducible yield. This

method suppresses the formation of 298, possibly by the increased rate of cross-coupling. No

attempt was made to apply these optimised conditions to the synthesis of the model system 291.

The Nazarov reaction of 297 proceeded with concomitant hydrolysis when promoted by

methanesulfonic acid (Scheme 3.25), giving 300 in excellent yield. A recent report by Trauner and

co-workers reported Nazarov reaction of related α-alkoxy precursors proceeding without

hydrolysis when promoted by catalytic aluminium chloride (Scheme 3.26).10 Accordingly, the non-

hydrolysed product 301 was obtained by treating the substrate 297 with 10 mol% of aluminium

chloride. This represents the first case of a specific α-alkoxy Nazarov substrate being selectively

cyclised in both an hydrolytic and non-hydrolytic manner (deliberately, and within a single group),

though it is likely that these divergent paths can be generally applied to Nazarov substrates lacking

significant bias towards a particular path.

OHO

O

(±±±±)-300, 99%

ACID (A)

DCM

( )4

OO

MeO

( )4

297

OAO

MeO

299

( )4

OO

MeO

(±±±±)-301, 85%

( )4

A= AlCl

3(cat.)

A=

MeSO 3H

Scheme 3.25; Hydrolytic and non-hydrolytic Nazarov reaction of substrate 297.

EtO

O

EtO

O

Ph

EtO

O

EtO

O

O

EtO

O

EtO

Ph

O

EtO

O

EtO

H

H

80%

40%

65%

75%

AlCl3 (10 mol%)

DCM

AlCl3 (10 mol%)

MeCN

AlCl3 (10 mol%)

MeCN

AlCl3 (10 mol%)

MeCN

Scheme 3.26; AlCl3 catalysed non-hydrolytic Nazarovs reported by Trauner.


- 52 -

3.5 Completing the Concise Synthesis of Roseophilin

Both possible products (300 and 301) of the Nazarov cyclisation of 297 were pursued

because they both possess key differences to Tius’ system (Scheme 3.27).49 We needed to consider

the prospective success of our synthesis with both 300 and 301. Of particular concern was the

viability of the Paal-Knorr reaction to form the ketopyrrole fragment 167. If we consider the

elaboration of the hydrolysed product 300 to a potential Paal-Knorr precursor we arrive at 302.

Precursor 302 lacks the 1,4-diketo regiochemistry present in Tius’ system 166, which he stipulates

may be critical for success of the Paal-Knorr reaction. Conversely, if the non-hydrolysed product

301 is similarly elaborated we arrive at 303. The stability of the enol-ether moiety in 303 may

hinder Knorr reaction due to the conformational restraint imposed by the bridge-head enol-ether

double-bond. Compare this to Tius’ system 166 which contains a hydrolytically labile benzoate

that converts to a ketone, giving an sp3 centre at the bridge-head position.

OHO

O

300

( )4

OO

MeO

( )4

297O

O

MeO

301

( )4H +Elimination

Hydrolysis

O

MeOO

303

HN

O

167

OR

OO

302

Mutiple

Steps

Mutiple

Steps

Knorr

Reaction

Knorr

Reaction

?

?

NAZAROV

O

BzOO

166

HN

O

167, 54%

Knorr

Reaction

From Tius' synthesis

Scheme 3.27; Influence of controlling the Nazarov reaction on the potential success of the Knorr reaction.

The non-hydrolysed product 301 was examined first on account of its greater similarity to

the successful system 166 reported in Tius’ synthesis (see Scheme 3.1). Ring closing metathesis of

301 was readily achieved with the Grubbs’ ruthenium carbene 233 to give 304 as a 3:2 mixture of

double-bond stereoisomers (Scheme 3.28). This reaction required high dilution (0.0005 M in 301,

higher concentrations give lower yields) to minimise cross-metathesis, which is a common

complication of macrocycle formation by olefin metathesis. Use of the more stable and reactive


- 53 -

second-generation catalyst 234 failed to give 304, returning only a mess of multiple,

uncharacterised species.

O

MeOO

OO

MeO

(±)-301

( )4

Grubbs' Catalyst233

RuPh

PCy3

PCy3

Cl

Cl

Grubbs' Catalyst(Second Generation)

234(±)-304, 91%

233 (5 mol%), DCM

Reflux, [301] = 0.0005 M

RuPh

PCy3

Cl

Cl

NNMes Mes

Scheme 3.28; Ring-closing metathesis of diene 301.

The olefin in macrocycle 304 was readily hydrogenated to give 303 using the conditions

reported by Tius and Harrington (Scheme 3.29).49 Unfortunately (as anticipated, see Scheme 3.27),

the stability of the enol-ether prevented the Knorr reaction of 303. Treatment of 303 with

ammonium acetate and titanium isopropoxide in propionic acid at 140ºC (in an analogous manner

to Tius’ reaction of 166) returned only starting material and small amounts of imine by-products.

The lack of any pyrrole products seems to indicate enol-ether hydrolysis is required to allow

sufficient flexibility for ring-closure.

O

MeOO

O

MeOO

(±)-304

Pd/C (10%), H2

THF

(±)-303, 98%

Knorr reaction

HN

O

(±)-167 Scheme 3.29; Attempted synthesis of ketopyrrole 167 by Knorr reaction of enol-ether 303.

We initially protected the hydrolysed product 300 as the acetate 305 in order to avoid any

possible attenuation of Grubbs’ catalyst activity by the enol (Scheme 3.30). Though acetylation

was readily achieved, the production of minor amounts of two doubly acetylated by-products was

unavoidable. The acidity of the indicated protons allows formation of enolates that are then

acetylated to give the observed diacetates, although the exact location of the second acetate for

either diacetate was not determined.


- 54 -

OHO

O

(±)-300

( )4 OAcO

O

(±)-305, 60-85%

( )4

Ac2O or AcCl

Et3N, DCM Acidic Protons

Scheme 3.30; Acetylation of 300.

The ring-closing metathesis of 305 was accomplished with Grubbs’ catalyst 233 in an

analogous manner to the enol-ether 301 (Scheme 3.31), in this case macrocycle 306 was isolated as

an 11:2 mixture of double-bond stereoisomers. The hydrogenation of acetate 306 was more

problematic than enol-ether 304, here the major stereoisomer readily hydrogenated, whereas the

olefin of the minor stereoisomer apparently migrated and would not hydrogenate in the original

reaction mixture. However, if the original load of catalyst was filtered off and a new portion was

added the reaction would proceed to completion when treated again with hydrogen.

OAc

OO

(±)-306, 90%

233 (5 mol%), DCM

Reflux, [305] = 0.0005 M

OAcO

O

(±)-305

( )4

OAc

OOPd/C (10%, 2 lots), H2

THF

(±)-307, 97% Scheme 3.31; Synthesis of Knorr substrate 307 by ring-closing metathesis.

A formal racemic synthesis of roseophilin was completed with the successful Knorr

reaction of macrocyclic acetate 307 to give the ketopyrrole fragment 167 (Scheme 3.32). Reaction

of 307 gave virtually identical results to Tius’ reaction of 166 (see Scheme 3.1).49a

HN

O

(±)-167, 56%

OAc

OO

(±)-307

NH4OAc, Ti(OiPr)4

Scheme 3.32; Synthesis of ketopyrrole 167 by Knorr reaction of 307.

We then decided to see whether protection of the enol in 300 was necessary for successful

elaboration to 167. Pleasingly we found we could readily ring-close 300 with Grubbs’ catalyst 233

(Scheme 3.33). The chromatography of macrocyclic enol product 308 was slightly problematic and

it was found that product loss could be best minimised by essentially filtering the crude reaction

o2EtCO H, 140 C


- 55 -

mixture through a plug of silica to remove catalyst by-products. The hydrogenation of 308 was

complicated by the same apparent olefin migration as observed with the acetate system 306,

accordingly the double-hydrogenation method required for the acetate was used on the enol 308 to

give 309 in excellent yield.

OH

OO

(±)-308, 79%

233 (6 mol%), DCM

Reflux, [300] = 0.0005 M

OHO

O

(±)-300

( )4

OH

OO

Pd/C (10%, 2 lots), H2

THF

(±)-309, 99%

Scheme 3.33; Synthesis of unprotected Knorr substrate 309 by ring-closing metathesis.

As expected, unprotected macrocyclic enol 309 was readily converted to the ketopyrrole

fragment 167 with the Knorr reaction (Scheme 3.34). It is significant to note the virtually identical

yields of 167 obtained through use of either unprotected enol 309, acetate 307 or regioisomeric

benzoate 166 (Schemes 3.34, 3.32 and 3.1, respectively). It seems initial ester hydrolysis of 307 or

166 is followed by an equilibration of the two tautomers 309 and 310 (Scheme 3.35), the 1,4-

diketone 310 can then irreversibly condense with ammonia to give the desired ketopyrrole 167.

HN

O

(±±±±)-167, 55%

OH

OO

(±±±±)-309

NH4OAc, Ti(OiPr)4

Scheme 3.34; Synthesis of ketopyrrole 167 by Knorr reaction of 309.

HN

O

167, ~55%

OAc

OO

307

O

HOO

310

OH

OO

309

O

BzOO

166

Hydrolysis

Hydrolysis

O

HONH

311

NH

HOO

312

NH3

NH 3

∆ H+

Scheme 3.35; Mechanism of the Knorr reaction of 307, 309 and 166.

2oEtCO H, 140 C


- 56 -

In conclusion, we have developed a ten step (longest linear sequence from 256, 260, 278

and 279) formal synthesis of racemic roseophilin (Scheme 3.36). This strategy affords the natural

product in a 12.5% overall yield, with the ketopyrrole fragment being constructed in seven steps

and 21.5% yield. This synthesis, albeit racemic thus far, is considerably more concise and efficient

than all previously reported approaches (see Scheme 1.43). Moreover, all reactants, reagents and

catalysts are comparatively inexpensive and available in significant quantities. Potential methods

for the introduction of asymmetry into our synthesis as well as the potential of this strategy to

generate analogues will be discussed in the following section.

O

OOH

( )4 ( )4 ( )4279

278 280, 80% 286, 99%

O

H

O

OMeMeO

PPh3 Br

MeOOMe

O

Z-261, 80%260

256

MeOCl

O

264, 97%

297, 65%

OH

OO

((((±±±±))))-308, 79%

OH

OO

((((±±±±))))-309, 99%

HN

O

((((±±±±))))-167, 55%

OH

OO

((((±±±±))))-300, 99%

OO

MeO

( )4

N

OMeO

NH

Cl

(±)-Roseophilin (156)

58%

i) ii)

iii) iv)

v) vi)

vii) viii) ix)

Scheme 3.36; Our formal synthesis of racemic roseophilin. i) BuLi, BF3.OEt2; ii) Dess-Martin periodinane; iii) DBU; iv) LiOH / (CO)2Cl2; v) Bu3SnH, Pd0, CuI; vi) MeSO3H; vii) Grubbs’ catalyst; viii) H2 / Pd0; ix) NH4OAc, Ti(OiPr)4.

3.6 Conclusion; Analoging and Asymmetry

A significant yield limiting factor of this current strategy is the moderate yield of the Paal-

Knorr reaction (Scheme 3.36, step ix). There is good precedent for significant improvements in the

efficacy of related Paal-Knorr reactions when performed under microwave-assisted conditions.63

However, due to time constraints, this possibility was not explored on our system.

Although as yet only racemic, the current synthetic strategy should be readily adapted to

generating analogues of roseophilin and the related prodigiosins (Scheme 3.37). An advantage of

using a Paal-Knorr reaction late in the synthetic strategy is the potential for divergent access to


- 57 -

furans 316, pyrroles 317 and thiophenes 318. Our initial strategy involving the use of intact

heteroaromatic rings may also prove valuable in the synthesis of analogues (Scheme 3.38). This

strategy may also be applicable to the production of furans and thiophene variants of 326 through

incorporation of these rings in the acid chloride 322.

R1

O

R2

R1

O

R2

PPh3

MeOOMe

O

Br

O

HR3

MeOCl

O

R3

MeO

O

R3 R1

R2O OH

O

O

R1R3

R2

O

R1R3

HNR2

O

R1R3

SR2

O

R1R3

O

R2

Y2

Y1

M

R4

R5

2 Steps

2 Steps

272 275 277

313155

256

314 315 317

318

316

319 Y2

Y1

Y3R2

R1R3

R4

R5

320

Scheme 3.37; Synthesis of racemic roseophilin and prodigiosin analogues (Y = NR, O, S).

O

Y3

R1

X

O

R2

R1

X O

Y3

R1

R2

O

O

X

Y3

R1

R2

O

Cl

O

Y3

R2

Y3

R1

R3

R2

OY2

Y1

M

R4

R5

319

320

R2

324 325 326321 322 323

Y2

Y1

Y3

R1R3

R4

R5

Scheme 3.38; Synthesis of roseophilin and prodigiosin analogues (Y = NR, O, S).

There are two possible ways our synthesis could be modified to produce enantiopure (or at

least enantioenriched) roseophilin. It may be possible to achieve the Nazarov reaction of 297 in an

asymmetric manner with a chiral catalyst (Scheme 3.39). The chiral Brønsted acid catalyst recently

developed by Rueping and co-workers seems ideal for this reaction (see Scheme 1.38)40, however,

time constraints did not allow the investigation of this possibility.

HN

O

167

OH

OO

300

N

OMeO

NH

Cl

Roseophilin (156)

58%

297

OO

MeO

( )4CHIRAL

CATALYST

Scheme 3.39; Potential synthesis of enantioenriched roseophilin based on a catalytic asymmetric Nazarov reaction.


- 58 -

The second possible method to introduce asymmetry into our synthesis is through the

incorporation of a chiral auxiliary (Scheme 3.40). Replacement of the methoxy group in 297 with

an appropriate hydrolytically labile (or at least readily removable) chiral auxiliary gives 327.

Reaction of 327 should give 300 in a stereocontrolled way, this would then be elaborated to the

ketopyrrole fragment 167 in the manner developed on the racemate (see Scheme 3.36).

Alternatively if complete torquoselectivity is not possible it may be necessary to perform the

Nazarov in a non-hydrolytic manner, and after separation of diastereoisomers, 328 should then be

readily elaborated to enantiopure ketopyrrole 167 assuming the auxiliary is readily removed.

ON

O

Ph

OO

HN

O

167

OH

OO

300 N

OMeO

NH

Cl

Roseophilin (156)

58%

327

OO

Aux

( )4H+

O

AuxO

328

AlCl3

Aux =

ba

Scheme 3.40; Potential synthesis of enantioenriched roseophilin based on an auxiliary-mediated asymmetric Nazarov.

This type of auxiliary system has not yet been explored, mainly because suitable strategies

for the syntheses of the appropriate substrates do not yet exist. Developing strategies for the

construction of these types of Nazarov substrates and the investigation of their reaction would be a

significant study in its own right. The ideal auxiliaries to examine first would be a and b as they

have already proven successful in mediating other variants of the Nazarov reaction (see Schemes

1.27-1.30, 2.11 and 2.19).

Chapter 4: The Asymmetric Nazarov Reaction

- 59 -

CHAPTER 4: THE ASYMMETRIC NAZAROV REACTION

During our work on roseophilin, it became apparent that the auxiliary controlled

asymmetric Nazarov reaction is more complicated than we had imagined. This is demonstrated by

the varied product distribution observed on reaction of the four auxiliary-bearing substrates below

(Scheme 4.1). Pridgen’s system 102a, gave 103a as the major product irrespective of whether

Lewis or Brønsted acid was used.15 Similarly, the co-cyclising system 108 gave 109 as the major

product with both Lewis and Brønsted acids.34 However, reaction of 105 could be controlled to

give either the thermodynamic trans-product 106 or kinetic cis-product 107 through the use of

either Lewis or Brønsted acids, respectively.9 In all these previous cases the torquoselectivity is the

same, but in our new system 206 (see Scheme 2.11), the torquoselectivity alternates with use of

either Lewis or Brønsted acids. These results prompted us to study the oxazolidinone auxiliary

mediated asymmetric Nazarov reaction in greater detail to better assess its requirements.

O

PrO

O

O

O

PrOO

O

PrOO

O

O

O

O

O

O

Ph

O

N

O

O PhO

Ph

O

N

O

O

PhO

Ph

O

N

O

O

Ph

105

Cu(OTf)2 MeSO3H

O

Ph

O

N

O

O Ph

108O

MeO

O

Ph

O

N

O

O

Ph

109(Major)

O

MeOO

Ph

O

N

O

O

Ph

110(Minor)

O

MeO

N

O

O Ph N

OO

PhN

OO

Ph

102a 103a(Major)

104a(Minor)

SnCl4 or

MeSO3H

106 107

N

OPh

O

N

O

Ph

O

N

OPh

O

N

O

Ph

O

N

O

O

PhO

N

Ph O

R-206207 (Major with minor 208) 208 (Major with minor 207)

MeSO3HCu(OTf)2

or FeCl3

or

MeSO3H

Cu(OTf)2

Scheme 4.1; Varied product distribution with auxiliary mediated Nazarov reactions.


- 60 -

4.1 Synthesis of Auxiliary-Bearing Nazarov Precursors

The requisite auxiliary-bearing substrates for our study on the asymmetric Nazarov reaction

were all synthesised by our previously developed methods. Auxiliary-bearing alkynes were

synthesised by our one-pot method from chiral oxazolidinones 332 and terminal acetylenes 272 or

equivalent dibromo-olefins 329 (Scheme 4.2). This procedure provided the required alkynes in

moderate to good yield without optimisation (Scheme 4.3).

R1

Br Br

R1

NO

O

R2

O

R1

Li

R1

OLiO OO Li N O

OO

O

Cl2 x BuLi

THF

CO2

R3

R1

R2 R3

R1 BuLi

THF

HN O

O

R2 R3

BuLi, THF

331 334330273329

272

332

333

Scheme 4.2; One-pot general access to auxiliary-bearing alkynes used in this study.

Ph

NO

O

Ph

O

Ph

NO

OO

NO

O

Ph

O

Ph

NO

O

Ph

O

NO

OO

NO

OO

H

H

NO

O

Ph

O

O

HN O

Ph

O

HN O

Ph Ph

O

HN O

H H

O

HN O

O

HN O

Ph

O

HN O

Ph

O

HN O

Br Br

Ph

Ph

281

281

281

281

S-202

340

338

336

335, 65%

341, 43%

339, 42%

337, 43%

184

342

342

R-202

344

S-202

R-204, 69%

345, 48%

343, 41%

Scheme 4.3; Synthesis of auxiliary-bearing alkynes.


- 61 -

Auxiliary-bearing Nazarov precursors were synthesised by our one-pot hydrostannylation-

coupling reaction (Scheme 4.4).9 Coupling of the above alkynes 334 with acid chlorides 347 gave

the Nazarov precursors 348 in good to excellent yield (Scheme 4.5); in all cases the kinetic Z-

configured alkenes were the sole products.

R1

NO

OO

Bu3Sn

R1

N

O

O

O

R1

N

O

O

OO

R2

R3

R2

R3

R2

R3

Cl

O

Bu3SnH, Pd0

THF Pd0/CuI

346334 348

347

Scheme 4.4; One-pot general access to auxiliary-bearing Nazarov substrates used in this study.

O

O

N

O

O PhNO

O

Ph

O

O

Cl

335

350, 99%

349

O

O

N

O

O Ph

O

O

ClO

335

355, 70%

354

NO

O

Ph

O

O

O

N

O

O Ph

MeO

O

ClMeO

335

357, 91%

356

NO

O

Ph

O

O

O

N

O

O Ph

Ph

NO

O

Ph

O

Ph O

Cl

339

352, 86%

349

O

O

N

O

O

H

H

NO

OO

H

H

O

Cl

341

353, 86%

349

O

O

N

O

ONO

OO

O

Cl

337

351, 81%

349

O

O

N

O

O Ph

N

PhNO

O

Ph

O

O

Cl

N

Ph

R-204

R-206, 91%

179

O

Ph

O

N

O

O Ph

Ph

NO

O

Ph

O

O

Cl

343

105, 88%

349

O

Ph

O

N

O

O Ph

O

O

ClO

343

358, 69%

354Ph

NO

O

Ph

O

O

Ph

O

N

O

O Ph

MeO

O

ClMeO

343

359, 79%

356Ph

NO

O

Ph

O

O

Ph

O

N

O

O

Ph

NO

OO

O

Cl

345

360, 92%

349

Scheme 4.5; Synthesis of auxiliary-bearing Nazarov substrates.


- 62 -

The only previously unreported acid chloride 354 was readily produced by lithiation of

dihydropyran (361), followed by reaction with carbon dioxide to give acid 363 (Scheme 4.6). The

crude acid was then converted to the acid chloride 354 with thionyl chloride.

O O LiO

OH

O

OCl

Ot -BuLiTHF

i) CO2

ii) HCl SOCl2, DCM

354, 36%361 362 363 Scheme 4.6; Synthesis of acid chloride 354.

4.2 Study Goals

The Nazarov reaction of an auxiliary-bearing substrate like S-SM can theoretically give

rise to eight regio- and stereoisomeric products (Scheme 4.7). The various steps in the Nazarov

mechanism can occur with different forms of selectivity, the degree of selectivity within each step

then determines the product distribution. Understanding the influence auxiliaries exert on the

selectivity of these steps when acting in association with various acid promoters (A) and substrate

substituents (R1-R3) is fundamental to developing this strategy as a predictable and practical

approach to enantiopure cyclopentenoids. Our aim was to examine various auxiliaries, acids and

substrate substitutions to define their relationships and optimise yields of single products.

O

R3

R2

R1

N

O

O

O R3

R2

R1

A-O

O

N

OO

R3

R2

R1

A-O

O

N

OO

R3

R2

R1

O

O

N

OO

R3

R2

R1

O

O

N

OO

R2

R1

O

O

N

OO

R3

R2

R1

O

O

N

OO

R3

R3

R2

R1

O

O

N

OO

R3

R2

R1

O

O

N

OO

Competitiveif R2+R 3 = alkyl

Competitive

if R2+R3 = alkyl

S-ββββ-exo-cis

S-αααα-exo-cis

S-SM

S-αααα-cat

S-ββββ-cat

R2

R1

O

O

N

OO

R3

R2

R1

O

O

N

OO

R3

ACID (A)

ACID (A)

Torquoselectivity(4π-electrocyclization)

Regioselectivity(hydrogen elimination)

Diastereoselectivity(α-epimerization)

H

H

S-αααα-cis(S-αααα-endo-cis)

S-ββββ-cis(S-ββββ-endo-cis)

S-αααα-trans(S-αααα-endo-trans)

S-ββββ-tr ans(S-ββββ-endo-t rans)

S-αααα-exo(S-αααα-exo-tr ans)

S-ββββ-exo(S-ββββ-exo-trans)

Scheme 4.7; Possible product distribution from the Nazarov reaction of auxiliary-bearing substrates S-SM.


- 63 -

The scheme above includes a semi-arbitrary structurally descriptive nomenclature that is

used in the following work. The S denotes the stereochemistry of the oxazolidinone auxiliary, the

α and β figures denote the stereochemistry at the β-position (α and β configured R1, respectively,

as drawn), the endo and exo terms describe the endocyclic or exocyclic placement of the double-

bond, whilst the cis and trans terms describe the relationship between the stereochemistries at the

α and β-positions. The order of these terms reflects the mechanistic order in which they are

established. For simplicity, the endo terms (and the trans term for exo products) are omitted.

The fist step of the auxiliary-controlled Nazarov reaction of S-SM is 4π-electrocyclisation

(Scheme 4.7), this can produce two possible allyl-cation intermediates (S-β-cat and S-α-cat), the

ratio of which is determined by the torquoselectivity. The next step is hydrogen migration, this

occurs by proton-elimination from a centre adjacent to the cation, most commonly producing

products with internal (endo) double-bonds (S-β-cis and S-α-cis). However, if the R2 substituent is

an alkyl group, proton elimination can occur from the R2 group to give products with exocyclic

double-bonds (S-β-exo-cis and S-α-exo-cis). Enol protonation (following the elimination step)

occurs from the less-hindered face to give the cis-isomers initially, however, the ease of

epimerisation of the α-centre typically facilitates formation of the trans-isomers (S-β-trans, S-α-

trans, S-β-exo and S-α-exo).

As you might expect, the individual isolation of all isomeric products (at times up to six) by

standard purification methods (column chromatography) is near impossible. In most cases the two

major products, trans-isomers S-β-trans and S-α-trans, were individually isolated and fully

characterised (see Chapter 4.6 for detailed stereochemical assignments). The product ratios were

primarily determined by NMR analysis of crude reaction mixtures, in all cases the crude mass

balance was near 100%. The structural and stereochemical assignments of minor isomers identified

in the crude NMR’s are discussed in detail in Section 4.6.

4.3 Auxiliary Evaluation

The lack of examples of substrates bearing alkyl groups at the β-position (R1) for Nazarov

reactions with this particular auxiliary system prompted us to first focus on the reaction of 350

(Scheme 4.8). The Nazarov reaction of this simple substrate proved to be quite complicated. A

mixture of products with internal double bonds (364 and 366) and external double bonds (365 and


- 64 -

367) formed as a result of the two competitive elimination pathways operating. Halogenated Lewis

acids are apparently not appropriate for this system, producing only minor amounts of 364-367 on

complete consumption of 350 (Entries 1 and 2). Torquoselectivity is greater with Brønsted acid

(MeSO3H) than with Lewis acid (Entries 3 and 4). Migration of the double-bond to the lower-

energy internal position occurs under relatively strong acidic conditions, accordingly an optimised

yield of 364 could be obtained on treatment of 350 with a ten-fold excess of methanesulfonic acid

(Entry 5). Crude NMR spectra of Entries 3-5 are included as Appendix A2. The absolute

stereochemistry of the major isomer 364 was confirmed by X-ray crystallography (Figure 4.1,

Appendix B).

O

O

N

O

O Ph O N

O

OO

PhO N

O

OO

PhO N

O

OO

PhO N

O

OO

Ph

367365 366, 24%isolated

364, 71%isolated

350

ACID

ENTRY CONDITIONS S-α-trans S-α-exo S-β-trans S-β-exo

1a FeCl3 (1.1 equiv.), -78ºC → rt, 1h, DCM 364, 20% 365, 0% 366, 5% 367, 0%

2a SnCl4 (1.1 equiv.), -78ºC → rt., 1h, DCM 364, 25% 365, 2% 366, 9% 367, 0%

3 Cu(OTf)2 (1.1 equiv.), -78ºC → rt, 1h, DCM 364, 48% 365, 13% 366, 31% 367, 8%

4 MeSO3H (1.1 equiv.), -78ºC → rt, 1h, DCM 364, 54% 365, 18% 366, 21% 367, 7%

5* MeSO3H (10 equiv.), -78ºC → rt, 12h, DCM 364, 74% 365, 0% 366, 26% 367, 0%

Scheme 4.8; Optimising the Nazarov reaction of 350 (NMR ratios, a = unknown products observed, * optimum conditions).

Figure 4.1; X-Ray crystal structure of the major product 364 (ORTEP).

It is significant to note that 364 bears the opposite stereochemistries at the new

stereocentres (relative to that of the auxiliary) than do the major products (103a, 106, 109 and 207)

of the previous Nazarov reactions with this auxiliary (see Scheme 4.1). The stereochemistry of the


- 65 -

minor isomer 366 was assigned on the basis that the low coupling constant between the α and β-

protons is indicative of a trans-relationship between the α and β-substituents and its configuration

at the β-position must be opposite to that of 364. Although they were never isolated, the structures

of 365 and 367 were assigned by the presence of two pairs of finely coupled (J = 3.0 Hz) vinylic

doublets in the 1H NMR spectrum of the crude reaction mixture (6.07 and 5.29 ppm for 365, 6.04

and 5.26 ppm for 367, see Section 4.6 for greater detail).

The optimised conditions developed above were then applied to equivalent substrates

bearing the different oxazolidinone auxiliaries (Scheme 4.9). None of these auxiliaries induced

significantly greater torquoselectivity than the original phenyl system 350. The similar results

obtained with all of these auxiliaries prompted us to persist with the original auxiliary on account

of its greater availability as well as its convenient NMR ‘handles’ (see Chapter 4.6). The

stereochemistries of 368-373 were all assigned by comparison with 364 and 366 (Rf and NMR, see

Section 4.6 for a detailed discussion on structural and stereochemical assignment based on NMR).

O

O

N

O

O PhO N

O

OO

PhO N

O

OO

Ph

366, 24%364, 71%350

O

O

N

O

O O N

O

OO

O N

O

OO

369, 21%368, 74%351

O

O

N

O

O PhO N

O

OO

PhO N

O

OO

Ph

371, 25%370, 71%352

Ph Ph Ph

O

O

N

O

O O N

O

OO

O N

O

OO

373, 23%372, 70%353

H

H H

H

H

H

MeSO3H, DCM

(NMR Ratio = 72:28)

MeSO3H, DCM

(NMR Ratio = 78:22)

MeSO3H, DCM

(NMR Ratio = 76:24)

MeSO3H, DCM

(NMR Ratio = 74:26)

Scheme 4.9; Auxiliary evaluation.


- 66 -

We also sought to examine auxiliary systems with less remote chirality. Known chiral

alkynyl-sulfoxide 37464 was readily coupled by our hydrostannylation-coupling reaction to give

dienone 376 (Scheme 4.10). Unfortunately, 376 proved resistant to cyclisation and attempted

Nazarov reactions were unsuccessful with a variety of acids, even at great excess. Significantly,

this is the first report of hydrostannylation of alkynyl-sulfoxides; this method of producing

stereodefined chiral vinyl-sulfoxides may be useful for other applications, for example the

preparation of chiral dienophiles for use in asymmetric Diels-Alder reactions.

O

Cl

349 O

SO

Bu3Sn SO

SO

376, 79%

Bu3SnH

Pd0 Pd0/CuI

VariousAcids

374 375 Scheme 4.10; Stereoselective synthesis of enantiopure vinyl sulfoxide 376, a non-viable Nazarov substrate.

4.4 Substrate Study

The stereochemical outcome observed in the reaction of 350 is replicated when the phenyl-

oxazolidinone auxiliary is used in the Nazarov reaction of other substrates bearing alkyl groups at

the β-position (Scheme 4.11). With β-alkyl substrates superior torquoselectivity is obtained with

Brønsted acid promotion and trans-products are obtained exclusively. Two equivalents of

methanesulfonic acid at -78ºC were more than sufficient to promote cyclisation of the polarised α-

alkoxy substrate 355 to give a good yield of 377 as the major product, whilst the aromatic system

357 is apparently on the borderline of reactivity and requires a large excess of methanesulfonic

acid and prolonged reaction at room temperature to provide a modest yield of indanone 379 as the

major product. The stereochemistries of 377-380 were all assigned by comparison with 364 and

366 (Rf and NMR, see Section 4.6 for a detailed discussion on structural and stereochemical

assignment based on NMR).


- 67 -

O

O

N

O

O PhO N

O

OO

PhO N

O

OO

Ph

366, 24%364, 71%350

MeSO3H, DCM

(NMR Ratio = 74:26)

O

O

N

O

O PhO N

O

OO

PhO N

O

OO

Ph

378, 27%377, 65%355

MeSO3H, DCM

(NMR Ratio = 72:28)O O O

O

O

N

O

O PhO N

O

OO

PhO N

O

OO

Ph

380, 26%379, 43%357

MeSO3H, DCM

(NMR Ratio = 46:26+21% 357)MeO MeOMeO

NMR Ratio With

Cu(OTf)2 = 62:38

Scheme 4.11; Nazarov products observed with β-alkyl substrates.

The product distribution is more complex when β-aryl substrates are cyclised with the

oxazolidinone auxiliary (Schemes 4.12, 4.13, 4.14 and 4.15). Here the sense of torquoselectivity is

reversed relative to that observed with β-alkyl substrates. Another difference is the presence of cis-

isomers, the acidic reaction conditions allow epimerisation at the α-centre and equilibration is

observed between the initially formed cis-isomers and the (seemingly only moderately) lower

energy trans-isomers. It was apparent that cupric triflate (and perhaps Lewis acids more generally)

exhibits greater bias towards the trans-isomers than does the protic methanesulfonic acid, even so,

significant reaction time is required to optimise the yield of the trans-products.

The tigloyl system 105 proved to be more complicated than the initial limited investigation

within our group indicated (Scheme 4.12, see also Scheme 1.28).9 Like the propyl variant 350 (see

Scheme 4.8) reaction of this substrate is complicated by the formation of products bearing

exocyclic double-bonds (381 and 384), however, the use of excess Brønsted-acid to optimise yield

of 106 by migrating the double-bond is inappropriate as these strong conditions produce an

equilibrium where the trans-configured 106 and cis-configured 107 are present in similar amounts

(Entry 2). A good yield of 106 was obtained by treatment of 105 with an equivalent of cupric

triflate for 18 hours (Entry 3), the fact 106 was isolated in greater yield than its crude ratio can be

accounted for by isomerisation of 107 and 381 on silica during chromatography. Performing the


- 68 -

reaction with catalytic quantities of cupric triflate was possible, however, the requirement for

elevated temperature led to reduced torquoselectivity (Entry 4). An equilibrium situation was

confirmed by treating a crude reaction mixture optimised for 106 (as Entry 3) with excess

methanesulfonic acid, this promoted a significant reversion of trans-products 106 and 382 to their

cis-isomers 107 and 383 (Entry 5, ratios similar to Entry 2). Isomeric 106, 107 and 382 were all

individually isolated and characterised, detailed NMR-based structural and stereochemical

assignments for these compounds, along with the unisolated 381, 383 and 384, are discussed in

detail in Section 4.6. Crude NMR spectra of Entries 1-3 are included as Appendix A3.

O

Ph

O

N

O

O Ph

O

Ph

N

O

OO

PhO

Ph

N

O

OO

Ph

106, 65% isolated 107

105

ACID

O

Ph

N

O

OO

Ph

382

O

Ph

N

O

OO

Ph

381

O

Ph

N

O

OO

Ph

384

O

Ph

N

O

OO

Ph

383 ENTRY ACID CONDITIONS S-β-trans S-β-cis S-β-exo S-α-trans S-α-cis S-α-exo

1 MeSO3H (1 eq.) -78ºC→0ºC, 10 h 106, <3% 107, 46% <2%a <2% 383, 16% <2% a

2 MeSO3H (10 eq.) -78ºC→RT, 18 h 106, 31% 107, 41% 381, 0% 382, 17% 383, 11% 384, 0%

3* Cu(OTf)2 (1 eq.) -78ºC→RT, 18 h 106, 60% 107, 8% 381, 10% 382, 16% 383, 2% 384, 4%

4 Cu(OTf)2 (10 mol%) Reflux 18 h (DCM) 106, 56% 107, 5% 381, 12% 382, 18% 383, 4% 384, 5%

5 Cu(OTf)2 as for Entry 3 then MeSO3H (10 eq.)

RT, 18 h 106, 38% 107, 32% 381, 0% 382, 15% 383, 7% 384, 0%

Scheme 4.12; Nazarov reaction of tigloyl system 105 (NMR ratios, * = optimum conditions). (a = other exocyclic products observed)

When the reaction is performed on the analogous substrate bearing an isopropyl-

oxazolidinone auxiliary 360 a similar product distribution is observed (Scheme 4.13). This result

seemingly eliminates the possibility that either the torquoselectivity reversal or the cis/trans

equilibration of products observed on reacting substrates bearing β-aryl substitution are associated

with π-stacking between the β-aryl group and the auxiliary phenyl-group. This is consistent with

the results for the reaction of 102b reported by Pridgen and co-workers (see Scheme 1.27).15 As

with the analogous phenyl-oxazolidinone system 105, the optimum yield of 385 was obtained upon

exposure of 360 to cupric triflate at room temperature over an extended period (Entry 4). See

Section 4.6 for NMR-based structural and stereochemical assignments.


- 69 -

O

Ph

O

N

O

O

O

Ph

N

O

OO

O

Ph

N

O

OO

385, 50% isolated 386

360

ACID

O

Ph

N

O

OO

388, 23% isolated

O

Ph

N

O

OO

387

O

Ph

N

O

OO

390

O

Ph

N

O

OO

389 ENTRY ACID CONDITIONS S-β-trans S-β-cis S-β-exo S-α-trans S-α-cis S-α-exo

1 MeSO3H (10 eq.) -78ºC→ RT, 1 h 385, 35% 386, 18% 387, 8% 388, 8% 389, 21% 390, 4%

2 MeSO3H (10 eq.) -78ºC→RT, 18 h 385, 37% 386, 22% 387, 4% 388, 21% 389, 12% 390, 2%

3 Cu(OTf)2 (1 eq.) -78ºC→RT, 10 min 385, 24% 386, 31% 387, 10% 388, 4% 389, 22% 390, 5%

4* Cu(OTf)2 (1 eq.) -78ºC→RT, 18 h 385, 52% 386, 2% 387, 11% 388, 23% 389, 3% 390, 5%

Scheme 4.13; Nazarov reaction of tigloyl system 360 (NMR ratios, * = optimum conditions).

The polarised system 358 (bearing a donor-acceptor relationship between the two reacting

ends) also gave an optimised yield of trans-product 391 after treatment with cupric triflate for an

extended period (Scheme 4.14). Isolation of 391 by chromatography on silica was problematic,

compromising the yield. No attempt was made to improve the purification of 391, however, it was

noted that this material was quite crystalline and crystallisation was successful for Pridgen with his

system (103a, Scheme 1.27)15. Chromatography on alumina may also be an option. See Section 4.6

for NMR-based structural and stereochemical assignments.

O

Ph

O

N

O

O Ph

O

Ph

N

O

OO

PhO

Ph

N

O

OO

Ph

391, 48% isolated 392

358

ACID

O

OO

O

Ph

N

O

OO

Ph

393

O

O

Ph

N

O

OO

Ph

394

Oδ+δ-

ENTRY ACID CONDITIONS S-β-trans S-β-cis S-α-trans S-α-cis

1 MeSO3H (1 eq.) -78ºC→RT, 1 h 391, 14% 392, 59% 393, 5% 394, 18%

2 Cu(OTf)2 (1 eq.) -78ºC→RT, 1 h 391, 32% 392, 46% 393, 5% 394, 16%

3* Cu(OTf)2 (1 eq.) -78ºC→RT, 24 h 391, 70% 392, 9% 393, 13% 394, 8%

Scheme 4.14; Nazarov reaction of polarised system 358 (NMR ratios, * = optimum conditions).


- 70 -

The aromatic system 359 exhibits significant resistance towards cyclisation with cupric

triflate (Entry 3) but is quite conveniently reacted with excess methanesulfonic acid (Scheme 4.15,

Entry 1). The equilibrium bias towards the trans-isomer 395 for this system is significantly better

than for the other β-aryl systems (Schemes 4.12-4.14) and this allows a good yield of 395 to be

obtained with excess methanesulfonic acid as the promoter. It is noteworthy that we did not

observe measurable quantities of 398, the equivalent of Pridgen’s largest minor isomer 104a (see

Scheme 1.27).15 Pridgen’s stereochemical assignment of the β-position in 104a was based on

derivation studies, however, his assignment of the α-position was based on the assumptions that

enol protonation was kinetically controlled and was directed by the auxiliary. It is most likely that

104a is trans-configured like 397, although spectral data for 104a were not reported for direct

comparison. See Section 4.6 for NMR-based structural and stereochemical assignments.

O

Ph

O

N

O

O Ph

O

Ph

N

O

OO

PhO

Ph

N

O

OO

Ph

395, 68% isolated 396

359

ACID

MeO

MeO MeO

O

Ph

N

O

OO

Ph

397

MeO

O

Ph

N

O

OO

Ph

398

MeO

ENTRY ACID CONDITIONS S-β-trans S-β-cis S-α-trans Other

1* MeSO3H (5 eq.) -78ºC→RT, 1 h 395, 71% 396, 15% 397, 13%

2 MeSO3H (5 eq.) -78ºC→RT, 24 h 395, 71% 396, 5% 397, 14% unknown

3 Cu(OTf)2 (1 eq.) Reflux, 48 h 395, 18% 396, <5% 397, <5% 72% 359

Scheme 4.15; Nazarov reaction of aromatic system 359 (NMR ratios, * = optimum conditions).

For the pyrrole systems used in our roseophilin work, an optimum yield of a single

diastereoisomer (207) was obtained by refluxing R-206 with ferric chloride in dichloromethane

overnight (Scheme 4.16, Entry 1). The fact 207 was isolated in greater yield than its crude ratio

can be accounted for by epimerisation of 399 on silica during chromatography. The

torquoselectivity observed here is opposite to what is observed with the other β-alkyl substrates

(see Scheme 4.11, note use of auxiliaries of opposite stereochemistry), as is the appearance of cis-

isomers. With Brønsted acid the observed torquoselectivity matches the other β-alkyl systems. A

respectable yield (not isolated) of 208 can be obtained by performing the reaction at -78ºC with

excess methanesulfonic acid, followed by prolonged reaction at room temperature to allow


- 71 -

complete isomerisation of the initially formed cis-isomer 399 to 207 (Entry 4). See Section 4.6 for

NMR-based structural and stereochemical assignments. Crude NMR spectra of Entries 1,2 and 4

are included in Appendix A1.

N

OPh

O

N

O

Ph

O

N

OPh

O

N

O

Ph

O

N

OPh

O

N

O

Ph

O

N

O

O

PhO

N

Ph O

R-206

207, 75%isolated

399

208, 21%isolated

ACID

ENTRY ACID CONDITIONS 207 399 208

1* FeCl3 (1 eq.) reflux, 18h 70% 8% 22%

2 Cu(OTf)2 (1 eq.) reflux, 24h 70% 0% 30%

3 MeSO3H (10 eq.) rt, 12h 25% 13% 62%

4 MeSO3H (10 eq.) -78 ºC → rt, 48h 32% 0% 68%

Scheme 4.16; Nazarov reaction of pyrrole system R-206 (NMR ratios, * = optimum conditions).

4.5 Product Distribution

The Nazarov reaction has quite a complicated mechanism and the various mechanistic

aspects are responsible for the sometimes complex product mixtures observed for reactions with

this auxiliary (see Scheme 4.7). The first and most important factor is the torquoselectivity of

conrotatory electrocyclisation which is responsible for the stereochemistry at the β-position of the

cyclised products (Scheme 4.17). It seems to be a general rule that substrates bearing alkyl groups

at the β-position are predisposed towards producing products that are α-configured (as drawn, for

S-oxazolidinones), whereas substrates bearing aryl groups at the β-position are predisposed

towards producing β-configured products (as drawn, for S-oxazolidinones). The class of acid

promoter has a relatively minor effect on torquoselectivity, Brønsted acids (methanesulfonic acid)

give the greater α-bias whilst Lewis acids (cupric triflate, ferric chloride and stannic chloride) give

the greater β-bias. Thus optimal results for β-alkyl substrates are obtained with Brønsted acid to

give optimum yield of α-configured products, whilst an optimum yield of β-configured products

can be obtained for β-aryl substrates with promotion by Lewis acid.


- 72 -

O Aux

O

O Aux

O

O Aux

OMeO

O Aux

OMeO

O Aux

On-PrO

O

O

O

R

Aux

O

O

R

Aux

O

0%100%

100%0%

50%

O Aux

ON

MeSO3H Cu(OTf)2 Cu(OTf )2

MeSO3H

MeSO3H SnCl4MeSO3H Cu(OTf )2 FeCl3

MeSO3H

R

O N

O

O

O

NAZAROVREACTION

O Aux

OO

O Aux

OO

MeSO3H Cu(OTf)2 Cu(OTf )2

MeSO3H

MeSO3H

α β

Scheme 4.17; Torquoselectivity (β-induction) with the oxazolidinone auxiliary.

While the fate of the allyl cations (S-α-cat and S-β-cat) generated by electrocyclisation is

generally simple with aliphatic β-substituents (Scheme 4.18, R1 = Alkyl), it can be quite complex

with aromatic β-substituents (R1 = Aryl). In both these systems hydrogen-elimination from the

allyl cations produces enols that are protonated initially from the less-hindered face to give cis-

products (S-β-cis and S-α-cis). With aliphatic β-substituents (R1 = Alkyl) these cis-products

rapidly epimerise completely to the lower energy trans-products (S-β-trans and S-α-trans).

However, with aromatic β-substituents (R1 = Aryl) the cis- and trans-products are apparently of

similar energies and equilibrate under the acidic conditions. Although the trans-products generally

dominate the equilibria, the bias towards trans-configuration is greater with Lewis acid. The

reaction mixture pH also seems important, with cis-products more prominent at lower pH.

O

R3

R2

R1

N

O

O

O R3

R2

R1

A-O

O

N

OO

R3

R2

R1

A-O

O

N

OO

R3

R2

R1

O

O

N

OO

R3

R2

R1

O

O

N

OO

R3

R2

R1

O

O

N

OO

R3

R2

R1

O

O

N

OO

S-ββββ-t ransS-ββββ-cis

S-αααα-tr ans

S-SM

S-αααα-cisS-αααα-cat

S-ββββ-catACID (A)

ACID (A)

H

H

R1 = Alkyl

R1 = Alkyl

R1 = Aryl

R1 = Aryl

MAJOR

R1 = Aryl

MAJOR

R1 = Alkyl

Scheme 4.18; The fate of allyl cation intermediates with substrates bearing aliphatic or aromatic β-substituents.


- 73 -

The variation in the amount of cis and trans products present at equilibrium as a function of

the nature and amount of acid present is not surprising as the protonated or Lewis acid complexed

forms of these isomers will also contribute to the equilibria. For example, it is possible that protic

acids promote the formation of cis-products when a β-aryl substituent is present due to an increase

in π-stacking interactions of the aryl group (HOMO) and protonated carbamate (LUMO). In the

case of Lewis acids the presence of chelate complexes in equilibrium may have a significant effect.

We have developed a tentative mnemonic for the diastereoselection associated with the

oxazolidinone auxiliary controlled asymmetric Nazarov reaction (Scheme 4.19). It is expected that

the two carbonyls of the N-acyloxazolidinone moiety (grey) adopt an antiperiplanar arrangement

due to dipole-dipole repulsion. In the protonated species A/B the plane of the N-acyloxazolidinone

is expected to sit perpendicular to the penta-1,4-dien-3-one backbone (black). Of the two

conformers A and B, A is preferred due to lower steric repulsion between the R and Ph groups (see

Newman projections A′/B′). As A approaches the transition state of the reaction C/H the N-

acyloxazolidinone moiety influences the torquoselectivity in the rotation of the group R. Where R

= Ph, an anticlockwise rotation is preferred, C, as a favourable π-stacking arrangement between the

Ph group and the N-acyloxazolidinone group develops to give D. However, when R = Alkyl a

clockwise rotation is favoured, H, due to the greater steric repulsion between the oxazolidinone

ring and the alkyl group relative to that between the oxygen of the carbonyl and the alkyl group,

giving I.

Protonation of enol D presumably occurs from the least hindered side to give initially the

cis conformer E, which then re-arranges to the alternative cis conformer F to relieve the steric

compression between the oxazolidinone and cyclopentenone rings present in E. This preference for

F over E is likely to come at the expense of the π-stacking in E. Key 1H-NMR evidence for

conformer F includes the downfield shift in H1 (observed ~4.75 ppm) caused by anisotropic effect

of the proximal carbonyl in the oxazolidinone ring, and the upfield shift of two aromatic hydrogens

Ho (observed at ~6.55 ppm, only one shown) due to the shielding effect of the Ph group

anisotropy. The absence of any significant anisotropic shielding of the protons on the

oxazolidinone ring rules out the face-to-face π-stacking interaction depicted in E.

Thermodynamically, trans-isomer G is favoured over F due to a further reduction in steric

congestion.


- 74 -

N

O

O

O

Ph

H

N

O

OO

Ph

N

O

OO

PhHO

H

N

O

OO

Ph

O

RH

N

O

OO

Ph

O

RH

H RN

O

OO

PhH R

H

H

R = Ph R = Alkyl

N

O

OO

H PhHO

Alkyl

torquoselectivity torquoselectivity

N

O

OO

PhHO

H

N

O

OO

H PhHO

Alkyl

N

O

O

O

Ph

O

H

H

NO

O

O

Ph

O

H

H1

N

O

O

O

Ph

O

H

HO

Alkyl

H

NO

O

O

Ph

HO

Alkyl

H

A B

C

D

E

F

G

H

I

J

K

Ho

A' B'

Scheme 4.19; Proposed origin of diastereoselectivity.

A similar kinetic protonation of I to give initially the cis-isomer J may occur, however, in

reactions where R = Alkyl, typically only trans-products are observed. This may be a result of the

lack of possible cis-stabilising π-stacking interactions (as seen in D and E), which allows rapid

conversion to the lower energy trans-isomer K without complicating equilibria.


- 75 -

4.6 Stereochemistry and Spectroscopy

In this work all trans-configured isomers were isolated and characterised individually

(Tables 4.1 and 4.2). The assignments of trans-configuration were based on the low coupling

constants between the vicinal protons of the cyclopentenone ring (H1 and H2, J1,2). A low coupling

constant is predicted for these protons by the Karplus relationship (Figure 4.2).65 The three sp2

carbons in the cyclopentenone ring enforce a near-planer conformation, thus the dihedral angle

between H1 and H2 (Ø) cannot be much less than 120º and a small coupling constant is expected.

In the case of the cis-isomers the vicinal protons (H1 and H2) are expected to be near-eclipsing (Ø

= 0-10º) and thus a larger coupling constant is expected.

Figure 4.2; Predicted cyclopentenone coupling constants.

In all cases the two trans-isomers isolated exhibit considerably different Rf’s on TLC

plates. Careful comparison of the NMR spectra of the diastereoisomeric pairs of trans-isomers

revealed consistent relationships between the relative chemical shifts and coupling constants of the

common protons (H1-H5, Table 4.1) and carbons (C1-C6, Table 4.2). Protons H1-H3 and carbons

C2 and C5 are all observed at higher chemical shifts in the higher Rf trans-isomers and are

accompanied by H3-H4 and H3-H5 coupling constants of 9.0 and 5.9 Hz respectively (Figure 4.3),

whilst for the lower Rf isomer protons H4 and H5 along with carbons C1, C2, C4 and C6 are seen at


- 76 -

higher chemical shifts and the H3-H4 and H3-H5 coupling constants are 8.3 and 2.7 Hz,

respectively. The consistent relationships between Rf and NMR spectral data are indicative of

common structural and conformational relationships between the pairs of diastereoisomers. The

absolute conformations of the higher Rf 103a15 and lower Rf 364 (see Figure 4.1) have both been

confirmed by X-ray crystal structure analysis, thus it would seem higher Rf trans-isomers are β-

configured at the β-position (S-β-trans) while lower Rf trans-isomers are α-configured at the β-

position (S-α-trans) as depicted in Figure 4.3.

Table 4.1; 1H NMR comparison of trans Nazarov products bearing the (S)-4-phenyloxazolidin-2-one auxiliary.

O

R

O

N

O

O

H2H1

H3

H4

H5

Rf ISOMER H

1

(ppm) H

2

(ppm) H

3

(ppm) H

4

(ppm) H

5

(ppm) J

1,2

(Hz) J

3,4

(Hz) J

3,5

(Hz) J

4,5

(Hz)

High Minor, S-β-trans, 366 4.92 3.22 5.46 4.71 4.21 br s 9.0 5.9 8.9

O

O

Aux

Low Major, S-α-trans*, 364 4.89 3.12 5.43 4.76 4.31 3.0 8.3 2.5 8.7


O

O

Aux

O

Low Major, S-α-trans, 377 4.86 3.05 5.43 4.75 4.29 1.8 8.4 2.7 8.7


O

O

Aux

MeO

Low Major, S-α-trans, 379 5.14 3.74 5.49 4.81 4.35 4.2 8.4 2.8 8.9

High Major, R-α-trans, 207 5.48 3.53 5.51 4.73 4.24 3.2 9.2 6.2 8.9

O

O

Aux

NBn

Low Minor, R-β-trans, 208 5.45 3.41 5.47 4.77 4.30 3.2 8.4 2.7 8.7

High Major, S-β-trans, 106 5.20 4.41 5.43 4.66 4.21 2.1 9.0 5.7 8.7

O

Ph

O

Aux

Low Minor, S-α-trans, 382 5.18 4.30 5.41 4.75 4.27 3.0 8.4 2.7 8.7

High Major, S-β-trans, 391 5.16 4.43 5.43 4.66 4.21 br s 8.9 6.2 8.9

O

Ph

O

Aux

O


High Major, S-β-trans, 395 5.48 5.07 5.48 4.70 4.27 5.7 9.2 5.6 8.9

O

Ph

O

Aux

MeO


High? Major, S-β-trans*, 103a 5.40 4.98 5.45 4.71 4.25 5.2 9.0 5.5 8.8

O

O

Aux

n-PrO

O

O


- 77 -

Table 4.2; 13C NMR comparison of trans Nazarov products bearing the (S)-4-phenyloxazolidin-2-one auxiliary.

O

C1

C3

C2

R

C4

O

NC5

C6O

O

Rf ISOMER C

1 (ppm) C

2 (ppm) C

3 (ppm) C

4 (ppm) C

5 (ppm) C

6 (ppm)

High Minor, S-β-trans, 366 199.9 56.6 45.5 168.4 58.4 69.7

O

O

Aux

Low Major, S-α-trans*, 364 201.1 56.0 46.5 168.8 58.1 69.8


O

O

Aux

O

Low Major, S-α-trans, 377 193.2 54.6 41.7 168.6 58.1 69.9


O

O

Aux

MeO

Low Major, S-α-trans, 379 198.7 59.6 41.5 168.3 58.1 69.9

High Major, R-α-trans, 207 182.7 61.4 43.7 169.1 58.5 69.7

O

O

Aux

NBn

Low Minor, R-β-trans, 208 183.8 60.8 44.7 169.3 58.1 69.8

High Major, S-β-trans, 106 199.7 60.5 51.0 167.4 58.3 69.7

O

Ph

O

Aux

Low Minor, S-α-trans, 382 200.9 59.9 52.0 167.9 58.4 70.0


O

Ph

O

Aux

O



O

Ph

O

Aux

MeO


High? Major, S-β-trans*, 103a 196.9 64.2 45.7 167.0 58.4 69.9

O

O

Aux

n-PrO

O

O

O

C1

C3

C2

R

C4

O

NC

5

C6O

O

H2

H1

H3

H4

H5 O

C1

C3

C2

H2

H1

R

HIGHER Rf trans-ISOMERS

(S-ββββ-trans)

LOWER Rf trans-ISOMERS

(S-αααα-trans)

C4

O

NC5

C6

OO

H3

H4

H5

9.0 Hz 8.8 Hz

5.9 Hz

0-3.5 Hz

2.7 Hz

8.7 Hz

8.3 Hz

0-3.5 Hz

Figure 4.3; Comparing the relative NMR resonances of both trans-isomers (circled nuclei observed at relatively

higher chemical shift in that particular isomer).

A striking feature in the spectra of trans-isomers that bear the oxazolidinone auxiliaries is

the large deshielding of H1, this proton is observed around 1.8 ppm downfield of the equivalent

proton in the analogous ester compounds (Table 4.3). The S-β-trans and S-α-trans isomers are

expected to adopt the conformations depicted below (Figure 4.4). The auxiliary’s imide carbonyls

likely adopt the trans-coplanar arrangement common for these systems (dipole repulsion). Steric

repulsion between H1 and O1 enforces the structures below where the C-H1 bond is nearly co-

planar with the N-carbonyl oxazolidinone system, thereby positioning H1 in close proximity to O2

which accounts for its significant deshielding (see Table 4.3). This conformation can be seen in the

X-ray crystal structure of 364 which has the S-α-trans configuration (see Figure 4.1).


- 78 -

Table 4.3; Downfield shift of H1 in S-β-trans and S-α-trans. STRUCTURE H1 (ppm) Y = COMPOUND

3.39 OMe 4009

5.20 Aux (trans, High Rf) 106

5.18 Aux (trans, Low Rf) 382

O

Y

O

H 1

Diff = 1.80

3.32 OMe 40113



O

Y

O

O

H1

Diff = 1.83

3.08 OMe 4029



O

Y

O

H1

Diff = 1.83

3.57 OEt 191



O

Y

O

NBn

H1

Diff = 1.91

H2

O1

NO

O2

Ph

H1O R

H2

S-ββββ-t rans

O1

NO

O2

Ph

H1

S-αααα-tr ans

O

R

Figure 4.4; General conformations of the S-β-trans and S-α-trans isomers.

The stereochemistries of the pairs of trans-isomers isolated from the reactions of the tigloyl

derived substrates bearing the alternative auxiliaries were determined by comparison with the

phenyloxazolidinone-bearing variants (Table 4.4). The logical hypothesis that similarly configured

auxiliaries induce the same sense of stereoselectivity is supported by the consistent relationship

between the relative Rf’s of the major and minor products within these two series (R = Pr and R =

Ph). The consistency of the correlation between relative Rf’s and the diastereoisomeric relationship

of these two trans-isomers is supported by consistent relationships between the relative chemical

shifts of the indicated common nuclei within this tigloyl series. The circled nuclei are consistently

observed at higher chemical shift (δ) in that particular isomer, supporting a consistent

diastereoisomeric relationship.


- 79 -

Table 4.4; NMR comparison of tigloyl-based trans-configured Nazarov products.

O

C1

Ca

C3

C2Cc

Cb

R

OO

C1

CaC

3

C2C

c

Cb

R

HIGHER Rf ISOMERS LOWER Rf ISOMERS

Aux

(Ha)3 (H

a)3

Aux

O

R Aux Rf Compound Ha (δ) C1 (δ) C2 (δ) C3 (δ) Ca (δ) Cb (δ) Cc (δ)

Higher 366 (minor) 1.97 199.9 56.6 45.5 172.6 15.0 8.2

O

N O

Ph Lower 364 (major) 2.00 201.1 56.0 46.5 173.2 15.0 8.1

Higher 369 (minor) 2.04 200.7 56.4 45.9 172.7 15.0 8.2

O

N O

t-Bu Lower 368 (major) 2.05 201.4 55.7 46.4 173.3 15.0 8.1

Higher 371 (minor) 2.00 200.1 56.7 45.9 172.5 15.0 8.2

O

N O

Ph Ph Lower 370 (major) 2.03 201.0 56.3 46.1 173.4 15.1 8.2

Higher 373 (minor) 2.05 200.7 56.0 46.9 172.0 15.0 8.2

n-Pr

O

N O

H H

Lower 372 (major) 2.07 201.0 56.0 46.4 173.2 15.1 8.2

Higher 106 (major) 1.79 199.7 60.5 51.0 170.8 15.3 8.5

O

N O

Ph Lower 382 (minor) 1.83 200.9 59.9 52.0 171.9 15.5 8.5

Higher 385 (major) 1.85 200.7 60.3 51.7 171.0 15.4 8.6

Ph

O

N O

i-Pr Lower 388 (minor) 1.86 201.0 59.9 52.2 171.7 15.5 8.5

Though in most cases they weren’t isolated, compounds with S-β-cis configuration were

assigned by comparison to the fully characterised 107,9 and also by monitoring reaction progress

(Table 4.5). As predicted by the Karplus correlation, these cis-isomers have a relatively high

coupling constant between the vicinal protons of the cyclopentenone (J1,2 ~ 8 Hz). A significant

feature in the spectra of these compounds is the upfield shift of certain protons on the R2 group.

The ortho-protons of the R2 phenyl in 107, 392 and 396 are observed at around 6.55 ppm whilst

one of the isopropyl methyl groups in compound 399 is seen at 0.35 ppm. The apparent shielding

of these positions by the auxiliary helps define the conformation of these systems (See Scheme

4.19, F Systems).


- 80 -

Table 4.5; S-β-cis NMR resonances.

O

Ph

N

O

OO

386

O

Ph

N

O

OO

Ph

392

O

O

Ph

N

O

OO

Ph

396

MeO

O

Ph

N

O

OO

Ph

107

O

R2

O

N

O

O

R1

H2H1

H3

H4

H5

O N

O

O

OPh

399

NBn

H

1 and H

2

(ppm) H

3

(ppm) H

4

(ppm) H

5

(ppm) Resonances on R

2

(ppm) J

1,2

(Hz) J

3,4

(Hz) J

3,5

(Hz) J

4,5

(Hz) 107 4.72, 4.52 5.22 4.57 4.10 6.52 (d, J = 7.5 Hz, 2H) 7.8 8.3 3.3 8.4

392 4.79, 4.53 5.20 4.55 4.10 6.53 (d, J = 7.5 Hz, 2H) 7.5 8.6 2.9 8.9

396 5.25 4.59 4.13 6.57 (d, J = 7.2 Hz, 2H) small

399 5.27, 3.50 5.52 4.73 4.44 0.35 (d, J = 6.6 Hz, 3H) 6.9 8.4 2.9 8.9

386 4.73 8.1

Compounds with the S-α-cis configuration were also not isolated, the S-α-cis configuration

was assigned from crude NMR peaks (Table 4.6). As with the S-β-cis compounds, the vicinal

protons of the cyclopentenone ring in the S-α-cis compounds have a relatively high coupling

constant as predicted by the Karplus correlation (J1,2 ~ 8 Hz). The most striking feature is the ~1

ppm upfield shift of the protons on the β-face of the oxazolidinone ring (H3 and H4, compare to

Tables 4.1 and 4.5). A similar pattern of oxazolidinone peaks is seen in the similarly configured

dihydrofuran 403.66 The X-ray crystal structure of 403 shows a face-to-face stacking of the

dihydrofuran phenyl group with the oxazolidinone ring (Figure 4.5), anisotropic shielding of H3

and H4 by the ring-current of the phenyl group explains their relatively low chemical shifts. The

NMR similarities indicate S-α-cis compounds 383, 394 and 390 are similarly configured and adopt

similar conformations to dihydrofuran 403.

Table 4.6; S-α-cis NMR resonances.

O

Ph

N

O

OO

Ph

383

O

Ph

N

O

OO

390

O

Ph

N

O

OO

Ph

394

O

O

Ph

O

N

O

O

R

H2H1

H3

H4

H5

OO

Ph

N

O

O

H5H4

Ph

H3

403

H1 and H

2 (ppm) H

3 (ppm) H

4 (ppm) H

5 (ppm) J

1,2 (Hz) J

3,4 (Hz) J

3,5 (Hz) J

4,5 (Hz)

383 4.96, 4.40 4.39 3.73 3.97 7.5 8.4 2.9 8.6

394 5.02, 4.41 4.37 3.73 3.97 7.8 ~8.5 2.6 8.9

403 4.47 3.71 3.98 8.6 2.5 8.6

390 4.97 3.43 3.29 3.86 8.1 ~8.5 2.1 8.7


- 81 -

Figure 4.5; X-ray crystal structure of dihydropyran 403 (ORTEP).66

Unisolated products with exocyclic double-bonds were primarily assigned this structure by

the presence of two finely coupling vinylic resonances at 6.0-6.2 and 5.2-5.4 ppm (Table 4.7, H1

and H2 respectively). Accompanying methyl doublets are also observed at 1.1-1.2 ppm. The

methine protons H3 and H4 are observed between 2.1 and 3.4 ppm. The absolute configurations

were assigned by assuming the stereochemistries at the β-position of the major and minor exo-

products correlate with those of the respective endo-products (S-β-trans, S-β-cis, S-α-trans and S-

α-cis).

Table 4.7; S-β-exo and S-α-exo NMR resonances.

O

R2

N

O

OO

R1

Me

H2

H1

H3 H4

O N

O

OO

Ph

Me

O N

O

OO

Ph

Me

O

Ph

N

O

OO

Ph

Me

O

Ph

N

O

OO

Ph

Me

O

Ph

N

O

OO

Me

O

Ph

N

O

OO

Me365367 384381 390387

H1 (ppm) H

2 (ppm) H

3 (ppm) H

4 (ppm) Me (ppm)

367 6.04 (d, 3.0 Hz, 1H) 5.26 (d, 3.0 Hz, 1H) 2.15-2.45 (m, 2H)

365 6.07 (d, 3.0 Hz, 1H) 5.29 (d, 3.0 Hz, 1H) 2.15-2.45 (m, 2H)

381 6.17 (d, 3.3 Hz, 1H) 5.36 (d, 3.3 Hz, 1H) 2.89 (m, 1H) 3.32 (t, 1H) 1.12 (d, 6.6 Hz, 3H)

384 6.20 (d, 3.3 Hz, 1H) 5.36 (d, 3.3 Hz, 1H) 2.89 (m, 1H) 3.24 (t, 1H) 1.16 (d, 6.9 Hz, 3H)

387 6.19 (d, 3.0 Hz, 1H) 5.38 (d, 3.0 Hz, 1H) 2.88 (m, 1H) ~3.4 1.17 (d, 3H)

390 6.19 (d, 3.0 Hz, 1H) 5.38 (d, 3.0 Hz, 1H) 2.88 (m, 1H) ~3.4 1.19 (d, 3H)


- 82 -

4.7 Summary

In utilising the oxazolidinone auxiliary to provide enantiopure cyclopentenoids via

asymmetric Nazarov reaction, the choice of optimal acid promoter is primarily determined by the

substitution at the β-position. Substrates with alkyl groups at the β-position are best cyclised with

Brønsted acid to give optimum yield of S-α-trans products, while substrates with aryl groups at the

β-position are best cyclised with Lewis acids to give optimum yield of S-β-trans products (Scheme

4.20). Of course, the opposite enantiomeric series can be obtained with the use of the R-configured

oxazolidinone auxiliary.

O

R2

R1

Alkyl

N

O

O

O

R2

R1

Alkyl

O

O

N

OO

S-SM-Ak S-αααα-trans

O

R2

R1

Aryl

N

O

O

O

S-SM-Ar

R2

R1

Aryl

O

O

N

OO

S-ββββ-tr ans

Protic Acid Lewis Acid

Scheme 4.20; General reaction of auxiliary-bearing Nazarov substrate

The oxazolidinone auxiliary can be readily removed or derived to other functional groups

(Scheme 4.21). Hydrolysis of 404 with lithium hydroxide in a THF/water mixture gives the lithium

salt 405 (see Scheme 2.12). Treatment of 404 with acid in an alcohol (R4OH) allows production of

esters 406.34 Auxiliary removal with decarboxylation can be achieved in the one-pot by refluxing

404 in an ethanol/water mixture in the presence of acid to give 407 (see Scheme 2.13).

R2

R1

R3

O

O

N

OO

404

R2

R1

R3

O

OLi

R2

R1

R3

R2

R1

R3

O

OR4

O

O

O

LiOH

H2O/THF

H+

R4OH

H+

H2O/EtOH

406

407

405

Scheme 4.21; Auxiliary removal or derivation of oxazolidinone-bearing Nazarov products.

Chapter 5: Miscellaneous Developments

- 83 -

CHAPTER 5: MISCELLANEOUS DEVELOPMENTS

5.1 Indenes by Tandem Friedel-Crafts / Nucleophilic Substitution

A reaction performed in the course of this research but not included in the main body of

work is described below (Scheme 5.1). The potential Nazarov substrate 411 was synthesised with

our hydrostannylation-coupling reaction (see Scheme 1.42), produced initially to address the lack

of amide examples in our initial Nazarov study.9 We were unable to achieve Nazarov reaction of

this substrate, treatment of 411 with various acids returned none of the desired indanone 412.

However, we did find that treating 411 with a large excess of methanesulfonic acid in the presence

of a chloride source allowed production of indene 413 in moderate yield after crystallisation.

MeO

OMe

OMe

NMe2O

O

ClMeO

MeO

OMe

OMe

Br

Br

O

NMe2

O

OMe

OMe

OMe

MeO

O

O

NMe2

OMe

OMeMeO

MeO

Cl

OMe

MeO

MeO

O

NMe2

OMe

2 × BuLi

O

Cl NMe2

408 410, 79% 411, 97%

409

356

(±±±±)-413, 55%

412

Bu3SnH, Pd0

CuI

MeSO3 H

FeCl3

Scheme 5.1; Formation of indene 413.

The proposed mechanism for this transformation is shown below (Scheme 5.2). The Z-

configured 411 is in equilibrium with the less-favoured E-isomer, E-411 can undergo an

intramolecular Friedel-Crafts reaction to give the tertiary alcohol 415. The strong acidic conditions

protonate this alcohol, which is then displaced by a nucleophile (Nu-) in an Sn2’ manner to give the

observed product 417 (413 when Nu = Cl). Significantly, it was found that the chloride can be

replaced with other nucleophiles in the reaction, e.g. alcohols, thiols and heteroaromatics (Scheme

5.3). A common complication is migration of the double-bond on silica to give the inseparable

regioisomer 418, however, this process can be driven to completion with extended exposure to

silica.


- 84 -

O NMe2

O

OMe

OMe

MeO

MeO

O NMe2

O

OMe

OMe

MeO

MeO

HHO

OMe

MeO

MeO

MeO

O

NMe2

H2O

OMe

MeO

MeO

MeO

O

NMe2

NuNu

OMe

MeO

MeO

O

NMe2

OMe

O

NMe2

O

OMe

OMe

OMe

MeO

H+

H+

- H+

Nu-

Z-411 E -411 414 415

416 417Nu

OMe

MeO

MeO

O

NMe2

OMe

418

SiO2

Scheme 5.2; Mechanism of formation of 413 (417 = 413 when Nu = Cl).

O

NMe2

O

OMe

OMe

OMe

MeO

Cl

OMe

MeO

MeO

O

NMe2

OMe

(±±±±)-413, 55%(crystallized)

OBu

OMe

MeO

MeO

O

NMe2

OMe

Cl

OMe

MeO

MeO

O

NMe2

OMe

OMe

MeO

MeO

O

NMe2

OMe

O

S

OMe

MeO

MeO

O

NMe2

OMe

MeO

OMe

MeO

MeO

O

NMe2

OMe

O

S

OMe

MeO

MeO

O

NMe2

OMe

MeO

SiO2

SiO2

SiO2

O

MeO SH

1-Butanol

FeCl3 or Bu4NCl

10 eq. MeSO3H

10 eq. MeSO3H

10 eq. MeSO3H

10 eq. MeSO3H

421

424

411

(±±±±)-420, 53%

(±±±±)-422 (±±±±)-423, 88%

(±±±±)-419, 62%

(±±±±)-425 (±±±±)-426, 55% Scheme 5.3; Synthesis of indenes from 411.

Our hydrostannylation-coupling protocol should be ideal for the production of substrates

more suitable for this reaction cascade (Scheme 5.4). The requisite E-stereochemistry could be

produced directly; this should remove the requirement for excess acid promoter. With some


- 85 -

development and a greater understanding of its scope, this process may be a good compliment to

our general Nazarov strategy in both target and diversity-oriented applications.

R1 O

R2 R2

R3

R1

O

R2

Nu

R3R1

R2

Nu

R3R1

Bu3SnH, R3X

Pd0, CuI

H+

Nu-

428427 429 430 431

R2

R3OH

R1

H+

Scheme 5.4; Potential general access to bicyclic systems through tandem Friedel-Crafts / nucleophilic substitution.

5.2 One-Pot Hydrostannylation-Coupling / Nazarov

In the course of our work towards the synthesis of roseophilin we identified

dichloromethane as a superior solvent for the hydrostannylation-coupling reaction of remotely

activated substrates (see Chapter 3.4). The notion of performing the hydrostannylation-coupling in

dichloromethane was appealing in that it is also an ideal solvent for Nazarov cyclisation.

Accordingly, the idea of performing the hydrostannylation-coupling and Nazarov reaction in the

one pot was investigated on alkyne-amide 432 and acid chloride 354 (Scheme 4.29). Palladium

catalysed hydrostannylation of alkyne 432 followed by addition of acid chloride 354 and copper

co-catalyst allowed formation of crude 433 and subsequent addition of methanesulfonic acid to the

crude reaction mixture gave tetrahydrocyclopentapyranone 434 in good yield. This one-pot

procedure may prove quite general and as such would be an improvement on our two-step

coupling and Nazarov protocol.

NMe2O

OCl

O O

O

NMe2

O OO

O

NMe2

Bu3SnH

Pd/CuTC

DCM

MeSO3H

354 432 433 (±±±±)-434, 73%

CuTC = Copper (I) 2-thiophenecarboxylate

Scheme 5.5; One-pot hydrostannylation-coupling / Nazarov reaction performed in dichloromethane.

Chapter 6: Experimental

- 86 -

CHAPTER 6: EXPERIMENTAL

All experiments were performed under an anhydrous atmosphere of nitrogen in flame-dried

glassware except as indicated. All reaction products were stored in sealed (parafilm) pre-dried

vials under an anhydrous atmosphere of nitrogen. Melting points were recorded with an

Electrothermal melting point apparatus and are uncorrected. Proton (1H) and carbon (13C) NMR

spectra were recorded on a Bruker Avance WB spectrometer operating at 300 MHz for proton and

75 MHz for carbon spectroscopy. All NMR spectra were recorded in (D)chloroform (CDCl3) at

30°C. The protonicities of the carbon atoms observed in the carbon NMR were determined using J-

modulated spin-echo (JMOD) experiments. Infrared spectra (IR) were obtained on a Varian

Scimitar Series FT-IR spectrometer fitted with PIKE Technologies Single Reflection Horizontal

MIRacle ATR accessory. Low-resolution mass spectra (LRMS) were recorded on a Micromass

Platform II quadrupole spectrometer using electrospray ionisation (ESI). High-resolution mass

spectra (HRMS) were recorded on a Waters Micromass LCT Premier XE Time of Flight mass

spectrometer fitted with either an electrospray (ESI) or Ion Sabre (APCI) ion source, or with a

Bruker Bioapex II mass spectrometer (ESI). Tetrahydrofuran and diethyl ether were distilled under

nitrogen from sodium benzophenone ketyl. Dichloromethane and 1,2-dichloroethane were distilled

from calcium hydride under nitrogen. Analytical thin layer chromatography (TLC) was conducted

on aluminium sheets coated with silica gel 60 GF254 (Merck). Flash chromatography was

performed on Merck Kieselgel 60.

1,1-Dibromo-3-methylbut-1-ene (184)

Triphenylphosphine (28.9 g, 109 mmol) was added to a stirred solution of

carbon tetrabromide (36.6 g, 109 mmol) in dry dichloromethane (350 mL) at 0ºC. Zinc

dust (14.6 g, 219 mmol) was then added and the resultant mixture was allowed to

warm to room temperature and was stirred under N2 for 18 hours. After this time

isobutyrylaldehyde (5.1 mL, 55 mmol) was added and the mixture was stirred for 4 hours. An

additional portion of isobutyrylaldehyde (5.1 mL, 55 mmol) was then added with stirring

continued for a further 2 hours. After this time the mixture was filtered through celite and the

liquid collected was concentrated under reduced pressure. The crude product was then extracted

from the resultant sludge with a 1:1 mixture of dichloromethane and hexane, (5 × 50 mL,

dichloromethane added first). The combined extracts were concentrated under reduced pressure

and flash chromatographed (silica gel, 85:15 hexane / dichloromethane) to return the title

Br Br


- 87 -

compound as a clear liquid (14.6 g, 59%). 1H NMR (300 MHz, CDCl3) δ 6.22 (d, J = 9.0 Hz, 1H),

2.58 (dsept., J = 9.0, 6.9 Hz, 1H), 1.03 (d, J = 6.9 Hz, 6H). Known compound.55

Ethyl 4-methylpent-2-ynoate (186)

Butyllithium (1.54 M in hexanes, 26.0 mL, 40.0 mmol) was added dropwise to

a stirred solution of dibromo-olefin 184 (4.56 g, 20.0 mmol) in tetrahydrofuran (60

mL) at –78ºC. After addition was complete the resultant solution was allowed to warm

to room temperature before being cooled again to -78ºC. Ethyl chloroformate (1.94

mL, 20.0 mmol) was added and the reaction mixture was allowed to warm to room temperature.

The reaction mixture was partitioned between diethyl ether (100 mL) and distilled water (100 mL)

and the organic phase was washed with distilled water (40 mL), dried over magnesium sulphate

and concentrated under reduced pressure to give the title compound as a clear oil (2.70 g, 96%). 1H

NMR (300 MHz, CDCl3) δ 4.22 (q, J = 7.2 Hz, 2H), 2.70 (sept, J = 6.9 Hz, 1H), 1.31 (t, J = 7.2

Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H). Known compound.55

1-Benzyl-1H-pyrrole-2-carbonyl chloride (179)

Trichloroacetyl chloride (4.3 mL, 38 mmol) was added slowly to a

stirred solution of N-benzylpyrrole (5.0 g, 31.8 mmol) in dry diethyl ether (80

mL). The reaction was allowed to stir for 24 hours before being concentrated

under reduced pressure. The solid residue was dissolved in ethanol (95%, 160

mL) and aqueous sodium hydroxide (4.0 M, 30 mL, 120 mmol) was added. This solution was

refluxed for 5 hours before being reduced in volume to 40 mL under reduced pressure. Diethyl

ether (60 mL) and distilled water (50 mL) were added and the aqueous phase was collected, the

organic phase was extracted with more distilled water (25 mL) and the combined aqueous extracts

were acidified to pH 2 with 5 M hydrochloric acid. This mixture was extracted with diethyl ether

(2 × 30 mL) and the organic extracts were dried over magnesium sulphate and concentrated under

reduced pressure to give crude acid 189 that was used without further purification.

Thionyl chloride (23.5 mL, 318 mmol) was added to the above material in dry diethyl ether

(160 mL) and the resultant solution was stirred for 4 hours. After this time the solution was

concentrated under reduced pressure to give the title compound as a dark solid (6.28 g, 90%). 1H

NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 4H), 7.15-7.05 (m, 3H), 6.27 (dd, J = 4.4 Hz, 2.6 Hz,

1H), 5.43 (s, 2H). Known compound.67

NO

Cl

OEtO


- 88 -

(Z)-Ethyl 2-(1-benzyl-1H-pyrrole-2-carbonyl)-4-methylpent-2-enoate (190)

Bis(dibenzylideneacetone)palladium(0) (148 mg, 0.257 mmol)

was added to a solution of triphenylphosphine (270 mg, 1.03 mmol) in

tetrahydrofuran (50 mL) and left to stir for 30 minutes at room

temperature. After this time alkyne 186 (1.26 g, 9.00 mmol) was added

with tetrahydrofuran (4 mL) being used to complete transfer. After

stirring for 30 minutes tributyltin hydride (2.52 mL, 9.0 mmol) was added dropwise and the

mixture was then stirred for 30 minutes. Acid chloride 179 (2.09 g, 9.5 mmol) and cuprous

chloride (630 mg, 6.3 mmol) were then added and the reaction stirred at room temperature for 24

hours. After this time potassium fluoride (10% w/v in distilled water, 80 mL) was added and the

triphasic mixture was stirred for 2 hours. To this mixture distilled water (60 ml) and diethyl ether

(80 mL) were added, after separation the aqueous phase was re-extracted with diethyl ether (60

mL) and the combined organic fractions were dried over magnesium sulphate and concentrated

onto silica gel (10 g) under reduced pressure. The solid residue was subjected to flash

chromatography (silica gel, 9:1 hexane / diethyl ether) giving the title compound as a discoloured

oil (2.40 g, 82%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 3H), 7.15 (d, J = 7.2 Hz, 2H), 6.95

(dd, J = 2.6, 1.7 Hz, 1H), 6.82 (dd, J = 4.1, 1.7 Hz, 1H), 6.32 (d, J = 9.9 Hz, 1H), 6.18 (dd, J = 4.1,

2.6 Hz, 1H), 5.60 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.21 (dsept, J = 9.9, 6.6 Hz, 1H), 1.20 (t, J =

7.2 Hz, 3H), 1.10 (d, J = 6.6 Hz, 6H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 182.8 (C), 165.6 (C),

154.4 (CH), 138.0 (C), 133.2 (C), 131.0 (CH), 130.0 (C), 128.5 (CH), 127.4 (CH), 127.2 (CH),

122.1 (CH), 108.8 (CH), 61.0 (CH2), 52.3 (CH2), 28.6 (CH), 22.0 (CH3), 13.9 (CH3). LRMS m/z

(%): 668.6 (10, 2×M+NH4+), 343.2 (10, M+ NH4

+), 326.2 (100, MH+). HRMS calcd for

C20H23NNaO3+: 348.1576. Found: 348.1575. IR (cm-1): 3031, 2964, 1718, 1634, 1465, 1407, 1216,

1084, 712. [for 1H and 13C NMR spectra see Appendix C1]. (E)-Isomer. 1H NMR (300 MHz,

CDCl3) δ 7.33-7.23 (m, 3H), 7.13 (d, J = 6.3 Hz, 2H), 6.99 (dd, J = 2.4, 1.5 Hz, 1H), 6.79 (dd, J =

3.9, 1.5 Hz, 1H), 6.76 (d, J = 11.1 Hz, 1H), 6.18 (dd, J = 3.9, 2.4 Hz, 1H), 5.66 (s, 2H), 4.14 (q, J =

7.2 Hz, 2H), 2.29 (dsept, J = 11.1, 6.6 Hz, 1H), 1.15 (t, J = 7.2 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H).

[for 1H NMR spectra of the E-isomer, see Appendix C90].

N

O

OEt

O


- 89 -

trans-Ethyl 1-benzyl-4-isopropyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-5-carboxylate

(191)

Methanesulfonic acid (1.10 mL, 16.6 mmol) was added dropwise

to a stirred solution of 190 (1.08 g, 3.31 mmol) in dichloromethane (13

mL) at room temperature and the mixture was stirred for 2 hours. After

this time the acid was quenched by gradual addition of sodium

bicarbonate solution (5% w/v, 60 mL). After stirring for 1 hour the mixture was taken up in extra

dichloromethane (40 mL) and the organic phase was separated, the aqueous phase was then re-

extracted with dichloromethane (2 × 20 mL). The combined organic extracts were dried over

magnesium sulphate and concentrated to give the title compound as a discoloured solid (1.08 g,

100%, mp = 68-69ºC). 1H NMR (300 MHz, CDCl3) δ 7.37-7.20 (m, 5H), 6.99 (d, J = 2.1 Hz, 1H),

6.10 (d, J = 2.1 Hz, 1H), 5.33-5.17 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.57 (d, J = 2.4 Hz, 1H), 3.33

(dd, J = 6.3, 2.4 Hz, 1H), 1.93 (app. octet, Japp = 6.7 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 0.99 (d, J =


153.9 (C), 136.8 (C), 134.7 (CH), 132.5 (C), 128.7 (CH), 127.9 (CH), 127.8 (CH), 106.4 (CH),

62.9 (CH), 61.1 (CH2), 50.8 (CH2), 45.4 (CH), 31.8 (CH), 20.1 (CH3), 19.7 (CH3), 14.1 (CH3).

LRMS m/z (%): 668.6 (25, 2×M+NH4+), 343.2 (10, M+ NH4

+), 326.2 (100, MH+). HRMS calcd

for C20H24NO3+: 326.1756. Found: 326.1751. IR (cm-1): 3034, 2980, 1719, 1680, 1407, 1243,

1157, 715. [for 1H and 13C NMR spectra see Appendix C2].

1-Benzyl-4-isopropyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one (194)

Sulfuric acid (880 µL, 16.2 mmol) was added dropwise to a stirred

mixture of ester 191 (878 mg, 2.70 mmol) and distilled water (1.5 mL) in

ethanol (95%, 10 mL), this solution was then refluxed for 7 hours. After this

time the reaction was cooled to room temperature and quenched with sodium

bicarbonate solution (5%, 100 mL) before addition of dichloromethane (50

mL) and separation of the organic phase. The aqueous phase was re-extracted with

dichloromethane (2 × 20 mL) and the combined organic extracts were dried over magnesium

sulphate and concentrated onto silica (3 g). Flash chromatography (silica gel, 85:15 in hexane /

ethyl acetate) gave the title compound as a white solid (683 mg, 93%, mp = 37-38ºC). 1H NMR

(300 MHz, CDCl3) δ 7.37-7.20 (m, 5H), 6.97 (d, J = 2.4 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 5.35-

5.20 (m, 2H), 3.02-2.87 (m, 2H), 2.57 (dd, J = 16.8, 1.2 Hz, 1H), 1.83 (app. octet, Japp = 6.5 Hz,

1H), 0.95 (d, J = 6.9 Hz, 6H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 191.1 (C), 154.6 (C), 137.3

NO

O

OEtRac

NO


- 90 -

(C), 134.0 (C), 133.4 (CH), 128.7 (CH), 127.8 (CH), 127.7 (CH), 106.2 (CH), 50.7 (CH2), 46.4

(CH2), 40.3 (CH), 32.2 (CH), 20.2 (CH3), 19.6 (CH3). LRMS m/z (%): 507.5 (35, 2×M+H+), 254.2

(100, MH+). HRMS calcd for C17H20NO+: 254.1545. Found: 254.1547. IR (cm-1): 3086, 2959,

2874, 1676, 1403, 1356, 1258, 1021, 729. [for 1H and 13C NMR spectra see Appendix C3].

trans-5-Allyl-1-benzyl-4-isopropyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one (197)

Lithium diisopropylamide (0.5 M in THF / cyclohexane, 0.59

mL, 0.30 mmol) was added slowly to a stirred solution of 194 (57.8 mg,

0.228 mmol) in tetrahydrofuran (2 mL) at -78ºC and the solution was

then allowed to warm to room temperature. This solution was then re-

cooled to -78ºC and allyl bromide (150 µL, 1.72 mmol) was added. The

solution was then allowed to come to room temperature and was stirred for 4 hours. After this time

the reaction was taken up in diethyl ether (20 mL) and distilled water (40 mL). The organic phase

was separated and the aqueous phase was re-extracted with diethyl ether (2 × 10 mL). The

combined organic extracts were dried over magnesium sulphate and concentrated onto silica (1 g).

Flash chromatography (silica gel, 91:9 hexane / diethyl ether) gave the title compound as a viscous

oil (55.0 mg, 82%). 1H NMR (300 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 6.98 (d, J = 1.8 Hz, 1H),

6.05 (d, J = 1.8 Hz, 1H), 5.77 (mc, 1H), 5.33-5.21 (m, 2H), 5.09 (dd, J = 17.1, 1.6 Hz, 1H), 5.00

(dd, J = 9.9, 1.6 Hz, 1H), 2.75 (dd, J = 5.6, 2.0 Hz, 1H), 2.67-2.52 (m, 2H), 2.43 (dt, J = 13.8, 7.5

Hz, 1H), 1.87 (app. octet, Japp = 6.5 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H). 13C

NMR (JMOD, 75 MHz, CDCl3) δ 192.7 (C), 153.0 (C), 138.6 (CH), 137.3 (C), 135.7 (CH), 133.8

(CH), 133.4 (C), 128.7 (CH), 127.8 (CH), 127.6 (CH), 116.8 (CH2), 106.3 (CH), 56.6 (CH), 50.7

(CH2), 45.7 (CH), 36.5 (CH2), 31.6 (CH), 20.8 (CH3), 19.1 (CH3). LRMS m/z (%): 604.6 (10,

2×M+NH4+), 587.5 (25, 2×M+H+), 294.2.2 (100, MH+). HRMS calcd for C20H24NO+: 294.1858.

Found: 294.1856. IR (cm-1): 3068, 2958, 1672, 1509, 1412, 1067, 913, 722. [for 1H and 13C NMR

spectra see Appendix C4].

trans-1-Benzyl-4-isopropyl-5-(pent-4-enyl)-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one (199)

Lithium diisopropylamide (0.5 M in THF / cyclohexane, 0.66

mL, 0.33 mmol) was added slowly to a stirred solution of 194 (60.0

mg, 0.237 mmol) in tetrahydrofuran (2 mL) at -78ºC and the solution

was then allowed to warm to room temperature. This solution was

NO

Rac

NO

Rac


- 91 -

then re-cooled to -78ºC and 5-iodopentene (70 mg, 0.36 mmol) was added. The solution was then

allowed to come to room temperature and was stirred for 4 hours. After this time the reaction was

taken up in diethyl ether (20 mL) and distilled water (40 mL). The organic phase was separated

and the aqueous phase was re-extracted with diethyl ether (2 × 10 mL). The combined organic

extracts were dried over magnesium sulphate and concentrated onto silica (1 g). Flash

chromatography (silica gel, 91:9 hexane / diethyl ether) gave the title compound as a viscous oil

(72.0 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 6.97 (d, J = 2.4 Hz, 1H), 6.05

(d, J = 2.4 Hz, 1H), 5.80 (mc, 1H), 5.27 (s, 2H), 5.03-4.92 (m, 2H), 2.69 (dd, J = 5.1, 1.4 Hz, 1H),

2.56 (ddd J = 6.9, 5.4, 1.4 Hz, 1H), 2.08 (app. q, Japp = 7.0 Hz, 2H), 1.92-1.42 (m, 5H), 1.01 (d, J =


138.7 (CH), 137.5 (C), 133.8 (CH), 133.7 (C), 128.8 (CH), 127.9 (CH), 127.7 (CH), 114.6 (CH2),

106.4 (CH), 57.2 (CH), 50.8 (CH2), 47.0 (CH), 34.1 (CH2), 32.1 (CH2), 32.0 (CH), 26.3 (CH2),

21.1 (CH3), 19.1 (CH3). LRMS m/z (%): 660.6 (10, 2×M+NH4+), 643.6 (35, 2×M+H+), 322.2 (100,

MH+). HRMS calcd for C22H28NO+: 322.2171. Found: 322.2170. IR (cm-1): 3067, 2928, 1673,

1509, 1412, 910, 722. [for 1H and 13C NMR spectra see Appendix C5].

(R)-3-(4-Methylpent-2-ynoyl)-4-phenyloxazolidin-2-one (R-204)

Butyllithium (2.0 M in cyclohexane, 5.0 mL, 10.0 mmol) was added

dropwise to a stirred solution of dibromo-olefin 184 (1.14 g, 5.00 mmol) in

tetrahydrofuran (15 mL) at -78ºC under nitrogen. After stirring for 30 minutes the

nitrogen was turned off and carbon dioxide was bubbled slowly through the

solution while it was warmed to 0ºC (ice bath) over the course of 30 minutes. The carbon dioxide

supply was then removed and replaced with the nitrogen atmosphere. The solution was again

cooled to -78ºC and pivaloyl chloride (635 µL, 5.00 mmol) was added. The solution was then

allowed to warm to room temperature and was stirred for 3 hours. The solution was then cooled

again to -78ºC and to it was added via cannula a solution of lithio-oxazolidinone R-203 (5.00

mmol, generated by addition of 2.5 mL of 2.0 M butyllithium solution to 816 mg of oxazolidinone

R-202 in 30 mL of tetrahydrofuran) at -78ºC. The solution was then allowed to warm to room

temperature and stirred for 2 hours. After this time the solution was concentrated to a volume of 10

mL under vacuum. Ethyl acetate (30 mL) and distilled water (30 mL) were then added and the

organic phase was separated, the aqueous phase was re-extracted with ethyl acetate (2 × 20 mL)

and the combined organic extracts were dried over magnesium sulphate and concentrated onto

silica gel (3 g) under reduced pressure. The solid residue was subjected to flash chromatography

O N

OO


- 92 -

(silica gel, 83:17 hexane / ethyl acetate) giving the title compound as a thick oil (887 mg, 69%). 1H

NMR (300 MHz, CDCl3) δ 7.45-7.25 (m, 5H), 5.43 (dd, J = 8.7, 3.6 Hz, 1H), 4.67 (app. t, Japp =

8.7 Hz, 1H), 4.27 (dd, J = 9.0, 3.6 Hz, 1H), 2.77 (sept, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H).

13C NMR (JMOD, 75 MHz, CDCl3) δ 152.2 (C), 150.4 (C), 138.4 (C), 129.2 (CH), 128.9 (CH),

126.0 (CH), 103.2 (C), 72.8 (C), 69.8 (CH2), 57.6 (CH), 21.5 (2×CH3), 21.1 (CH). LRMS m/z (%):

532.2 (10, 2×M+NH4+), 275.2 (60, M+NH4

+), 258.2 (100, MH+). HRMS calcd for C15H15NNaO3+:

280.0950. Found: 280.0941. IR (cm-1): 3034, 2976, 2231, 1789, 1664, 1319, 1195, 1056, 712.

(R,Z)-1-(1-Benzyl-1H-pyrrol-2-yl)-2-(2-methylpropylidene)-3-(2-oxo-4-phenyloxazolidin-3-

yl)propane-1,3-dione (R-206)

Bis(dibenzylideneacetone)palladium(0) (41 mg, 0.071

mmol) was added to a stirred solution of triphenylphosphine (75

mg, 0.285 mmol) in tetrahydrofuran (10 mL) and left to stir for

30 minutes at room temperature. After this time alkyne R-204

(643 mg, 2.50 mmol) was added with tetrahydrofuran (6 mL) being used to complete transfer.

After stirring for 30 minutes tributyltin hydride (700 µL, 2.50 mmol) was then added dropwise and

the mixture was then stirred for 30 minutes. Acid chloride 179 (578 mg, 2.63 mmol) and cuprous







chromatography (silica gel, 4:1 hexane / ethyl acetate) giving the title compound as a lightly

discoloured solid (1000 mg, 91%, mp = 60-62ºC). 1H NMR (300 MHz, CDCl3) δ 7.45-7.20 (m,

8H), 7.15 (d, J = 6.9 Hz, 2H), 7.94-6.85 (m, 2H), 6.58 (d, J = 10.5 Hz, 1H), 6.17 (mc, 1H), 5.55-

5.42 (m, 3H), 4.69 (app. t, Japp = 8.7 Hz, 1H), 4.22 (dd, J = 8.7, 4.2 Hz, 1H), 2.47 (mc, 1H), 1.07 (d,

J = 6.6 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 182.2 (C), 165.7

(C), 153.9 (CH), 153.0 (C), 138.7 (C), 138.2 (C), 136.3 (C), 130.1 (CH), 129.3 (C), 129.0 (CH),

128.6 (CH), 128.5 (CH), 127.42 (CH), 127.35 (CH), 126.0 (CH), 122.0 (CH), 108.7 (CH), 70.3

(CH2), 57.5 (CH), 51.9 (CH2), 29.7 (CH), 21.94 (CH3), 21.91 (CH3). LRMS m/z (%): 902.5 (10,

2×M+NH4+), 443.4 (100, MH+). HRMS calcd for C27H27N2O4

+: 443.1971. Found: 443.1983. IR

N

O

O

N

O

O


- 93 -

(cm-1): 2964, 1782, 1692, 1614, 1385, 1319, 1201, 1083, 699. [for 1H and 13C NMR spectra see

Appendix C6].

(R)-3-[(4S,5S)-1-Benzyl-4-isopropyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-5-

carbonyl]-4-phenyloxazolidin-2-one (207)

Ferric chloride (72 mg, 0.443 mmol) was added to a

stirred solution of R-206 (178 mg, 0.403 mmol) in dry

dichloromethane (2.5 mL) at room temperature. This mixture

was then refluxed for 18 hours. After cooling to room

temperature the reaction was quenched by gradual addition of sodium bicarbonate solution (5% in

distilled water, 20 mL). Extra dichloromethane (15 mL) was then added and the organic phase was

separated. The aqueous phase was then re-extracted with dichloromethane (2 × 10 mL). The

combined organic extracts were dried over magnesium sulphate and concentrated onto silica gel (2

g) under reduced pressure. The solid residue was subjected to flash chromatography (silica gel,

sequential elution 4:1 / 3:1 hexane / ethyl acetate) giving the title compound as a clear glass (133

mg, 75%, mp = 64-66ºC). 1H NMR (300 MHz, CDCl3) δ 7.48-7.40 (m, 2H), 7.39-7.25 (m, 6H),

7.22-7.17 (m, 2H), 6.93 (d, J = 2.4 Hz, 1H), 6.07 (d, J = 2.4 Hz, 1H), 5.51 (dd, J = 9.2, 6.2 Hz,

1H), 5.48 (br s, 1H), 5.20 (s, 2H), 4.73 (app. t, Japp = 9.0 Hz, 1H), 4.24 (dd, J = 8.9, 6.2 Hz, 1H),

3.53 (dd, J = 6.8, 3.2 Hz, 1H), 1.94 (app. octet, Japp = 6.8 Hz, 1H), 1.01 (d, J = 6.6 Hz, 3H), 0.96

(d, J = 6.9 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 182.7 (C), 169.1 (C), 153.9 (C), 153.8

(C), 138.3 (C), 136.9 (C), 134.6 (CH), 131.6 (C), 129.0 (CH), 128.7 (CH), 128.3 (CH), 127.9

(CH), 127.7 (CH), 126.0 (CH), 106.4 (CH), 69.7 (CH2), 61.4 (CH), 58.5 (CH), 50.7 (CH2), 43.7

(CH), 31.5 (CH), 20.3 (CH3), 20.0 (CH3). LRMS m/z (%): 902.3 (20, 2×M+NH4+), 460.3 (10,

M+NH4+), 443.4 (100, MH+). HRMS calcd for C27H27N2O4

+: 443.1971. Found: 443.1960. IR (cm-

1): 3032, 2959, 1776, 1676, 1354, 1198, 1062, 698. [for 1H and 13C NMR spectra see Appendix

C7]. Minor Isomer (208) (37 mg, 21%, thick gum); 1H NMR (300 MHz, CDCl3) δ 7.42-7.20 (m,

10H), 6.97 (d, J = 2.3 Hz, 1H), 6.09 (d, J = 2.3 Hz, 1H), 4.97

(d, J = 3.2 Hz, 1H), 5.46 (dd, J = 8.4, 2.7 Hz, 1H), 5.23 (s, 2H),

4.77 (app. t, Japp = 8.6 Hz, 1H), 4.30 (dd, J = 8.7, 2.7 Hz, 1H),

3.41 (dd, J = 6.8, 3.2 Hz, 1H), 1.94 (app. octet, Japp = 6.7 Hz,

1H), 0.97 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H). 13C

NMR (JMOD, 75 MHz, CDCl3) δ 183.8 (C), 169.3 (C), 154.3 (C), 153.8 (C), 139.3 (C), 136.8 (C),

134.7 (CH), 131.8 (C), 129.1 (CH), 128.8 (CH), 128.5 (CH), 127.9 (CH), 127.7 (CH), 125.6 (CH),

N

O

N

O

OO

N

O

N

O

OO


- 94 -

106.5 (CH), 69.8 (CH2), 60.8 (CH), 58.1 (CH), 50.8 (CH2), 44.7 (CH), 31.4 (CH), 20.1 (CH3), 19.9

(CH3). LRMS m/z (%): 902.5 (35, 2×M+NH4+), 443.4 (100, MH+). HRMS calcd for C27H27N2O4

+:

443.1971. Found: 443.1974. IR (cm-1): 3033, 2959, 1776, 1675, 1410, 1354, 1194, 1062, 761, 698.

[for 1H and 13C NMR spectra see Appendix C8].

(R)-1-Benzyl-4-isopropyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one (R-194)


mixture of R-207 (273 mg, 0.617 mmol) and distilled water (0.35 mL) in

ethanol (95%, 2.5 mL), this solution was refluxed for 7 hours. After this time

the reaction was cooled to room temperature and quenched with aqueous

sodium bicarbonate solution (5%, 25 mL) before addition of dichloromethane

(15 mL) and separation of the organic phase. The aqueous phase was re-extracted with

dichloromethane (2 × 10 mL) and the combined organic extracts were dried over magnesium

sulphate and concentrated onto silica (1.5 g). Flash chromatography (silica gel, sequential elution

85:15 / 1:1 dichloromethane / ethyl acetate) gave the title compound as a white solid (154 mg,

99%, mp = 54-56ºC) as well as recovered oxazolidinone R-202 (71 mg, 71%). Spectra identical to

that of the racemate (±)-194 (above).

N,N-Dimethylpent-4-enamide (217)


dropwise to a stirred solution of diisopropylamine (5 mL, 38.2 mmol) in

tetrahydrofuran (60 mL) at -78ºC, this solution was then stirred for 10 minutes. Dry N,N-

dimethyacetamide (3.23 mL, 34.7 mmol) was added and the reaction mixture was allowed to warm

to room temperature before again being cooled to -78ºC. Allyl bromide (3.33 mL, 38.2 mmol) was

added and the reaction mixture was warmed to room temperature and was stirred for 18 hours. The

reaction mixture was partitioned between diethyl ether (100 mL) and distilled water (100 mL), the

organic phase was then washed with distilled water (40 mL). The combined aqueous phases were

re-extracted with diethyl ether (50 mL), and this extract was washed with distilled water (30 mL).

The combined organic extracts were dried over magnesium sulphate and concentrated under

reduced pressure giving title compound as a clear oil (2.37 g, 54%). 1H NMR (300 MHz, CDCl3)

δ 5.87 (mc, 1H), 5.11-4.96 (m, 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.43-2.37 (m, 4H). Known

compound.68

NO

O

NMe2


- 95 -

1-(1H-Pyrrol-2-yl)pent-4-en-1-one (212)

Phosphorus oxychloride (3.07 mL, 32.7 mmol) was added to a stirred solution

of amide 217 (3.78 g, 29.7 mmol) in 1,2-dichloroethane (2 mL) and this mixture was

stirred for 8 hours. Pyrrole (2.22 mL, 31.2 mmol) in 1,2-dichloroethane (11 mL) was

added and the reaction mixture was stirred for 8 hours. The reaction was quenched by

the addition of saturated sodium acetate solution (30 mL). This biphasic mixture was stirred for 1

hour before being partitioned between diethyl ether (50 mL) and distilled water (50 mL). The

organic phase was washed with distilled water (20 mL) and the combined aqueous phases were re-

extracted with diethyl ether (30 mL), this extract was washed with distilled water (20 mL). The

combined organic extracts were dried over magnesium sulphate and concentrated under reduced

pressure. Flash chromatography (silica gel, 9:1 hexane / ethyl acetate) gave the title compound as a

clear oil (3.17 g, 72%). 1H NMR (300 MHz, CDCl3) δ 9.32 (br s, 1H), 7.02 (mc, 1H), 6.92 (mc,

1H), 6.29 (mc, 1H), 5.89 (mc, 1H), 5.13-4.96 (m, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.48 (mc, 2H).

Known compound.57

2-(Pent-4-enyl)-1H-pyrrole (214)

Sodium borohydride (3.40 g, 86 mmol) was added to a stirred solution of

keto-pyrrole 212 (3.17 g, 21.2 mmol) in isopropanol (180 mL) and the resultant

mixture was refluxed for 18 hours. The reaction mixture was then concentrated to 30

mL under reduced pressure and taken up in diethyl ether (60 mL) and distilled water

(60 mL). The phases were separated and the organic phase was washed with additional distilled

water (60 mL). The organic phase was concentrated under reduced pressure and the oil residue was

flash chromatographed (silica gel, 9:1 hexane / diethyl ether) to give the title compound as a clear

oil (2.45 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.90 (br s, 1H), 6.67 (d, J = 1.5 Hz, 1H), 6.14

(mc, 1H), 5.93 (br s, 1H), 5.83 (mc, 1H), 5.10-4.95 (m, 2H), 2.63 (t, J = 7.7 Hz, 2H), 2.13 (app. q,

Japp = 7.1 Hz, 2H), 1.74 (app. quin, Japp = 7.5 Hz, 2H). Known compound.57

1-Benzyl-2-(pent-4-enyl)-1H-pyrrole (219)

Sodium hydride (60%, 0.94 g, 24 mmol) was added gradually to a stirred

solution of pyrrole 214 (2.45 g, 18.1 mmol) in N,N-dimethylformamide (22 mL) at

0ºC. To the resultant mixture was added benzyl chloride (2.8 mL, 24 mmol) and this

solution was stirred at 0ºC for 1 hour. After this time the solution was taken up in

H

NO

H

N

N


- 96 -

diethyl ether (60 mL) and washed with distilled water (2 × 40 mL). The organic phase was dried

over magnesium sulphate and concentrated under reduced pressure. The residue obtained was flash

chromatographed (silica gel, 98.5:1.5 hexane / diethyl ether) to give the title compound as a clear

oil (3.94 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.35-7.21 (m, 3H), 6.99 (d, J = 7.2 Hz, 2H), 6.62

(br s, 1H), 6.14 (d, J = 3.3 Hz, 1H), 5.97 (d, J = 3.3 Hz, 1H), 5.76 (mc, 1H), 5.04 (s, 2H), 5.03-4.90

(m, 2H), 2.47 (t, J = 7.8 Hz, 2H), 2.08 (app. q, Japp = 7.1 Hz, 2H), 1.66 (app. quin, Japp = 7.6 Hz,

2H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 138.7 (C), 138.5 (CH), 133.2 (C), 128.8 (CH), 127.4

(CH), 126.4 (CH), 120.9 (CH), 114.9 (CH2), 107.3 (CH), 106.2 (CH), 50.3 (CH2), 33.4 (CH2), 28.1

(CH2), 25.7 (CH2). HRMS calcd for C16H20N+: 226.1596. Found: 226.1597. IR (cm-1): 3066, 2931,

1640, 1453, 1296, 1074, 911, 698. [for 1H and 13C NMR spectra see Appendix C9].

1-Benzyl-5-(pent-4-enyl)-1H-pyrrole-2-carbonyl chloride (220)

Trichloroacetyl chloride (2.4 mL, 21 mmol) was added slowly to a

stirred solution of pyrrole 219 (3.41 g, 17.5 mmol) in dry diethyl ether (44

mL). The reaction was allowed to stir for 24 hours before being concentrated

under reduced pressure. The solid residue was dissolved in ethanol (95%, 88

mL) and aqueous sodium hydroxide (4.0 M, 23 mL, 92 mmol) was added. This

solution was refluxed for 5 hours before being reduced in volume to 40 mL under reduced

pressure. Diethyl ether (60 mL) and distilled water (50 mL) were added and the aqueous phase was

collected, the organic phase was extracted with more distilled water (25 mL) and the combined

aqueous extracts were acidified to pH 2 with 5 M hydrochloric acid. This mixture was extracted

with diethyl ether (2 × 30 mL) and the organic extracts were dried over magnesium sulphate and

concentrated under reduced pressure to give the crude acid. [for crude 1H NMR spectra of the

intermediate trichloromethyl ketone and acid, see Appendices C90 and C91]

Thionyl chloride (13 mL, 175 mmol) was added to the above material in dry diethyl ether

(88 mL) and the resultant solution was stirred for 4 hours. After this time the solution was

concentrated under reduced pressure to give the title compound as a dark oil (4.67 g, 93%). 1H

NMR (300 MHz, CDCl3) δ 7.38 (d, J = 4.2 Hz, 1H), 7.34-7.20 (m, 3H), 6.91 (d, J = 7.5 Hz, 2H),

6.15 (d, J = 4.2 Hz, 1H), 5.73 (mc, 1H), 5.48 (s, 2H), 5.04-4.95 (m, 2H), 2.54 (t, J = 7.7 Hz, 2H),

2.08 (app. q, Japp = 7.1 Hz, 2H), 1.69 (app. quin, Japp = 7.5 Hz, 2H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 156.4 (C), 147.2 (C), 137.4 (CH), 136.9 (C), 128.6 (CH), 127.3 (CH), 127.2 (CH), 125.7

(CH), 124.1 (C), 115.4 (CH2), 109.6 (CH), 48.5 (CH2), 33.0 (CH2), 27.0 (CH2), 25.8 (CH2). IR

NO

Cl


- 97 -

(cm-1): 3066, 2935, 1722, 1481, 1377, 1230, 1050, 804. [for 1H and 13C NMR spectra see

Appendix C10].

(S)-3-(4-Methylpent-2-ynoyl)-4-phenyloxazolidin-2-one (S-204)


dropwise to a stirred solution of dibromo-olefin 184 (4.19 g, 18.4 mmol) in



solution while it was warmed to 0ºC (ice bath) over the course of 30 minutes. The

carbon dioxide supply was then removed and replaced with the nitrogen atmosphere. The solution

was again cooled to -78ºC and pivaloyl chloride (2.34 mL, 18.4 mmol) was added. The solution

was then allowed to warm to room temperature and was stirred for 3 hours. The solution was then

cooled again to -78ºC and to it was added via cannula a solution of lithio-oxazolidinone S-203

(18.4 mmol, generated by addition of 9.2 mL of 2.0 M butyllithium solution to 3.00 g of

oxazolidinone S-202 in 110 mL of tetrahydrofuran) at -78ºC. The solution was then allowed to

warm to room temperature and stirred for 2 hours. After this time the solution was concentrated to

a volume of 20 mL under reduced pressure. Ethyl acetate (50 mL) and distilled water (50 mL)

were then added and the organic phase was separated, the aqueous phase was re-extracted with

ethyl acetate (2 × 20 mL) and the combined organic extracts were dried over magnesium sulphate

and concentrated onto silica gel (10 g) under reduced pressure. The solid residue was subjected to

flash chromatography (silica gel, 82:18 hexane / ethyl acetate) to give the title compound as a thick

oil (1.89 g, 40%). Spectra identical to that of its enantiomer R-204 (above). [for 1H and 13C NMR


(S,Z)-1-[1-Benzyl-5-(pent-4-enyl)-1H-pyrrol-2-yl]-2-(2-methylpropylidene)-3-(2-oxo-4-

phenyloxazolidin-3-yl)propane-1,3-dione (S-221)


mmol) was added to a stirred solution of triphenylphosphine

(170 mg, 0.646 mmol) in tetrahydrofuran (40 mL) and left to stir

for 30 minutes at room temperature. After this time alkyne S-

204 (1.45 g, 5.65 mmol) was added with tetrahydrofuran (5 mL) being used to complete transfer.

After stirring for 30 minutes tributyltin hydride (1.57, mL, 5.65 mmol) was then added dropwise

and the mixture was then stirred for 30 minutes. Acid chloride 220 (1.63 g, 5.66 mmol) and

N

O

O

N

O

O

O N

OO


- 98 -

cuprous chloride (450 mg, 4.5 mmol) were then added and the reaction stirred at room temperature

for 24 hours. After this time potassium fluoride (30% w/v in distilled water, 30 mL) was added and

the triphasic mixture was stirred for 2 hours. To this mixture was added distilled water (60 ml) and

diethyl ether (80 mL). After separation the aqueous phase was re-extracted with diethyl ether (60



chromatography (silica gel, 82:18 hexane / ethyl acetate) giving the title compound as a

discoloured oil (2.23 g, 78%). 1H NMR (300 MHz, CDCl3) δ 7.42-7.16 (m, 8H), 6.98-6.88 (m,

3H), 6.55 (d, J = 10.5 Hz, 1H), 6.04 (d, J = 3.9 Hz, 1H), 5.74 (mc, 1H), 5.63-5.44 (m, 3H), 5.03-

4.92 (m, 2H), 4.67 (app. t, Japp = 8.9 Hz, 1H), 4.21 (dd, J = 8.9, 4.1 Hz, 1H), 2.53-2.37 (m, 3H),

2.07 (app. q, Japp = 7.0 Hz, 2H), 1.66 (app. quin, Japp = 7.5 Hz, 2H), 1.06 (d, J = 6.6 Hz, 3H), 1.00

(d, J = 6.6 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 181.5 (C), 165.8 (C), 153.4 (CH), 152.9

(C), 143.4 (C), 138.7 (C), 138.5 (C), 137.8 (CH), 136.3 (C), 129.3 (C), 129.0 (CH), 128.5 (CH),

128.4 (CH), 126.8 (CH), 126.01 (CH), 125.98 (CH), 122.4 (CH), 115.1 (CH2), 107.7 (CH), 70.2

(CH2), 57.5 (CH), 48.1 (CH2), 33.1 (CH2), 29.7 (CH), 27.3 (CH2), 25.8 (CH2), 21.8 (CH3, 2

carbons). LRMS m/z (%): 1038.5 (5, 2×M+NH4+), 528.6 (10, M+NH4

+), 511.3 (100, MH+). HRMS

calcd for C32H35N2O4+: 511.2597. Found: 511.2613. IR (cm-1): 3032, 2961, 1784, 1694, 1606,


(S)-3-[(4R,5R)-1-Benzyl-4-isopropyl-6-oxo-2-(pent-4-enyl)-1,4,5,6-tetrahydrocyclopenta[b]-

pyrrole-5-carbonyl]-4-phenyloxazolidin-2-one (222)

Ferric chloride (50 mg, 0.305 mmol) was added to a

stirred solution of S-221 (156 mg, 0.305 mmol) in dry

dichloromethane (50 mL) at room temperature, this mixture

was then refluxed for 24 hours. After cooling to room

temperature the reaction was quenched by gradual addition of saturated sodium bicarbonate

solution (30 mL). The phases were separated and the aqueous phase was re-extracted with

dichloromethane (20 mL). The combined organic extracts were dried over magnesium sulphate


flash chromatography (silica gel, sequential elution 78:22 / 7:3 hexane / ethyl acetate) giving the

title compound as a thick gum (109 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.42 (dd, J = 8.0, 1.7

Hz, 2H), 7.35-7.22 (m, 6H), 7.02 (dd, J = 7.2, 2.1 Hz, 2H), 5.93 (s, 1H), 5.71 (mc, 1H), 5.50 (dd, J

= 9.2, 6.4 Hz, 1H), 5.43 (br s, 1H), 5.24 (s, 2H), 5.02-4.92 (m, 2H), 4.72 (app. t, Japp = 9.0 Hz, 1H),

N

O

N

O

OO


- 99 -

4.21 (dd, J = 9.0, 6.4 Hz, 1H), 3.51 (dd, J = 6.8, 2,9 Hz, 1H), 2.48-2.40 (m, 2H), 2.03 (app. q, Japp

= 7.1 Hz, 2H), 1.96 (app. octet, Japp = 6.7 Hz, 1H), 1.59 (app. quin, Japp = 7.7 Hz, 2H), 1.01 (d, J =


153.9 (C), 153.8 (C), 149.3 (C), 138.3 (C), 137.7 (CH), 137.3 (C), 131.3 (C), 129.1 (CH), 128.8

(CH), 128.4 (CH), 127.5 (CH), 126.9 (CH), 126.1 (CH), 115.4 (CH2), 105.3 (CH), 69.7 (CH2),

61.3 (CH), 58.7 (CH), 47.7 (CH2), 43.7 (CH), 33.2 (CH2), 31.7 (CH), 27.4 (CH2), 25.9 (CH2), 20.5

(CH3), 20.1 (CH3). LRMS m/z (%): 1038.7 (5, 2×M+NH4+), 533.4 (10, M+Na+), 511.4 (100,

MH+). HRMS calcd for C32H34N2NaO4+: 533.2416. Found: 533.2409. IR (cm-1): 3065, 2958, 1777,

1673, 1475, 1386, 1200, 910, 727. [for 1H and 13C NMR spectra see Appendix C13]. Minor

Isomer (224) (34 mg, 22%, thick gum); 1H NMR (300 MHz, CDCl3) δ 7.44-20 (m, 8H), 7.05 (d, J

= 6.9 Hz, 2H), 5.96 (s, 1H), 5.71 (mc, 1H), 5.47 (dd, J = 8.3, 2.6

Hz, 1H), 5.43 (d, J = 3.0 Hz, 1H), 5.33-5.20 (m, 2H), 5.02-4.93

(m, 2H), 4.76 (app. t, Japp = 8.6 Hz, 1H), 4.29 (dd, J = 8.9, 2.6

Hz, 1H), 3.39 (dd, J = 6.6, 3.0 Hz, 1H), 2.46 (t, J = 7.7 Hz, 2H),

2.05 (app. q, Japp = 7.1 Hz, 2H), 1.95 (app. octet, Japp = 6.7 Hz,

1H), 1.62 (app. quin, Japp = 7.7 Hz, 2H), 0.98 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H). 13C

NMR (JMOD, 75 MHz, CDCl3) δ 183.0 (C), 169.8 (C), 154.2 (C), 154.0 (C), 149.6 (C), 139.5 (C),

137.7 (CH), 137.3 (C), 131.6 (C), 129.2 (CH), 128.8 (CH), 128.6 (CH), 127.6 (CH), 126.8 (CH),

125.7 (CH), 115.4 (CH2), 105.4 (CH), 69.9 (CH2), 60.6 (CH), 58.2 (CH), 47.7 (CH2), 44.9 (CH),

33.2 (CH2), 31.6 (CH), 27.4 (CH2), 25.9 (CH2), 20.3 (CH3), 20.1 (CH3). LRMS m/z (%): 1021.7 (5,

2×M+H+), 533.4 (10, M+Na+), 511.5 (100, MH+). HRMS calcd for C32H34N2NaO4+: 533.2416.

Found: 533.2404. IR (cm-1): 3032, 2957, 1777, 1698, 1672, 1474, 1385, 1194, 911, 712. [for 1H

and 13C NMR spectra see Appendix C14].

(Z)-Ethyl 2-[1-benzyl-5-(pent-4-enyl)-1H-pyrrole-2-carbonyl]-4-methylpent-2-enoate (228)


was added to a stirred solution of triphenylphosphine (150 mg, 0.570

mmol) in tetrahydrofuran (35 mL) and left to stir for 30 minutes at

room temperature. After this time alkyne 186 (0.701 g, 5.00 mmol)

was added with tetrahydrofuran (2 mL) being used to complete

transfer. After stirring for 30 minutes tributyltin hydride (1.40 mL, 5.0 mmol) was added dropwise

and the mixture was then stirred for 30 minutes. Acid chloride 220 (1.44 g, 5.0 mmol) and cuprous


N

O

OEt

O

N

O

N

O

OO


- 100 -






chromatography (silica gel, sequential elution 94:6 / 87:13 hexane / diethyl ether) giving the title

compound as a discoloured oil (1.09 g, 55%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.20 (m, 3H),

6.95 (d, J = 7.5 Hz, 2H), 6.82 (d, J = 4.2 Hz, 1H), 6.27 (d, J = 9.9 Hz, 1H), 6.03 (d, J = 4.2 Hz,

1H), 5.74 (mc, 1H), 5.68 (s, 2H), 5.02-4.94 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.21 (dsept, J = 9.9,

6.6 Hz, 1H), 2.51 (t, J = 7.8 Hz, 2H), 2.07 (app. q, Japp = 7.1 Hz, 2H), 1.67 (app. quin, Japp = 7.5

Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H), 1.09 (d, J = 6.6 Hz, 6H). 13C NMR (JMOD, 75 MHz, CDCl3)

δ 182.2 (C), 165.8 (C), 153.8 (CH), 144.3 (C), 138.3 (C), 137.7 (CH), 133.3 (C), 129.9 (C), 128.4

(CH), 126.9 (CH), 126.0 (CH), 122.4 (CH), 115.2 (CH2), 107.9 (CH), 60.6 (CH2), 48.2 (CH2), 33.1

(CH2), 28.5 (CH), 27.3 (CH2), 25.6 (CH2), 22.1 (CH3), 14.0(CH3). LRMS m/z (%): 804.7 (25,

2×M+NH4+), 394.5 (100, MH+). HRMS calcd for C25H32NO3

+: 394.2382. Found: 394.2376. IR

(cm-1): 3066, 2961, 1719, 1638, 1623, 1478, 1215, 1183, 1032, 727. [for 1H and 13C NMR spectra

see Appendix C15].

trans-Ethyl 1-Benzyl-4-isopropyl-6-oxo-2-(pent-4-enyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-5-

carboxylate (229)

Methanesulfonic acid (0.70 mL, 10.5 mmol) was added

dropwise to a stirred solution of 228 (825 mg, 2.10 mmol) in

dichloromethane (11 mL) at room temperature and the mixture was

stirred for 20 minutes. After this time the acid was quenched by gradual

addition of sodium bicarbonate solution (5% w/v, 60 mL). After stirring for 1 hour the mixture was

taken up in extra dichloromethane (40 mL) and the organic phase was separated, the aqueous

phase was then re-extracted with dichloromethane (2 × 20 mL). The combined organic extracts

were dried over magnesium sulphate and concentrated giving the title compound as a thick oil (817

mg, 99%). 1H NMR (300 MHz, CDCl3) δ 7.32-7.18 (m, 3H), 7.08 (d, J = 7.5 Hz, 2H), 5.97 (s, 1H),

5.73 (mc, 1H), 5.35-5.22 (m, 2H), 5.03-4.94 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.56 (d, J = 2.7 Hz,

1H), 3.31 (dd, J = 6.3, 2.7 Hz, 1H), 2.49 (t, J = 7.8 Hz, 2H), 2.06 (app. q, Japp = 7.1 Hz, 2H), 1.94

(app. octet, Japp = 6.7 Hz, 1H), 1.64 (app. quin, Japp = 7.5 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.00 (d,


NO

O

OEt

Rac


- 101 -

(C), 153.6 (C), 149.4 (C), 137.6 (CH), 137.2 (C), 132.2 (C), 128.6 (CH), 127.4 (CH), 126.8 (CH),

115.3 (CH2), 105.1 (CH), 62.7 (CH), 61.1 (CH2), 47.6 (CH2), 45.4 (CH), 33.1 (CH2), 31.8 (CH),

27.2 (CH2), 25.8 (CH2), 20.1 (CH3), 19.7 (CH3), 14.1 (CH3). LRMS m/z (%): 804.6 (20,

2×M+NH4+), 394.5 (100, MH+). HRMS calcd for C25H32NO3

+: 394.2382. Found: 394.2367. IR


Appendix C16].

1-Benzyl-4-isopropyl-2-(pent-4-enyl)-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one (230)


mixture of ester 229 (817 mg, 2.08 mmol) and distilled water (1.2 mL) in

ethanol (95%, 8 mL), this solution was then refluxed for 8 hours. After this

time the reaction was cooled to room temperature and quenched with aqueous

sodium bicarbonate solution (5%, 100 mL) before addition of

dichloromethane (30 mL) and separation of the organic phase. The aqueous phase was re-extracted

with dichloromethane (2 × 20 mL) and the combined organic extracts were dried over magnesium

sulphate and concentrated onto silica (3 g). Flash chromatography (silica gel, sequential elution 9:1

/ 88:12 hexane / ethyl acetate) gave the title compound as a discoloured oil (601 mg, 90%). 1H

NMR (300 MHz, CDCl3) δ 7.32-7.20 (m, 3H), 7.08 (d, J = 7.5 Hz, 2H), 5.94 (s, 1H), 5.73 (mc,

1H), 5.31 (s, 2H), 5.02-4.94 (m, 2H), 2.99 (ddd, J = ~6.6, 6.3, 1.6, 1H), 2.90 (dd, J = 17.8, 6.3 Hz,

1H), 2.54 (dd, J = 17.8, 1.6 Hz, 1H), 2.48 (t, J = 7.8 Hz, 2H), 2.06 (app. q, Japp = 7.1 Hz, 2H), 1.84

(app. octet, Japp = 6.6 Hz, 1H), 1.64 (app. quin, Japp = 7.5 Hz, 2H), 0.96 (d, J = 6.9 Hz, 6H). 13C

NMR (JMOD, 75 MHz, CDCl3) δ 190.1 (C), 154.2 (C), 147.9 (C), 137.7 (CH), 137.6 (C), 133.6

(C), 128.6 (CH), 127.3 (CH), 126.7 (CH), 115.2 (CH2), 104.8 (CH), 47.4 (CH2), 46.1 (CH2), 40.3

(CH), 33.1 (CH2), 32.1 (CH), 27.4 (CH2), 25.7 (CH2), 20.2 (CH3), 19.6 (CH3). LRMS m/z (%):

643.5 (50, 2×M+H+), 322.2 (100, MH+). HRMS calcd for C22H28NO+: 322.2171. Found: 322.2168.

IR (cm-1): 3065, 2956, 1668, 1470, 1389, 1259, 911, 721. [for 1H and 13C NMR spectra see

Appendix C17].

NO


- 102 -

trans-1-Benzyl-4-isopropyl-2,5-di(pent-4-enyl)-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one

(231)

Butyllithium (1.92 M in cyclohexane, 1.07 mL, 2.05 mmol)

was added dropwise to a stirred solution of diisopropylamine (269 µL,

2.05 mmol) in tetrahydrofuran (2 mL) at -78ºC, this solution was then

stirred for 10 minutes. Ketone 230 (507 mg, 1.58 mmol) in

tetrahydrofuran (4 mL) was added and the reaction mixture was allowed to warm to room

temperature before again being cooled to -78ºC. 5-Iodopentene 198 (341 mg, 1.74 mmol) was

added and the reaction mixture was warmed to room temperature and was stirred for 4 hours. After

this time the reaction was taken up in diethyl ether (20 mL) and distilled water (40 mL). The

organic phase was separated and the aqueous phase was re-extracted with diethyl ether (2 × 10

mL). The combined organic extracts were dried over magnesium sulphate and concentrated onto

silica (3 g). Flash chromatography (silica gel, 92:8 hexane / ethyl acetate) gave the title compound

as a viscous oil (488 mg, 79%). 1H NMR (300 MHz, CDCl3) δ 7.31-7.20 (m, 3H), 7.05 (d, J = 7.5

Hz, 2H), 5.91 (s, 1H), 5.88-5.66 (m, 2H), 5.31 (s, 2H), 5.04-4.91 (m, 4H), 2.69 (dd, J = 5.3, 1.7

Hz, 1H), 2.54 (ddd, J = 7.7, 4.8, 1.7 Hz, 1H), 2.48 (t, J = 7.8 Hz, 2H), 2.12-2.02 (m, 4H), 1.94-1.73

(m, 2H), 1.72-1.58 (m, 3H), 1.56-1.43 (m, 2H), 1.02 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H).

13C NMR (JMOD, 75 MHz, CDCl3) δ 192.3 (C), 152.1 (C), 147.9 (C), 138.4 (CH), 137.7 (C),

137.6 (CH), 133.2 (C), 128.5 (CH), 127.2 (CH), 126.6 (CH), 115.1 (CH2), 114.4 (CH2), 104.8

(CH), 56.7 (CH), 47.3 (CH2), 46.9 (CH), 34.0 (CH2), 33.1 (CH2), 32.0 (CH2), 31.9 (CH), 27.3

(CH2), 26.1 (CH2), 25.7 (CH2), 20.9 (CH3), 19.0 (CH3). LRMS m/z (%): 779.7 (20, 2×M+H+),

390.5 (100, MH+). HRMS calcd for C27H36NO+: 390.2797. Found: 390.2795. IR (cm-1): 3072,


(1,2-Dimethoxy-2-oxoethyl)triphenylphosphonium bromide (256)

A mixture of methyl methoxyacetate (14.3 mL, 144 mmol), N-

bromosuccinimide (25.0 g, 138 mmol) and benzoyl peroxide (70 mg, 0.29 mmol)

in carbon tetrachloride (550 mL) was refluxed for 4 hours. The reaction mixture

was then cooled to 0ºC and filtered to remove the precipitated succinamide. The solvent was

removed under reduced pressure to give crude bromomethoxyacetate 259 as a clear liquid.

A solution of triphenylphosphine (34.3 g, 132 mmol) in toluene (35 mL) was added

gradually to a vigorously stirred solution of the crude 259 in toluene (35 mL) at room temperature

(water bath), stirring was then continued for 5 hours. The reaction mixture was then filtered and

NO

Rac

MeOOMe

O

PPh3 Br


- 103 -

the precipitate washed thoroughly with diethyl ether. This precipitate was ground to a fine powder

and dried at 50ºC for 24 hours under vacuum. This procedure gave the title compound as a white

powder (45.2 g, 86%). 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 13.3 Hz, 1H), 8.03-7.94 (m,

6H), 7.82-7.74(m, 3H), 7.71-7.63 (m, 6H), 3.92 (s, 3H), 3.60 (s, 3H). Known compound.58

(Z)-Methyl 2-methoxyhepta-2,6-dienoate (Z-261)

1,8-Diazabicyclo[5.4.0]undec-7-ene (3.90 mL, 25.5 mmol) was

added dropwise to a stirred suspension of phosphonium salt 256 (11.4 g, 25.5

mmol) in tetrahydrofuran (100 mL) at 0ºC. The resultant mixture was

allowed to warm to room temperature over 30 minutes before being heated to 50ºC for 30 minutes.

After cooling to room temperature 4-pentenal 260 (2.17 mL, 21.3 mmol) was added and the

reaction was allowed to stir under N2 for 5 days. The solvent was then removed under reduced

pressure and the residue partitioned between ethyl acetate (60 mL) and saturated aqueous

ammonium chloride (100 mL). The organic phase was washed with brine (100 mL), the combined

aqueous washings were extracted with ethyl acetate (50 mL) which was then washed with brine

(50 mL). The combined organic extracts were dried over magnesium sulphate and concentrated

onto silica. Flash chromatography (silica gel, 98:2 hexanes / ethyl acetate) gave the title compound

as a clear oil (2.88 g, 80%). 1H NMR (300 MHz, CDCl3) δ 6.25 (t, J = 7.5 Hz, 1H), 5.82 (mc, 1H),

5.12-4.97 (m, 2H), 3.78 (s, 3H), 3.66 (s, 3H), 2.35 (app. q, Japp = 7.4 Hz, 2H), 2.18 (app. q, Japp =

7.0 Hz, 2H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 164.1 (C), 146.2 (C), 137.3 (CH), 128.0 (CH),

115.2 (CH2), 59.9 (CH3), 51.7 (CH3), 32.6 (CH2), 24.8 (CH2). IR (cm-1): 3038, 2952, 2845, 1725,


(Z)-Methyl 2-methoxyhepta-2,6-dienoate (Z-261) from 4-penten-1-ol

Dimethyl sulfoxide (12.1 mL, 171 mmol) was added dropwise to a stirred solution of

oxalyl chloride (7.5 mL, 85 mmol) in dry dichloromethane (100 mL) at -78ºC. After 10 minutes 4-

pentenol 262 (5.1 mL, 50 mmol) was added and the solution was stirred for 30 minutes.

Triethylamine (39 mL) was then added and the reaction mixture was allowed to warm to room

temperature. The reaction was washed with 5% hydrochloric acid (120 mL) then 5% sodium

bicarbonate solution (120 mL), the aqueous phase was re-extracted with dichloromethane (50 mL)

and the combined organic extracts were dried over magnesium sulphate. This solution was then

filtered into a stirred solution of the appropriate ylide (60 mmol) in tetrahydrofuran /

dichloromethane (generated by gradual addition of 9.2 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene

MeOOMe

O


- 104 -

to 26.7 g of phosphonium salt 256 in 35 mL of dichloromethane, followed by addition of 110 mL

of tetrahydrofuran), tetrahydrofuran (30 mL) was used to complete transfer. After stirring for 2

days the solvent was removed under reduced pressure and the residue partitioned between ethyl

acetate (60 mL) and saturated aqueous ammonium chloride (100 mL). The organic phase was

washed with brine (100 mL), the combined aqueous washings were extracted with ethyl acetate

(50 mL) which was then washed with brine (50 mL). The combined organic extracts were dried

over magnesium sulphate and concentrated onto silica. Flash chromatography (silica gel, 98:2

hexanes / ethyl acetate) gave the title compound as a clear oil (4.94 g, 58%).

(Z)-2-Methoxyhepta-2,6-dienoyl chloride (264)

Lithium hydroxide monohydrate (3.55 g, 85 mmol) was added to a

stirred mixture of ester Z-261 (2.88 g, 16.9 mmol) and distilled water (15 mL)

in tetrahydrofuran (76 mL), this mixture was refluxed for 3 hours. After cooling

to room temperature diethyl ether (80 mL) and distilled water (100 mL) were added and the

aqueous phase was separated, the organic phase was re-extracted with distilled water (50 mL). The

combined aqueous extracts were acidified to pH 2 with 2.0 M hydrochloric acid and extracted with

ethyl acetate (50 mL). The organic phase was washed with brine (30 mL) and the combined

aqueous phases were re-extracted with ethyl acetate (50 mL), this organic phase was washed with

brine (30 mL). The combined ethyl acetate extracts were dried over magnesium sulphate and

concentrated under reduced pressure to give the crude acid 263. [for 1H NMR spectra of 263, see

Appendix C93].

N,N-Dimethylformamide (1 drop, ~19 mg) was added to a stirred solution of the crude acid

263 and oxalyl chloride (4.4 mL, 51 mmol) in dichloromethane (24 mL) at 0ºC (ice bath) under a

slow nitrogen flow. After stirring for 20 minutes the reaction mixture was warmed to room

temperature (water bath) and stirred at this temperature for 3 hours. After this time the reaction

was concentrated under reduced pressure to give the title compound as a lightly discoloured liquid

(2.85 g, 97%). 1H NMR (300 MHz, CDCl3) δ 6.72 (t, J = 7.5 Hz, 1H), 5.81 (mc, 1H), 5.13-5.02 (m,

2H), 3.70 (s, 3H), 2.43 (app. q, Japp = 7.3 Hz, 2H), 2.24 (app. q, Japp = 7.0 Hz, 2H). 13C NMR

(JMOD, 75 MHz, CDCl3) δ 164.2 (C), 149.1 (C), 136.9 (CH), 136.7 (CH), 115.8 (CH2), 60.3

(CH3), 32.1 (CH2), 25.8 (CH2). IR (cm-1): 2935, 1759, 1695, 1631, 1321, 1043, 698. [for 1H and

13C NMR spectra see Appendix C20].

MeOCl

O


- 105 -

(2Z,4Z)-4-Methoxy-2-(2-methylpropylidene)-1-[(S)-2-oxo-4-phenyloxazolidin-3-yl]nona-4,8-

diene-1,3-dione (266)


was added to a stirred solution of triphenylphosphine (30 mg, 0.11

mmol) in tetrahydrofuran (4 mL) and left to stir for 30 minutes at room

temperature. After this time alkyne S-204 (264 mg, 1.02 mmol) was

added with tetrahydrofuran (3 mL) being used to complete transfer. After stirring for 30 minutes

tributyltin hydride (290 µL, 1.04 mmol) was added dropwise (water bath used) and the mixture

was then stirred for 30 minutes. Acid chloride 264 (184 mg, 1.05 mmol) and cuprous chloride (80

mg, 0.80 mmol) were added and the reaction stirred at room temperature for 24 hours. After this

time potassium fluoride (10% w/v in distilled water, 30 mL) was added and the triphasic mixture

was stirred for 2 hours. To this mixture distilled water (20 ml) and diethyl ether (20 mL) were

added, after separation the aqueous phase was re-extracted with diethyl ether (20 mL) and the

combined organic fractions were dried over magnesium sulphate and concentrated onto silica gel

(2 g) under reduced pressure. The solid residue was subjected to flash chromatography (silica gel,

4:1 hexane / ethyl acetate) giving the title compound as a yellow oil (230 mg, 57%). 1H NMR (300

MHz, CDCl3) δ 7.43-7.32 (m, 5H), 6.79 (d, J = 10.8 Hz, 1H), 5.97 (t, J = 7.5 Hz, 1H), 5.83 (mc,

1H), 5.50 (dd, J = 8.9, 4.4 Hz, 1H), 5.12-4.98 (m, 2H), 4.73 (app. t, Japp = 8.9 Hz, 1H), 4.28 (dd, J

= 8.9, 4.4 Hz, 1H), 3.55 (s, 3H), 2.50-2.32 (m, 3H), 2.25-2.15 (m, 2H), 1.05 (d, J = 6.6 Hz, 3H),

1.01 (d, J = 6.6 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 187.6 (C), 165.1 (C), 155.4 (CH),

153.0 (C), 152.2 (C), 138.6 (C), 137.6 (CH), 134.9 (C), 128.9 (CH), 128.5 (CH), 127.2 (CH),

126.0 (CH), 115.2 (CH2), 70.4 (CH2), 58.9 (CH3), 57.4 (CH), 32.7 (CH2), 29.6 (CH), 24.7 (CH2),

21.7 (CH3), 21.6 (CH3). [for 1H and 13C NMR spectra see Appendix C21].

Tridec-1-en-9-yn-7-ol (282)


dropwise to a stirred solution of 1-pentyne (2.10 mL, 21.0 mmol) in

tetrahydrofuran (50 mL) at -78ºC and the mixture was stirred for 30 minutes.

After this time boron trifluoride diethyl etherate (2.70 mL, 21.3 mmol) was

slowly added and the solution was stirred for a further 30 minutes. 1,2-Epoxy-7-octene (2.00 mL,

13.3 mmol) pre-dissolved in tetrahydrofuran (2 mL) was then added and the mixture was stirred

for 2.5 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride

(100 mL), followed by warming to room temperature. After addition of diethyl ether (50 mL) the

MeO

O

O

N

O

PhO

OH


- 106 -

phases were separated and the organic phase was washed with brine (40 mL), the combined

aqueous phases were re-extracted with diethyl ether (50 mL) which was then washed with brine


under reduced pressure. Flash chromatography (silica gel, 94:6 hexanes / ethyl acetate) gave the

title compound as a clear oil (2.39 g, 93%). 1H NMR (300 MHz, CDCl3) δ 5.81 (mc, 1H), 5.05-

4.91 (m, 2H), 3.69 (app. quin, Japp = 5.9 Hz, 1H), 2.41 (ddt, J = 16.5, 4.5, 2.4 Hz, 1H), 2.27 (ddt, J

= 16.5, 6.9, 2.4 Hz, 1H), 2.16 (tt, J = 6.9, 2.4, 2H), 2.07 (app. q, Japp = 6.80 Hz, 2H), 1.88 (br s,

1H), 1.59-1.35 (m, 8H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 138.6

(CH), 114.1 (CH2), 82.5 (C), 76.3 (C), 70.0 (CH), 35.8 (CH2), 33.5 (CH2), 28.7 (CH2), 27.5 (CH2),

24.9 (CH2), 22.2 (CH2), 20.6 (CH2), 13.2 (CH3). IR (cm-1): 3365, 3078, 2931, 1641, 1459, 1434,

1083, 992, 909. [for 1H and 13C NMR spectra see Appendix C22].

7-Acetoxy-tridec-1-en-9-yne (283)

A solution of alcohol 282 (446 mg, 2.30 mmol), acetic anhydride

(0.58 mL, 6.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and 4-

(dimethylamino)pyridine (33 mg, 0.27 mmol) in dichloromethane (15 mL)

was stirred under nitrogen at room temperature until TLC revealed complete

consumption of the alcohol. The reaction mixture was then partitioned between diethyl ether (40

mL) and distilled water (30 mL), the organic phase was washed with distilled water (10 mL), the

combined aqueous washings were re-extracted with diethyl ether (20 mL), this extract was then

washed with distilled water (10 mL). The combined organic extracts were dried over magnesium

sulphate, concentrated under reduced pressure and flash chromatographed (silica gel, 97.5:2.5

hexanes / ethyl acetate) to give the title compound as a clear oil (447 mg, 70%). 1H NMR (300

MHz, CDCl3) δ 5.80 (mc, 1H), 5.04-4.91 (m, 2H), 4.90 (mc, 1H), 2.42 (dt, J = 6.0, 2.4 Hz, 2H),

2.16-2.02 (m, 4H), 2.06 (s, 3H), 1.73-1.60 (m, 2H), 1.55-1.44 (m, 2H), 1.46-1.29 (m, 2H), 0.97 (t,

J = 7.4 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 170.3 (C), 138.5 (CH), 114.3 (CH2), 82.0

(C), 75.3 (C), 72.2 (CH), 33.4 (CH2), 32.7 (CH2), 28.5 (CH2), 24.4 (CH2), 24.1 (CH2), 22.2 (CH2),

20.9 (CH3), 20.5 (CH2), 13.2 (CH3). IR (cm-1): 3077, 2933, 1738, 1373, 1235, 1024, 910. [for 1H


OAc


- 107 -

Tridec-1-en-9-yn-7-one (287)

Dess-Martin periodinane (5.02 g, 11.8 mmol) was added to a stirred

solution of alcohol 282 (1.92 g, 9.86 mmol) in dry dimethyl sulfoxide (15

mL) at room temperature (water bath). The resultant solution was stirred for

30 minutes before the addition of diethyl ether (20 mL), hexanes (20 mL)

and distilled water (50 mL). This mixture was filtered through celite with hexanes (40 mL) used to

complete transfer. The phases were separated and the organic phase was washed with distilled

water (20 mL), the combined aqueous phases were then further extracted with hexanes (40 mL).


reduced pressure to give the title compound as a clear oil (1.88 g. 99%). 1H NMR (300 MHz,

CDCl3) δ 5.80 (mc, 1H), 5.05-4.92 (m, 2H), 3.21 (t, J = 2.4 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.19

(tt, J = 7.0, 2.4 Hz, 2H), 2.07 (app. q, Japp = 7.1 Hz, 2H), 1.68-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz,

3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 205.3 (C), 138.3 (CH), 114.5 (CH2), 84.6 (C), 72.4 (C),

40.8 (CH2), 34.1 (CH2), 33.3 (CH2), 28.2 (CH2), 23.0 (CH2), 22.0 (CH2), 20.6 (CH2), 13.3 (CH3).

IR (cm-1): 3077, 2932, 1947, 1722, 1681, 1459, 994, 910. [for 1H and 13C NMR spectra see

Appendix C24].

(5Z,8E)-8-Butylidene-6-methoxyhexadeca-1,5,15-triene-7,10-dione (291)

Tributyltin hydride (420 µL, 1.5 mmol) was added

dropwise to a stirred solution of alkyne 287 (96.2 mg, 0.500

mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg,

0.050 mmol) in tetrahydrofuran (3 mL). After 1 hour acid

chloride 264 (96.0 mg, 0.550 mmol) and cuprous chloride (35 mg, 0.35 mmol) were added and the

reaction was stirred at room temperature for 48 hours. After this time potassium fluoride (30% w/v

in distilled water, 15 mL) was added and the triphasic mixture was stirred for 2 hours. To this

mixture distilled water (20 ml) and diethyl ether (30 mL) were added, after separation the aqueous

phase was re-extracted with diethyl ether (2 × 20 mL) and the combined organic fractions were

dried over magnesium sulphate and concentrated onto silica gel (2 g) under reduced pressure. The

solid residue was subjected to flash chromatography (silica gel, 92:8 hexanes / diethyl ether)

giving the title compound as a discoloured oil (48.1 mg, 29%). 1H NMR (300 MHz, CDCl3) δ 6.74

(t, J = 7.5 Hz, 1H), 5.88-5.70 (m, 2H), 5.65 (t, J = 7.5 Hz, 1H), 5.08-4.89 (m, 4H), 3.58 (s, 3H),

3.45 (s, 2H), 2.48 (t, J = 7.4 Hz, 2H), 2.34 (app. q, Japp = 7.2 Hz, 2H), 2.22-2.10 (m, 4H), 2.04

(app. q, Japp = 7.1 Hz, 2H), 1.64-1.32 (m, 6H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR (JMOD, 75 MHz,

O

OO

MeO


- 108 -

CDCl3) δ 207.2 (C), 193.2 (C), 153.0 (C), 147.3 (CH), 138.4 (CH), 137.7 (CH), 134.9 (C), 125.3

(CH), 115.0 (CH2), 114.5 (CH2), 58.4 (CH3), 42.4 (CH2), 40.4 (CH2), 33.4 (CH2), 32.9 (CH2), 31.2

(CH2), 28.3 (CH2), 24.5 (CH2), 23.1 (CH2), 21.8 (CH2), 13.7 (CH3). LRMS m/z (%): 682.7 (35,

2×M+NH4+), 350.3 (10, M+NH4

+), 333.3 (100, MH+). HRMS calcd for C21H32NaO3+: 355.2249.

Found: 355.2250. IR (cm-1): 3077, 2931, 1716, 1640, 1454, 1284, 1095, 911, 761. [for 1H and 13C

NMR spectra see Appendix C25].

trans-5-(But-3-enyl)-2-hydroxy-3-(2-oxo-oct-7-enyl)-4-propylcyclopent-2-enone (294)

Methanesulfonic acid (0.5 M in dichloromethane, 0.13

mL, 0.065 mmol) was added to a stirred solution of 291 (19.6

mg, 0.0590 mmol) in dichloromethane (2 mL) at room

temperature. After being allowed to react for 30 minutes

saturated sodium bicarbonate (10 mL) was added and the resultant biphasic mixture was stirred for

30 minutes. After this time diethyl ether (20 mL) was added and the phases were separated, the

organic phase was washed with distilled water (10 mL), the combined aqueous washings were re-

extracted with diethyl ether (20 mL), this extract was then washed with distilled water (10 mL).


reduced pressure to give the title compound as a lightly discoloured oil which solidified in the

freezer (18.6 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 6.35 (br s, 1H), 5.84-5.70 (m, 2H), 5.07-

4.88 (m, 4H), 3.68 (d, J = 15.8 Hz, 1H), 3.26 (d, J = 15.8 Hz, 1H), 2.56-2.43 (m, 3H), 2.20-2.00

(m, 6H), 1.81-1.20 (m, 9H), 0.91 (t, J = 6.9 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 206.2

(C), 204.6 (C), 149.0 (C), 140.9 (C), 138.2 (CH), 137.7 (CH), 115.2 (CH2), 114.6 (CH2), 48.4

(CH), 43.9 (CH), 42.7 (CH2), 40.6 (CH2), 34.9 (CH2), 33.3 (CH2), 31.2 (CH2), 30.7 (CH2), 28.2

(CH2), 23.0 (CH2), 19.8 (CH2), 14.2 (CH3). LRMS m/z (%): 319.2 (100, MH+). IR (cm-1): 3323,


2-Methyldodec-11-en-3-yn-6-ol (280)


dropwise to a stirred solution of 3-methyl-1-butyne (1.00 mL, 9.77 mmol)

in tetrahydrofuran (24 mL) at -78ºC and the mixture was stirred for 30

minutes. After this time boron trifluoride diethyl etherate (1.32 mL, 10.4

mmol) was slowly added and the solution was stirred for a further 30 minutes. 1,2-Epoxy-7-octene

(0.98 mL, 6.5 mmol) pre-dissolved in tetrahydrofuran (1 mL) was then added and the mixture was

OH

OH OO

Rac


- 109 -

stirred for 2.5 hours. The reaction was quenched by addition of saturated aqueous ammonium

chloride (50 mL), followed by warming to room temperature. After addition of diethyl ether (30

mL) the phases were separated and the organic phase was washed with brine (30 mL), the

combined aqueous phases were re-extracted with diethyl ether (40 mL) which was then washed

with brine (30 mL). The combined organic extracts were dried over magnesium sulphate and

concentrated under reduced pressure. Flash chromatography (silica gel, sequential elution 98:2 /

96:4 / 94:6 hexanes / ethyl acetate) gave the title compound as a clear oil (1.01 g, 80%). 1H NMR

(300 MHz, CDCl3) δ 5.82 (mc, 1H), 5.05-4.92 (m, 2H), 3.68 (app. quin, Japp = 5.8 Hz, 1H), 2.55

(sept.t, J = 6.6, ~2.1 Hz, 1H), 2.40 (ddd, J = 16.5, 4.7, 2.3 Hz, 1H), 2.26 (ddd, J = 16.5, 6.9, 2.1

Hz, 1H), 2.07 (app. q, Japp = 6.5 Hz, 2H), 1.89 (br s, 1H), 1.57-1.36 (m, 6H), 1.16 (d, J = 6.6 Hz,

6H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 138.6 (CH), 114.2 (CH2), 88.7 (C), 75.2 (C), 70.0

(CH), 35.8 (CH2), 33.5 (CH2), 28.7 (CH2), 27.6 (CH2), 24.9 (CH2), 23.2 (CH3), 20.4 (CH). IR (cm-

1): 3366, 3077, 2970, 2931, 1641, 1461, 1320, 992, 910. [for 1H and 13C NMR spectra see

Appendix C27].

2-Methyldodec-11-en-3-yn-6-one (286)

Dess-Martin periodinane (4.84 g, 11.4 mmol) was added to a stirred

solution of alcohol 280 (1.85 g, 9.50 mmol) in dry dimethyl sulfoxide (15

mL) at room temperature (water bath). The resultant solution was stirred

for 30 minutes before the addition of diethyl ether (20 mL), hexanes (20

mL) and distilled water (50 mL). This mixture was filtered through celite with hexanes (40 mL)

used to complete transfer. The phases were separated and the organic phase was washed with

distilled water (20 mL), the combined aqueous phases were further extracted with hexanes (40 mL)

which was then washed with distilled water (20 mL). The combined organic extracts were dried

over magnesium sulphate and concentrated under reduced pressure to give the title compound as a

clear oil (1.81 g. 99%). 1H NMR (300 MHz, CDCl3) δ 5.77 (mc, 1H), 5.03-4.89 (m, 2H), 3.17 (d, J

= 1.8 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.55 (sept.t, J = 6.9, 1.8 Hz, 1H), 2.04 (app. q, Japp = 7.1

Hz, 2H), 1.60 (app. quin, Japp = 7.5 Hz, 2H), 1.38 (app. quin, Japp = 7.4 Hz, 2H), 1.14 (d, J = 6.9

Hz, 2H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 205.4 (C), 138.3 (CH), 114.5 (CH2), 90.3 (C), 71.6

(C), 40.7 (CH2), 34.1 (CH2), 33.3 (CH2), 28.2 (CH2), 23.0 (CH2), 22.9 (CH3), 20.5 (CH). IR (cm-1):

3077, 2971, 2932, 1721, 1641, 1461, 1320, 994, 910. [for 1H and 13C NMR spectra see Appendix

C28].

O


- 110 -

(5Z,8E)-6-Methoxy-8-(2-methylpropylidene)hexadeca-1,5,15-triene-7,10-dione (297)

A solution of tributyltin hydride (1.30 mL, 4.8 mmol)

in dichloromethane (15 mL) was added dropwise over the

course of 1 hour to a stirred solution of alkyne 286 (769 mg,

4.00 mmol) and tetrakis(triphenylphosphine)palladium(0)

(231 mg, 0.20 mmol) in dichloromethane (25 mL), this solution was then stirred for 30 minutes.

After this time acid chloride 264 (768 mg, 4.40 mmol) and copper(I) thiophenecarboxylate (76 mg,

0.40 mmol) were added and the reaction was stirred for 18 hours. After this time the solvent was

removed under reduced pressure and the residue was dissolved in diethyl ether (40 mL). Aqueous

potassium fluoride (10%, 40 mL) was added and the resultant triphasic mixture was stirred for 1

hour. The liquid phases were separated and the organic phase was washed with aqueous potassium

fluoride (10%, 20 mL), the combined aqueous phases were re-extracted with diethyl ether (40 mL)

which was then washed with further potassium fluoride solution (20 mL). The combined organic

extracts were dried over magnesium sulphate, concentrated and flash chromatographed (silica gel,

92:8 hexanes / diethyl ether) giving the title compound as a discoloured oil (864 mg, 65%). 1H

NMR (300 MHz, CDCl3) δ 6.51 (d, J = 9.9 Hz, 1H), 5.87-5.69 (m, 2H), 5.66 (t, J = 7.4 Hz, 1H),

5.08-4.88 (m, 4H), 3.57 (s, 3H), 3.44 (s, 2H), 2.52 (dsept, J = 9.9, 6.6 Hz, 1H), 2.48 (t, J = 7.4 Hz,

2H), 2.34 (app. q, Japp = 7.1 Hz, 2H), 2.17 (app. q, Japp = 6.6 Hz, 2H), 2.03 (app q, Japp = 7.1 Hz,

2H), 1.58 (app. quin, Japp = 7.5 Hz, 2H), 1.36 (app. quin, Japp = 7.6 Hz, 2H), 1.02 (d, J = 6.6 Hz,

6H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 207.3 (C), 193.6 (C), 153.5 (CH), 153.1 (C), 138.4

(CH), 137.8 (CH), 132.3 (C), 125.7 (CH), 115.2 (CH2), 114.6 (CH2), 58.4 (CH3), 42.5 (CH2), 40.5

(CH2), 33.5 (CH2), 33.0 (CH2), 28.8 (CH), 28.4 (CH2), 24.6 (CH2), 23.2 (CH2), 22.0 (CH3). LRMS

m/z (%): 682.6 (30, 2×M+NH4+), 350.3 (10, M+NH4

+), 333.3 (100, MH+). HRMS calcd for

C21H32NaO3+: 355.2249. Found: 355.2251. IR (cm-1): 3077, 2931, 1785, 1716, 1640, 1317, 1096,


(9E,11E)-9,11-Bis(2-methylpropylidene)nonadeca-1,18-diene-7,10,13-trione (298)

Isolated as the major by-product in

tetrahydrofuran variants of the previous reaction

(discoloured oil). 1H NMR (300 MHz, CDCl3) δ 6.34

(d, J = 9.9 Hz, 2H), 5.79 (mc, 2H), 5.05-4.91 (m, 4H),

3.46 (s, 4H), 2.55 (dsept, J = 9.9, 6.6 Hz, 2H), 2.47 (t, J = 7.4 Hz, 4H), 2.05 (app. q, Japp = 6.9 Hz,

4H), 1.59 (app. quin, Japp = 7.6 Hz, 4H), 1.38 (app. quin, Japp = 7.6 Hz, 4H), 1.05 (d, J = 6.6 Hz,

OO

MeO

OOO


- 111 -

12H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 207.6 (C), 199.5 (C), 152.9 (CH), 138.4 (CH), 131.4

(C), 114.5 (CH2), 42.3 (CH2), 41.0 (CH2), 33.5 (CH2), 28.7 (CH), 28.4 (CH2), 23.2 (CH2), 22.0

(CH3). LRMS m/z (%): 846.8 (40, 2×M+NH4+), 432.5 (20, M+NH4

+), 415.5 (100, MH+). HRMS

calcd for C27H43O3+: 415.3212. Found: 415.3206. IR (cm-1): 3077, 2959, 2930, 1714, 1636, 1321,


trans-5-(But-3-enyl)-2-hydroxy-3-(2-oxooct-7-enyl)-4-isopropylcyclopent-2-enone (300)

Methanesulfonic acid (66 µL, 1.0 mmol) was added to a

stirred mixture of 297 (166 mg, 0.499 mmol) and distilled

water (2 drops) in dichloromethane (5 mL) at room

temperature. After being allowed to react for 30 minutes

saturated sodium bicarbonate (20 mL) was added and the resultant biphasic mixture was stirred for

30 minutes. After this time diethyl ether (20 mL) was added and the phases were separated, the

organic phase was washed with distilled water (10 mL), the combined aqueous washings were re-

extracted with diethyl ether (20 mL), this extract was then washed with distilled water (10 mL).


reduced pressure to give the title compound as a lightly discoloured oil which solidified in the

freezer (157 mg. 99%). 1H NMR (300 MHz, CDCl3) δ 6.15 (br s, 1H), 5.85-5.70 (m, 2H), 5.07-

4.91 (m, 4H), 3.72 (d, J = 15.8 Hz, 1H), 3.20 (d, J = 15.8 Hz, 1H), 2.57-2.50 (m, 3H), 2.21-2.01

(m, 6H), 1.72-1.58 (m, 4H), 1.39 (app. quin, Japp = 7.5 Hz, 2H), 1.01 (d, J = 6.9 Hz, 3H), 0.63 (d, J

= 6.9 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 206.3 (C), 204.8 (C), 149.4 (C), 140.0 (C),

138.3 (CH), 137.9 (CH), 115.2 (CH2), 114.8 (CH2), 49.5 (CH), 43.2 (CH), 42.9 (CH2), 40.7 (CH2),

33.4 (CH2), 31.9 (CH2), 30.5 (CH2), 28.3 (CH2), 28.2 (CH), 23.0 (CH2), 21.3 (CH3), 15.90 (CH3).

LRMS m/z (%): 654.6 (20, 2×M+NH4+), 336.4 (60, M+NH4

+), 319.2 (100, MH+). HRMS calcd for

C20H31O3+: 319.2273. Found: 319.2268. IR (cm-1): 3310, 3077, 2929, 1697, 1653, 1386, 1121, 995,

910. [for 1H and 13C NMR spectra see Appendix C31].

trans-2-Methoxy-3-(but-3-enyl)-5-(2-oxooct-7-enyl)-4-isopropylcyclopent-2-enone (301)

Aluminium trichloride (40 mg, 0.30 mmol) was added

to a stirred solution of 297 (990 mg, 2.98 mmol) in dry

dichloromethane (45 mL) at room temperature and the

resultant mixture was stirred overnight. After this time

saturated aqueous sodium bicarbonate solution (50 mL) was added and the biphasic mixture was

O OMeO

Rac

OH OO

Rac


- 112 -

stirred for 1 hour. The organic phase was separated and the aqueous phase was re-extracted with

dichloromethane (30 mL). The combined organic extracts were dried over magnesium sulphate,

concentrated under reduced pressure and flash chromatographed (silica gel, 92:8 hexanes / ethyl

acetate) to give the title compound as a discoloured oil (843 mg, 85%). 1H NMR (300 MHz,

CDCl3) δ 5.89-5.72 (m, 2H), 5.10-4.92 (m, 4H), 3.88 (s, 3H), 2.78-2.64 (m, 3H), 2.47-2.39 (m,

4H), 2.37-2.10 (m, 4H), 2.06 (app. q, Japp = 7.1 Hz, 2H), 1.59 (app. quin, Japp = 7.6 Hz, 2H), 1.39

(app. quin, Japp = 7.6 Hz, 2H), 0.99 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 6.9 Hz, 3H). 13C NMR (JMOD,

75 MHz, CDCl3) δ 208.4 (C), 204.1 (C), 158.1 (C), 152.3 (C), 138.4 (CH), 137.4 (CH), 115.4

(CH2), 114.7 (CH2), 58.5 (CH3), 48.2 (CH), 44.3 (CH2), 43.0 (CH2), 40.6 (CH), 33.5 (CH2), 31.1

(CH2), 28.4 (CH2), 28.0 (CH), 25.9 (CH2), 23.2 (CH2), 21.1 (CH3), 16.0 (CH3). LRMS m/z (%):

682.6 (35, 2×M+NH4+), 350.3 (10, M+NH4

+), 333.3 (100, MH+). HRMS calcd for C21H33O3+:

333.2430. Found: 333.2431. IR (cm-1): 3077, 2933, 1701, 1640, 1452, 1359, 1105, 910. [for 1H


trans-15-Isopropyl-13-methoxybicyclo[10.2.1]pentadeca-8,12-diene-3,14-dione (304)

Grubbs’ catalyst 233 (10.4 mg, 0.0127 mmol) was added to a

refluxing solution of 301 (42.0 mg, 0.127 mmol) in dichloromethane (265

mL), this refluxing solution was then stirred overnight. The reaction mixture

was evaporated onto silica (2 g) under reduced pressure and flash

chromatographed (silica gel, 89:11 hexanes / ethyl acetate) to give the title

compound as a dark oil (35.1 mg, 91%, 60:40 isomer ratio). High Rf Isomer; 1H NMR (300 MHz,

CDCl3) δ 5.43 (dt, J = 15.3, 6.8 Hz, 1H), 5.30 (dt, J = 15.3, 6.5 Hz, 1H), 3.96 (s, 3H), 2.98 (dd, J =

15.3, 5.4 Hz, 1H), 2.87 (ddd, J = 14.1, 9.6, 4.2 Hz, 1H), 2.50 (dd, J = 15.3, 5.7 Hz, 1H), 2.44-2.26

(m, 5H), 2.23-1.92 (m, 5H), 1.68-1.40 (m, 4H), 1.03 (d, J = 7.2 Hz, 3H), 0.69 (d, J = 6.9 Hz, 3H).

13C NMR (JMOD, 75 MHz, CDCl3) δ 209.0 (C), 203.7 (C), 159.6 (C), 153.3 (C), 133.1 (CH),

129.3 (CH), 58.4 (CH3), 47.6 (CH), 44.0 (CH2), 41.8 (CH2), 41.1 (CH), 32.4 (CH2), 30.1 (CH2),

28.2 (CH), 26.7 (CH2), 24.9 (CH2), 22.7 (CH2), 21.3 (CH3), 15.8 (CH3). [for 1H and 13C NMR

spectra see Appendix C34]. Low Rf Isomer; 1H NMR (300 MHz, CDCl3) δ 5.40-5.24 (m, 2H),

3.93 (s, 3H), 2.98 (dd, J = 15.2, 5.7 Hz, 1H), 2.82 (ddd, J = 13.1, 9.3, 4.1 Hz, 1H), 2.53 (dd, J =

15.2, 5.6 Hz, 1H), 2.43 (br s, 1H), 2.38-2.05 (m, 7H), 2.00 (app. q, Japp = 5.7 Hz, 2H), 1.64 (app.

quin, Japp = 6.6 Hz, 2H), 1.58-1.37 (m, 2H), 1.04 (d, J = 6.9 Hz, 3H), 0.68 (d, J = 6.9 Hz, 3H). 13C

NMR (JMOD, 75 MHz, CDCl3) δ 209.1 (C), 203.7 (C), 159.1 (C), 153.1 (C), 130.2 (CH), 129.5

(CH), 58.5 (CH3), 47.0 (CH), 43.4 (CH2), 41.3 (CH), 41.2 (CH2), 28.3 (CH), 26.9 (CH2), 25.3

O

MeOO

Rac


- 113 -

(CH2), 24.9 (CH2), 24.5 (CH2), 21.0 (CH3), 20.7 (CH2), 15.7 (CH3). [for 1H and 13C NMR spectra

see Appendix C35]. LRMS m/z (%): 626.6 (30, 2×M+NH4+), 322.3 (60, M+NH4

+), 305.3 (100,

MH+). HRMS calcd for C19H28NaO3+: 327.1936. Found: 327.1933. IR (cm-1): 2931, 1701, 1636,

1450, 1360, 1101, 980.

trans-15-Isopropyl-13-methoxybicyclo[10.2.1]pentadec-12-ene-3,14-dione (303)

A mixture of alkene 304 (18.0 mg, 59.1 µmol) and palladium on

carbon (10%, 5.8 mg, 5.5 µmol) in dry tetrahydrofuran (1.5 mL) was stirred

under an atmosphere of hydrogen (balloon) for 3 hours. After this time the

catalyst was filtered off and the reaction mixture was concentrated under

reduced pressure to give the title compound as a clear gum (17.7 mg, 98%).

1H NMR (300 MHz, CDCl3) δ 3.93 (s, 3H), 2.94 (dd, J = 15.0, 6.3 Hz, 1H), 2.71-2.58 (m, 2H),

2.50-2.24 (m, 4H), 2.17-2.02 (m, 2H), 1.75-1.00 (m, 12H), 1.05 (d, J = 6.9 Hz, 3H), 0.66 (d, J =

6.9 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 209.2 (C), 203.9 (C), 158.8 (C), 153.7 (C), 58.5

(CH3), 46.6 (CH), 44.2 (CH2), 42.7 (CH2), 41.3 (CH), 28.4 (CH), 26.4 (CH2), 25.9 (CH2), 25.32

(CH2), 25.31 (CH2), 25.1 (CH2), 24.3 (CH2), 22.4 (CH2), 21.2 (CH3), 15.6 (CH3). LRMS m/z (%):

630.6 (30, 2×M+NH4+), 324.3 (60, M+NH4

+), 307.3 (100, MH+). HRMS calcd for C19H30NaO3+:

329.2093. Found: 329.2088. IR (cm-1): 2928, 2860, 1703, 1641, 1461, 1354, 1102. [for 1H and 13C


trans-2-Acetoxy-5-(but-3-enyl)-3-(2-oxooct-7-enyl)-4-isopropylcyclopent-2-enone (305)

Triethylamine (1.0 M in dichloromethane, 0.324 mL,

0.324 mmol) was added slowly to a stirred solution of enol 300

(101 mg, 0.316 mmol) and acetyl chloride (1.0 M in

dichloromethane, 0.324 mL, 0.324 mmol) in dichloromethane

at 0ºC, stirring was then continued for 30 minutes. The reaction mixture was partitioned between

diethyl ether (30 mL) and distilled water (30 mL), the organic phase was washed with distilled

water (10 mL), the combined aqueous washings were re-extracted with diethyl ether (20 mL), this

extract was then washed with distilled water (10 mL). The combined organic extracts were dried

over magnesium sulphate, concentrated under reduced pressure and flash chromatographed (silica

gel, 88:12 hexanes / ethyl acetate) to give the title compound as a clear oil (97 mg, 85%). 1H NMR

(300 MHz, CDCl3) δ 5.84-5.68 (m, 2H), 5.07-4.90 (m, 4H), 3.55 (d, J = 15.9 Hz, 1H), 3.20 (d, J =

15.9 Hz, 1H), 2.65 (br d, J = 2.7 Hz, 1H), 2.47 (t, J = 7.2 Hz, 2H), 2.24 (s, 3H), 2.22-2.00 (m, 6H),

AcO OO

Rac

O

MeOO

Rac


- 114 -

1.72-1.53 (m, 4H), 1.37 (app. quin, Japp = 7.5 Hz, 2H), 1.02 (d, J = 6.9 Hz, 3H), 0.68 (d, J = 6.9 Hz,

3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 204.4 (C), 202.0 (C), 167.2 (C), 156.8 (C), 146.8 (C),

138.2 (CH), 137.9 (CH), 115.2 (CH2), 114.9 (CH2), 50.1 (CH), 43.7 (CH), 43.0 (CH2), 41.0 (CH2),

33.4 (CH2), 32.0 (CH2), 30.4 (CH2), 28.3 (CH), 28.3 (CH2), 23.1 (CH2), 21.2 (CH3), 20.3 (CH3),

15.9 (CH3). LRMS m/z (%): 738.7 (20, 2×M+NH4+), 378.5 (20, M+NH4

+), 361.3 (100, MH+).

HRMS calcd for C22H32NaO4+: 383.2198. Found: 383.2197. IR (cm-1): 3077, 2932, 1777, 1714,

1642, 1371, 1188, 1089, 912. [for 1H and 13C NMR spectra see Appendix C37]. High Rf

Diacetate; 1H NMR (300 MHz, CDCl3) δ 5.98 (d, J = 1.5 Hz, 1H), 5.84-5.66 (m, 2H), 5.02-4.87

(m, 4H), 3.30 (br s, 1H), 2.83 (dd, J = 8.0, 4.1 Hz, 1H), 2.49-2.40 (m, 2H), 2.27 (mc, 1H), 2.21 (s,

3H), 2.17 (s, 3H), 2.12-1.89 (m, 4H), 1.68-1.53 (m, 3H), 1.47-1.32 (m, 3H), 1.00 (d, J = 6.9 Hz,

3H), 0.73 (d, J = 6.9 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 199.4 (C), 166.3 (C), 166.1

(C), 158.8 (C), 153.8 (C), 138.6 (CH), 138.0 (CH), 134.5 (C), 114.9 (CH2), 114.5 (CH2), 114.0

(CH), 49.3 (CH), 44.3 (CH2), 39.9 (CH), 33.6 (CH2), 32.6 (CH2), 30.6 (CH2), 30.5 (CH), 28.5


2×M+H+), 403.4 (100, MH+), 361.3 (50). HRMS calcd for C24H34NaO5+: 425.2304. Found:

425.2302. IR (cm-1): 3078, 2932, 1779, 1718, 1589, 1369, 1197, 1169, 1001, 910. [for 1H and 13C

NMR spectra see Appendix C38]. Low Rf Diacetate; 1H NMR (300 MHz, CDCl3) δ 5.86-5.68 (m,

2H), 5.64 (s, 1H), 5.07-4.92 (m, 4H), 2.64 (d, J = 3.0 Hz, 1H), 2.46-2.38 (m, 2H), 2.23 (s, 3H),

2.16 (s, 3H), 2.25-2.00 (m, 6H), 1.78-1.36 (m, 6H), 1.01 (d, J = 7.2 Hz, 3H), 0.68 (d, J = 6.6 Hz,


144.7 (C), 138.3 (CH), 137.9 (CH), 115.2 (CH2), 114.8 (CH2), 107.9 (CH), 50.2 (CH), 43.6 (CH),

34.2 (CH2), 33.3 (CH2), 32.4 (CH2), 30.6 (CH2), 29.4 (CH), 28.1 (CH2), 26.1 (CH2), 21.4 (CH3),

21.0 (CH3), 20.3 (CH3), 15.8 (CH3). LRMS m/z (%): 822.6 (20, 2×M+NH4+), 403.4 (100, MH+),

361.3 (10). HRMS calcd for C24H34NaO5+: 425.2304. Found: 425.2300. IR (cm-1): 3077, 2932,


trans-15-Isopropyl-10,14-dioxobicyclo[10.2.1]pentadeca-4,12-dien-13-yl acetate (306)

Grubbs’ catalyst 233 (29 mg, 35 µmol) in dry dichloromethane (2 mL)

was added to a refluxing solution of diene 305 (250 mg, 0.694 mmol) in dried

dichloromethane (1.39 L), this solution was then allowed to stir at reflux for 1

hour. After this time additional Grubbs’ catalyst 233 (1 mg, 1 µmol) was added

and stirring at reflux was continued for a further 1 hour. The solvent was then

removed under reduced pressure and the residue subjected to flash chromatography (silica gel,

OAc

OO

Rac


- 115 -

84:16 hexanes / ethyl acetate) to give the title compound as a discoloured oil (209 mg, 90%) which

was predominantly (>85%) one stereoisomer. 1H NMR (300 MHz, CDCl3) δ 5.40-5.15 (m, 2H),

3.60-3.50 (m, 1H), 3.08-2.97 (m, 1H), 2.83-2.55 (m, 2H), 2.44-2.31 (m, 2H), 2.28 (s, 3H), 2.26-

1.30 (m, 11H), 1.05-0.98 (m, 3H), 0.69-0.63 (m, 3H). 13C NMR (JMOD, 75 MHz, CDCl3)

δ MAJOR ISOMER; 205.7 (C), 202.0 (C), 167.4 (C), 158.2 (C), 148.4 (C), 131.7 (CH), 129.4

(CH), 47.3 (CH), 43.8 (CH), 42.7 (CH2), 39.5 (CH2), 29.3 (CH2), 27.7 (CH), 26.8 (CH2), 24.8

(CH2), 22.4 (CH2), 21.6 (CH2), 21.1 (CH3), 20.2 (CH3), 15.4 (CH3), MINOR ISOMER (partial);

131.6 (CH), 131.0 (CH), 48.0 (CH), 43.6 (CH), 42.1 (CH2), 41.3 (CH2), 32.0 (CH2), 28.9 (CH2),


2×M+NH4+), 333.3 (100, MH+). HRMS calcd for C20H28NaO4

+: 355.1885. Found: 355.1883. IR


Appendix C40].

trans-15-Isopropyl-10,14-dioxobicyclo[10.2.1]pentadec-12-en-13-yl acetate (307)

A mixture of alkene 306 (209 mg, 0.627 mmol) and palladium on

carbon (10%, 66.7 mg, 0.0627 mmol) in dry tetrahydrofuran (10 mL) was

stirred under an atmosphere of hydrogen (balloon) for 5 hours. After this time

the catalyst was filtered off and the reaction mixture was concentrated under

reduced pressure. The residue was re-dissolved in tetrahydrofuran (10 mL) and

additional palladium on carbon (10%, 66.7 mg, 0.0627 mmol) was added, the reaction mixture was

then stirred under an atmosphere of hydrogen (balloon) for 24 hours. After this time the catalyst

was filtered off and the reaction mixture was concentrated under reduced pressure to give the title

compound as a clear oil (203 mg, 97%). 1H NMR (300 MHz, CDCl3) δ 3.73 (d, J = 11.9 Hz, 1H),

3.04 (d, J = 11.9 Hz, 1H), 2.81 (ddd, J = 19.1, 11.7, 2.5 Hz, 1H), 2.43-2.11 (m, 8H), 2.01 (mc, 1H),

1.40-1.05 (mc, 11H), 1.03 (d, J = 6.3 Hz, 3H), 0.90 (mc, 1H), 0.65 (d, J = 6.9 Hz, 3H). 13C NMR

(JMOD, 75 MHz, CDCl3) δ 204.3 (C), 202.2 (C), 167.5 (C), 157.5 (C), 148.5 (C), 48.1 (CH), 43.4

(CH), 42.6 (CH2), 39.6 (CH2), 29.6 (CH2), 27.7 (CH), 27.3 (CH2), 26.1 (CH2), 24.2 (CH2), 23.5


2×M+NH4+), 352.3 (25, M+NH4

+), 335.2 (100, MH+). HRMS calcd for C20H30NaO4+: 357.2042.



OAc

OO

Rac


- 116 -

trans-4,5-Dihydro-4-(1-methylethyl)-2,5-octanocyclopenta[b]pyrrol-6(1H)-one (167)

A mixture of 307 (135 mg, 0.403 mmol), ammonium acetate (1.71 g, 22.2

mmol) and titanium isopropoxide (250 µL, 0.83 mmol) in propionic acid (8.5

mL) was stirred at 140ºC for 7 hours. After being cooled to room temperature the

reaction mixture was transferred to a stirred 250 mL beaker with ethyl acetate (30

mL) and distilled water (10 mL). A solution of sodium hydroxide (2.5 M, 35 mL) was added

slowly to this stirred mixture, followed by careful addition of saturated sodium bicarbonate

solution (50 mL). The phases were separated and the organic phase was washed with brine (20

mL), the combined aqueous washings were re-extracted with ethyl acetate (30 mL), this extract

was then washed with brine (20 mL). The combined organic extracts were dried over magnesium

sulphate, concentrated under reduced pressure and flash chromatographed (silica gel, sequential

elution 9:1 / 4:1 hexanes / ethyl acetate) to give the title compound as a white solid that gradually

discoloured (61.4 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 11.30 (br s, 1H), 5.98 (d, J = 1.5 Hz,

1H), 2.86 (dt, J = 13.8, 5.0 Hz, 1H), 2.82 (app. t, Japp = 4.2 Hz, 1H), 2.68 (ddd, J = 13.8, 10.5, 5.7

Hz, 1H), 2.63 (d, J = 6.6 Hz, 1H), 1.96-1.74 (m, 4H), 1.41-1.14 (m, 4H), 1.10-0.75 (m, 5H), 1.01

(d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 0.50-0.33 (m, 2H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 193.9 (C), 157.3 (C), 150.6 (C), 133.5 (C), 107.0 (CH), 58.7 (CH), 48.3 (CH), 33.0

(CH), 32.0 (CH2), 28.3 (2 × CH2), 28.1 (CH2), 27.4 (CH2), 27.3 (CH2), 25.5 (CH2), 24.8 (CH2),

21.4 (CH3), 19.9 (CH3). LRMS m/z (%): 547.3 (10, 2×M+H+), 296.2 (10, M+Na+), 274.5 (100,

M+H+). Known compound.47 [for 1H and 13C NMR spectra see Appendix C42].

trans-14-Hydroxy-15-isopropylbicyclo[10.2.1]pentadeca-1(14),8-diene-3,13-dione (308)

Grubbs’ catalyst 233 in three pre-dissolved portions (8.7 mg/8.7 mg/4.3

mg, 0.026 mmol) was added at 45 minute intervals to a refluxing solution of

diene 300 (168 mg, 0.527 mmol) in dry dichloromethane (1060 mL), this

solution was then stirred for a further 1 hour. After this time the solvent was

removed under reduced pressure and the residue flash chromatographed

through a plug of silica gel (sequential elution 9:1 / 4:1 hexanes / ethyl acetate) to give the title

compound as a discoloured gum (121 mg, 79%). 1H NMR (300 MHz, CDCl3) δ 6.07 (br s, 1H),

5.33-5.13 (m, 2H), 3.85-3.72 (m, 1H), 3.05-2.95 (m, 1H), 2.73-2.48 (m, 2H), 2.47-1.36 (m, 13H),

1.06-0.98 (m, 3H), 0.66-0.59 (m, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ MAJOR ISOMER;

207.7 (C), 205.3 (C), 150.9 (C), 141.3 (C), 131.3 (CH), 129.6 (CH), 46.1 (CH), 43.3 (CH), 41.8

(CH2), 40.3 (CH2), 29.2 (CH2), 27.7 (CH), 27.2 (CH2), 25.0 (CH2), 22.8 (CH2), 21.8 (CH2), 21.2

HN

O

Rac

OH

OO

Rac


- 117 -

(CH3), 15.3 (CH3). LRMS m/z (%): 603.6 (10, 2×M+Na+), 308.2 (60, M+NH4+), 291.2 (100,

MH+), MINOR ISOMER; 208.0 (C), 204.6 (C), 150.5 (C), 140.7 (C), 131.3 (CH), 130.8 (CH),

47.5 (CH), 43.1 (CH), 41.5 (CH2), 41.3 (CH2), 31.5 (CH2), 29.2 (CH2), 27.53 (CH), 27.49 (CH2),

26.3 (CH2), 22.6 (CH2), 21.3 (CH3), 15.2 (CH3). LRMS m/z (%): 603.6 (10, 2×M+Na+), 308.2 (60,

M+NH4+), 291.2 (100, MH+). HRMS calcd for C18H26NaO3

+: 313.1780. Found: 313.1775. IR (cm-


C43].

trans-14-Hydroxy-15-isopropylbicyclo[10.2.1]pentadec-1(14)-ene-3,13-dione (309)

A mixture of alkene 308 (41.9 mg, 0.144 mmol) and palladium on

carbon (10%, 15.3 mg, 0.0144 mmol) in dried tetrahydrofuran (4 mL) was

stirred under an atmosphere of hydrogen (balloon) for 5 hours. After this time

the catalyst was filtered off and the reaction mixture was concentrated under

reduced pressure. The residue was re-dissolved in tetrahydrofuran (4 mL) and

additional palladium on carbon (10%, 15.3 mg, 0.0144 mmol) was added, the reaction mixture was

then stirred under an atmosphere of hydrogen (balloon) for 24 hours. After this time the Palladium

on carbon was filtered off and the reaction mixture was concentrated under reduced pressure to

give the title compound as a white solid (41.8 mg, 99%, mp = 113-116ºC). 1H NMR (300 MHz,

CDCl3) δ 6.41 (br s, 1H), 3.95 (d, J = 11.7 Hz, 1H), 2.98 (d, J = 11.7 Hz, 1H), 2.77 (ddd, J = 18.5,

11.4, 2.6 Hz, 1H), 2.40-2.26 (m, 4H), 2.16 (mc, 1H), 1.98 (mc, 1H), 1.40-1.00 (m, 11H), 1.01 (d, J

= 6.3 Hz, 3H), 0.86 (mc, 1H), 0.61 (d, J = 6.9 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 206.0

(C), 205.4 (C), 151.2 (C), 140.6 (C), 47.3 (CH), 43.1 (CH), 42.1 (CH2), 39.9 (CH2), 29.4 (CH2),

27.64 (CH), 27.61 (CH2), 26.4 (CH2), 24.9 (CH2), 24.3 (CH2), 21.6 (CH2), 21.4 (CH2), 21.2 (CH3),

15.5 (CH3). LRMS m/z (%): 310.3 (100, M+NH4+), 293.3 (95, MH+). HRMS calcd for

C18H28NaO3+: 315.1936. Found: 315.1934. IR (cm-1): 3294, 2930, 2869, 1715, 1691, 1650, 1390,


trans-4,5-Dihydro-4-(1-methylethyl)-2,5-octanocyclopenta[b]pyrrol-6(1H)-one (167)

A mixture of 309 (41.8 mg, 0.143 mmol), ammonium acetate (613 mg,

7.95 mmol) and titanium isopropoxide (89 µL, 0.30 mmol) in propionic acid (3.6

mL) was stirred at 140ºC for 7 hours. After being cooled to room temperature the

reaction mixture was transferred to a stirred 100 mL beaker with ethyl acetate (20

mL) and distilled water (5 mL). A solution of sodium hydroxide (2.5 M, 15 mL) was added slowly

OH

OO

Rac

HN

O

Rac


- 118 -

to this stirred mixture, followed by careful addition of saturated sodium bicarbonate solution (20

mL). The phases were separated and the organic phase was washed with brine (10 mL), the

combined aqueous washings were re-extracted with ethyl acetate (20 mL), this extract was then

washed with brine (20 mL). The combined organic extracts were dried over magnesium sulphate,

concentrated under reduced pressure and flash chromatographed (silica gel, sequential elution 9:1 /

4:1 hexanes / ethyl acetate) to give the title compound as a white solid that gradually discoloured

(21.5 mg, 55%).

(S)-3-Hex-2-ynoyl-4-phenyloxazolidin-2-one (335)


dropwise to a stirred solution of 1-pentyne (1.20 mL, 12.0 mmol) in




carbon dioxide supply was then removed and replaced with the nitrogen atmosphere. The solution

was again cooled to -78ºC and pivaloyl chloride (1.24 mL, 10.0 mmol) was added. The solution

was then allowed to warm to room temperature and was stirred for 3 hours. The solution was then

cooled again to -78ºC and to it was added via cannula a solution of lithiated oxazolidinone (10.0

mmol, generated by addition of 5.5 mL of 1.82 M butyllithium solution to 1.63 g of oxazolidinone

202 in 60 mL of tetrahydrofuran) at -78ºC. The solution was then allowed to warm to room

temperature and stirred for 2 hours. After this time the solution was concentrated to a volume of 20

mL under vacuum. Ethyl acetate (50 mL) and distilled water (50 mL) were then added and the

organic phase was separated, the aqueous phase was re-extracted with ethyl acetate (30 mL) and

the combined organic extracts were dried over magnesium sulphate and concentrated onto silica

gel (5 g) under reduced pressure. The solid residue was subjected to flash chromatography (silica

gel, 5:5:1 hexane / dichloromethane / diethyl ether) giving the title compound as a viscous oil (1.67

g, 65%). 1H NMR (300 MHz, CDCl3) δ 7.42-7.27 (m, 5H), 5.43 (dd, J = 8.7, 3.6 Hz, 1H), 4.68

(app. t, Japp = 8.7 Hz, 1H), 4.28 (dd, J = 8.7, 3.6 Hz, 1H), 2.41 (t, J = 7.1 Hz, 2H), 1.65 (app. sext, J

= 7.2 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 152.2 (C), 150.1

(C), 138.6 (C), 129.0 (CH), 128.5 (CH), 125.8 (CH), 98.3 (C), 73.8 (C), 69.8 (CH2), 57.4 (CH),

21.0 (CH2), 20.8 (CH2), 13.3 (CH3). LRMS m/z (%): 537.4 (20), 275.2 (70, M+NH4+), 258.2 (100,

MH+). HRMS calcd for C15H16NO3+: 258.1130. Found: 258.1128. IR (cm-1): 2967, 2238, 2221,


NO

OO


- 119 -

(S)-4-tert-Butyl-3-hex-2-ynoyloxazolidin-2-one (337)

Butyllithium (1.45 M in hexanes, 2.1 mL, 3.0 mmol) was added dropwise to

a stirred solution of 1-pentyne (320 µL, 3.15 mmol) in tetrahydrofuran (5 mL) at -

78ºC under nitrogen. After stirring for 30 minutes the nitrogen was turned off and

carbon dioxide was bubbled slowly through the solution while it was warmed to 0ºC

(ice bath) over the course of 30 minutes. The carbon dioxide supply was then

removed and replaced with the nitrogen atmosphere. The solution was again cooled to -78ºC and

pivaloyl chloride (370 µL, 3.0 mmol) was added. The solution was then allowed to warm to room

temperature and was stirred for 3 hours. The solution was then cooled again to -78ºC and added via

cannula to a stirred suspension of lithiated oxazolidinone (3.0 mmol, generated by addition of 2.1

mL of 1.45 M butyllithium solution to 434 mg of oxazolidinone 336 in 13 mL of tetrahydrofuran)

at -78ºC. The solution was then allowed to warm to room temperature and stirred for 2 hours. After

this time distilled water (30 mL) and diethyl ether (30 mL) were added and the biphasic mixture

was separated. The organic phase was washed with distilled water (15 mL) and the combined

aqueous washings were re-extracted with ethyl acetate (20 mL) which was then washed with brine


onto silica (2 g). The solid residue was subjected to flash chromatography (silica gel, 5:5:1 hexane

/ dichloromethane / diethyl ether) giving the title compound as a viscous oil (306 mg, 43%). 1H

NMR (300 MHz, CDCl3) δ 4.40 (dd, J = 7.4, 1.7 Hz, 1H), 4.29 (dd, J = 9.2, 1.7 Hz, 1H), 4.23 (dd,

J = 9.2, 7.4 Hz, 1H), 2.43 (t, J = 7.1 Hz, 2H), 1.67 (app. sext, Japp = 7.2 Hz, 2H), 1.06 (t, J = 7.4

Hz, 3H), 0.96 (s, 9H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 153.0 (C), 151.0 (C), 98.5 (C), 73.4

(C), 65.1 (CH2), 61.2 (CH), 35.7 (C), 25.4 (CH3), 21.1 (CH2), 20.9 (CH2), 13.3 (CH3). LRMS m/z

(%): 255.3 (65, M+NH4+), 238.2 (100, MH+). HRMS calcd for C13H19NNaO3

+: 260.1263. Found:

260.1252. IR (cm-1): 2965, 2241, 2219, 1790, 1666, 1324, 1295, 1183, 1090. [for 1H and 13C NMR


(4S,5R)-3-Hex-2-ynoyl-4,5-diphenyloxazolidin-2-one (339)

Butyllithium (1.45 M in hexanes, 1.38 mL, 2.0 mmol) was added

dropwise to a stirred solution of 1-pentyne (210 µL, 2.1 mmol) in

tetrahydrofuran (5 mL) at -78ºC under nitrogen. After stirring for 30 minutes

the nitrogen was turned off and carbon dioxide was bubbled slowly through

the solution while it was warmed to 0ºC (ice bath) over the course of 30

minutes. The carbon dioxide supply was then removed and replaced with the nitrogen atmosphere.

NO

OO

NO

OO


- 120 -

The solution was again cooled to -78ºC and pivaloyl chloride (250 µL, 2.0 mmol) was added. The

solution was then allowed to warm to room temperature and was stirred for 3 hours. The solution

was then cooled again to -78ºC and added via cannula to a stirred suspension of lithiated

oxazolidinone (2.0 mmol, generated by addition of 1.38 mL of 1.45 M butyllithium solution to 488

mg of oxazolidinone 338 in 10 mL of tetrahydrofuran) at -78ºC. The solution was then allowed to

warm to room temperature and stirred for 2 hours. After this time distilled water (30 mL) and

diethyl ether (30 mL) were added and the biphasic mixture was separated. The organic phase was

washed with distilled water (20 mL) and the combined aqueous washings were re-extracted with

ethyl acetate (20 mL) which was then washed with brine (20 mL). The combined organic extracts

were dried over magnesium sulphate and concentrated onto silica (2 g). The solid residue was

subjected to flash chromatography (silica gel, 5:5:1 hexane / dichloromethane / diethyl ether)

giving the title compound as a white solid (280 mg, 42%, mp = 131-133ºC). 1H NMR (300 MHz,

CDCl3) δ 7.16-7.07 (m, 6H), 7.01-6.94 (m, 2H), 6.91-6.84 (m, 2H), 5.89 (d, J = 7.5 Hz, 1H), 5.67

(d, J = 7.5 Hz, 1H), 2.44 (t, J = 7.1 Hz, 2H), 1.68 (app. sext, Japp = 7.3 Hz, 2H), 1.06 (t, J = 7.4 Hz,

3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 152.2 (C), 150.0 (C), 133.9 (C), 132.7 (C), 128.4 (CH),

128.23 (CH), 128.18 (CH), 128.0 (CH), 126.6 (CH), 126.1 (CH), 98.8 (C), 80.1 (CH), 73.8 (C),

62.7 (CH), 21.2 (CH2), 20.9 (CH2), 13.4 (CH3). LRMS m/z (%): 684.5 (50, 2×M+NH4+), 351.3

(60, M+NH4+), 334.2 (100, MH+). HRMS calcd for C21H19NNaO3

+: 356.1263. Found: 356.1257.

IR (cm-1): 3035, 2966, 2262, 2214, 1771, 1663, 1362, 1341, 1315, 1192, 1022, 729. [for 1H and

13C NMR spectra see Appendix C47].

(3aS,8aR)-3-Hex-2-ynoyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (341)


dropwise to a stirred solution of 1-pentyne (210 µL, 2.1 mmol) in



solution while it was warmed to 0ºC (ice bath) over the course of 30 minutes.

The carbon dioxide supply was then removed and replaced with the nitrogen atmosphere. The

solution was again cooled to -78ºC and pivaloyl chloride (250 µL, 2.0 mmol) was added. The

solution was then allowed to warm to room temperature and was stirred for 3 hours. The solution

was then cooled again to -78ºC and added via cannula to a stirred suspension of lithiated

oxazolidinone (2.0 mmol, generated by addition of 1.38 mL of 1.45 M butyllithium solution to 358

mg of oxazolidinone 340 in 17 mL of tetrahydrofuran) at -78ºC. The solution was then allowed to

NO

OO

H

H


- 121 -

warm to room temperature and stirred for 2 hours. After this time distilled water (40 mL) and

diethyl ether (40 mL) were added and the biphasic mixture was separated. The organic phase was

washed with distilled water (30 mL) and the combined aqueous washings were re-extracted with

ethyl acetate (20 mL) which was then washed with brine (20 mL). The combined organic extracts

were dried over magnesium sulphate and concentrated onto silica (2 g). The solid residue was

subjected to flash chromatography (silica gel, 5:5:1 hexane / dichloromethane / diethyl ether)

giving the title compound as a viscous oil (232 mg, 43%). 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J

= 7.8 Hz, 1H), 7.39-7.23 (m, 3H), 5.93 (d, J = 6.9 Hz, 1H), 5.28 (ddd, J = 6.9, 4.2, 3.0 Hz, 1H),

3.40 (app. d, Japp = 3.0 Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H), 1.66 (app. sext, Japp = 7.3 Hz, 2H), 1.05 (t,

J = 7.4 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 151.4 (C), 151.1 (C), 139.3 (C), 138.5 (C),

129.9 (CH), 128.1 (CH), 127.2 (CH), 125.1 (CH), 99.2 (C), 77.9 (CH), 73.5 (C), 62.9 (CH), 37.9

(CH2), 21.2 (CH2), 20.9 (CH2), 13.3 (CH3). LRMS m/z (%): 556.4 (10, 2×M+NH4+), 287.3 (70,

M+NH4+), 270.2 (100, MH+). HRMS calcd for C16H15NNaO3

+: 292.0950. Found: 292.0944. IR

(cm-1): 2966, 2250, 2224, 1787, 1656, 1360, 1324, 1189, 1101, 1032, 753. [for 1H and 13C NMR


(S)-4-Phenyl-3-(3-phenylpropioloyl)oxazolidin-2-one (343)


dropwise to a stirred solution of phenylacetylene (1.12 mL, 10.0 mmol) in




carbon dioxide supply was then removed and replaced with the nitrogen

atmosphere. The solution was again cooled to -78ºC and pivaloyl chloride (1.24 mL, 10.0 mmol)

was added. The solution was then allowed to warm to room temperature and was stirred for 3

hours. The solution was then cooled again to -78ºC and added via cannula to a stirred suspension

of lithiated oxazolidinone (10.0 mmol, generated by addition of 5.2 mL of 1.92 M butyllithium

solution to 1.63 g of oxazolidinone 202 in 60 mL of tetrahydrofuran) at -78ºC. The solution was

then allowed to warm to room temperature and stirred for 2 hours. After this time distilled water

(100 mL) and diethyl ether (100 mL) were added and the biphasic mixture was separated. The

organic phase was washed with distilled water (60 mL) and the combined aqueous washings were

re-extracted with ethyl acetate (40 mL) which was then washed with brine (30 mL). The combined

organic extracts were dried over magnesium sulphate and concentrated onto silica (5 g). The solid

NO

OO


- 122 -

residue was subjected to flash chromatography (silica gel, 4:1 hexane / ethyl acetate) giving the

title compound as a white solid (1.19 g, 41%). 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 7.2 Hz,

2H), 7.49-7.30 (m, 8H), 5.50 (dd, J = 8.7, 3.6 Hz, 1H), 4.73 (app. t, Japp = 8.7 Hz, 1H), 4.33 (dd, J

= 8.7, 3.6 Hz, 1H). Known compound.69

(S)-4-Isopropyl-3-(3-phenylpropioloyl)oxazolidin-2-one (345)


dropwise to a stirred solution of phenylacetylene (520 µL, 4.65 mmol) in

tetrahydrofuran (7.5 mL) at -78ºC under nitrogen. After stirring for 30 minutes the



carbon dioxide supply was then removed and replaced with the nitrogen

atmosphere. The resultant slurry was cooled to -78ºC and pivaloyl chloride (580 µL, 4.7 mmol)

was added. The slurry was then allowed to warm to room temperature and was stirred for 3 hours,

over which time the solid dissolved. The solution was then cooled again to -78ºC and added via

cannula to a stirred suspension of lithiated oxazolidinone (4.65 mmol, generated by addition of

2.39 mL of 1.97 M butyllithium solution to 600 mg of oxazolidinone 344 in 25 mL of

tetrahydrofuran) at -78ºC. The solution was then allowed to warm to room temperature and stirred

for 3 hours. After this time distilled water (50 mL) and diethyl ether (30 mL) were added and the

biphasic mixture was separated. The organic phase was washed with distilled water (30 mL) and

the combined aqueous washings were re-extracted with ethyl acetate (30 mL) which was then

washed with brine (20 mL). The combined organic extracts were dried over magnesium sulphate

and concentrated under reduced pressure. The residue was subjected to flash chromatography

(silica gel, 83:17 hexanes / ethyl acetate) giving the title compound as a white solid (520 mg, 48%,

mp = 91-93ºC). 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 7.2 Hz, 2H), 7.49-7.33 (m, 3H), 4.48

(ddd, J = 8.1, 4.2, 3.0 Hz, 1H), 4.30 (app. t, Japp = 8.6 Hz, 1H), 4.23 (dd, J = 9.0, 3.0 Hz, 1H), 2.44

(sept.d, J = 6.9, 4.2 Hz, 1H), 0.95 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H). 13C NMR (JMOD,

75 MHz, CDCl3) δ 152.6 (C), 150.9 (C), 133.3 (CH), 131.0 (CH), 128.6 (CH), 119.9 (C), 94.5 (C),

81.3 (C), 63.4 (CH2), 58.7 (CH), 28.6 (CH), 18.0 (CH3), 14.8 (CH3). LRMS m/z (%): 275.2 (45,

M+NH4+), 258.2 (100, MH+). HRMS calcd for C15H16NO3

+: 258.1130. Found: 258.1124. IR (cm-


C49].

NO

OO


- 123 -

3,4-Dihydro-2H-pyran-6-carbonyl chloride (354)

t-Butyllithium (1.70 M in pentane, 15.0 mL, 25.5 mmol) was added

dropwise to a stirred solution of dihydropyran 361 (2.90 mL, 30.6 mmol) in

tetrahydrofuran (40 mL) at –78ºC. After addition was complete the resultant

solution was allowed to warm to room temperature before being cooled again to -78ºC. The

nitrogen was turned off and carbon dioxide was bubbled slowly through the solution while it was

warmed to 0ºC (ice bath) over the course of 30 minutes. The carbon dioxide supply was then

removed and the reaction mixture was partitioned between diethyl ether (60 mL) and distilled

water (60 mL). The aqueous phase was collected and the organic phase was re-extracted with

distilled water (60 mL). The combined aqueous extracts were acidified to pH 2 with 2 M

hydrochloric acid. This mixture was extracted with ethyl acetate (4 × 30 mL) and the organic

extracts were dried over magnesium sulphate and concentrated under reduced pressure to give 1.74

g of crude acid 363 that was used without further purification.

Crude acid 363 was dissolved in dry dichloromethane (25 mL) and to it was added thionyl

chloride (7.0 mL, 95 mmol). After stirring for 24 hours the reaction mixture concentrated under

reduced pressure to give the title compound as a discoloured oil (1.34 g, 36%). 1H NMR (300

MHz, CDCl3) δ 6.43 (t, J = 4.4 Hz, 1H), 4.10 (t, J = 5.1 Hz, 2H), 2.27 (td, J = 6.4, 4.4 Hz, 2H),

1.85 (tt, J = 6.4, 5.1 Hz, 2H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 163.6 (C), 146.7 (C), 119.4

(CH), 67.1 (CH2), 21.4 (CH2), 20.8 (CH2). IR (cm-1): 2939, 1755, 1626, 1168, 1055, 934, 746. [for

1H and 13C NMR spectra see Appendix C50].

(2Z,4E)-2-Butylidene-4-methyl-1-[(S)-2-oxo-4-phenyloxazolidin-3-yl]hex-4-ene-1,3-dione

(350)

Bis(dibenzylideneacetone)palladium(0) (38 mg, 0.066 mmol) was

added to a stirred solution of triphenylphosphine (70 mg, 0.267 mmol) in


temperature. Alkyne 335 (598 mg, 2.32 mmol) was added, followed by dropwise addition of

tributyltin hydride (650 µL, 2.32 mmol), the mixture was then stirred for 30 minutes. Tigloyl

chloride (289 mg, 2.44 mmol) and cuprous chloride (162 mg, 1.6 mmol) were then added and the

reaction stirred at room temperature for 18 hours. After this time potassium fluoride (30% w/v in

distilled water, 15 mL) was added and the triphasic mixture was stirred for 12 hours. To this



O

O

N

O

O

OCl

O


- 124 -


solid residue was subjected to flash chromatography (silica gel, 10:10:1, hexane / dichloromethane

/ diethyl ether) giving the title compound as a white crystalline solid (783 mg, 99%, mp = 104-

105ºC). 1H NMR (300 MHz, CDCl3) δ 7.50-7.30 (m, 5H), 6.62 (t, J = 7.7 Hz, 1H), 6.52 (q, J = 6.6

Hz, 1H), 5.52 (dd, J = 8.9, 4.1 Hz, 1H), 4.73 (app. t, Japp = 8.9 Hz, 1H), 4.27 (dd, J = 8.7, 4.1 Hz,

1H), 2.13 (app. q, Japp = 7.4 Hz, 2H), 1.86 (s, 3H), 1.82 (d, J = 6.6 Hz, 3H), 1.47 (app. sext, Japp =

7.4 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 194.8 (C), 165.7 (C),

153.1 (C), 148.7 (CH), 138.6 (C), 137.5 (CH), 137.3 (C), 135.5 (C), 129.0 (CH), 128.5 (CH),

126.0 (CH), 70.4 (CH2), 57.4 (CH), 31.7 (CH2), 21.7 (CH2), 14.3 (CH3), 13.7 (CH3), 12.6 (CH3).

LRMS m/z (%): 700.4 (20, 2×M+NH4+), 359.3 (20, M+NH4

+), 342.2 (100, MH+), 179 (15). HRMS

calcd for C20H24NO4+: 342.1705. Found: 342.1704. IR (cm-1): 2924, 1779, 1718, 1693, 1489, 1332,


(2Z,4E)-1-[(S)-4-tert-Butyl-2-oxo-oxazolidin-3-yl]-2-butylidene-4-methylhex-4-ene-1,3-dione

(351)

Bis(dibenzylideneacetone)palladium(0) (9.0 mg, 0.016 mmol) was


tetrahydrofuran (4 mL) and left to stir for 30 minutes at room temperature.

Alkyne 337 (135 mg, 0.569 mmol) was added, followed by dropwise addition of tributyltin

hydride (159 µL, 0.569 mmol), the mixture was then stirred for 30 minutes. Tigloyl chloride (0.92

M in tetrahydrofuran, 0.68 mL, 0.63 mmol) and cuprous chloride (45 mg, 0.45 mmol) were then

added and the reaction stirred at room temperature for 18 hours. After this time potassium fluoride

(30% w/v in distilled water, 5 mL) was added and the triphasic mixture was stirred for 12 hours.

To this mixture distilled water (20 ml) and diethyl ether (20 mL) were added, after separation the

aqueous phase was re-extracted with diethyl ether (2 × 20 mL) and the combined organic fractions

were dried over magnesium sulphate and concentrated onto silica gel (2 g) under reduced pressure.

The solid residue was subjected to flash chromatography (silica gel, 88:12 hexane / ethyl acetate)

giving the title compound as a thick oil (147 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 6.60 (t, J =

7.8 Hz, 1H), 6.55 (mc, 1H) 4.48 (dd, J = 6.3, 3.0 Hz, 1H), 4.33-4.26 (m, 2H), 2.31-2.19 (m, 2H),

1.88-1.82 (m, 6H), 1.54 (app. sext, Japp = 7.3 Hz, 2H), 1.02 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H). 13C

NMR (JMOD, 75 MHz, CDCl3) δ 195.2 (C), 166.3 (C), 154.1 (C), 147.9 (CH), 137.8 (C), 137.5

(CH), 135.2 (C), 65.6 (CH2), 61.1 (CH), 35.9 (C), 32.0 (CH2), 25.5 (CH3), 21.7 (CH2), 14.2 (CH3),

13.7 (CH3), 12.5 (CH3). LRMS m/z (%): 660.7 (20, 2×M+NH4+), 339.3 (25, M+NH4

+), 322.2 (100,

O

O

N

O

O


- 125 -

MH+). HRMS calcd for C18H27NNaO4+: 344.1838. Found: 344.1830. IR (cm-1): 2964, 1780, 1699,


(2Z,4E)-2-Butylidene-4-methyl-1-[(4S,5R)-2-oxo-4,5-diphenyloxazolidin-3-yl]hex-4-ene-1,3-

dione (352)



tetrahydrofuran (3.5 mL) and left to stir for 30 minutes at room

temperature. Alkyne 339 (167 mg, 0.500 mmol) was added, followed by

dropwise addition of tributyltin hydride (140 µL, 0.500 mmol), the

mixture was then stirred for 30 minutes. Tigloyl chloride (0.92 M in tetrahydrofuran, 0.60 mL,

0.55 mmol) and cuprous chloride (40 mg, 0.40 mmol) were then added and the reaction stirred at

room temperature for 18 hours. After this time potassium fluoride (30% w/v in distilled water, 5

mL) was added and the triphasic mixture was stirred for 12 hours. To this mixture distilled water

(20 ml) and diethyl ether (20 mL) were added, after separation the aqueous phase was re-extracted

with diethyl ether (2 × 20 mL) and the combined organic fractions were dried over magnesium

sulphate and concentrated onto silica gel (2 g) under reduced pressure. The solid residue was

subjected to flash chromatography (silica gel, 87:13 hexane / ethyl acetate) giving the title

compound as a discoloured solid (180 mg, 86%, mp = 52-54ºC). 1H NMR (300 MHz, CDCl3)

δ 7.15-7.07 (m, 6H), 6.99-6.92 (m, 4H), 6.68 (t, J = 7.8 Hz, 1H), 6.59 (q, J = 6.9, Hz, 1H), 5.95 (d,

J = 7.7 Hz, 1H), 5.77 (d, J = 7.7 Hz, 1H), 2.19 (app. q, Japp = 7.6 Hz, 2H), 1.91 (s, 3H), 1.87 (d, J =

6.9 Hz, 3H), 1.52 (app. sext, Japp = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR (JMOD, 75

MHz, CDCl3) δ 195.0 (C), 165.6 (C), 153.1 (C), 148.8 (CH), 137.7 (CH), 137.6 (C), 135.5 (C),

134.2 (C), 132.9 (C), 128.3 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 126.8 (CH), 126.2 (CH),

80.7 (CH), 62.5 (CH), 31.9 (CH2), 21.8 (CH2), 14.3 (CH3), 13.8 (CH3), 12.7 (CH3). LRMS m/z

(%): 852.3 (15, 2×M+NH4+), 435.3 (40, M+NH4

+), 418.5 (100, MH+). HRMS calcd for


697. [for 1H and 13C NMR spectra see Appendix C53].

O

O

N

O

O


- 126 -

(2Z,4E)-2-Butylidene-4-methyl-1-[(3aS,8aR)-2-oxo-2H-indeno[1,2-d]oxazol-3(3aH,8H,8aH)-

yl]hex-4-ene-1,3-dione (353)




temperature. Alkyne 341 (151 mg, 0.561 mmol) was added, followed by

dropwise addition of tributyltin hydride (157 µL, 0.561 mmol), the mixture was then stirred for 30

minutes. Tigloyl chloride (0.92 M in tetrahydrofuran, 0.67 mL, 0.62 mmol) and cuprous chloride

(45 mg, 0.45 mmol) were then added and the reaction stirred at room temperature for 18 hours.

After this time potassium fluoride (30% w/v in distilled water, 5 mL) was added and the triphasic

mixture was stirred for 12 hours. To this mixture distilled water (20 ml) and diethyl ether (20 mL)

were added, after separation the aqueous phase was re-extracted with diethyl ether (2 × 20 mL) and

the combined organic fractions were dried over magnesium sulphate and concentrated onto silica


gel, 84:16 hexane / ethyl acetate) giving the title compound as a thick oil (170 mg, 86%). 1H NMR

(300 MHz, CDCl3) δ 7.77 (d, J = 7.2 Hz, 1H), 7.39-7.26 (m, 3H), 6.64, (t, J = 7.8 Hz, 1H), 6.50 (q,

J = 6.8 Hz, 1H), 6.03 (d, J = 6.9 Hz, 1H), 5.32 (mc, 1H), 3.47-3.31 (m, 2H), 2.29-2.19 (m, 2H),

1.82 (s, 3H), 1.78 (d, J = 6.8 Hz, 3H), 1.58-1.43 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR

(JMOD, 75 MHz, CDCl3) δ 194.6 (C), 166.8 (C), 152.4 (C), 148.4 (CH), 139.5 (C), 139.0 (C),

137.8 (CH), 137.5 (C), 135.6 (C), 129.9 (CH), 128.2 (CH), 127.3 (CH), 125.3 (CH), 78.8 (CH),

63.0 (CH), 38.0 (CH2), 32.0 (CH2), 21.8 (CH2), 14.4 (CH3), 13.9 (CH3), 12.6 (CH3). LRMS m/z

(%): 724.5 (30, 2×M+NH4+), 371.3 (15, M+NH4

+), 354.2 (100, MH+). HRMS calcd for



(2E,5Z)-3-Methyl-5-[(S)-p-tolylsulfinyl]nona-2,5-dien-4-one (376)

Bis(dibenzylideneacetone)palladium(0) (8.0 mg, 0.014 mmol) was added

to a stirred solution of triphenylphosphine (15 mg, 0.057 mmol) in

tetrahydrofuran (3.5 mL) and left to stir for 30 minutes at room temperature.

Alkyne 374 (103 mg, 0.500 mmol) was added, followed by dropwise addition of

tributyltin hydride (140 µL, 0.500 mmol), the mixture was then stirred for 30

minutes. Tigloyl chloride (0.92 M in tetrahydrofuran, 0.55 mL, 0.50 mmol) and cuprous chloride

(40 mg, 0.40 mmol) were then added and the reaction stirred at room temperature for 3 hours.

O

O

N

O

OH

H

O

SO


- 127 -

After this time potassium fluoride (30% w/v in distilled water, 5 mL) was added and the triphasic

mixture was stirred for 12 hours. To this mixture distilled water (20 ml) and ethyl acetate (20 mL)

were added, after separation the aqueous phase was re-extracted with ethyl acetate (2 × 20 mL) and



gel, 84:16 hexane / ethyl acetate) giving the title compound as a discoloured oil (114 mg, 79%). 1H

NMR (300 MHz, CDCl3) δ 7.39 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 6.60 (t, J = 7.7 Hz,

1H), 6.42 (q, J = 7.1 Hz, 1H), 2.37 (s, 3H), 2.14 (app. q, Japp = 7.4 Hz, 2H), 1.75 (d, J = 7.1 Hz,

3H), 1.62 (s, 3H), 1.49 (app. sext, Japp = 7.3 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (JMOD,

75 MHz, CDCl3) δ 193.5 (C), 145.4 (C), 144.8 (CH), 141.9 (C), 139.08 (C), 139.07 (C), 137.6

(CH), 129.7 (CH), 125.1 (CH), 31.7 (CH2), 22.0 (CH2), 21.4 (CH3), 15.0 (CH3), 13.7 (CH3), 10.3

(CH3). LRMS m/z (%): 313.2 (40, M+Na+), 291.2 (100, MH+). HRMS calcd for C17H22NaO2S+:

313.1238. Found: 313.1235. IR (cm-1): 2959, 2929, 1632, 1242, 1083, 1055, 809. [for 1H and 13C


(S,Z)-2-Butylidene-1-(3,4-dihydro-2H-pyran-6-yl)-3-(2-oxo-4-phenyloxazolidin-3-yl)propane-

1,3-dione (355)

Tributyltin hydride (280 µL, 1.00 mmol) was added dropwise

to a stirred solution of alkyne 335 (252 mg, 0.981 mmol) and

tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030 mmol) in

tetrahydrofuran (7 mL). After 30 minutes acid chloride 354 (154 mg,

1.05 mmol) and cuprous chloride (70 mg, 0.70 mmol) were added and the reaction was stirred at

room temperature for 18 hours. After this time potassium fluoride (30% w/v in distilled water, 15

mL) was added and the triphasic mixture was stirred for 2 hours. To this mixture distilled water

(20 ml) and diethyl ether (30 mL) were added, after separation the aqueous phase was re-extracted

with diethyl ether (2 × 20 mL) and the combined organic fractions were dried over magnesium

sulphate and concentrated onto silica gel (2 g) under reduced pressure. The solid residue was

subjected to flash chromatography (silica gel, 7:3 hexanes / ethyl acetate) giving the title

compound as a discoloured oil (252 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.48-7.30 (m, 5H),

7.00 (t, J = 8.0 Hz, 1H), 5.96 (t, J = 4.1 Hz, 1H), 5.51 (dd, J = 8.7, 4.2 Hz, 1H), 4.72 (app. t, Japp =

8.7 Hz, 1H), 4.31 (dd, J = 9.0, 4.2 Hz, 1H), 4.00-3.90 (m, 2H), 2.24-2.06 (m, 4H), 1.88-1.80 (m,

2H), 1.47 (app. sext, Japp = 7.4 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 184.7 (C), 165.2 (C), 153.1 (C), 150.3 (C), 149.4 (CH), 138.7 (C), 135.7 (C), 128.9

O

O

N

O

O

O


- 128 -

(CH), 128.5 (CH), 126.2 (CH), 111.8 (CH), 70.3 (CH2), 66.1 (CH2), 57.2 (CH), 31.6 (CH2), 21.6

(CH2), 21.4 (CH2), 20.5 (CH2), 13.7 (CH3). LRMS m/z (%): 756.4 (10, 2×M+ NH4+), 387.4 (60,

M+NH4+), 370.3 (100, MH+), 164.0 (80). HRMS calcd for C21H24NNaO5

+: 392.1474. Found:



(S,Z)-2-Butylidene-1-(3-methoxyphenyl)-3-(2-oxo-4-phenyloxazolidin-3-yl)propane-1,3-dione

(357)




30 minutes at room temperature. Alkyne 335 (515 mg, 2.00 mmol) was added, followed by

dropwise addition of tributyltin hydride (560 µL, 2.00 mmol), the mixture was then stirred for 30

minutes. 3-Anisoyl chloride 356 (300 µL, 2.1 mmol) and cuprous chloride (140 mg, 1.4 mmol)

were then added and the reaction stirred at room temperature for 18 hours. After this time

potassium fluoride (30% w/v in distilled water, 15 mL) was added and the triphasic mixture was

stirred for 12 hours. To this mixture distilled water (50 ml) and diethyl ether (50 mL) were added,

after separation the aqueous phase was re-extracted with diethyl ether (2 × 30 mL) and the

combined organic fractions were dried over magnesium sulphate and concentrated onto silica gel

(3 g) under reduced pressure. The solid residue was subjected to flash chromatography (silica gel,

50:50:4 hexane / dichloromethane / diethyl ether) giving the title compound as a thick discoloured

oil (712 mg, 91%). 1H NMR (300 MHz, CDCl3) δ 7.45-7.30 (m, 8H), 7.08 (mc, 1H), 6.65 (t, J =

7.8 Hz, 1H), 5.57 (dd, J = 8.9, 4.4 Hz, 1H), 4.75 (app. t, Japp = 8.9 Hz, 1H), 4.28 (dd, J = 8.9, 4.4

Hz, 1H), 3.83 (s, 3H), 2.20 (app. q, Japp = 7.5 Hz, 2H), 1.47 (app. sext, Japp = 7.4 Hz, 2H), 0.90 (t, J


150.6 (CH), 138.7 (C), 138.3 (C), 137.9 (C), 129.2 (CH), 129.0 (CH), 128.5 (CH), 126.0 (CH),

122.1 (CH), 118.3 (CH), 114.2 (CH), 70.6 (CH2), 57.3 (CH), 55.2 (CH3), 31.8 (CH2), 21.7 (CH2),

13.7 (CH3). LRMS m/z (%): 804.5 (20, 2×M+NH4+), 411.4 (40, M+NH4

+), 394.4 (100, MH+).

HRMS calcd for C23H24NO5+: 394.1654. Found: 394.1661. IR (cm-1): 3034, 2962, 1779, 1696,


O

O

N

O

O

MeO


- 129 -

(2Z,4E)-2-Benzylidene-4-methyl-1-[(S)-2-oxo-4-phenyloxazolidin-3-yl]hex-4-ene-1,3-dione

(105)

Tributyltin hydride (192 µL, 0.686 mmol) was added dropwise to

a stirred solution of alkyne 343 (200 mg, 0.686 mmol) and


tetrahydrofuran (5 mL). After 30 minutes tigloyl chloride (97 mg, 0.82

mmol) and cuprous chloride (48 mg, 0.48 mmol) were added and the

reaction was stirred at room temperature for 18 hours. After this time potassium fluoride (30% w/v

in distilled water, 15 mL) was added and the triphasic mixture was stirred for 6 hours. To this




solid residue was subjected to flash chromatography (silica gel, 78:22 hexanes / ethyl acetate)

giving the title compound as a white crystalline solid (222 mg, 86%, mp = 116-117ºC). 1H NMR

(300 MHz, CDCl3) δ 7.42 (br s, 5H), 7.36 (s, 1H), 7.27 (mc, 1H), 7.17-7.09 (m, 4H), 6.64 (q, J =

7.1 Hz, 1H), 5.56 (dd, J = 8.7 Hz, 3.5 Hz, 1H), 4.73 (app. t, Japp = 8.9 Hz, 1H), 4.35 (dd, J = 8.9

Hz, 3.5 Hz, 1H), 1.93 (s, 3H), 1.88 (d, J = 7.1 Hz, 3H). Known compound.9 [for 1H NMR spectra

see Appendix C58].

(2Z,4E)-2-Benzylidene-1-[(S)-4-isopropyl-2-oxooxazolidin-3-yl]-4-methylhex-4-ene-1,3-dione

(360)

Tributyltin hydride (280 µL, 1.00 mmol) was added dropwise to a

stirred solution of alkyne 345 (257 mg, 1.00 mmol) and


tetrahydrofuran (7 mL). After 30 minutes tigloyl chloride (142 mg, 1.2

mmol) and cuprous chloride (70 mg, 0.70 mmol) were added and the reaction was stirred for 18


triphasic mixture was stirred for 2 hours. Diethyl ether (30 mL) was added to this mixture and the

liquid phases were separated, after separation the aqueous phase was re-extracted with diethyl

ether (30 mL) and the combined organic fractions were dried over magnesium sulphate and

concentrated onto silica gel (2 g) under reduced pressure. The solid residue was subjected to flash

chromatography (silica gel, 83:17 hexanes / ethyl acetate) giving the title compound as a white

solid (315 mg, 92%, mp = 117-119ºC). 1H NMR (300 MHz, CDCl3) δ 7.41-7.32 (m, 6H), 6.67 (q,

O

O

N

O

O

O

O

N

O

O


- 130 -

J = 6.8 Hz, 1H), 4.53 (ddd, J = 8.1, 3.8, 3.3 Hz, 1H), 4.28 (app. t, Japp = 8.6 Hz, 1H), 4.21 (dd, J =

9.0, 3.3 Hz, 1H), 2.51 (sept.d, J = 6.8, 3.8 Hz, 1H), 1.91 (s, 3H), 1.89 (d, J = 6.8 Hz, 3H), 0.95 (d,


(C), 153.4 (C), 142.5 (CH), 138.3 (CH), 136.0 (C), 135.5 (C), 133.6 (C), 130.1 (CH), 129.2 (CH),

128.8 (CH), 63.9 (CH2), 58.5 (CH), 28.5 (CH), 17.8 (CH3), 14.7 (CH3), 14.4 (CH3), 12.8 (CH3).

LRMS m/z (%): 700.6 (20, 2×M+NH4+), 359.4 (15, M+NH4

+), 342.4 (100, MH+). HRMS calcd for



(S,Z)-2-Benzylidene-1-(3,4-dihydro-2H-pyran-6-yl)-3-(2-oxo-4-phenyloxazolidin-3-

yl)propane-1,3-dione (358)

Tributyltin hydride (280 µL, 1.00 mmol) was added dropwise to

a stirred solution of alkyne 343 (290 mg, 1.00 mmol) and


tetrahydrofuran (7 mL). After 30 minutes acid chloride 354 (154 mg,

1.05 mmol) and cuprous chloride (70 mg, 0.70 mmol) were added and the reaction was stirred for

18 hours. After this time potassium fluoride (10% w/v in distilled water, 20 mL) was added and the

triphasic mixture was stirred for 2 hours. Diethyl ether (30 mL) was added to this mixture and the

liquid phases were separated, after separation the aqueous phase was re-extracted with diethyl

ether (30 mL) and the combined organic fractions were dried over magnesium sulphate and

concentrated onto silica gel (2 g) under reduced pressure. The solid residue was subjected to flash

chromatography (silica gel, 65:35 hexanes / ethyl acetate) giving the title compound as a white

solid (279 mg, 69%, mp = 70-72ºC). 1H NMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.43-7.10 (m,

10H), 6.04 (t, J = 4.1 Hz, 1H), 5.50 (dd, J = 8.6, 3.5 Hz, 1H), 4.62 (app. t, Japp = 8.7 Hz, 1H), 4.33

(dd, J = 9.0, 3.5 Hz, 1H), 3.97 (br s, 2H), 2.27-2.19 (m, 2H), 1.92-1.81 (m, 2H). 13C NMR (JMOD,

75 MHz, CDCl3) δ 184.9 (C), 166.0 (C), 152.8 (C), 150.5 (C), 143.5 (CH), 138.2 (C), 133.3 (C),

133.2 (C), 130.1 (CH), 129.5 (CH), 129.0 (CH), 128.64 (CH), 128.55 (CH), 126.8 (CH), 112.4

(CH), 70.3 (CH2), 66.2 (CH2), 57.4 (CH), 21.5 (CH2), 20.6 (CH2). LRMS m/z (%): 824.4 (10,

2×M+NH4+), 421.2 (35, M+NH4

+), 404.2 (100, MH+). HRMS calcd for C24H21NNaO5+: 426.1317.

Found: 426.1316. IR (cm-1): 2926, 1779, 1692, 1619, 1260, 1200, 756, 696. [for 1H and 13C NMR


O

O

N

O

O

O


- 131 -

(S,Z)-2-Benzylidene-1-(3-methoxyphenyl)-3-(2-oxo-4-phenyloxazolidin-3-yl)propane-1,3-

dione (359)




30 minutes at room temperature. Alkyne 343 (291 mg, 1.00

mmol) was added, followed by dropwise addition of tributyltin

hydride (280 µL, 1.00 mmol), the mixture was then stirred for 30 minutes. 3-Anisoyl chloride 356

(150 µL, 1.05 mmol) and cuprous chloride (70 mg, 0.70 mmol) were then added and the reaction

stirred at room temperature for 18 hours. After this time potassium fluoride (30% w/v in distilled

water, 10 mL) was added and the triphasic mixture was stirred for 12 hours. To this mixture

distilled water (30 ml) and diethyl ether (30 mL) were added, after separation the aqueous phase

was re-extracted with diethyl ether (2 × 20 mL) and the combined organic fractions were dried

over magnesium sulphate and concentrated onto silica gel (2 g) under reduced pressure. The solid

residue was subjected to flash chromatography (silica gel, 10:10:1 hexane / dichloromethane /

diethyl ether) giving the title compound as a white solid (337 mg, 79%, mp = 146-148ºC). 1H

NMR (300 MHz, CDCl3) δ 7.50-7.35 (m, 9H), 7.29 (mc, 1H), 7.22-7.00 (m, 5H), 5.62 (dd, J = 8.7,

3.5 Hz, 1H), 4.76 (app. t, Japp = 8.7 Hz, 1H), 4.37 (dd, J = 8.7, 3.5 Hz, 1H), 3.85 (s, 3H). 13C NMR

(JMOD, 75 MHz, CDCl3) δ 194.1 (C), 165.8 (C), 159.5 (C), 153.1 (C), 144.8 (CH), 138.4 (C),

138.2 (C), 135.4 (C), 132.7 (C), 130.5 (CH), 129.6 (CH), 129.4 (CH), 129.1 (CH), 128.7 (CH),

126.7 (CH), 122.2 (CH), 118.5 (CH), 114.2 (CH), 70.6 (CH2), 57.4 (CH), 55.4 (CH3). LRMS m/z

(%): 872.4 (30, 2×M+NH4+), 445.3 (55, M+NH4

+), 428.3 (100, MH+). HRMS calcd for



(S)-3-[(1S,5S)-3,4-Dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]-4-phenyloxazolidin-2-

one (364)

Methanesulfonic acid (370 µL, 5.55 mmol) was added dropwise to

a stirred solution of 350 (190 mg, 0.555 mmol) in dichloromethane (4

mL) at -78ºC. This solution was allowed to warm to room temperature

over a period of 2 hours, and then allowed to stir for a further 12 hours.

After this time the acid was quenched by gradual addition of sodium bicarbonate solution (5% w/v,

10 mL). After stirring for 1 hour the mixture was taken up in extra dichloromethane (15 mL) and

O

O

N

O

O

MeO

O

O

N

O

O


- 132 -

water (20 mL) and the organic phase was separated, the aqueous phase was then re-extracted with

dichloromethane (2 × 10 mL). The combined organic extracts were dried over magnesium sulphate


flash chromatography (silica gel, 50:50:7 hexane / dichloromethane / diethyl ether) giving the title

compound as a white solid (134 mg, 71% mp = 167-169ºC). 1H NMR (300 MHz, CDCl3) δ 7.44-

7.25 (m, 5H), 5.43 (dd, J = 8.3, 2.5 Hz, 1H), 4.89 (d, J = 3.0 Hz, 1H), 4.76 (app. t, Japp = 8.6 Hz,

1H), 4.31 (dd, J = 8.7, 2.5 Hz, 1H), 3.12 (mc, 1H), 2.00 (s, 3H), 1.75 (mc, 1H), 1.68 (s, 3H), 1.37-

1.11 (m, 3H), 0.84 (t, J = 7.1 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 201.1 (C), 173.2 (C),

168.8 (C), 153.7 (C), 139.2 (C), 133.9 (C), 129.0 (CH), 128.5 (CH), 125.6 (CH), 69.8 (CH2), 58.1

(CH), 56.0 (CH), 46.5 (CH), 33.8 (CH2), 20.4 (CH2), 15.0 (CH3), 13.8 (CH3), 8.1 (CH3). LRMS

m/z (%): 700.4 (20, 2×M+NH4+), 359.4 (10, M+NH4

+), 342.2 (100, MH+). HRMS calcd for

C20H24NO4+: 342.1705. Found: 342.1699. IR (cm-1): 2925, 1778, 1716, 1691, 1489, 1197, 1023,

699. [for 1H and 13C NMR spectra see Appendix C62]. Minor Isomer (366) (45 mg, 24%,

discoloured solid, mp = 76-78ºC); 1H NMR (300 MHz, CDCl3) δ 7.41-

7.23 (m, 5H), 5.46 (dd, J = 9.0, 5.9 Hz, 1H), 4.92 (br s, 1H), 4.71 (app. t,

Japp = 8.9 Hz, 1H), 4.21 (dd, J = 8.9, 5.9 Hz, 1H), 3.22 (mc, 1H), 1.97 (s,

3H), 1.77 (mc, 1H), 1.63 (s, 3H), 1.36-1.20 (m, 3H), 0.93 (t, J = 6.9 Hz,

3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 199.9 (C), 172.6 (C), 168.4

(C), 153.7 (C), 138.1 (C), 133.7 (C), 129.0 (CH), 128.4 (CH), 125.9 (CH), 69.7 (CH2), 58.4 (CH),

56.6 (CH), 45.5 (CH), 34.0 (CH2), 20.6 (CH2), 15.0 (CH3), 14.0 (CH3), 8.2 (CH3). LRMS m/z (%):

700.5 (20, 2×M+NH4+), 359.3 (10, M+NH4

+), 342.2 (100, MH+). HRMS calcd for C20H24NO4+:

342.1705. Found: 342.1718. IR (cm-1): 2928, 1779, 1688, 1649, 1354, 1320, 1206, 755, 700. [for


(S)-4-tert-Butyl-3-[(1S,5S)-3,4-dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]oxazolidin-2-

one (368)

Methanesulfonic acid (247 µL, 3.72 mmol) was added dropwise to a

stirred solution of 351 (110 mg, 0.342 mmol) in dichloromethane (4 mL) at -

78ºC. This solution was allowed to warm to room temperature over a period

of 2 hours, and then allowed to stir for a further 12 hours. After this time the

acid was quenched by gradual addition of sodium bicarbonate solution (5% w/v, 10 mL). After

stirring for 1 hour the mixture was taken up in extra dichloromethane (15 mL) and water (20 mL)

and the organic phase was separated, the aqueous phase was then re-extracted with

O

O

N

O

O

O

O

N

O

O


- 133 -





4.37-4.29 (m, 3H), 3.29 (mc, 1H), 2.05 (s, 3H), 1.85 (mc, 1H), 1.67 (s, 3H), 1.42-1.29 (m, 3H), 0.96

(s, 9H), 0.96 (t, J = 6.6 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 201.4 (C), 173.3 (C), 169.1

(C), 155.1 (C), 133.7 (C), 65.2 (CH2), 62.3 (CH), 55.7 (CH), 46.4 (CH), 35.5 (C), 34.0 (CH2), 25.7

(CH3), 20.6 (CH2), 15.0 (CH3), 13.9 (CH3), 8.1 (CH3). LRMS m/z (%): 660.5 (30, 2×M+NH4+),

339.3 (15, M+NH4+), 322.3 (100, MH+). HRMS calcd for C18H29NNaO4

+: 344.1838. Found:

344.1828. IR (cm-1): 2962, 1778, 1690, 1643, 1365, 1182, 1053, 706. [for 1H and 13C NMR spectra

see Appendix C64]. Minor Isomer (369) (23 mg, 19%, clear oil); 1H NMR (300 MHz, CDCl3)

δ 4.98 (br s, 1H), 4.52 (dd, J = 7.7, 1.9 Hz, 1H), 4.33 (dd, J = 9.3, 1.9 Hz,

1H), 4.27 (dd, J = 9.3, 7.7 Hz, 1H), 3.28 (mc, 1H), 2.04 (s, 3H), 1.77 (mc,

1H), 1.69 (s, 3H), 1.36-1.23 (m, 3H), 0.99-0.90 (m, 12H). 13C NMR (JMOD,

75 MHz, CDCl3) δ 200.7 (C), 172.7 (C), 169.5 (C), 154.3 (C), 133.9 (C),

65.0 (CH2), 61.2 (CH), 56.4 (CH), 45.9 (CH), 36.2 (C), 33.9 (CH2), 25.4 (CH3), 20.4 (CH2), 15.0

(CH3), 14.0 (CH3), 8.2 (CH3). LRMS m/z (%): 660.5 (20, 2×M+NH4+), 339.2 (10, M+NH4

+), 322.3

(100, MH+). HRMS calcd for C18H29NNaO4+: 344.1838. Found: 344.1832. IR (cm-1): 2961, 1775,


(4S,5R)-3-[(1S,5S)-3,4-Dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]-4,5-

diphenyloxazolidin-2-one (370)

Methanesulfonic acid (178 µL, 2.69 mmol) was added dropwise to a

stirred solution of 352 (112 mg, 0.269 mmol) in dichloromethane (4 mL) at -

78ºC. This solution was allowed to warm to room temperature over a period

of 2 hours, and then allowed to stir for a further 12 hours. After this time the

acid was quenched by gradual addition of sodium bicarbonate solution (5% w/v, 10 mL). After

stirring for 1 hour the mixture was taken up in extra dichloromethane (15 mL) and water (20 mL)

and the organic phase was separated, the aqueous phase was re-extracted with dichloromethane (2

× 10 mL). The combined organic extracts were dried over magnesium sulphate and concentrated


chromatography (silica gel, 50:50:4 hexane / dichloromethane / diethyl ether) giving the title

compound as a white solid (80 mg, 71%, mp = 143-145ºC). 1H NMR (300 MHz, CDCl3) δ 7.17-

O

O

N

OO

Ph

Ph

O

O

N

O

O


- 134 -

7.07 (m, 6H), 7.02-6.96 (m, 2H), 6.89-6.84 (m, 2H), 6.02 (d, J = 7.4 Hz, 1H), 5.63 (d, J = 7.4 Hz,

1H), 5.00 (d, J = 3.0 Hz, 1H), 3.20 (mc, 1H), 2.03 (s, 3H), 1.80 (mc, 1H), 1.71 (s, 3H), 1.43-1.25

(m, 3H), 0.90 (t, J = 6.8 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 201.0 (C), 173.4 (C),

168.3 (C), 154.0 (C), 134.5 (C), 133.8 (C), 132.6 (C), 128.3 (CH), 128.2 (CH), 128.0 (CH), 127.9

(CH), 126.4 (CH), 126.1 (CH), 80.3 (CH), 63.5 (CH), 56.3 (CH), 46.1 (CH), 33.9 (CH2), 20.5

(CH2), 15.1 (CH3), 13.9 (CH3), 8.2 (CH3). LRMS m/z (%): 852.2 (20, 2×M+NH4+), 435.5 (25,

M+NH4+), 418.3 (100, MH+). HRMS calcd for C26H27NNaO4

+: 440.1838. Found: 440.1833. IR


see Appendix C66]. Minor Isomer (371) (29 mg, 26%, clear oil); 1H NMR (300 MHz, CDCl3)

δ 7.16-6.95 (m, 10H), 5.92 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 8.1 Hz, 1H), 4.95

(br s, 1H), 3.26 (mc, 1H), 2.00 (s, 3H), 1.80 (mc, 1H), 1.65 (s, 3H), 1.38-1.22

(m, 3H), 0.95 (t, J = 6.8 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 200.1

(C), 172.5 (C), 168.4 (C), 153.4 (C), 133.83 (C), 133.81 (C), 133.1 (C), 128.3

(CH), 128.0 (CH), 127.90 (CH), 127.86 (CH), 126.8 (CH), 126.3 (CH), 79.8

(CH), 63.1 (CH), 56.7 (CH), 45.9 (CH), 34.1 (CH2), 20.7 (CH2), 15.0 (CH3), 14.0 (CH3), 8.2

(CH3). LRMS m/z (%): 435.5 (10, M+NH4+), 418.4 (100, MH+). HRMS calcd for C26H27NNaO4

+:

440.1838. Found: 440.1833. IR (cm-1): 2928, 1778, 1690, 1643, 1341, 1183, 1041, 729, 697. [for


(3aS,8aR)-3-[(1S,5S)-3,4-Dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]-3,3a,8,8a-

tetrahydro-2H-indeno[1,2-d]oxazol-2-one (372)

Methanesulfonic acid (218 µL, 3.14 mmol) was added dropwise

to a stirred solution of 353 (111 mg, 0.314 mmol) in dichloromethane (4


over a period of 2 hours, and then allowed to stir for a further 12 hours.

After this time the acid was quenched by gradual addition of sodium bicarbonate solution (5% w/v,

10 mL). After stirring for 1 hour the mixture was taken up in extra dichloromethane (15 mL) and

water (20 mL) and the organic phase was separated, the aqueous phase was re-extracted with





7.40-7.24 (m, 3H), 5.92 (d, J = 6.7 Hz, 1H), 5.35 (ddd, J = 6.7, 4.5, 2.4 Hz, 1H), 4.86 (d, J = 3.3

O

O

N

O

O

H

H

O

O

N

OO

Ph

Ph


- 135 -

Hz, 1H), 3.47-3.32 (m, 3H), 2.07 (s, 3H), 1.80 (mc, 1H), 1.71 (s, 3H), 1.39-1.21 (m, 3H), 0.88 (t, J


139.5 (C), 139.2 (C), 133.9 (C), 129.7 (CH), 128.0 (CH), 126.9 (CH), 125.2 (CH), 78.1 (CH), 63.8

(CH), 56.0 (CH), 46.4 (CH), 37.6 (CH2), 33.8 (CH2), 20.3 (CH2), 15.1 (CH3), 13.8 (CH3), 8.2

(CH3). LRMS m/z (%): 724.3 (30, 2×M+NH4+), 371.2 (10, M+NH4

+), 354.2 (100, MH+). HRMS

calcd for C21H23NNaO4+: 376.1525. Found: 376.1520. IR (cm-1): 2928, 1776, 1686, 1643, 1360,

1183, 1043, 755, 727. [for 1H and 13C NMR spectra see Appendix C68]. Minor Isomer (373) (25

mg, 23%, lightly discoloured solid, mp = 130-132ºC); 1H NMR (300

MHz, CDCl3) δ 7.48 (d, J = 7.5 Hz, 1H), 7.36-7.20 (m, 3H), 6.00 (d, J =

7.2 Hz, 1H), 5.31 (dt, J = 7.2, 3.9 Hz, 1H), 4.81, (br s, 1H), 3.41 (app. d,

Japp = 3.9 Hz, 2H), 3.26 (mc, 1H), 2.05 (s, 3H), 1.81 (mc, 1H), 1.68 (s,

3H), 1.44-1.24 (m, 3H), 0.95 (t, J = 7.1 Hz, 3H). 13C NMR (JMOD, 75

MHz, CDCl3) δ 200.7 (C), 172.0 (C), 170.4 (C), 152.8 (C), 139.1 (C), 138.6 (C), 134.4 (C), 129.8

(CH), 128.2 (CH), 127.2 (CH), 124.9 (CH), 77.9 (CH), 63.1 (CH), 56.0 (CH), 46.9 (CH), 37.9


2×M+NH4+), 371.4 (20, M+NH4

+), 354.3 (100, MH+). HRMS calcd for C21H23NNaO4+: 376.1525.



(S)-3-[(5S,6S)-7-Oxo-5-propyl-2,3,4,5,6,7-hexahydrocyclopenta[b]pyran-6-carbonyl]-4-

phenyloxazolidin-2-one (377)


stirred solution of 355 (113 mg, 0.307 mmol) in dichloromethane (3


over a period of 2 hours. After this time the acid was quenched by

gradual addition of sodium bicarbonate solution (5% w/v, 10 mL). After stirring for 1 hour the

mixture was taken up in extra dichloromethane (20 mL) and water (20 mL) and the organic phase

was separated, the aqueous phase was re-extracted with dichloromethane (2 × 10 mL). The

combined organic extracts were dried over magnesium sulphate and concentrated onto silica gel (2

g) under reduced pressure. The solid residue was subjected to flash chromatography (silica gel,

sequential elution 5:5:1 / 5:5:2 hexane / dichloromethane / diethyl ether) giving the title compound

as a white solid (87 mg, 65%, mp = 178-180ºC). 1H NMR (300 MHz, CDCl3) δ 7.41-7.22 (m, 5H),

5.43 (dd, J = 8.4, 2.7 Hz, 1H), 4.86 (d, J = 1.8 Hz, 1H), 4.75 (app. t, Japp = 8.7 Hz, 1H), 4.29 (dd, J

O

O

N

OO

H

H

O

O

N

OO

O


- 136 -

= 8.7, 2.7 Hz, 1H), 4.17-3.99 (m, 2H), 3.05 (mc, 1H), 2.40 (dt, J = 18.9, 6.8 Hz, 1H), 2.24 (dt, J =

18.9, 5.5 Hz, 1H), 1.93 (app. quin, Japp = 5.7 Hz, 2H), 1.70 (mc, 1H), 1.40-1.10 (m, 3H), 0.83 (t, J =

7.2 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 193.2 (C), 168.6 (C), 153.7 (C), 148.9 (C),

148.6 (C), 139.2 (C), 129.1 (CH), 128.7 (CH), 125.8 (CH), 69.9 (CH2), 66.9 (CH2), 58.1 (CH),

54.6 (CH), 41.7 (CH), 34.3 (CH2), 22.3 (CH2), 21.4 (CH2), 20.2 (CH2), 13.9 (CH3). LRMS m/z

(%): 756.5 (20, 2×M+NH4+), 387.4 (20, M+NH4

+), 370.3 (100, MH+). HRMS calcd for


1071, 762, 701. [for 1H and 13C NMR spectra see Appendix C70]. Minor Isomer (378) (31 mg,

27%, greasy solid); 1H NMR (300 MHz, CDCl3) δ 7.43-7.25 (m, 5H),

5.49 (dd, J = 9.0, 6.2 Hz, 1H), 4.93 (br s, 1H), 4.74 (app. t, Japp = 9.0

Hz, 1H), 4.25 (dd, J = 8.9, 6.2 Hz, 1H), 4.15-4.00 (m, 2H), 3.25 (mc,

1H), 2.43 (dt, J = 18.6, 6.6 Hz, 1H), 2.24 (dt, J = 18.9, 5.6 Hz, 1H),

1.94 (app. quin, Japp = 6.0 Hz, 2H), 1.73 (mc, 1H), 1.42-1.27 (m, 3H),

0.95 (t, J = 7.1 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 191.8 (C), 168.1 (C), 153.8 (C),

148.3 (C), 148.2 (C), 137.9 (C), 129.2 (CH), 128.6 (CH), 126.0 (CH), 69.8 (CH2), 66.8 (CH2), 58.7

(CH), 55.4 (CH), 40.1 (CH), 34.5 (CH2), 22.3 (CH2), 21.4 (CH2), 20.5 (CH2), 14.1 (CH3). LRMS

m/z (%): 756.3 (15, 2×M+NH4+), 387.2 (35, M+NH4

+), 370.1 (100, MH+). HRMS calcd for



(S)-3-[(1S,2S)-5-Methoxy-3-oxo-1-propyl-2,3-dihydro-1H-indene-2-carbonyl]-4-


Methanesulfonic acid (360 µL, 5.4 mmol) was added


dichloromethane (2 mL) at -78ºC. This solution was allowed to

warm to room temperature over a period of 2 hours, and then

allowed to stir for a further 18 hours. After this time the acid was quenched by gradual addition of

sodium bicarbonate solution (5% w/v, 10 mL). After stirring for 1 hour the mixture was taken up

in extra dichloromethane (20 mL) and water (20 mL) and the organic phase was separated, the

aqueous phase was re-extracted with dichloromethane (2 × 10 mL). The combined organic extracts


The solid residue was subjected to flash chromatography (silica gel, sequential elution 20:20:1 /

10:10:1 hexane / dichloromethane / diethyl ether) giving the title compound as a white solid (87

O

O

N

OO

O

O

O

N

OO

MeO


- 137 -

mg, 43%, mp = 166-168ºC. 1H NMR (300 MHz, CDCl3) δ 7.41-7.30 (m, 6H), 7.20 (dd, J = 8.4,

2.6 Hz, 1H), 7.13 (d, J = 2.6 Hz, 1H), 5.49 (dd, J = 8.4, 2.8 Hz, 1H), 5.14 (d, J = 4.2 Hz, 1H), 4.81

(app. t, Japp = 8.7 Hz, 1H), 4.35 (dd, J = 8.9, 2.8 Hz, 1H), 3.83 (s, 3H), 3.74 (mc, 1H), 1.93 (mc,

1H), 1.57 (mc, 1H), 1.37-1.18 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 198.7 (C), 168.3 (C), 159.7 (C), 153.8 (C), 150.2 (C), 139.1 (C), 135.9 (C), 129.1 (CH),

128.6 (CH), 125.8 (CH), 125.7 (CH), 124.4 (CH), 105.3 (CH), 69.9 (CH2), 59.6 (CH), 58.1 (CH),

55.5 (CH3), 41.5 (CH), 36.6 (CH2), 20.7 (CH2), 13.8 (CH3). LRMS m/z (%): 411.5 (10, M+NH4+),

394.5 (100, MH+). HRMS calcd for C23H24NO5+: 394.1654. Found: 394.1665. IR (cm-1): 2923,

1778, 1712, 1685, 1490, 1344, 1229, 1201, 759. [for 1H and 13C NMR spectra see Appendix C72].

Minor Isomer (380) (52 mg, 26%, thick oil); 1H NMR (300 MHz, CDCl3) δ 7.47-7.28 (m, 6H),

7.20 (dd, J = 8.4, 2.7 Hz, 1H), 7.11 (d, J = 2.7 Hz, 1H), 5.52

(dd, J = 9.0, 5.7 Hz, 1H), 5.18 (br s, 1H), 4.77 (app. t, Japp = 9.0

Hz, 1H), 4.29 (dd, J = 9.0, 5.7 Hz, 1H), 3.85 (mc, 1H), 3.81 (s,

3H), 1.96 (mc, 1H), 1.58 (mc, 1H), 1.44-1.31 (m, 2H), 0.96 (t, J

= 7.4 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 197.6 (C),

168.0 (C), 159.6 (C), 153.7 (C), 149.9 (C), 138.1 (C), 135.8 (C), 129.0 (CH), 128.5 (CH), 125.9

(CH), 125.8 (CH), 124.4 (CH), 105.3 (CH), 69.8 (CH2), 60.1 (br s, CH), 58.4 (CH), 55.5 (CH3),

40.5 (CH), 36.8 (CH2), 20.8 (CH2), 14.0 (CH3). LRMS m/z (%): 804.2 (25, 2×M+NH4+), 411.3

(40, M+NH4+), 394.5 (100, MH+). HRMS calcd for C23H24NO5

+: 394.1654. Found: 394.1641. IR


see Appendix C73].

(S)-3-[(1R,5S)-3,4-Dimethyl-2-oxo-5-phenylcyclopent-3-enecarbonyl]-4-phenyloxazolidin-2-

one (106)

Cupric triflate (75.0 mg, 0.207 mmol) was added to a stirred

solution of 105 (73.9 mg, 0.197 mmol) in dichloromethane (2 mL) at -

78ºC. The reaction was stirred for 1 hour at this temperature before being

allowed to warm to room temperature where it was stirred for 18 hours.

After this time the acid was quenched by addition of sodium bicarbonate solution (5% w/v, 10

mL). After stirring for 1 hour the mixture was taken up in extra dichloromethane (20 mL) and

water (20 mL) and the organic phase was separated, the aqueous phase was re-extracted with



O

O

N

O

O

O

O

N

OO

MeO


- 138 -


compound as a white solid (47.7 mg, 65%, mp = 158-159ºC). 1H NMR (300 MHz, CDCl3) δ 7.48-

7.22 (m, 8H), 7.14 (d, J = 6.3 Hz, 2H), 5.43 (dd, J = 9.0 Hz, 5.7 Hz, 1H), 5.20 (d, J = 2.1 Hz, 1H),

4.66 (app. t, Japp = 9.0 Hz, 1H), 4.41 (d, J = 2.1, 1H), 4.21 (dd, J = 8.7 Hz, 5.7 Hz, 1H), 1.79 (s,

3H), 1.75 (s, 3H). [for 1H NMR spectra see Appendix C74]. Known compound.9 Minor Isomer

(382) (greasy solid); 1H NMR (300 MHz, CDCl3) δ 7.41-7.22 (m, 8H),

7.08 (dd, J = 7.8, 1.5 Hz, 2H), 5.41 (dd, J = 8.4, 2.7 Hz, 1H), 5.18 (d, J =

3.0 Hz, 1H), 4.75 (app. t, Japp = 8.6 Hz, 1H), 4.30 (br s, 1H), 4.27 (dd, J =

8.7, 2.7 Hz, 1H), 1.83 (s, 3H), 1.79 (s, 3H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 200.9 (C), 171.9 (C), 167.9 (C), 153.6 (C), 139.9 (C), 139.1 (C),

134.7 (C), 129.2 (CH), 129.0 (CH), 128.7 (CH), 127.9 (CH), 127.5 (CH), 125.8 (CH), 70.0 (CH2),

59.9 (CH), 58.4 (CH), 52.0 (CH), 15.5 (CH3), 8.5 (CH3). LRMS m/z (%): 768.5 (20, 2M+NH4+),

393.4 (10, M+NH4+), 376.3 (100, MH+). HRMS calcd for C23H21NNaO4

+: 398.1368. Found:



(S)-3-[(1R,5S)-3,4-Dimethyl-2-oxo-5-phenylcyclopent-3-enecarbonyl]-4-isopropyloxazolidin-

2-one (385)

Cupric triflate (109 mg, 0.30 mmol) was added to a stirred solution

of 360 (100 mg, 0.293 mmol) in dichloromethane (2 mL) at -78ºC. The

reaction was stirred for 1 hour at this temperature before being allowed to

warm to room temperature where it was stirred for 18 hours. After this time

the acid was quenched by addition of sodium bicarbonate solution (5% w/v, 15 mL). After stirring

for 1 hour the mixture was taken up in extra dichloromethane (15 mL) and water (20 mL) and the

organic phase was separated, the aqueous phase was re-extracted with dichloromethane (10 mL).

The combined organic extracts were dried over magnesium sulphate and concentrated onto silica


gel, 50:50:4 hexane / dichloromethane / diethyl ether) giving the title compound as a thick oil (50

mg, 50%). 1H NMR (300 MHz, CDCl3) δ 7.37-7.25 (m, 3H), 7.16 (d, J = 7.5 Hz, 2H), 5.23 (d, J =

3.3 Hz, 1H), 4.51-4.42 (m, 2H), 4.27-4.19 (m, 2H), 2.35 (sept.d, J = 6.9, 3.8 Hz, 1H), 1.85 (s, 3H),

1.79 (s, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 200.7 (C), 171.0 (C), 168.4 (C), 153.7 (C), 140.2 (C), 134.6 (C), 129.1 (CH), 128.0

(CH), 127.5 (CH), 63.1 (CH2), 60.3 (CH), 58.7 (CH), 51.7 (CH), 28.3 (CH), 17.9 (CH3), 15.4

O

O

N

OO

O

O

N

O

O


- 139 -

(CH3), 14.5 (CH3), 8.6 (CH3). LRMS m/z (%): 700.4 (15, 2×M+NH4+), 359.4 (10, M+NH4

+), 342.2



Minor Isomer (388) (thick oil); 1H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 3H), 7.15 (d, J = 7.5

Hz, 2H), 5.16 (d, J = 3.3 Hz, 1H), 4.44 (br s, 1H), 4.39-4.15 (m, 3H), 2.32

(mc, 1H), 1.86 (s, 3H), 1.78 (s, 3H), 0.92 (d, J = 6.9 Hz, 3H), 0.85 (d, J =

6.9 Hz, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 201.0 (C), 171.7 (C),

168.2 (C), 154.2 (C), 140.1 (C), 134.6 (C), 129.1 (CH), 127.9 (CH), 127.6

(CH), 63.8 (CH2), 59.9 (CH), 59.8 (CH), 52.0 (CH), 29.3 (CH), 18.1 (CH3),

15.5 (CH3), 15.2 (CH3), 8.5 (CH3). LRMS m/z (%): 700.3 (20, 2×M+NH4+), 359.3 (15, M+NH4

+),

342.2 (100, MH+). HRMS calcd for C20H23NNaO4+: 364.1525. Found: 364.1520. IR (cm-1): 2964,


(S)-3-[(5S,6R)-7-Oxo-5-phenyl-2,3,4,5,6,7-hexahydrocyclopenta[b]pyran-6-carbonyl]-4-


Cupric triflate (100 mg, 0.277 mmol) was added to a stirred

solution of 358 (102 mg, 0.252 mmol) in dichloromethane (2 mL) at -

78ºC. The reaction was stirred for 1 hour at this temperature before

being allowed to warm to room temperature where it was stirred for

24 hours. After this time the acid was quenched by addition of sodium bicarbonate solution (5%

w/v, 10 mL). After stirring for 1 hour the mixture was taken up in extra dichloromethane (20 mL)

and water (20 mL) and the organic phase was separated, the aqueous phase was re-extracted with



flash chromatography (silica gel, sequential elution 50:50:7 / 50:50:12 hexane / dichloromethane /

diethyl ether) giving the title compound as a white solid (48 mg, 48%, mp = 102-104ºC). 1H NMR

(300 MHz, CDCl3) δ 7.44-7.26 (m, 8H), 7.18 (d. J = 7.8 Hz, 2H), 5.43 (dd, J = 8.9, 6.2 Hz, 1H),

5.16 (s, 1H), 4.66 (app. t, Japp = 9.0 Hz, 1H), 4.43 (s, 1H), 4.21 (dd, J = 8.9, 6.2 Hz, 1H), 4.15-4.05

(m, 2H), 2.13-2.05 (m, 2H), 1.93-1.84 (m, 2H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 191.6 (C),

167.1 (C), 153.4 (C), 148.8 (C), 146.9 (C), 139.7 (C), 138.1 (C), 129.2 (CH), 129.1 (CH), 128.6

(CH), 127.7 (CH), 127.6 (CH), 126.0 (CH), 69.8 (CH2), 67.1 (CH2), 58.9 (CH), 58.5 (CH), 45.7

(CH), 22.2 (CH2), 21.3 (CH2). LRMS m/z (%): 421.3 (30, M+NH4+), 404.4 (100, MH+). HRMS


O

O

N

OO

O

O

O

N

OO


- 140 -

1333, 1201, 1109, 1055, 702. [for 1H and 13C NMR spectra see Appendix C78]. Minor Isomer

(393) (white solid, mp = 68-70ºC); 1H NMR (300 MHz, CDCl3)

δ 7.41-7.22 (m, 8H), 7.10 (dd, J = 7.8, 1.5 Hz, 2H), 5.42 (dd, J = 8.4,

2.8 Hz, 1H), 5.13 (d, J = 2.7 Hz, 1H), 4.74 (app. t, Japp = 8.6 Hz, 1H),

4.26 (dd, J = 8.7, 2.8 Hz, 1H), 4.24 (d, J = 2.7 Hz, 1H), 4.17-4.09 (m,

2H), 2.16-2.07 (m, 2H), 1.98-1.86 (m, 2H). 13C NMR (JMOD, 75

MHz, CDCl3) δ 192.8 (C), 167.7 (C), 153.5 (C), 149.2 (C), 147.5 (C), 139.5 (C), 139.0 (C), 129.2

(CH), 129.1 (CH), 128.7 (CH), 127.7 (CH), 127.6 (CH), 125.8 (CH), 70.0 (CH2), 67.1 (CH2), 58.3

(CH), 58.0 (CH), 47.0 (CH), 22.3 (CH2), 21.3 (CH2). LRMS m/z (%): 421.5 (40, M+NH4+), 404.4



(S)-3-[(1S,2R)-5-Methoxy-3-oxo-1-phenyl-2,3-dihydro-1H-indene-2-carbonyl]-4-


Methanesulfonic acid (90 µL, 1.32 mmol) was added


dichloromethane (2 mL) at -78ºC. This solution was allowed to

warm to room temperature over a period of 2 hours, and then

allowed to stir for a further 18 hours. After this time the acid was quenched by gradual addition of

sodium bicarbonate solution (5% w/v, 10 mL). After stirring for 1 hour the mixture was taken up

in extra dichloromethane (15 mL) and water (20 mL) and the organic phase was separated, the

aqueous phase was re-extracted with dichloromethane (2 × 10 mL). The combined organic extracts


The solid residue was subjected to flash chromatography (silica gel, 50:50:6 hexane /

dichloromethane / diethyl ether) giving the title compound as a white solid (77 mg, 68%, mp = 80-

82ºC). 1H NMR (300 MHz, CDCl3) δ 7.50-7.05 (m, 13H), 5.48 (dd, J = 9.2, 5.6 Hz, 1H), 5.48 (br

s, 1), 5.07 (d, J = 5.7 Hz, 1H), 4.70 (app. t, Japp = 9.0 Hz, 1H), 4.27 (dd, J = 8.9, 5.6 Hz, 1H), 3.84

(s, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 196.9 (C), 166.9 (C), 159.9 (C), 153.5 (C), 148.6

(C), 141.5 (C), 138.3 (C), 135.7 (C), 129.1 (CH), 128.9 (CH), 128.5 (CH), 128.1 (CH), 127.4

(CH), 127.1 (CH), 125.9 (CH), 124.7 (CH), 105.1 (CH), 69.8 (CH2), 64.0 (CH), 58.3 (CH), 55.6

(CH3), 46.0 (CH). LRMS m/z (%): 872.4 (25, 2×M+NH4+), 445.3 (40, M+NH4

+), 428.3 (100,

MH+). HRMS calcd for C26H21NNaO5+: 450.1317. Found: 450.1314. IR (cm-1): 2923, 1778, 1718,

1692, 1489, 1333, 1279, 1023, 699. [for 1H and 13C NMR spectra see Appendix C80]. Minor

O

O

N

OO

O

O

O

N

OO

MeO


- 141 -

Isomer (397) (thick oil); 1H NMR (300 MHz, CDCl3) δ 7.40-7.08 (m, 13H), 5.50 (dd, J = 8.4, 2.9

Hz, 1H), 5.46 (d, J = 5.0 Hz, 1H), 4.97 (d, J = 5.0 Hz, 1H), 4.79

(app. t, Japp = 8.7 Hz, 1H), 4.29 (dd, J = 8.9, 2.9 Hz, 1H), 3.86

(s, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 198.1 (C), 167.6

(C), 160.1 (C), 153.7 (C), 149.0 (C), 141.4 (C), 138.9 (C), 136.0

(C), 129.2 (CH), 129.0 (CH), 128.7 (CH), 128.0 (CH), 127.5

(CH), 127.4 (CH), 125.8 (CH), 124.9 (CH), 105.3 (CH), 70.1 (CH2), 63.4 (CH), 58.3 (CH), 55.7

(CH3), 47.2 (CH). LRMS m/z (%): 450.1 (20, M+Na+), 428.3 (100, MH+), 265.2 (40). HRMS



N,N-Dimethyl-3-(3,4,5-trimethoxyphenyl)propiolamide (410)


dropwise to a stirred solution of dibromostyrene 408 (1.60 g, 4.55 mmol) in

tetrahydrofuran (13 mL) at -78ºC. After addition was complete the resultant

solution was allowed to warm to room temperature before being cooled again

to -78ºC. Dimethylcarbamyl chloride (426 µL, 4.55 mmol) was added and the

reaction mixture was allowed to warm to room temperature. The reaction

mixture was partitioned between ethyl acetate (30 mL) and brine (30 mL), the organic phase was

washed with distilled water (20 mL), dried over magnesium sulphate and concentrated under

reduced pressure to give the title compound as a discoloured solid (953 mg, 79%, mp = 81-83ºC).

1H NMR (300 MHz, CDCl3) δ 6.79 (s, 2H), 3.88 (s, 3H), 3.86 (s, 6H), 3.30 (s, 3H), 3.04 (s, 3H).

13C NMR (JMOD, 75 MHz, CDCl3) δ 154.7 (C), 153.2 (C), 140.4 (C), 115.4 (C), 109.8 (CH), 90.5

(C), 80.8 (C), 61.0 (CH3), 56.3 (CH3), 38.4 (CH3), 34.2 (CH3). LRMS m/z (%): 527.5 (10,

2×M+H+), 286.2 (10, M+Na+), 264.2 (100, MH+). HRMS calcd for C14H17NNaO4+: 286.1055.



(Z)-2-(3-Methoxybenzoyl)-N,N-dimethyl-3-(3,4,5-trimethoxyphenyl)acrylamide (411)




30 minutes at room temperature. Alkyne 410 (527 mg, 2.00

NMe2O

OMe

MeO OMe

O

MeONMe2

O

OMe

OMe

OMe

O

O

N

OO

MeO


- 142 -

mmol) was added, followed by dropwise addition of tributyltin hydride (560 µL, 2.0 mmol), the

mixture was then stirred for 30 minutes. 3-Anisoyl chloride 356 (300 µL, 2.1 mmol) and cuprous




(40 mL) were added, after separation the aqueous phase was re-extracted with ether (30 mL) and



gel, 4:6 hexane / ethyl acetate) giving the title compound as a yellow resin (774 mg, 97%). 1H

NMR (300 MHz, CDCl3) δ 7.44-7.34 (m, 3H), 7.17 (s, 1H), 7.13 (dt, J = 7.4, 2.3 Hz, 1H), 6.78 (s,

2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.84 (s, 6H), 3.10 (s, 3H), 2.89 (s, 3H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 193.2 (C), 167.7 (C), 159.2 (C), 152.9 (C), 141.5 (CH), 139.9 (C), 138.5 (C), 134.5 (C),

129.1 (CH), 128.3 (C), 121.3 (CH), 117.9 (CH), 113.7 (CH), 106.6 (CH), 60.2 (CH3), 55.6 (CH),

54.9 (CH), 37.0 (CH), 33.9 (CH). LRMS m/z (%): 816.6 (10, 2×M+NH4+), 799.4 (10, 2×M+H+),

400.3 (100, MH+). HRMS calcd for C22H25NNaO6+: 422.1580. Found: 422.1579. IR (cm-1): 2937,

2838, 1628, 1577, 1504, 1332, 1266, 1123, 1001. [for 1H and 13C NMR spectra see Appendix

C83].

1-Chloro-4,5,6-trimethoxy-3-(3-methoxyphenyl)-N,N-dimethyl-1H-indene-2-carboxamide

(413)


stirred solution of acrylamide 411 (99.3 mg, 0.249 mmol) and ferric

chloride (45.0 mg, 0.275 mmol) in dichloromethane (2.5 mL) at room

temperature and the mixture was stirred for 18 hours. After this time

the acid was quenched by gradual addition of sodium bicarbonate solution (5% w/v, 15 mL). After

stirring for 1 hour the mixture was taken up in extra dichloromethane (10 mL) and the organic

phase was separated, the aqueous phase was then re-extracted with dichloromethane (10 mL). The

combined organic extracts were dried over magnesium sulphate, concentrated under reduced

pressure and crystallised from dichloromethane / pentane to give the title compound (57.0 mg,

55%, mp = 109-110ºC). 1H NMR (300 MHz, CDCl3) δ 7.29 (t, J = 8.1 Hz, 1H), 7.08 (d, J = 8.1

Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 7.02 (s, 1H), 6.94 (dd, J = 8.1, 2.5 Hz, 1H), 5.73 (s, 1H), 3.94 (s,

3H), 3.87 (s, 3H), 3.82 (s, 3H), 3.37 (s, 3H), 2.89 (s, 3H), 2.58 (s, 3H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 166.3 (C), 158.9 (C), 153.9 (C), 149.4 (C), 143.5 (C), 142.0 (C), 139.8 (C), 136.5 (C),

OMe

MeO

MeOCl

O

NMe2

OMe


- 143 -

134.9 (C), 128.6 (CH), 126.0 (C), 121.0 (CH), 114.7 (CH), 113.5 (CH), 105.1 (CH), 61.4 (CH3),


MH+, Cl37), 418.2 (15, MH+, Cl35), 382.2 (100, M-Cl-). HRMS calcd for C22H25ClNO5+: 418.1421.

Found: 418.1415. IR (cm-1): 3014, 2933, 1624, 1593, 1468, 1349, 1118, 1042. [for 1H and 13C


3-Chloro-5,6,7-trimethoxy-1-(3-methoxyphenyl)-N,N-dimethyl-1H-indene-2-carboxamide

(419)


stirred solution of acrylamide 411 (66.0 mg, 0.165 mmol) and

tetrabutylammonium chloride (57.0 mg, 0.198 mmol) in

dichloromethane (2.5 mL) at room temperature and the mixture was

stirred for 18 hours. After this time the acid was quenched by gradual addition of sodium

bicarbonate solution (5% w/v, 10 mL). After stirring for 1 hour the mixture was taken up in extra

dichloromethane (10 mL) and the organic phase was separated, the aqueous phase was then re-

extracted with dichloromethane (10 mL). The combined organic extracts were dried over

magnesium sulphate, concentrated under reduced pressure and flash chromatographed (silica gel,

3:2 hexane / ethyl acetate) to give a mixture of the title compound and the kinetic regioisomer 413

(42.6 mg, 62%). This material was dissolved in dichloromethane (10 mL) and silica gel (2g) was

added, the biphasic mixture was then stirred under nitrogen for 1 week before being evaporated

and re-chromatographed to give the title compound as a discoloured resin. 1H NMR (300 MHz,

CDCl3) δ 7.14 (t, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.76 (d, J = 8.1, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.66

(s, 1H), 5.11 (s, 1H), 3.96 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H), 3.51 (s, 3H), 2.93 (s, 3H), 2.74 (s,


140.0 (C), 138.2 (C), 136.5 (C), 129.5 (CH), 129.0 (C), 128.4 (C), 119.9 (CH), 113.2 (CH), 112.9

(CH), 99.5 (CH), 61.1 (CH3), 60.0 (CH3), 56.4 (CH3), 55.3 (CH), 54.8 (CH3), 37.4 (CH3), 34.6

(CH3). LRMS m/z (%): 420.4 (35, MH+, Cl37), 418.4 (100, MH+, Cl35), 382.4 (5, M-Cl-). HRMS

calcd for C22H24ClNNaO5+: 440.1241. Found: 440.1233. IR (cm-1): 2935, 1629, 1598, 1467, 1347,


OMe

MeO

MeOCl

O

NMe2

OMe


- 144 -

1-Butoxy-4,5,6-trimethoxy-3-(3-methoxyphenyl)-N,N-dimethyl-1H-indene-2-carboxamide

(420)


stirred solution of acrylamide 411 (54.8 mg, 0.137 mmol) and n-

butanol (65 µL, 0.70 mmol) in dichloromethane (2 mL) at room

temperature and the mixture was stirred for 18 hours. After this time

the acid was quenched by gradual addition of sodium bicarbonate solution (5% w/v, 10 mL). After

stirring for 1 hour the mixture was taken up in extra dichloromethane (10 mL) and the organic

phase was separated, the aqueous phase was then re-extracted with dichloromethane (10 mL). The

combined organic extracts were dried over magnesium sulphate, concentrated under reduced

pressure and flash chromatographed (silica gel, 1:1 hexane / ethyl acetate) to give the title

compound as a discoloured resin (32.9 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 7.26 (t, J = 8.0

Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 2.6 Hz, 1H), 6.93 (s, 1H), 6.89 (dd, J = 8.4, 2.6 Hz,

1H), 5.39 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.78-3.54 (m, 2H), 3.32 (s, 3H), 2.85 (s,

3H), 2.59 (s, 3H), 1.65-1.52 (m, 2H), 1.46-1.32 (m, 2H), 0.91 (s, 3H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 167.9 (C), 159.0 (C), 153.6 (C), 149.3 (C), 143.2 (C), 141.9 (C), 139.8 (C), 138.2 (C),

135.8 (C), 128.6 (CH), 126.1 (C), 121.1 (CH), 114.4 (CH), 113.5 (CH), 104.8 (CH), 84.0 (CH),

69.3 (CH2), 61.5 (CH3), 61.1 (CH3), 56.4 (CH3), 55.4 (CH3), 37.6 (CH3), 34.5 (CH3), 32.4 (CH2),

19.3 (CH2), 13.9 (CH3). LRMS m/z (%): 478.4 (10, M+Na+), 456.5 (100, MH+), 382.4 (80, M-

BuO-). HRMS calcd for C26H33NNaO6+: 478.2206. Found: 478.2198. IR (cm-1): 2933, 1626, 1602,

1465, 1352, 1121, 1039, 731. [for 1H and 13C NMR spectra see Appendix C86].

5,6,7-Trimethoxy-1-(3-methoxyphenyl)-3-(4-methoxyphenylthio)-N,N-dimethyl-1H-indene-2-

carboxamide (423)


stirred solution of acrylamide 411 (162 mg, 0.404 mmol) and 4-

methoxybenzenethiol 421 (60 µL, 0.49 mmol) in dichloromethane (3

mL) at room temperature and the mixture was stirred for 4 hours.

After this time the acid was quenched by gradual addition of sodium

bicarbonate solution (5% w/v, 20 mL). After stirring for 1 hour the

mixture was taken up in extra dichloromethane (10 mL) and the organic phase was separated, the

aqueous phase was then re-extracted with dichloromethane (10 mL). The combined organic

extracts were dried over magnesium sulphate, concentrated under reduced pressure and flash

OMe

MeO

MeOS

O

NMe2

OMe

MeO

OMe

MeO

MeOOBu

O

NMe2

OMe


- 145 -

chromatographed (silica gel, 3:2 hexane / ethyl acetate) to give a mixture of the title compound and

the kinetic regioisomer 422 (186 mg, 88%). This material was dissolved in dichloromethane (10

mL) and silica gel (2g) was added, the biphasic mixture was then stirred under nitrogen for 1 week

before being evaporated and re-chromatographed to give the title compound as a discoloured resin.

1H NMR (300 MHz, CDCl3) δ 7.37 (d, J = 8.7 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 8.7

Hz, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.56 (s, 1H), 5.13 (s, 1H), 3.82 (s, 3H),

3.78 (s, 3H), 3.73 (s, 6H), 3.52 (s, 3H), 2.72 (s, 3H), 2.59 (s, 3H). 13C NMR (JMOD, 75 MHz,

CDCl3) δ 166.5 (C), 159.7 (C), 159.4 (C), 154.0 (C), 149.6 (C), 145.8 (C), 141.4 (C), 138.9 (C),

138.7 (C), 132.8 (CH), 131.6 (C), 129.8 (C), 129.4 (CH), 122.7 (C), 120.0 (CH), 114.8 (CH),

113.3 (CH), 112.7 (CH), 100.9 (CH), 61.0 (CH3), 59.9 (CH3), 56.2 (CH3), 56.1 (CH3), 55.4 (CH3),

55.2 (CH), 37.5 (CH3), 34.3 (CH3). LRMS m/z (%): 1043.5 (10, 2×M+H+), 544.3 (10, M+Na+),

522.3 (100, MH+). HRMS calcd for C29H31NNaO6S+: 544.1770. Found: 544.1760. IR (cm-1): 2936,

1623, 1596, 1492, 1464, 1339, 1245, 1107, 1035, 729. [for 1H and 13C NMR spectra see Appendix

C87].

3-(Furan-2-yl)-5,6,7-trimethoxy-1-(3-methoxyphenyl)-N,N-dimethyl-1H-indene-2-

carboxamide (426)


stirred solution of acrylamide 411 (61.5 mg, 0.154 mmol) and furan

(112 µL, 1.54 mmol) in dichloromethane (2 mL) at room temperature

and the mixture was stirred for 18 hours. After this time the acid was

quenched by gradual addition of saturated sodium bicarbonate solution

(10 mL). After stirring for 1 hour the mixture was taken up in extra dichloromethane (10 mL) and

the organic phase was separated, the aqueous phase was then re-extracted with dichloromethane

(10 mL). The combined organic extracts were dried over magnesium sulphate, concentrated under

reduced pressure and flash chromatographed (silica gel, 1:1 hexane / ethyl acetate) to give a

mixture of the title compound and the kinetic regioisomer 425 (37.7 mg, 55%). This material was

dissolved in dichloromethane (10 mL) and silica gel (2g) was added, the biphasic mixture was then

stirred under nitrogen for 1 week before being evaporated and re-chromatographed to give the title

compound as a discoloured resin. 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 1.7 Hz, 1H), 7.27 (s,

1H), 7.13 (t, J = 8.1 Hz, 1H), 6.75 (ddd, J = 8.3, 2.1, 1.4 Hz, 1H), 6.73-6.67 (m, 2H), 6.64 (d, J =

3.3 Hz, 1H), 6.51 (dd, J = 3.3, 1.7 Hz, 1H), 5.14 (s, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 3.74 (s, 3H),

3.55 (s, 3H), 2.90 (s, 3H), 2.38 (s, 3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 167.9 (C), 159.7 (C),

OMe

MeO

MeO

O

NMe2

OMe

O


- 146 -

154.1 (C), 149.8 (C), 148.7 (C), 142.8 (CH), 141.5 (C), 140.1 (C), 139.0 (C), 137.1 (C), 130.8 (C),

129.3 (CH), 128.2 (C), 120.2 (CH), 113.3 (CH), 112.8 (CH), 111.6 (CH), 109.7 (CH), 102.1 (CH),

61.1 (CH3), 60.0 (CH3), 56.5 (CH3), 56.1 (CH3), 55.3 (CH), 37.2 (CH3), 34.4 (CH3). LRMS m/z

(%): 899.5 (10, 2×M+H+), 472.4 (10, M+Na+), 420.2 (100, MH+). HRMS calcd for

C26H27NNaO6+: 472.1736. Found: 472.1730. IR (cm-1): 2936, 1602, 1465, 1347, 1119, 1040, 729.

[for 1H and 13C NMR spectra see Appendix C88].

trans-N,N-Dimethyl-7-oxo-5-phenyl-2,3,4,5,6,7-hexahydrocyclopenta[b]pyran-6-carboxamide

(434)

Tributyltin hydride (280 µL, 1.0 mmol) was added dropwise to a

stirred solution of alkyne 432 (173 mg, 1.00 mmol) and


dichloromethane (7 mL), this solution was then stirred for 30 minutes. After

this time acid chloride 354 (161 mg, 1.10 mmol) and copper(I) thiophenecarboxylate (19 mg, 0.10

mmol) were added and the reaction was stirred for 4 hours. After this time methanesulfonic acid

(133 µL, 2.0 mmol) was added and the reaction stirred for a further 1 hour. The solvent was then

removed under reduced pressure and the residue was dissolved in ethyl acetate (20 mL), saturated

sodium bicarbonate (20 mL) was added and the resultant mixture was stirred for 1 hour. The liquid

phases were separated and the organic phase was washed with aqueous potassium fluoride (20%,

20 mL), the combined aqueous phases were re-extracted with ethyl acetate (20 mL) which was

then washed with further potassium fluoride solution (10 mL). The combined organic extracts

were dried over magnesium sulphate, concentrated and flash chromatographed (silica gel, 3:7

hexanes / ethyl acetate) giving the title compound as a crystalline solid (209 mg, 73%, mp = 157-

160ºC). 1H NMR (300 MHz, CDC3) δ 7.38-7.24 (m, 3H), 7.17 (dd, J = 8.1, 1.2 Hz, 2H), 4.47 (d, J

= 1.5 Hz, 1H), 4.21-4.08 (m, 2H), 3.63 (d, J = 1.5 Hz, 1H), 3.10 (s, 3H), 2.99 (s, 3H), 2.25 (mc,

1H), 2.09 (mc, 1H), 2.05-1.82 (m, 2H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 195.2 (C), 167.4 (C),

149.7 (C), 148.3 (C), 140.8 (C), 129.1 (CH), 127.6 (CH), 127.5 (CH), 67.0 (CH2), 57.3 (CH), 47.8

(CH), 38.1 (CH3), 36.2 (CH3), 22.3 (CH2), 21.4 (CH2). LRMS m/z (%): 308.3 (10, M+Na+), 286.2


1628, 1492, 1400, 1124, 709. [for 1H and 13C NMR spectra see Appendix C89].

OO

O

NMe2

Rac

Chapter 7: References

- 147 -

CHAPTER 7: REFERENCES 1) Recent Nazarov reaction reviews; a) Tius, M. Eur. J. Org. Chem. 2005, 2193. b) Pellissier, H.

Tetrahedron, 2005, 61, 6479. c) Frontier, A.J.; Collison, C. Tetrahedron, 2005, 61, 7577.

2) For the first of Nazarov's publications in this area, see: Nazarov, I.N.; Zaretskaya, I.I., Izv. Akad.

Nauk. USSR, Ser. Khim. 1941, 211.

3) Woodward, R.B. Chem. Soc. Special Publication No. 21, 1967, 237.

4) Peel, M.R.; Johnson, C.R. Tetrahedron Lett. 1986, 27, 5947.

5) Denmark, S.E.; Jones, T.K. J. Am. Chem. Soc. 1982, 104, 2642.

6) Denmark, S.E.; Klix, R.C. Tetrahedron, 1988, 44, 4043.

7) Marino, J.P.; Linderman, R.J. J. Org. Chem. 1981, 46, 3696.

8) Andrews, J.F.P.; Regan, A.C. Tetrahedron Lett. 1991, 32, 7731.

9) Kerr, D.J.; Metje, C.; Flynn, B.L. Chem. Commun. 2003, 1380.

10) Liang, G.; Gradl, S.N.; Trauner, D. Org. Lett. 2003, 5, 4931.

11) Larini, P.; Guarna, A.; Occhiato, E.G. Org. Lett. 2006, 8, 781.

12) Ichikawa, J. Pure Appl. Chem. 2000, 72, 1685.

13) He, W.; Sun, X.; Frontier, A.J. J. Am. Chem. Soc. 2003, 125, 14278.

14) Tius, M.A. Acc. Chem. Res. 2003, 36, 284.

15) Pridgen, L.N.; Huang, K.; Shilcrat, S.; Tickner-Eldridge, A.; DeBrosse, C.; Haltiwanger, R.C.

Synlett, 1999, 9, 1612.

16) Yin, W.; Ma, Y.; Xu, J.; Zhao, Y. J. Org. Chem. 2006, 71, 4312.

17) Bee, C.; Leclerc, E.; Tius, M.A. Org. Lett. 2003, 5, 4927.

18) Malona, J.A.; Colbourne, J.M.; Frontier, A.J. Org. Lett. 2006, 8, 5661.

19) a) Janka, M.; Frontier, A.J.; Eisenberg, R. J. Am. Chem. Soc. 2004, 126, 6864. b) Janka, M.;

He, W.; Frontier, A.J.; Flaschemreim, C.; Eisenberg, R. Tetrahedron, 2005, 61, 6193.

20) Douelle, F.; Tal, L.; Greaney, F. Chem. Commun. 2005, 660.

21) Giese, S.; West, F.G. Tetrahedron, 2000, 56, 10221.

22) Giese, S.; West, F.G. Tetrahedron Lett. 1998, 39, 8393.

23) Bender, J.A.; Blize, A.E.; Browder, C.C.; Giese S.; West, F.G. J. Org. Chem. 1998, 63, 2430.

24) Browder C.C.; West, F.G. Synlett. 1999, 1363.

25) Browder, C.C.; Marmsater, F.P.; West, F.G.; Org. Lett. 2001, 3, 3033.

26) Bender, J.A.; Arif, A.M.; West, F.G.; J. Am. Chem. Soc. 1999, 121, 7443.

27) Wang, Y.; Arif, A.M.; West, F.G. J. Am. Chem. Soc. 1999, 121, 876.


- 148 -

28) Wang, Y.; Schill, B.D.; Arif, A.M.; West, F.G. Org. Lett. 2003, 5, 2747.

29) Giese, S.; Kastrup, L.; Stiens, D.; West, F.G. Angew. Chem., Int. Ed. Engl. 2000, 39, 1970.

30) a) Jones, T.K.; Denmark, S.E. Helv. Chim. Acta, 1983, 66, 2397. b) Denmark, S.E.; Habermas,

K.L.; Hite, G.A.; Jones, T.K. Tetrahedron, 1986, 42, 2821.

31) Denmark, S.E.; Wallace, M.A.; Walker, C.B. J. Org. Chem. 1990, 55, 5543.

32) Occhiato, E.G.; Prandi, C.; Ferrali, A.; Guarna, A. J. Org. Chem. 2005, 70, 4542.

33) Hu, H.; Smith, D.; Cramer, E.; Tius, M.A. J. Am. Chem. Soc. 1999, 121, 9895.

34) Chaplin, J.H.; Flynn, B.L. Unpublished results.

35) delos Santos, D.B.; Banaag, A.R.; Tius M.A. Org. Lett. 2006, 8, 2579, and references cited

therein.

36) Aggarwal, V.K.; Belfield, A.J. Org. Lett. 2003, 5, 5075.

37) He, W.; Frontier, A.J. Unpublished results (disclosed in Frontier’s Nazarov review, Ref. 1c).

38) Leclerc, E.; Tius, M.A. Unpublished results (disclosed in Frontier’s Nazarov review, Ref. 1c).

39) Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544.

40) Rueping, M.; Ieawsuwan, W.; Antonchick, A.P.; Nachtsheim, B.J. Angew. Chem., Int. Ed.

Engl. 2007, 46, 2097.

41) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata K. Tetrahedron Lett. 1992, 33, 2701.

42) Boger D.L.; Hong, J. J. Am. Chem. Soc. 2001, 123, 8515.

43) Detailed information concerning the cytotoxic properties of roseophilin and the prodigiosins,

assayed in the standard 60-cell line panel are available at the homepage of the National Cancer

Institute (NCI), Bethesda, at http://www.dtp.nci.nih.gov.

44) Fürstner, A. Angew. Chem. Int. Ed. 2003 42, 3582.

45) Fürstner, A.; Reinecke, K.; Prinz, H.; Waldmann, H. ChemBioChem, 2004, 5, 1575.

46) a) Fürstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817. b) Fürstner, A.; Weintritt, H.

J. Am. Chem. Soc. 1997, 119, 2944.

47) Kim, S.H.; Figueroa, I.; Fuchs, P.L. Tetrahedron Lett. 1997, 38, 2601.

48) a) Bamford, S.J.; Luker, T.; Speckamp, W.N.; Hiemstra, H. Org. Lett. 2000, 2, 1157. b)

Bamford, S.J.; Goubitz, K.; van Lingen, H.L.; Luker, T.; Schenk, H.; Hiemstra, H. J. Chem. Soc.

Perkin Trans. 1, 2000, 345.

49) a) Harrington, P.E.; Tius, M.A. J. Am. Chem. Soc. 2001, 123, 8509. b) Harrington, P.E.; Tius,

M.A. Org. Lett. 1999, 1, 649.

50) Boger, D.L.; Hong, J.; J. Am. Chem. Soc. 2001, 123, 8515.


- 149 -

51) Trost, B.M.; Doherty, G.A. J. Am. Chem. Soc. 2000, 122, 3801.

52) Mochizuki, T.; Itoh, E.; Shibata, N.; Nakatani, S.; Katoh, T.; Terashima, S. Tetrahedron Lett.

1998, 39, 6911.

53) a) Robertson, J.; Hatley, R.J.D.; Watkin, D.J. J. Chem. Soc. Perkin Trans. 1, 2000, 3389. b)

Robertson, J.; Hatley, R.J.D. Chem. Commun. 1999, 1455.

54) Song, C.; Knight, D.W.; Whatton, M.A. Org. Lett. 2006, 8, 163.

55) Organ, M.G.; Bratovanov, S. Tetrahedron Lett. 2000, 41, 6945.

56) Parker, R.A.; Ku, G. Eur. Pat. Appl., 1990, 15 pp. CODEN: EPXXDW; English; EP381142.

57) Fürstner, A.; Grabowski, J.; Lehmann, C.W. J. Org. Chem. 1999, 64, 8275.

58) Senici, P.; Leger, I.; Souchet, M.; Nadler, G. Tetrahedron, 1997, 53, 17097.

59) The production of this material was based on the reported synthesis by Senici and co-workers

(Ref 58), they did neglect to mention the use of a solvent in their experimental, we found CCl4 to

be appropriate.

60) Marshall, J.A.; Bourbeau, M.P. Tetrahedron Lett. 2003, 44, 1087.

61) Yamaguchi, M.; Ichiro, H. Tetrahedron Lett. 1983, 24, 391.

62) a) Hoye, T.R.; Humpal, P.E.; Jimenez, J.I.; Mayer, M.J.; Tan, L.; Ye, Z. Tetrahedron Lett.

1994, 35, 7517 (R-enantiomer). b) Herb, C.; Dettner, F.; Maier, M. E. Eur. J. Org. Chem. 2005,

728 (S-enantiomer).

63) a) Minetto, G.; Raveglia, L.F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277. b)

Werner, S.; Iyer, P.S.; Synlett. 2005, 1405.

64) Kosugi, H.; Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J. Org. Chem. 1987, 52, 1078.

65) a) Karplus, M. J. Chem. Phys. 1959, 30, 11. b) Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870.

66) Batsanov, A.S.; Byerley, A.L.J.; Howard, J.A.K.; Steel, P.G. Synlett, 1996, 401.

67) De Martino, G.; Scalzo, M.; Massa, S.; Giuliano, R. Farmaco, Edizione Scientifica, 1973, 28,

976.

68) Hobbs, C.F.; Weingarten, H. J. Org. Chem. 1968, 33, 2385.

69) Fonquerna, S.; Moyano, A.; Pericas, M.A.; Riera, A. Tetrahedron: Asymmetry, 1997, 8, 1685.

- 150 -

APPENDICES

Appendix A; NMR-Based Optimization of Auxiliary-

Mediated Asymmetric Nazarov Reactions

Appendix B; X-Ray Crystal Structure of Asymmetric

Nazarov Product 364

Appendix C; 1H and 13C NMR Spectra of All New

Compounds

Appendix A; NMR-Based Optimization of Auxiliary-Mediated Asymmetric Nazarov Reactions

Appendix A

Appendix A; NMR-Based Optimization of

Auxiliary-Mediated Asymmetric Nazarov

Reactions

Selected Crude Reaction Mixture NMR Spectra of the

Cyclisations of Substrates R-206, S-221, 350 and 105


Appendix A1

N

N

OO

O

O

N

OO

O

O

N

5.2

0(s

,2

H)

6.0

7(d

,1H

)

6.9

3(d

,1

H)

3.5

3(d

d,1H

)

5.4

8(b

rs,

1H

)

5.5

1(d

d,1

H)

4.7

3(t

,1H

)4

.24

(dd,1

H)

N

OO

O

O

N

5.2

2(s

,2H

)

6.1

0(d

,1H

)

6.9

8(d

,1

H)

3.4

2(d

d,1

H)

5.4

7(d

,1H

)

5.4

6(d

d,

1H

)

4.7

5(t

,1

H)

4.2

8(d

d,

1H

)

N

OO

O

O

N

3.5

0(d

d,1

H)

5.2

7(d

,1H

)

5.5

2(d

d,1

H)

4.7

3(t

,1H

)4

.44

(dd,1

H)

0.3

5(d

,3H

)0.8

4(d

,3H

)

AC

ID

R-2

06

207

399

208

N

N

OO

O

O

N

OO

O

O

N

5.2

4(s

,2

H)

5.9

3(s

,1

H)3.5

1(d

d,1

H)

5.4

5(b

rs,

1H

)

5.5

0(d

d,1

H)

4.7

2(t

,1H

)4

.21

(dd,1

H)

N

OO

O

O

N

5.2

6(s

,2H

)

5.9

6(s

,1H

)3.3

9(d

d,1

H)

5.4

3(d

,1H

)

5.4

7(d

d,1

H)

4.7

6(t

,1

H)

4.2

9(d

d,

1H

)

N

OO

O

O

N5.2

7(d

,1H

)

5.5

2(d

d,1

H)

4.7

3(t

,1H

)4

.43

(dd,1

H)

0.4

0(d

,3

H)

0.8

4(d

,3

H)

AC

ID

S-2

21

222

223

224

3.5

0(d

d,1

H)

5.9

1(s

,1

H)

5.3

0(s

,2H

)

Ap

pen

dix

A1

;A

sy

mm

etr

icN

azaro

vR

eacti

on

of

Pyrr

ole

-Base

dS

ub

str

ate

s(C

rud

eN

MR

Sp

ectr

a)

Mod

elS

yst

emR

-206

(1H

-NM

RR

eso

na

nces

)

Syst

em

S-2

21

(1H

-NM

RR

eso

na

nces)

Re

action

Of

S-2

21

With

Fe

Cl 3

Ap

pe

nd

ixA

1.4

Re

actio

nO

fR

-20

6W

ith

MeS

O3H

Ap

pe

nd

ixA

1.1

Re

actio

nO

fR

-20

6W

ithC

u(O

Tf)

2A

pp

en

dix

A1

.2R

eactio

nO

fR

-20

6W

ith

FeC

l 3A

pp

en

dix

A1

.3


Appendix A1.1


Appendix A1.2


Appendix A1.3


Appendix A1.4


Appendix A2

N

OO

O

O

N

OO

O

O

3.1

2(m

c,1H

)4.8

9(d

,1H

)

5.4

3(d

d,

1H

)

4.7

6(t

,1

H)

4.3

1(d

d,

1H

)

AC

ID

35

0

364

0.8

6(t

,3H

)

2.0

0(s

,3H

)

1.6

8(s

,3H

)

N

OO

O

O

3.2

2(b

rs,

1H

)4.9

2(b

rs,1

H)

5.4

6(d

d,1H

)

4.7

1(t

,1

H)

4.2

1(d

d,1H

)

366

0.9

3(t

,3H

)

1.9

7(s

,3H

)

1.6

3(s

,3H

)

N

OO

O

O

2.4

5-2

.15

(m,

2H

)

365

6.0

7(d

,1H

)5

.29

(d,1H

)N

OO

O

O

2.4

5-2

.15

(m,2H

)

367

6.0

4(d

,1

H)

5.2

6(d

,1

H)

Ap

pen

dix

A2;

Asym

metr

icN

azaro

vR

eacti

on

of

Su

bs

trate

sW

ith

Alip

ha

tic

β βββ-G

rou

ps

(Cru

de

NM

RS

pectr

a)

Syst

em

350

(1H

-NM

RR

eso

na

nce

s)

Re

actio

nO

f3

50

With

Cu

(OT

f)2

Ap

pen

dix

A2

.1R

ea

ctio

nO

f3

50

With

Me

SO

3H

(1E

q.)

Ap

pe

nd

ixA

2.2

Re

actio

nO

f3

50

With

Me

SO

3H

(10

Eq.)

Ap

pen

dix

A2

.3


Appendix A2.1


Appendix A2.2


Appendix A2.3


Appendix A3

N

OO

O

O

N

OO

O

O

4.3

0(b

rs,1H

)

5.1

8(d

,1H

)

5.4

1(d

d,

1H

)

4.7

5(t

,1

H)

4.2

7(d

d,

1H

)

AC

ID

10

5

382

1.8

3(s

,3H

)

1.7

9(s

,3H

)

N

OO

O

O

4.4

1(b

rs,1H

)

5.2

0(d

,1H

)

5.4

3(d

d,

1H

)

4.6

6(t

,1

H)

4.2

1(d

d,

1H

)

10

6

1.7

9(s

,3H

)

1.7

5(s

,3H

)

N

OO

O

O

38

4

6.2

0(d

,1H

)5.3

6(d

,1H

)

N

OO

O

O

38

1

6.1

7(d

,1H

)5

.36

(d,

1H

)

N

OO

O

O

4.4

0(d

,1

H)

4.9

6(d

,1H

)

4.3

9(d

d,1

H)

3.9

7(d

d,1

H)

3.7

3(t

,1H

)

38

3

N

OO

O

O

4.5

2(d

,1H

)

4.7

2(d

,1

H)

5.2

2(d

d,1H

)

4.5

7(t

,1

H)

4.1

0(d

d,1H

)

107

1.8

2(s

,3H

)

1.7

8(s

,3H

)

3.2

4(t

,1

H)

1.1

6(d

,3H

)

3.3

2(t

,1

H)

1.1

2(d

,3H

)

~2

.9(m

,1

H)

~2.9

(m,1

H)

6.5

2(d

,2

H)

Ap

pen

dix

A3

;A

sy

mm

etr

icN

aza

rov

Rea

cti

on

of

Su

bs

tra

tes

Wit

hA

rom

ati

cβ βββ-G

rou

ps

(Cru

de

NM

RS

pec

tra

)

Sy

stem

10

5(1

H-N

MR

Reso

na

nce

s)

Re

actio

nO

f1

05

With

Me

SO

3H

(1E

q.)

Ap

pe

nd

ixA

3.1

Re

actio

nO

f1

05

With

Me

SO

3H

(10

Eq

.)A

ppe

nd

ixA

3.2

Re

actio

nO

f1

05

With

Cu

(OT

f)2

App

en

dix

A3

.3


Appendix A3.1


Appendix A3.2


Appendix A3.3

Appendix B; X-Ray Crystal Structure of Asymmetric Nazarov Product 364

Appendix B

Appendix B; X-Ray Crystal Structure of

Asymmetric Nazarov Product 364

Confirming the S-α-trans Configuration as the Major Product

in Cyclisations of Substrates Bearing Aliphatic β-Substituents

Compound 364 was prepared as described in the experimental (Chapter 6). Suitable crystals were

obtained by crystallization of 364 from hot methanol. X-Ray crystallographic analysis was carried

out by Professor Jonathan White at the Bio21 Institute (Melbourne University).

Diffraction data were recorded on an Enraf Nonius CAD4f diffractometer operating in the θ/2θ

scan mode at low temperature. The data were corrected for Lorentz and Polarization effects and for

absorption (SHELX 76).1 Structures were solved by direct methods (SHELXS-86)

2 and were

refined on F2 (SHELXL-97).3

1 SHELX76: Sheldrick, G. M. Program for Crystal Structure Determination, Cambridge, England, 1976. 2 SHELXS-86: Sheldrick, G. M. Crystallographic Computing 3; Sheldrick, G. M. , Kruger, C.; Goddard, R.; Eds;

Oxford University Press, Oxford, England, 1985; pp 175-189. 3 SHELXL-93: Sheldrick, G. M. Program for Crystal Structure Refinement. Univ. of Gottingen, Germany, 1993.


Appendix B

Table 1. Crystal data and structure refinement for jmwbf2 (364)

Identification code jmwbf2

Empirical formula C20 H23 N O4

Formula weight 341.39

Temperature 293(2) K

Wavelength 1.54180 A

Crystal system, space group Orthorhombic, P212121

Unit cell dimensions a = 7.793(2) alpha = 90 deg.

b = 13.870(3) beta = 90 deg.

c = 16.681(5) gamma = 90 deg.

Volume 1803.0(8) 3

Z, Calculated density 4, 1.258 Mg/m^3

Absorption coefficient 0.710 mm-1

F(000) 728

Crystal size 0.4 x 0.3 x 0.2 mm

Theta range for data collection 4.15 to 69.93 deg.

Limiting indices 0<=h<=9, 0<=k<=16, 0<=l<=20

Reflections collected / unique 1971 / 1971 [R(int) = 0.0000]

Completeness to theta = 69.93 99.8 %

Absorption correction None

Refinement method Full-matrix least-squares on F^2

Data / restraints / parameters 1971 / 0 / 230

Goodness-of-fit on F^2 1.072

Final R indices [I>2sigma(I)] R1 = 0.0467, wR2 = 0.1160

R indices (all data) R1 = 0.0548, wR2 = 0.1238

Absolute structure parameter -0.1(4)

Extinction coefficient 0.0194(15)

Largest diff. peak and hole 0.236 and -0.216 e. -3


Appendix B

Table 2. Atomic coordinates ( x 10^4) and equivalent isotropic

displacement parameters (A^2 x 10^3) for jmwbf2 (364).

U(eq) is defined as one third of the trace of the orthogonalized

Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

C(1) -425(3) 6863(2) 869(2) 43(1)

C(2) 686(4) 6851(2) 1516(2) 59(1)

C(3) 1928(5) 6140(3) 1577(2) 73(1)

C(4) 2060(5) 5442(2) 998(3) 74(1)

C(5) 950(5) 5439(2) 361(3) 72(1)

C(6) -288(4) 6155(2) 300(2) 55(1)

C(7) -1839(3) 7612(2) 786(2) 42(1)

C(8) -3542(4) 7281(2) 1142(2) 53(1)

C(9) -2808(4) 8657(3) 1807(2) 65(1)

C(10) -150(3) 9097(2) 1044(2) 44(1)

C(11) 276(3) 9951(2) 1555(2) 48(1)

C(12) -195(4) 10888(2) 1112(2) 55(1)

C(13) 1300(4) 11519(2) 1115(2) 56(1)

C(14) 2634(4) 11059(2) 1435(2) 54(1)

C(15) 2210(3) 10059(2) 1736(2) 51(1)

C(16) 2655(4) 9919(2) 2619(2) 58(1)

C(17) 2397(5) 8909(2) 2936(2) 69(1)

C(18) 3016(6) 8792(3) 3792(2) 89(1)

C(19) 4428(4) 11440(3) 1504(2) 76(1)

C(20) 1254(6) 12519(2) 771(3) 77(1)

N(1) -1528(3) 8493(2) 1246(1) 43(1)

O(1) 677(3) 8888(2) 456(1) 59(1)

O(2) -2931(4) 9309(2) 2265(2) 119(1)

O(3) -3973(3) 7958(2) 1749(1) 82(1)

O(4) -1591(3) 11051(2) 812(2) 83(1)

________________________________________________________________

Table 3. Bond lengths [A] and angles [deg] for jmwbf2 (364).

_____________________________________________________________

C(1)-C(6) 1.370(4)

C(1)-C(2) 1.384(4)

C(1)-C(7) 1.521(3)

C(2)-C(3) 1.386(5)

C(3)-C(4) 1.371(5)

C(4)-C(5) 1.370(5)

C(5)-C(6) 1.388(4)

C(7)-N(1) 1.464(3)

C(7)-C(8) 1.524(4)

C(8)-O(3) 1.422(4)

C(9)-O(2) 1.187(4)

C(9)-O(3) 1.331(4)

C(9)-N(1) 1.387(3)

C(10)-O(1) 1.208(3)

C(10)-N(1) 1.403(3)

C(10)-C(11) 1.497(3)

C(11)-C(12) 1.540(4)

C(11)-C(15) 1.544(4)


Appendix B

C(12)-O(4) 1.219(4)

C(12)-C(13) 1.457(4)

C(13)-C(14) 1.332(4)

C(13)-C(20) 1.501(5)

C(14)-C(19) 1.499(4)

C(14)-C(15) 1.512(4)

C(15)-C(16) 1.526(4)

C(16)-C(17) 1.510(4)

C(17)-C(18) 1.516(5)

C(6)-C(1)-C(2) 118.9(3)

C(6)-C(1)-C(7) 118.9(2)

C(2)-C(1)-C(7) 122.1(2)

C(1)-C(2)-C(3) 120.2(3)

C(4)-C(3)-C(2) 120.2(3)

C(5)-C(4)-C(3) 120.0(3)

C(4)-C(5)-C(6) 119.6(3)

C(1)-C(6)-C(5) 121.1(3)

N(1)-C(7)-C(1) 113.8(2)

N(1)-C(7)-C(8) 101.1(2)

C(1)-C(7)-C(8) 112.9(2)

O(3)-C(8)-C(7) 106.5(2)

O(2)-C(9)-O(3) 123.1(3)

O(2)-C(9)-N(1) 128.1(3)

O(3)-C(9)-N(1) 108.8(2)

O(1)-C(10)-N(1) 117.4(2)

O(1)-C(10)-C(11) 122.3(2)

N(1)-C(10)-C(11) 120.3(2)

C(10)-C(11)-C(12) 110.0(2)

C(10)-C(11)-C(15) 113.8(2)

C(12)-C(11)-C(15) 104.2(2)

O(4)-C(12)-C(13) 127.1(3)

O(4)-C(12)-C(11) 124.6(3)

C(13)-C(12)-C(11) 108.3(2)

C(14)-C(13)-C(12) 109.8(3)

C(14)-C(13)-C(20) 127.9(3)

C(12)-C(13)-C(20) 122.3(3)

C(13)-C(14)-C(19) 126.2(3)

C(13)-C(14)-C(15) 113.7(3)

C(19)-C(14)-C(15) 120.1(3)

C(14)-C(15)-C(16) 112.8(2)

C(14)-C(15)-C(11) 103.7(2)

C(16)-C(15)-C(11) 113.5(2)

C(17)-C(16)-C(15) 115.2(3)

C(16)-C(17)-C(18) 112.7(3)

C(9)-N(1)-C(10) 128.0(2)

C(9)-N(1)-C(7) 111.8(2)

C(10)-N(1)-C(7) 119.97(19)

C(9)-O(3)-C(8) 111.9(2)

_____________________________________________________________

Symmetry transformations used to generate equivalent atoms:


Appendix B

Table 4. Anisotropic displacement parameters (A^2 x 10^3) for

jmwbf2 (364). The anisotropic displacement factor exponent takes the form:

-2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]

_______________________________________________________________________

U11 U22 U33 U23 U13 U12

_______________________________________________________________________

C(1) 39(1) 38(1) 51(1) 4(1) 2(1) -1(1)

C(2) 61(2) 54(2) 61(2) 2(1) -15(2) -1(2)

C(3) 58(2) 67(2) 95(2) 18(2) -21(2) 3(2)

C(4) 51(2) 56(2) 115(3) 12(2) 5(2) 12(2)

C(5) 68(2) 49(2) 100(2) -12(2) 11(2) 9(2)

C(6) 51(2) 49(1) 63(2) -10(1) -3(1) 1(1)

C(7) 38(1) 42(1) 45(1) -1(1) -1(1) 0(1)

C(8) 42(1) 51(1) 65(2) 1(1) 4(1) -6(1)

C(9) 48(2) 82(2) 66(2) -27(2) 18(2) -16(2)

C(10) 38(1) 44(1) 48(1) -4(1) 4(1) -1(1)

C(11) 38(1) 46(1) 59(2) -11(1) 7(1) -4(1)

C(12) 45(2) 48(1) 71(2) -13(1) 4(1) 3(1)

C(13) 55(2) 51(2) 62(2) -11(1) 8(1) -4(1)

C(14) 42(1) 62(2) 56(2) -11(1) 9(1) -12(1)

C(15) 39(1) 55(2) 59(2) -14(1) 3(1) 1(1)

C(16) 46(2) 62(2) 64(2) -10(1) -3(1) 2(1)

C(17) 62(2) 67(2) 78(2) 1(2) 2(2) 2(2)

C(18) 83(3) 98(3) 86(2) 20(2) -11(2) 7(3)

C(19) 50(2) 92(2) 87(2) -1(2) 7(2) -21(2)

C(20) 83(2) 57(2) 92(2) 4(2) 13(2) -4(2)

N(1) 39(1) 43(1) 48(1) -4(1) 9(1) -4(1)

O(1) 57(1) 60(1) 59(1) -14(1) 20(1) -14(1)

O(2) 79(2) 144(3) 132(2) -90(2) 59(2) -49(2)

O(3) 59(1) 104(2) 84(2) -35(1) 30(1) -37(1)

O(4) 53(1) 65(1) 132(2) -1(2) -21(2) 3(1)

_______________________________________________________________________


Appendix B

An

iso

trop

ic d

isp

lace

men

t el

lip

soid

plo

t o

f a

mo

lecu

le o

f 364

der

ived

fro

m a

cry

stal

log

rap

hic

stu

dy

Appendix C; 1H and

13C NMR Spectra of All New Compounds

Appendix C

Appendix C; 1H and

13C NMR Spectra of All

New Compounds

All Compounds at Flash Chromatography or Crude Purity

All spectra were recorded in (D)chloroform (CDCl3) at 30°C on a Bruker Avance WB

spectrometer operating at 300 MHz for proton and 75 MHz for carbon spectroscopy. The

protonicities of the carbon atoms observed in the carbon NMR were determined using J-modulated

spin echo (JMOD) experiments, CH and CH3 are displayed in the positive phase whilst C and CH2

are displayed in the negative phase.

Appendix C; 1H and


Appendix C1

(Z)-Ethyl 2-(1-benzyl-1H-pyrrole-2-carbonyl)-4-methylpent-2-enoate (190)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C2

(4R*,5R*)-Ethyl 1-benzyl-4-isopropyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-5-carboxylate

(191)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C3

1-Benzyl-4-isopropyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one (194)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C4

(4R*,5R*)-5-Allyl-1-benzyl-4-isopropyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one (197)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C5

(4R*,5R*)-1-Benzyl-4-isopropyl-5-(pent-4-enyl)-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one

(199)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C6

(R,Z)-1-(1-Benzyl-1H-pyrrol-2-yl)-2-(2-methylpropylidene)-3-(2-oxo-4-phenyloxazolidin-3-yl)-

propane-1,3-dione (R-206)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C7

(R)-3-[(4S,5S)-1-Benzyl-4-isopropyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-5-carbonyl]-4-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C8

(R)-3-[(4R,5R)-1-Benzyl-4-isopropyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-5-carbonyl]-4-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C9

1-Benzyl-2-(pent-4-enyl)-1H-pyrrole (219)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C10

1-Benzyl-5-(pent-4-enyl)-1H-pyrrole-2-carbonyl chloride (220)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C11

(S)-3-(4-Methylpent-2-ynoyl)-4-phenyloxazolidin-2-one (S-204)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C12

(S,Z)-1-[1-Benzyl-5-(pent-4-enyl)-1H-pyrrol-2-yl]-2-(2-methylpropylidene)-3-(2-oxo-4-phenyloxazolidin-3-

yl)propane-1,3-dione (S-221)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C13

(S)-3-[(4R,5R)-1-Benzyl-4-isopropyl-6-oxo-2-(pent-4-enyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-5-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C14

(S)-3-[(4S,5S)-1-Benzyl-4-isopropyl-6-oxo-2-(pent-4-enyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-5-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C15

(Z)-Ethyl 2-[1-benzyl-5-(pent-4-enyl)-1H-pyrrole-2-carbonyl]-4-methylpent-2-enoate (228)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C16

(4R*,5R*)-Ethyl 1-Benzyl-4-isopropyl-6-oxo-2-(pent-4-enyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-

5-carboxylate (229)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C17

1-Benzyl-4-isopropyl-2-(pent-4-enyl)-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one (230)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C18

(4R*,5R*)-Benzyl-4-isopropyl-2,5-di(pent-4-enyl)-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one (231)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C19

(Z)-Methyl 2-methoxyhepta-2,6-dienoate (Z-261)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C20

(Z)-2-Methoxyhepta-2,6-dienoyl chloride (264)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C21

(2Z,4Z)-4-Methoxy-2-(2-methylpropylidene)-1-[(S)-2-oxo-4-phenyloxazolidin-3-yl]nona-4,8-

diene-1,3-dione (266)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C22

Tridec-1-en-9-yn-7-ol (282)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C23

7-Acetoxy-tridec-1-en-9-yne (283)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C24

Tridec-1-en-9-yn-7-one (287)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C25

(5Z,8E)-8-Butylidene-6-methoxyhexadeca-1,5,15-triene-7,10-dione (291)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C26

(4R*,5R*)-5-(But-3-enyl)-2-hydroxy-3-(2-oxo-oct-7-enyl)-4-propylcyclopent-2-enone (294)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C27

2-Methyldodec-11-en-3-yn-6-ol (280)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C28

2-Methyldodec-11-en-3-yn-6-one (286)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C29

(5Z,8E)-6-Methoxy-8-(2-methylpropylidene)hexadeca-1,5,15-triene-7,10-dione (297)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C30

(9E,11E)-9,11-Bis(2-methylpropylidene)nonadeca-1,18-diene-7,10,13-trione (298)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C31

(4R*,5R*)-5-(But-3-enyl)-2-hydroxy-3-(2-oxooct-7-enyl)-4-isopropylcyclopent-2-enone (300)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C32

(4S*,5S*)-2-Methoxy-3-(but-3-enyl)-5-(2-oxooct-7-enyl)-4-isopropylcyclopent-2-enone (301)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C33

(1S*,15S*)-15-Isopropyl-13-methoxybicyclo[10.2.1]pentadeca-8,12-diene-3,14-dione (304)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C34

(1S*,15S*)-15-Isopropyl-13-methoxybicyclo[10.2.1]pentadeca-8,12-diene-3,14-dione (304) 1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C35

(1S*,15S*)-15-Isopropyl-13-methoxybicyclo[10.2.1]pentadeca-8,12-diene-3,14-dione (304)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C36

(1S*,15S*)-15-Isopropyl-13-methoxybicyclo[10.2.1]pentadec-12-ene-3,14-dione (303)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C37

(4R*,5R*)-2-Acetoxy-5-(but-3-enyl)-3-(2-oxooct-7-enyl)-4-isopropylcyclopent-2-enone (305)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C38

High Rf Diacetate of 300

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C39

Low Rf Diacetate of 300

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C40

(1R*,15R*)-15-Isopropyl-10,14-dioxobicyclo[10.2.1]pentadeca-4,12-dien-13-yl acetate (306)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C41

(1R*,15R*)-15-Isopropyl-10,14-dioxobicyclo[10.2.1]pentadec-12-en-13-yl acetate (307)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C42

(4R*,5R*)-4,5-Dihydro-4-(1-methylethyl)-2,5-octanocyclopenta[b]pyrrol-6(1H)-one (167)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C43

(1R*,15R*)-14-Hydroxy-15-isopropylbicyclo[10.2.1]pentadeca-1(14),8-diene-3,13-dione (308)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C44

(1R*,15R*)-14-Hydroxy-15-isopropylbicyclo[10.2.1]pentadec-1(14)-ene-3,13-dione (309)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C45

(S)-3-Hex-2-ynoyl-4-phenyloxazolidin-2-one (335)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C46

(S)-4-tert-Butyl-3-hex-2-ynoyloxazolidin-2-one (337)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C47

(4S,5R)-3-Hex-2-ynoyl-4,5-diphenyloxazolidin-2-one (339)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C48

(3aS,8aR)-3-Hex-2-ynoyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (341)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C49

(S)-4-Isopropyl-3-(3-phenylpropioloyl)oxazolidin-2-one (345)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C50

3,4-Dihydro-2H-pyran-6-carbonyl chloride (354)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C51

(2Z,4E)-2-Butylidene-4-methyl-1-[(S)-2-oxo-4-phenyloxazolidin-3-yl]hex-4-ene-1,3-dione

(350)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C52

(2Z,4E)-1-[(S)-4-tert-Butyl-2-oxo-oxazolidin-3-yl]-2-butylidene-4-methylhex-4-ene-1,3-dione (351)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C53

(2Z,4E)-2-Butylidene-4-methyl-1-[(4S,5R)-2-oxo-4,5-diphenyloxazolidin-3-yl]hex-4-ene-1,3-dione

(352)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C54

(2Z,4E)-2-Butylidene-4-methyl-1-[(3aS,8aR)-2-oxo-2H-indeno[1,2-d]oxazol-3(3aH,8H,8aH)-

yl]hex-4-ene-1,3-dione (353)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C55

(2E,5Z)-3-Methyl-5-[(S)-p-tolylsulfinyl]nona-2,5-dien-4-one (376)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C56

(S,Z)-2-Butylidene-1-(3,4-dihydro-2H-pyran-6-yl)-3-(2-oxo-4-phenyloxazolidin-3-yl)propane-

1,3-dione (355)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C57

(S,Z)-2-Butylidene-1-(3-methoxyphenyl)-3-(2-oxo-4-phenyloxazolidin-3-yl)propane-1,3-dione

(357)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C58

(2Z,4E)-2-Benzylidene-4-methyl-1-[(S)-2-oxo-4-phenyloxazolidin-3-yl]hex-4-ene-1,3-dione

(105)

1H NMR

Appendix C; 1H and


Appendix C59

(2Z,4E)-2-Benzylidene-1-[(S)-4-isopropyl-2-oxooxazolidin-3-yl]-4-methylhex-4-ene-1,3-dione

(360)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C60

(S,Z)-2-Benzylidene-1-(3,4-dihydro-2H-pyran-6-yl)-3-(2-oxo-4-phenyloxazolidin-3-yl)propane-1,3-

dione (358)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C61

(S,Z)-2-Benzylidene-1-(3-methoxyphenyl)-3-(2-oxo-4-phenyloxazolidin-3-yl)propane-1,3-dione

(359)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C62

(S)-3-[(1S,5S)-3,4-Dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]-4-phenyloxazolidin-2-

one (364)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C63

(S)-3-[(1R,5R)-3,4-Dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]-4-phenyloxazolidin-2-

one (366)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C64

(S)-4-tert-Butyl-3-[(1S,5S)-3,4-dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]oxazolidin-2-one

(368)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C65

(S)-4-tert-Butyl-3-[(1R,5R)-3,4-dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]oxazolidin-2-one

(369)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C66

(4S,5R)-3-[(1S,5S)-3,4-Dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]-4,5-diphenyloxazolidin-

2-one (370)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C67

(4S,5R)-3-[(1R,5R)-3,4-Dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]-4,5-

diphenyloxazolidin-2-one (371)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C68

(3aS,8aR)-3-[(1S,5S)-3,4-Dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]-3,3a,8,8a-tetrahydro-

2H-indeno[1,2-d]oxazol-2-one (372)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C69

(3aS,8aR)-3-[(1R,5R)-3,4-Dimethyl-2-oxo-5-propylcyclopent-3-enecarbonyl]-3,3a,8,8a-

tetrahydro-2H-indeno[1,2-d]oxazol-2-one (373)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C70

(S)-3-[(5S,6S)-7-Oxo-5-propyl-2,3,4,5,6,7-hexahydrocyclopenta[b]pyran-6-carbonyl]-4-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C71

(S)-3-[(5R,6R)-7-Oxo-5-propyl-2,3,4,5,6,7-hexahydrocyclopenta[b]pyran-6-carbonyl]-4-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C72

(S)-3-[(1S,2S)-5-Methoxy-3-oxo-1-propyl-2,3-dihydro-1H-indene-2-carbonyl]-4-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C73

(S)-3-[(1R,2R)-5-Methoxy-3-oxo-1-propyl-2,3-dihydro-1H-indene-2-carbonyl]-4-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C74

(S)-3-[(1R,5S)-3,4-Dimethyl-2-oxo-5-phenylcyclopent-3-enecarbonyl]-4-phenyloxazolidin-2-

one (106)

1H NMR

Appendix C; 1H and


Appendix C75

(S)-3-[(1S,5R)-3,4-Dimethyl-2-oxo-5-phenylcyclopent-3-enecarbonyl]-4-phenyloxazolidin-2-one

(382)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C76

(S)-3-[(1R,5S)-3,4-Dimethyl-2-oxo-5-phenylcyclopent-3-enecarbonyl]-4-isopropyloxazolidin-2-one

(385)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C77

(S)-3-[(1S,5R)-3,4-Dimethyl-2-oxo-5-phenylcyclopent-3-enecarbonyl]-4-isopropyloxazolidin-2-one

(388)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C78

(S)-3-[(5S,6R)-7-Oxo-5-phenyl-2,3,4,5,6,7-hexahydrocyclopenta[b]pyran-6-carbonyl]-4-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C79

(S)-3-[(5R,6S)-7-Oxo-5-phenyl-2,3,4,5,6,7-hexahydrocyclopenta[b]pyran-6-carbonyl]-4-phenyloxazolidin-

2-one (393)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C80

(S)-3-[(1S,2R)-5-Methoxy-3-oxo-1-phenyl-2,3-dihydro-1H-indene-2-carbonyl]-4-


1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C81

(S)-3-[(1R,2S)-5-Methoxy-3-oxo-1-phenyl-2,3-dihydro-1H-indene-2-carbonyl]-4-phenyloxazolidin-2-

one (397)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C82

N,N-Dimethyl-3-(3,4,5-trimethoxyphenyl)propiolamide (410)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C83

(Z)-2-(3-Methoxybenzoyl)-N,N-dimethyl-3-(3,4,5-trimethoxyphenyl)acrylamide (411)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C84

1-Chloro-4,5,6-trimethoxy-3-(3-methoxyphenyl)-N,N-dimethyl-1H-indene-2-carboxamide (413)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C85

3-Chloro-5,6,7-trimethoxy-1-(3-methoxyphenyl)-N,N-dimethyl-1H-indene-2-carboxamide (419)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C86

1-Butoxy-4,5,6-trimethoxy-3-(3-methoxyphenyl)-N,N-dimethyl-1H-indene-2-carboxamide (420)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C87

5,6,7-Trimethoxy-1-(3-methoxyphenyl)-3-(4-methoxyphenylthio)-N,N-dimethyl-1H-indene-2-

carboxamide (423)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C88

3-(Furan-2-yl)-5,6,7-trimethoxy-1-(3-methoxyphenyl)-N,N-dimethyl-1H-indene-2-

carboxamide (426)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C89

(5S*,6R*)-N,N-Dimethyl-7-oxo-5-phenyl-2,3,4,5,6,7-hexahydrocyclopenta[b]pyran-6-

carboxamide (434)

1H NMR

13C NMR (JMOD)

Appendix C; 1H and


Appendix C90

(E)-Ethyl 2-(1-benzyl-1H-pyrrole-2-carbonyl)-4-methylpent-2-enoate (E-190) 1H NMR

1-[1-Benzyl-5-(pent-4-enyl)-1H-pyrrol-2-yl]-2,2,2-trichloroethanone 1H NMR

Appendix C; 1H and


Appendix C91

1-Benzyl-5-(pent-4-enyl)-1H-pyrrole-2-carboxylic acid 1H NMR

(S)-3-[(4R,5S)-1-Benzyl-4-isopropyl-6-oxo-2-(pent-4-enyl)-1,4,5,6-

tetrahydrocyclopenta[b]pyrrole-5-carbonyl]-4-phenyloxazolidin-2-one (223) 1H NMR

Appendix C; 1H and


Appendix C92

(S)-3-[(4R,5R)-1-Benzyl-4-isopropyl-6-oxo-2-(pent-3-enyl)-1,4,5,6-


(S)-3-[(4S,5S)-1-Benzyl-4-isopropyl-6-oxo-2-(pent-3-enyl)-1,4,5,6-


Appendix C; 1H and


Appendix C93

(Z)-2-Methoxyhepta-2,6-dienoic acid (263) 1H NMR

(4Z)-Ethyl 4-methoxy-2-(2-methylpropylidene)-3-oxonona-4,8-dienoate (265) 1H NMR

Appendix C; 1H and


Appendix C94

cis-Ethyl 4-(but-3-enyl)-2-hydroxy-5-isopropyl-3-oxocyclopent-1-enecarboxylate? 1H NMR

trans-Ethyl 4-(but-3-enyl)-2-hydroxy-5-isopropyl-3-oxocyclopent-1-enecarboxylate? 1H NMR

Appendix C; 1H and


Appendix C95

(4R*,5R*)-4,5-Dihydro-4-(methylethyl)-5,2-[3]octenocyclopenta[b]pyrroles-6(1H)-one 1H NMR

(E)-2-Ethoxy-6-methylhepta-1,4-dien-3-one 1H NMR

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DK - PhD Thesis (FINAL)