NEW METHODS IN CARBOHYDRATE CHEMISTRY: DEHYDRATIVE

NEW METHODS IN CARBOHYDRATE CHEMISTRY: DEHYDRATIVE

GLYCOSYLATION WITH CYCLIC PHOSPHONIUM ANHYDRIDES AND α-

SELECTIVE GLYCOSYLATION OF GLYCOSYL PHOSPHINITES

By Lance Taylor Dockery

B.S. Mount Saint Mary’s University, 2013

A thesis submitted to the� faculty of the

Graduate school of the University of Colorado in

Partial fulfillment of the requirement for the degree of

Master of Science

2016�

ii

The thesis entitled:

New Methods in Carbohydrate Chemistry: Dehydrative Glycosylation with Cyclic

Phosphonium Anhydrides and α-Selective Glycosylation of Glycosyl Phosphinites

written by Lance Dockery

has been approved by the Department of Chemistry at the University of Colorado

Boulder

Maciej Walczak

Tarek Sammakia

Date

This thesis has been examined by the above signatories and approved to meet the

Requirements for the Masters of Science in chemistry degree.

iii

Dockery, Lance Taylor (M.S., Chemistry)

New Methods in Carbohydrate Chemistry: Dehydrative Glycosylation with Cyclic

Phosphonium Anhydrides and α-Selective Glycosylation of Glycosyl Phosphinites

Thesis directed by Assistant Professor Maciej Walczak

Achieving a high level of efficiency in carbohydrate synthesis is dependent upon

reactions that can provide high yields and stereoselectivity at the anomeric position. The

nature of the glycosidic bond as either α or β configuration poses the greatest obstacle.

The development of methods to control this inherent feature while also giving high yields

is a primary goal for the field of carbohydrate chemistry. This thesis examines the

potential for two new methods to overcome these challenges: dehydrative glycosylation

with cyclic phosphonium anhydrides and glycosylation of glycosyl phosphinites. A

collection of cyclic phosphonium anhydrides were prepared and tested with a range of

glycosylation substrates. These glycosylations demonstrated good yield and selectivities

for a number of examples and represent a new and practical type of dehydrative

glycosylation. A number of 1D and 2D NMR experiments were carried out to better

understand the mechanistic nature of this reaction. A collection of glycosyl phosphinites

were also prepared and evaluated in their potential to give highly α-selective

glycosylations through in situ anomerization. This method was used with a number of

substrates giving good yield and high selectivities. The high α-selectivity of this method

was explored through a number of 31P NMR experiments.

iv

Acknowledgements

I thank all members of the Walczak lab who I have worked closely with over the years.

Without their support this work would not have been possible. I would like to especially

thank Dr. Rajendar Dyapa and Dr. Jie Guang who I worked closely with on the research

discussed here. I am grateful for their assistance in teaching me how to become a better

chemist in many ways. I thank Prof. Maciej Walczak for his guidance and assistance over

the course of this work. I would like to extend a special thanks to Prof. Richard

Shoemaker for his wonderful assistance in obtaining the mechanistic NMR data in this

work. Lastly I would like to thank the University of Colorado Boulder for providing the

financial means to pursue this degree.

v

Contents

Chapter 1: Introduction………………………………………………………………1

1.1: General Chemical Glycosylation……………………………………..……1

1.2: Dehydrative Glycosylation………………………………………………...3

1.3: α-selective Glycosylation with Glycosyl Phosphinites………………..…..7

Chapter 2: Dehydrative Glycosylation………………………………………………..9

2.1: Cyclic phosphonium anhydrides……………………………………………9

2.1.1: Preparation of cyclic phosphonium anhydrides………………….10

2.2: Optimization and glycosylations……………………………………………13

2.2.1: Evaluation of cyclic phosphonium anhydrides……………………13

2.2.2: Evaluation reaction conditions……………………………………15

2.2.3: Improved selectivities through anomeric iodides…………………16

2.3: Mechanistic studies………………………….………………………………21

2.3.1: Cyclic phosphonium-glycosyl donor interaction studies……….…21

2.3.2: Cyclic phosphonium-glycosyl acceptor interaction studies………26

2.4: Methods………………….………………….………………………………29

2.4.1 Preparation of cyclic phosphonium anhydrides……………….…..30

2.4.2: Mechanistic studies donor & cyclic phosphonium……………….38

2.4.3 General dehydrative glycosylation procedure…………….……….39

2.4.4 General glycosylation procedure with TBAI………….…………..40

2.4.5: Mechanistic TFE studies………………….………………………46

vi

Chapter 3: α-Selective Glycosylation of Glycosyl Phosphinites…….……………….46

3.1: α-selective glycosylation reactions………..………….…………….………46

3.2: Preparation of glycosyl phosphinites………………….……………………48

3.3: Substrate scope………………….………………….……………………….50

3.4: Mechanistic studies………………….………………….…………………..51

3.5: Methods………………….………………….………………………………55

3.5.1: Preparation of glycosyl phosphinites……………………………..56

3.5.2: Optimization of glycosyl phosphinites……………………………57

3.5.3: Glycosylations with glycosyl phosphinites……………………….58

Chapter 4: Conclusions………………….………………….………………………….62

4.1: Dehydrative glycosylations………………….………………………………62

4.2: Glycosyl phosphinites………………….……………………………………63

References………………….……………………….……………………….…………..64

Appendix………………….……………………….……………………….……………71

vii

Tables

Table 2.1 31P NMR for cyclic phosphonium triflate salts……………..……………..12

Table 2.2 Optimization of dehydrative glycosylations……………..……………….15

Table 2.3 Scope of dehydrative glycosylation with TBAI modification…………….20

Table 3.1 Base optimizations for the preparation of glycosyl phosphinites. ……..…49

Table 3.2 Optimization of glycosyl phosphinites in α-selective glycosylations.……..50

Table 3.3 Reaction scope of glycosylation with anomeric phosphinites.……………..51

viii

Figures

Figure 1.1 Selected glycosylation methods. ……………………………………………2

Figure 1.2 The Gin method for dehydrative glycosylation. ……………………………5

Figure 1.3 Historical dehydrative glycosylation methods. ……………………………..6

Figure 1.4 Cyclic phosphonium anhydrides in dehydrative glycosylations. …………..7

Figure 1.5 Methods for α-selective glycosylations via in situ anomerization…………8

Figure 2.1 Library of cyclic phosphonium anhydrides. ………………………………11

Figure 2.2 X-ray crystal structure of cyclic phosphonium anhydride 3. ………...……12

Figure 2.3 31P NMR of cyclic phosphonium anhydride and 31P NMR of cyclic

phosphonium anhydride mixed with 2,3,4,6-tetra-O-benzyl-D-glucopyranoside……..23

Figure 2.4 Proposed glycosylation intermediate 10 with observed coupling

interactions to C-2 and nearby 31P nuclei. ……………………………………….……24

Figure 2.5 a) 31P Coupled 1H NMR spectra of α-anomeric proton in 17 b-c) 1H NMR

spectra of 17 with 31P Selective decoupling at δ 73.7 and 73.2 ppm c) 1H NMR spectra of

17 with broadband 31P decoupling. ……………………………………………………25

Figure 2.6 31P NMR of cyclic phosphonium 10 (a) following addition of 0.5 (b), 1.0 (c),

and 2.0 (d) equiv of TFE. ……………………………………………………………..28

Figure 2.7 NOESY spectra of cyclic phosphonium 10 after addition of

2.0 equiv. of TFE…………………………………………………….……………..…29

Figure 3.1 glycosyl phosphinite 19 reacted with iodomethane observed via 31P NMR

each hour over the course of 12 hours. ……………………………….………………53

Figure 3.2 31P NMR of glycosyl intermediate 13 reacted with cyclohexanol over the

course of 3 days. ……………………………………………………………………54

1

Chapter 1: Introduction

1.1: General Chemical Glycosylation

The role of carbohydrates as essential molecules for all biological organisms with

key roles in structural support, energy storage, and molecular signaling demonstrates the

importance of research into their chemical preparation. Synthesis of carbohydrates has

been a challenge to the scientific community for decades. Studies into the biosynthetic

processes of carbohydrate natural products have revealed a number of powerful enzymes

capable of carrying out these transformations. The biosynthesis of carbohydrates in vivo

proceeds with ease,1-2 so much so that part of the field of biochemistry exists to explore

the potential to apply these reactions in vitro towards carbohydrate synthesis. Achieving

the same high level of efficiency in carbohydrate synthesis from chemical methods in

terms of high yields and stereoselectivity remains a challenge. The glycosidic bond exists

as either α or β configuration highlights one of the main challenges posed to

carbohydrate chemists. Numerous methods have been developed over the years with the

goal of excellent α/β glycosidic bond formation in mind.3

Some of the earliest research in chemical glycosylation by Michael,4 Fischer,5-7

Helfrich,8 and Koenigs-Knorr9 provided methods for the preparation of simple

carbohydrates using various activated glycosyl donor intermediates (Figure 1.1). In the

case of the Fischer method, activation of the anomeric alcohol by an acid catalyst enables

glycosylation by the incoming glycosyl acceptor, usually a solvent. The troublesome

nature of this method as an equilibrium-driven process was improved upon by Koenigs

2

and Knorr who used anomeric halides (e.g. bromide) activated by a suitable Lewis acid.

Direct O-alkyation10,11 also represents another approach to glycosylation; however, it in

addition to the earlier methods all have significant limitations in terms of yield and

compatibility with a wide range of substrates.

Figure 1.1 Selected glycosylation methods.

Schmidt12 reported the use of trichloroacetimide as a leaving group (Figure 1.1) in

chemical glycosylations. The trichloroacetimide glycosyl donor (the Schmidt donor) can

be activated by a wide range of Lewis acids (e.g., BF3•OEt2 or TMSOTf) give the product

in high yields.13,14 Other similar Schmidt-type donors include N-

phenyltrifluoroacetimidate15 and N-Aryl-trifluoroacetimidate16 donors. It is clear that

among the goals for new glycosylation methods the design must incorporate easily

available glycosyl donors and have high yielding reaction conditions but the primary

O(HO)n

OH

Brønsted/Lewis Acid O(HO)n

OR

a) Fischer

O(RO)n

Br

b) Koenigs-Knorr

ROH, Ag2CO3 O(RO)n

OR

c) Schmidt

O(RO)n

OH

NaH or K2CO3, Cl3CCN O

(RO)n

OCNHCCl3

ROHO

(RO)n

OR

BF3•OEt2 or TMSOTf

d) O-alkylation

O(RO)n

OH

NaH, DMF O(RO)n

O

R-OTf O(RO)n

OR

ROH

3

challenge moving forward in carbohydrate chemistry lies in the search for conditions

which can give greater control over α/β selectivities.

The classical approach to control of α/β glycosylation relies upon careful design

of protecting groups17-20 wherein those groups direct the glycosylation to favor a

particular anomer. Use of so-called participating groups (acetyl, benzoyl) at the C-2

position in the glycosyl ring can enhance this process. Formation of almost exclusively

the β product is observed through via neighboring group participation through formation

of an ortho-ester intermediate.21 Formation of the β-glycosylation product via

neighboring group participation is widely useful for a number of standard glycosylation

methods, however it necessitates additional steps in the preparation of more complex

carbohydrates whereby numerous protecting group manipulations over the course of the

reaction lower overall yields and erode efficiency. Methods to obtain the desired

selectivities with fewer protecting group manipulations and good overall yield are of

primary interest. Dehydrative glycosylation and glycosylations of glycosyl phosphinites

were the focus of two particular techniques to be discussed in this thesis intended to

overcome these challenges facing carbohydrate chemistry today and provide better routes

to high yielding and stereoselective glycosylations.

1.2: Dehydrative Glycosylation

Direct activation of the anomeric alcohol via dehydrative glycosylations originate

with the early work by Fischer but overcoming the inherent limitations of this

equilibrium-driven reaction would be the focus of work by many groups over the next

4

few years. Historically, dehydrative glycosylation methods have focused on glycosyl

halide intermediates,22, 23 glycosyl sulfonate intermediates,24 Lewis acid catalysts,25, 26 and

oxophosphonium intermediates27-30 as the most prominent developments and applications.

More recently the seminal work with glycosyl oxosulfonium intermediates31 in the

activation of glycosyl donors by Gin has set the standard for a widely applicable

dehydrative glycosylation method (Figure 1.3).

This method uses diphenyl sulfoxide and triflic anhydride to prepare diphenyl

sulfide bis(triflate) which, when reacting with the glycosyl donor 1, forms the

corresponding oxosulfonium species 2 (Figure 1.3). This method was then applied to a

number of glycosyl donor and acceptor substrates giving good yields and variable

selectivities. A series of mechanistic experiments using anomeric 18O labled glycosyl

donors and low temperature 1H NMR were also explored by Gin to identify the

mechanistic basis of this dehydrative glycosylation experiment. The results show that

glycosyl donor 1 is activated to form oxosulfonium species 2 and anomeric pyridinium 3

which subsequently gave rise to the glycosylation product 4. Mechanistic NMR

experiments indicated anomeric pyridinium 3 to be the predominant species in this

glycosylation but based on the anomeric ratios of the products, glycosylation must

proceed at least in part through other reactive intermediates such as oxosulfonium species

2.

5

Figure 1.2 The Gin method for dehydrative glycosylation with oxosulfonium triflate.

Early work by Mukaiyama29 demonstrated the feasibility of dehydrative

glycosylations using Hendrickson’s reagent30,31 (POP) and similar oxophosphonium

reagents on simple ribofuranose substrates (Figure 1.3). Among the oxophosphonium

reagents examined were examples with R = phenyl, naphthyl, cyclohexyl, and n-Butyl.29

The substrate scope for this reaction was limited to 2,3,5-tri-O-benzyl-D-ribofuranose

and the yields were reported for cyclohexanol, cholesterol, propanol, and azide glycosyl

acceptors. Hendrickson’s reagent was further expanded to dehydrative glycosylation

reactions on a wider range of substrates by Panza.32 The use of Hendrickson’s reagent in

this case, however, led to significant amounts of homocoupling product 5, resulting in

significantly lower yields when added directly to the glycosyl donor. Careful addition of

the POP-activated glycosyl acceptor was required, significantly limiting the scope of this

methodology.

O

OH(RO)n

O

Nu(RO)n

Ph2SO, Tf2O

2-Cl-pyr, NuH

O

O(RO)n S

Ph

Ph

OTf

1

2

O

N(RO)n

3

Cl

4

N

Cl

6

Figure 1.3 Historical dehydrative glycosylation methods using oxophosphonium

species.

With these limitations in mind, a new method was developed by Lance Dockery

and Dr. Rajendar Dyapa to incorporate the enhanced electrophilic character of cyclic

phosphonium salts (based on preliminary 31P chemical shifts) as dehydrative

glycosylation reagents (Figure 1.3). Dehydrative glycosylations stand out as a promising

method in carbohydrate chemistry because it allows glycosylations to proceed directly in

one step from the anomeric alcohol, whereas the most prevalent method today (Schmidt

glycosylation) represents a two-step process to the product via the Schmidt donor

intermediate.

Knowing the limited substrate scope and applications of the more common

oxophosphonium dehydrative glycosylations derived from Hendrickson’s reagent, cyclic

O OH

BnO OBn

BnO

CH2Cl2 0°C

+ 'ROH

O OR'

BnO OBn

BnO

O

OHRO

O

OR'RO

a) Mukaiyama

b) Panza

Yield: 75-99%, 82:12-87:13 α:β

Yield: 72-98%, 44:56-25:75 α:β

OPPh3Ph3P

-OTf-OTf

POP, R'OH

CH2Cl2, 0˚C

CH2Cl2, 0˚CPOP

ORO

O

OOR

7

phosphonium reagents for dehydrative glycosylation represent a potential new direction

for oxophosphonium species in dehydration reactions. If the cyclic phosphonium reagents

are more stable than traditional POP reagents, they can be utilized in glycosylations that

should proceed easily without the limited yields and selectivities of the aforementioned

methods or necessarily purification of the intermediates in a traditional 2-step

glycosylation.

The work in this thesis demonstrates how cyclic phosphoniums derived from

corresponding bis-phosphine oxides are able to activate glycosyl donors for one-pot

glycosylations with high yields and selectivities for a variety of substrates. The

mechanistic nature of the cyclic phosphonium anhydrides as dehydrative reagents was

further examined. Of particular interest were conditions using 1,4-

bis(diphenylphosphino)butane, triflic anhydride, and 2,4,6-tri-tert-butylpyridine.

Figure 1.4 Cyclic phosphonium anhydrides as reagents for dehydrative glycosylations.

1.3: α-selective Glycosylation with Glycosyl Phosphinites

While there exist numerous methods (e.g., Schmidt donor, thioether, sulfoxide,

phosphonium) which lead can to β-selective glycosylations in the presence of C-2

participating groups, in general these reactions tend to exhibit poor α-selectivity.

Common C-2 sterically nondemanding/participating groups such as alkyl ethers can often

give rise to α-glycosylation but not the extent desired for practical applications. Current

O(RO)n

OH

DPPBO2, Tf2O TTBP

CH2Cl2, 0˚C

O

(RO)n OP

O PPh2

OTf ROH O(RO)n

OR

8

methods for α-selective glycosylations rely primarily upon either careful design of SN1

reactions on an oxocarbenium intermediate,33 in situ anomerization of an activated

glycosylation intermediate,34 or the use of heterogeneous catalysts.35,36

Of these methods, in situ anomerization represents the easiest route to highly α-

selective glycosylation reactions. The earliest application of in situ anomerization was

reported by Lemieux using anomeric bromides in the presence of tetraethylamonium

bromide (Et4NBr) and a suitable glycosyl acceptor37 (Figure 1.5). Mukaiyama later

reported the use of glycosyl phosphinites activated by iodomethane followed by addition

of the glycosyl acceptor38-40 (Figure 1.5). In both cases it was assumed that the reactive

intermediate (either anomeric bromide or oxo-phosphonium species) exists in equilibrium

between the α or β anomer where the less stable stable β-intermediate undergoes

displacement to give the predominant α-glycosylation product.

Figure 1.5 Common methods for α-selective glycosylations via in situ anomerization

O(RO)n

Br

Et3NBr O(RO)n Br O

(RO)nOR

ROH

a) Lemieux

O(RO)n O

b) Mukaiyama

PPh2

O(RO)n

OPPh2

MeI

CH2Cl2

O(RO)n O

PPh2

ROH O(RO)n

ORMe

Me

I-

I-

42-65% yield, >99:1 α:β

44-96% yield, 99:1-91:9 α:β

9

A method to improve upon current α-selective glycosylation techniques was

developed by Lance Dockery to stand Jie Guang to establish mild conditions for the

preparation of glycosyl phosphinites. These glycosyl phosphinites were then reacted in a

variety of glycosylation substrates displaying high selectivities and yields. Mechanistic

studies of this reaction were then conducted with a series of NMR techniques to better

explain the origin of high selectivities in these reactions.

Chapter 2: Dehydrative Glycosylation

2.1: Cyclic phosphonium anhydrides

The preparation and characterization of a small series of cyclic phosphonium

anhydrides was previously reported by Elson.40 These reagents were reported to have

unique 31P NMR chemical shifts indicating the potential for enhanced electrophilicity as

compared to the better-known Hendrickson’s (POP) reagent.30-31 Specifically, the reported

chemical shift of cyclic phosphonium anhydrides (31P NMR δ 92 ppm) as compared to

the POP reagent (31P NMR δ 72 ppm) supported this hypothesis.

Work by Panza32 (Figure 1.3) indicated the potential to use the POP reagent in a

limited fashion for dehydrative glycosylation. The scope of this method was limited by

the tendency to form homocoupling product. As a result the Panza method required the

glycosyl acceptor to be mixed with the POP reagent and then added to the donor, still

with significant byproduct formed. It was envisioned the stability of the cyclic

phosphonium species and corresponding oxophosphonium glycosylation intermediate

10

would prevent formation of the homocoupling product and provide a simpler and more

efficient dehydrative glycosylation method.

The work described herein shows how a library of cyclic phosphonium

anhydrides were prepared and characterized from the corresponding bis-phosphine oxides

by 1H, 31P, and 13C NMR and in one case X-ray crystallography. It was envisioned that

the corresponding cyclic phosphonium analogues could be screened as dehydrating

agents and subsequently used in dehydrative glycosylations which would exhibit

enhanced yield and selectivities compared to more common methods. The optimized

reaction conditions were then successfully used by Dr. Rajendar Dyapa in a series of

glycosylation reactions with various glycosyl donor and acceptors exhibiting high yields

and strong selectivities.

2.1.1: Preparation of cyclic phosphonium anhydrides

A series of bis-phosphine oxides exhibiting a variety of electronic,

stereochemical, and steric properties in addition to previously reported cyclic POP

anhydrides were selected to generate a library of potential dehydrating agents (Figure

2.1). Characterization of the cyclic phosphonium anhydrides was done by 1H, 31P, and 13C

NMR. Under inert atmosphere the corresponding bis-phosphine oxides (1 equiv) were

dissolved in deuterated methylene chloride and mixed with trifluoromethanesulfonic

anhydride (1.25 equiv).

11

Figure 2.1 Library of cyclic phosphonium anhydrides.

The cyclic phosphonium anhydride reagents exhibited a range of 31P NMR

chemical shifts indicating varied electrophilic potential (Table 2.1) as compared to

Hendrickson’s reagent (31P NMR δ 77 ppm). To further characterize the cyclic

phosphonium anhydrides a series of recrystallization and X-ray crystallography

experiments were performed. A crystal structure of cyclic phosphonium 8 was

successfully obtained (Figure 2.2), supporting the proposed structure and of this

particular compound. A key difference is that the bond lengths observed for cyclic

Ph2P PPh2

O

OTfOTf

Ph2P PPh2

O

OTfOTf

PPh2O

Ph2P

OTfOTf

PPh2O

Ph2P

OTfOTf

PPh2

OPh2P

OTfOTf

Ph2P PPh2O

OTfOTf

P(tBu)2

O

P(tBu)2

OTf

OTf

Fe

PPh2

PPh2

O

OTf

OTf

PPh2

PPh2

O

OTf

OTf

PPh2

PPh2

O

OTfOTf

PPh2O

Ph2P

OTfOTf

PPh2O

Ph2P

O O O O

OTf

OTf

OTfP

R R

O

PR

R

O

Tf2O, CH2Cl2, 0°CP

R R

PR

R

O

OTf

6 7 8 9

10 11 12 13

(R)-14 (S)-14(R)-15 (S)-15

12

phosphonium 8 are longer than that reported for Hendrickson’s reagent (1.612 Å vs 1.597

Å), providing further support to the electrophilic potential of this particular cyclic

phosphonium. This library of cyclic phosphonium anhydrides was prepared in situ and

evaluated as dehydrative glycosylation reagents for a variety of reaction conditions (see

below).

Anhydride 31P δ Anhydride 31P NMR δ

6 60.2 12 95.8

7 85.4 13 79.2

8 90.6 (R)-14 40.9

9 62.0 (S)-14 40.9

10 51.8 (R)-15 58.4

11 68.7 (S)-15 58.4

Table 2.1 31P NMR chemical shifts for the library of prepared cyclic

phosphonium triflate salts.

Figure 2.2 X-ray crystal structure of cyclic phosphonium anhydride 3.

13

2.2: Optimization and glycosylations

With a library of cyclic phosphoniums prepared, optimization experiments were

undertaken to evaluate the potential of these reagents in dehydrative glycosylation

reactions. Each cyclic phosphonium anhydride was prepared in situ from

trifluoromethanesulfonic anhydride and reacted with 2,3,4,6-tetra-O-benzyl

glucopyranoside in the presence of 2,4,6-tri-tert-butylpyridine. A suitable glycosyl

acceptor (either cyclohexanol or benzyl alcohol) was then added to the reaction mixture

(See Table 2.2).

2.2.1: Evaluation of cyclic phosphonium anhydrides in glycosylations

Evaluation of the optimization reactions proceeded as follows: cyclic

phosphoniums 1-10 were prepared from their corresponding bis-phosphine oxides and

trifluoromethanesulfonic anhydride (15 min) before adding the glycosyl donor (30 min)

followed by cyclohexanol. Cyclic phosphonium anhydrides 6, 8, 10, and (S)-15 were the

most promising (Table 2.2) in terms of both yields and selectivities. Cyclic phosphonium

8 with an observed yield of 91% had the highest yield and selectivity with cyclohexanol,

despite lackluster selectivity with benzyl alcohol. The ease of these reactions to form the

presumed cyclic intermediate 24 could further explain their reactivity in glycosylation

reactions. A particular outlier in the screened examples was cyclic phosphonium 7, which

gave only trace amounts of product. A number of mechanistic studies with cyclic

phosphonium 7 later revealed that it interacts poorly with the glycosyl donor and does not

14

activate it for dehydration. The exact explanation for this phenomenon remains to be

determined is likely due to its either unique molecular geometry or electrophilic

character.

While cyclic phosphonium 10 showed moderate yield and good selectivity with

cyclohexanol, larger similar phosphoniums 11-13 gave poor yield. It is likely that the

bulky size of these anhydrides led to poor interaction with the glycosyl donor. It is

notable that while the 31P δ values for phosphoniums such as 8 reflected high yielding

glycosylation reactions, other larger phosphoniums (7, 12, 13) having similarly high 31P δ

values acted poorly in glycosylation reactions. This is likely due to the combination of

electrophilic and steric factors affecting the stability of the cyclic phosphonium-glycosyl

donor intermediate. The various chiral cyclic phosphonium anhydrides prepared had

both greatly reduced yields and limited control over selectivity with the exception of

chiral cyclic phosphonium (S)-15; however, the difference between corresponding R and

S enantiomers likely indicates little effect on phosphonium configurations. The high yield

and dr. of glycosylation with 8 combined with the easy commercial availability of the

precursor [1,4-bis(diphenylphosphino)butane] ultimately led to the selection of this

reagent as the dehydrating agent for the future reactions.

Anhydride ROH Yield α:β

6 CyOH 56% 36:64

O

OH(RO)n

O

OR'(RO)n

CH2Cl2 0 °C4ÅMS

1) Tf2O, anhydride, TTBPy 15 min2) glycosyl donor, 30 min3) glycosyl acceptor, 15 min - 1hr

15

6 BnOH 69% 55:45

7 CyOH <5% N.D.

8 CyOH 83% 35:65

8 BnOH 91% 55:45

9 CyOH 56% 33:67

10 CyOH 72% 33:67

11 CyOH <5% N.D.

12 CyOH <5% N.D.

13 CyOH <5% N.D.

(R)-14 CyOH 36% 40:60

(S)-14 CyOH 23% 38:62

(R)-15 CyOH 54% 36:64

(S)-15 CyOH 75% 37:63

Table 2.2 Optimization of cyclic phosphonium anhydrides in dehydrative

glycosylations.

2.2.2: Evaluation of dehydrative glycosylation reaction conditions

With cyclic phosphonium 8 selected as the optimal dehydrating agent, additional

optimizations were undertaken to determine the effect of various solvents, reaction times,

and reaction temperatures on the glycosylation reactions.

Despite evaluation of different solvents (PhMe, THF, Et2O, MeCN) and solvent

mixtures in glycosylation reactions, methylene chloride was found to give both the

16

highest yields and selectivities. Other solvents and mixtures severely decreased the

solubility of 8 and hindered the formation of the presumed cyclic phosphonium

intermediate. For these reactions no glycosylation was observed and the primary product

was elimination (2,3,4,6-tetra-O-benzyl-D-glucal) or no reaction at all. The overall yield

for the reaction was highest when allowing the prepared cyclic phosphonium anhydride

to react with the glycosyl donor for 20 min followed by addition of the glycosyl acceptor.

Less reaction time resulted in leftover unreacted glycosyl donor while longer reaction

times gave poor yield due to elimination. Reactions carried out at 0°C were found to be

optimal as increased (room temperature) or decreased (-20 °C and -78 °C) temperatures

gave significant amounts of elimination products or unreacted starting material,

respectively and only trace amounts of the desired glycosylation product.

2.2.3: Improved glycosylation selectivities through anomeric iodides

Based on work by Mukaiyama and other work disclosed in this thesis (Chapter 3)

it was known that glycosylation of anomeric iodides via in situ anomerization proceeds

well with high α–selectivity.37-39 While the work by Dr. Rajendar Dyapa demonstrated the

applicability of this method for a wide range of glycosyl donors and acceptors with good

selectivity and yield, there were still examples from these studies where the observed

selectivities were not satisfactory. It was thus envisioned that once the glycosyl donor

was activated by cyclic phosphonium 8, addition of tetrabutylammonium iodide (TBAI)

could furnish the corresponding anomeric iodide (Scheme 2.1). Addition of the glycosyl

17

acceptor would then give the product in high α–selectivity due to in situ anomerization to

the reactive β-iodide and subsequent glycosylation.

Scheme 2.1 Dehydrative glycosylation in the presence of TBAI.

The first step to evaluate the potential for TBAI in highly α–selective

glycosylations was to identify conditions which would lead to formation of the anomeric

iodide but minimize the formation of elimination product. Direct addition of TBAI to

activated glycoside 17 gave almost exclusively elimination product and trace amounts of

the glycosylation product. It was hypothesized that in these reactions conversion to the

anomeric iodide in the presence of TBAI proceeded rapidly and in high concentrations

the unstable anomeric iodide (reacting with glycosyl acceptor) would undergo

elimination before it had sufficient time to react with the glycosyl acceptor. As a way to

overcome this problem a protocol was devised whereby a solution of TBAI (0.03 M in

DCM) and the glycosyl acceptor were added slowly via syringe pump (3.7 mL/hr) to

activated glycoside 17 at 0 °C. In this new procedure activated glycoside 17 would

O

OH(RO)n

O(RO)n

CH2Cl2 0 °C

OTfOTf

PPh2O

Ph2P

O

O

OR'(RO)n

R'OH

TBAI

O(RO)n

I

O(RO)n I

OTf

PPh2O

Ph2P

18

rapidly convert to the iodide and undergo glycosylation nearly simultaneously with

limited time for the formation of elimination byproducts.

19

Entry Donor Acceptor Product Yield α:β

1

19

CyOH

64% 71:29

2

18

22

N.D. N.R. N.D

3

20

CyOH

76% only α

4

21

CyOH

72% 63:37

5

18

PhOH

>5% 71:29

6

18

23

89%* 85:15

O

OHBnO

OBn

OBnOBnO

OBn

OBn

OCy

O

OHBnOBnO

BnO

OBn

O

O

HOO

O

O

BnOOBn

BnOOH O

BnO OBn

OCyBnO

O

OBnOBnO

O

Ph

OHO

BnOOOPh

OBn

OCy

O

OHBnOBnO

BnO

OBnO

OPhBnOBnOBnO

OBn

O

OHBnOBnO

BnO

OBnOBnO

BnOBnO

OH

OMe

O

BnOBnOBnO

OBn

O

BnOBnOBnO

OMe

O

20

Table 2.3 Reaction scope of dehydrative glycosylation with TBAI modification.

*Reaction carried out in a 1:1 ratio of DCM:DCE.

With the ideal conditions screened a series of reactions were performed (Table

2.3) with a variety of substrates and glycosyl acceptors in order to evaluate the potential

for this method to afford improved α-selectivities in dehydrative glycosylation reactions.

The experiments with 2,3,4-tri-O-benzyl-D-fucose/cyclohexanol gave moderate yields

with promising selectivities, prompting further exploration of this method. Attempting

this method with a highly hindered secondary alcohol donor (Entry 2) was unsuccessful

as was also the result under standard conditions. Further experiments with 2,3,5-tri-O-

benzyl-D-ribose and cyclohexanol (Entry 3) were more promising, with exclusively the

α -product observed in 76% yield. Reaction of 2,3-di-O-benzyl-4,6-O-[(R)-

phenylmethylene]-D-mannose and 2,3,4,6-tetra-O-benzyl-D-glucose/phenol (Entries 4-5)

both gave moderate to poor yields with poor selectivities. Benzyl glucose reacted with

methyl 2,3,4-tri-O-benzyl-D-glucopyranoside gave to corresponding product in high

yield and moderate selectivity with a modified method using a 1:1 ratio of methylene

chloride:1,2,-dichloroethane (DCE) as the solvent mixture (Entry 6).

The most promising result of this method came when reacting benzyl glucose

with cholesterol as the glycosyl acceptor (Entry 7). The corresponding glycosylation

7

18

Cholesterol

88% 64:36 O

BnOOHBnO

OBn OBnO

OBnOBnOBnO

OBn H

HH

H

21

product was observed in 88% yield although with diminished selectivities. Regardless,

this result was promising due to it being the first application of this glycosylation method

with a large and complex glycosyl, indicating promise for expanding the method further

to glycosylations which could be essential for synthesizing natural products.

2.3: Mechanistic studies

With the knowledge that cyclic phosphonium 8 functions as an efficient

dehydrating agent however, we were unable to observe any trehalose products, a series of

mechanistic NMR studies were undertaken to better understand the nature of this

reaction. Of particular interest was an explanation for the lack of observed homocoupling

product and a clearer understanding of the reactive intermediates responsible for the

glycosylation, potentially due to a stable oxophosphonium intermediate between the

intact cyclic phosphonium and the glycosyl donor.

2.3.1: Cyclic phosphonium-glycosyl donor interaction studies

Initial work into the investigation of the dehydrative glycosylation mechanism

focused on identifying and characterizing the intermediate formed upon addition of the

cyclic phosphonium anhydride to the glycosyl donor in the proposed mechanism

(Scheme 2.2). Supported by the lack of observed homocoupling product in these

dehydrative glycosylation reactions it was expected that the cyclic phosphonium remains

intact once activating the glycosyl donor yielding intermediate 24, the reactive species in

22

the glycosylation. A series of 1H, 13C, 31P, and 2D NMR experiments were performed to

identify this intermediate.

Scheme 2.2 Proposed dehydrative glycosylation mechanism

Studies into the intermediate generated from addition of the cyclic phosphonium

8 to the glycosyl donor were carried out under inert atmosphere in an NMR tube at room

temperature on a 400 MHz NMR spectrometer. 2,3,4,6-Tetra-O-benzyl-D-

glucopyranoside was added to cyclic phosphonium 8 (31P NMR δ 91.8 ppm) and

thoroughly mixed. Upon addition of the glycosyl donor to cyclic phosphonium 8 (Figure

2.3), new 31P chemical shifts were observed at 73.7, 73.2, 43.1, 42.8, and 32.5 ppm. 1H

NMR, 13C NMR, COSY, HSQC, and HMBC NMR were also recorded for this sample.

Based on the 2D NMR experiments the protons located at 1H NMR δ=6.0 ppm, δ=5.8

ppm (JH 3.3, 6.8 Hz) represent α-anomeric protons observed as a doublet of doublets.

O

OH(RO)n

O(RO)n

CH2Cl2 0 °C

OTfOTf

PPh2O

Ph2P

OTf

PPh2O

Ph2P

O

OR'(RO)n

R'OH

24

25

O

23

Figure 2.3 a) 31P NMR of cyclic phosphonium anhydride 3 b) 31P NMR of cyclic

phosphonium anhydride 3 mixed with 2,3,4,6-tetra-O-benzyl-D-glucopyranoside.

The pattern of the 31P signals observed as symmetric doublets is predicted to be

the result of two separate anomeric insertions at the chiral phosphorus atom with the

relative ratios of the peaks corresponding to the relative ratios of the 1H anomeric protons

observed at δ=6.0 ppm, δ=5.8 ppm. Examination of the anomeric peaks in COSY

spectroscopy indicated coupling to only one other proton, supporting that those anomeric

peaks were coupled to an additional spin ½ nuclei, presumed to be 31P. A series of

selective 31P-1H decoupled experiments were performed to confirm the interaction

between the anomeric peak and the nearby 31P nuclei proposed in the initial mechanism

(Figure 2.4).

05101520253035404550556065707580859095100105110f1 (ppm)

0

100

200

300

400

500

32

.46

42

.80

43

.14

73

.15

73

.68

5101520253035404550556065707580859095100105110f1 (ppm)

0

1000

2000

3000

400091

.77

24

Figure 2.4 Proposed glycosylation intermediate 24 with observed coupling interactions

to C-2 and nearby 31P nuclei.

Selective 31P NMR decoupling at 73.7, 43.1, and 32.1 ppm ppm revealed 1H-31P

coupling between the anomeric proton and the phosphorus nuclei represented by δ 73

ppm with the decoupling reducing the doublet of doublets to a doublet (Figure 2.5). The

alternate anomeric peak was also reduced to a triplet due to decoupled overlap of the

neighboring nuclei in the 31P spectrum. Decoupling experiments between the anomeric

protons at 31P δ 43.1 ppm and δ 32.1 ppm showed no change in the 1H spectra.

Broadband 31P decoupling reduced both anomeric peaks to doublets and no other changes

were observed. A1H-31P HMBC spectrum was obtained for the proposed intermediate 24

to further support the results of the selective 1H-31P decoupling experiments (Appendix

7).

O

OTfPPh2

OPh2P

OBn

BnOBnO

BnOH

1H-1H = 3.3 Hz1H-31P = 6.8 Hz

O

25

Figure 2.5 a) 31P Coupled 1H NMR spectra of α-anomeric proton in 17 b-c) 1H NMR

spectra of 17 with 31P Selective decoupling at δ 73.7 and 73.2 ppm c) 1H NMR spectra of

17 with broadband 31P decoupling.

From these experiments it is evident that the cyclic phosphonium 8 reacts with

the glycosyl donor smoothly to provide a number of intermediates with 31P 73.7 ppm,

43.1 ppm, and 32.1 ppm. Long range 1H-31P coupling experiments confirm the interaction

between the anomeric proton and the nearby phosphonium species at 73.7 ppm, similar to

that described in proposed intermediate 24. The 31P signal observed at 32.1 ppm is

predicted to be that of the decomposed intermediate 24 to the corresponding elimination

product and DPPBO2 based on observations that this 31P signal grows in intensity as the

NMR experiment proceeds and the C-1 elimination 1H signal becomes more prominent. It

5.655.705.755.805.855.905.956.006.056.106.156.20f1 (ppm)

0

40

5.7

75

.78

5.7

85

.79

5.9

55

.96

5.9

75

.98

5.655.705.755.805.855.905.956.006.056.106.156.20f1 (ppm)

0

10

20

5.7

75

.78

5.9

55

.96

5.9

7

5.605.655.705.755.805.855.905.956.006.056.106.156.20f1 (ppm)

0

5

10

15

5.7

75

.78

5.7

9

5.9

55

.96

5.605.655.705.755.805.855.905.956.006.056.106.15f1 (ppm)

0

5

10

15

205.7

75

.78

5.9

55

.96

a)

b)

c)

d)

26

is possible that this peak could be assigned to a brief open chain P=O intermediate. That

no homocoupling product is observed supports the relative stability of cyclic intermediate

24, and further suggesting it is the predominant intermediate responsible for the

glycosylation. Direct evidence for the prevalence of this intermediate in glycosylation

reactions could most easily be supported through X-ray crystal structure of proposed

intermediate 24. Due to the long term instability of intermediate 24 observed in the

mechanistic studies, another model system would need to be developed which would be

more stable.

2.3.2: Cyclic phosphonium-glycosyl acceptor interaction studies

In order to determine the nature of the incoming glycosyl acceptor in this

glycosylation a series of experiments were performed to determine the extent to which an

incoming glycosyl acceptor may interact with both the cyclic phosphonium and the

proposed glycosylation intermediate 24 (Scheme 2.2). Two model acceptors were

examined: cyclohexanol and 2,2,2-trifluoroethanol (TFE).

The reaction of cyclohexanol with 24 was found to occur too rapidly on the NMR

time scale to observe via 1H and 31P NMR. The glycosylation product was observed in

addition to elimination byproduct (2,3,4,6-tetra-O-benzyl-D-glucal). Addition of

cyclohexanol to the POP-butane 24 caused decomposition of 24 into the corresponding

bis-phosphine oxide. As a result of these experiments a less nucleophilic glycosyl

acceptor without β-protons (TFE) was used which may be more stable and likely to

directly interact with the POP-butane and intermediate 24.

27

Addition of TFE to POP-butane in 0.5 equivalent increments up to 2.0 equiv

resulted in the attachment of TFE to the phosphonium as observed in 31P and NOESY

NMR spectra (Figure 2.7) with the peaks at 31P NMR 80.0 ppm representing the mono-

TFE-bound phosphonium and the peak at 60.3 ppm and 59.0 ppm representing the TFE

saturated phosphorus (Figure 2.6). Despite an excess of TFE there was always an

equilibrium observed between bound and non-bound TFE. These experiments suggest the

possibility for intermediate 24 to interact with the incoming glycosyl acceptor in a

manner in which the free phosphonium may become bound and in turn allow for

intramolecular delivery of the glycosyl acceptor, a unique concept with dehydrative

glycosylation reactions.

28

Figure 2.6 31P NMR of cyclic phosphonium 8 (a) following addition of 0.5 (b), 1.0 (c),

and 2.0 (d) equiv of TFE.

101214161820222426283032343638404244464850525456586062646668707274767880828486889092949698100102104106108110f1 (ppm)

93.6

0

101214161820222426283032343638404244464850525456586062646668707274767880828486889092949698100102104106108110f1 (ppm)

59.0

060.2

5

79.6

6

101214161820222426283032343638404244464850525456586062646668707274767880828486889092949698100102104106108110f1 (ppm)

59.0

060.2

5

79.6

6

1520253035404550556065707580859095100105110f1 (ppm)

58.8

159.9

7

79.6

2

a)

b)

c)

d)

29

Figure 2.7 NOESY spectra of cyclic phosphonium 8 after addition of 2.0 equiv. of TFE

showing long-range interaction between CH2 protons of TFE and the aryl protons in 8.

2.4: Methods

General: All chemicals used were reagent grade without further purification, unless

otherwise noted. DCM, THF, Et2O, PhME, and DMF were filtered through a column of

activated alumina prior to use. All reactions were carried out under dry N2 atmosphere.

Glassware used was dried in an oven. Trifluoromethanesulfonic anhydride was distilled

NOESY (300 MHz, CD2Cl2)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f2 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

f1 (

pp

m)

30

from phosphorus pentoxide. TLC analyses were performed on Merck TLC plates and

visualizations were performed with Hanessian stain. Column chromatography was

performed on silica gel (230-400 mesh). 1H and 13C NMR spectra were recorded on

Bruker/Varian/Varian 300/400/500 MHz instruments are reported as follows: chemical

shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m =

multiplet), coupling constants (Hz), and integration. NMR experiments carried out under

inert atmosphere were performed within a glovebox. The residual solvent reference peaks

were used from published literature.43 2D NMR experiments were performed using

standard parameters (200 and More NMR Experiments, S. Berger, S. Braun, Wiley-VCH,

2004). IR measurements were performed on Agilent Cary 630 FT/IR instrument and

optical rotations were measured on JASCO P-1030 and are reported as an average of ten

data points.

2.4.1: Preparation of cyclic phosphonium anhydrides

1,2-Bis(diphenylphosphine oxide)ethane. A solution of 1,2-Bis(diphenyl-

phosphino)ethane (0.298 g, 0.748 mmol) in anhydrous THF (8 mL) was treated with 33%

H2O2 (2.5 mL) added slowly via syringe. The reaction was stirred at rt for 2 h, excess

THF was removed by rotary evaporator and the precipitated solid was filtered, washed

with cold H2O and dried overnight under high vacuum with spectra matching reported

data44: 1H NMR (300 MHz, CDCl3) δ 7.75 – 7.61 (m, 8H), 7.57 – 7.50 (m, 4H), 7.50 –

7.38 (m, 8H), 2.03 (s, 4H); 31P NMR (122 MHz, CDCl3) δ 32.6.

31

1,3-Bis(diphenylphosphine oxide)propane. A solution of 1,3-

bis(diphenylphosphino)propane (0.526 g, 1.28 mmol) in anhydrous THF (10 mL) was

treated with 33% H2O2 (4 mL) added slowly via syringe. The reaction was stirred at rt for

2 h, excess THF was removed by rotary evaporator and the remaining water removed by

high vacuum over night in a 50 °C oil bath. After overnight drying the product was

formed a white powder with spectra matching reported data45: 1H NMR (300 MHz,

CDCl3) δ 7.95 – 7.61 (m, 8H), 7.59 – 7.36 (m, 12H), 2.51 (d, J = 2.6 Hz, 4H), 1.69 (s,

2H); 31P NMR (122 MHz, CDCl3) δ 29.2.

1,4-Bis(diphenylphosphie oxide)butane. A solution of 1,4-

bis(diphenylphosphino)butane (3.05 g, 7.15 mmol) in anhydrous THF (20 mL) was

treated with 33% H2O2 (10 mL) added via syringe. The reaction was stirred at rt for 2 h

as the reaction mixture turned from opaque to a clear solution upon completion. THF was

removed by rotary evaporator, and the precipitate was filtered, washed with cold H2O,

and dried overnight under high vacuum with spectra matching reported data45: 1H NMR

(300 MHz, CDCl3) δ 7.77 – 7.62 (m, 8H), 7.60 – 7.36 (m, 12H), 2.23 (ddd, J = 11.3, 8.5,

5.1 Hz, 4H), 1.75 – 1.64 (m, 4H); 31P NMR (122 MHz, CDCl3) δ 31.8.

1,5-Bis(diphenylphosphie oxide)pentane. A solution of 1,5-

bis(diphenylphosphino)pentane (0.510 g, 1.16 mmol) in anhydrous THF (9 mL) was

treated with 33% H2O2 (3 mL) added via syringe. The reaction was stirred at rt for 2 h,

THF was removed by rotary evaporator and the product partially precipitated in the

32

remaining aqueous layer. The water was removed under high vacuum overnight at 50 °C

to afford a flaky white solid with spectra matching reported data46: 1H NMR (300 MHz,

CDCl3) δ 7.84 – 7.62 (m, 8H), 7.57 – 7.36 (m, 12H), 2.32 – 2.11 (m, 4H), 1.69 – 1.44 (m,

6H); 31P NMR (122 MHz, CDCl3) δ 32.9.

1,1'-(1,2-phenylene)bis(1,1-diphenyl-phosphine oxide. A solution of 1,1'-(1,2-

phenylene)bis(1,1-diphenyl-phosphine) (0.3 g, 0.6 mmol) in anhydrous THF (8 mL) was

treated with 33% H2O2 (2.5 mL) added via syringe. The reaction was stirred at rt for 2 h,

THF was removed by rotary evaporator, and the remaining water was removed under

high vacuum overnight to give a white powder with spectra matching reported data47: 1H

NMR (300 MHz, CDCl3) δ 7.82 – 7.65 (m, 2H), 7.59 (ddq, J = 5.5, 3.7, 2.1 Hz, 2H), 7.54

– 7.38 (m, 9H), 7.36 – 7.20 (m, 7H); 31P NMR (122 MHz, CDCl3) δ 32.3.

1,8-Bis(diphenylphosphine oxide)naphthalene. A solution of 1,4-

bis(diphenylphosphino)naphthalene (0.15 g, 0.30 mmol) in anhydrous THF (4 mL) was

treated with 33% H2O2 (1.1 mL) added via syringe. The reaction mixture was stirred at rt

for 2 h as the mixture turned from opaque to a clear upon completion. THF was removed

by rotary evaporator and the precipitated solid was filtered, washed with cold H2O and

dried overnight under high vacuum with spectra matching reported data48: 1H NMR (400

MHz, CDCl3) δ 8.10 – 7.93 (m, 2H), 7.79 – 7.64 (m, 2H), 7.59 – 7.28 (m, 20H); 13C

NMR (101 MHz, CDCl3) δ 138.2, 137.8, 137.7, 137.1, 134.3, 132.9, 131.5, 131.4, 130.5,

127.8, 127.7, 124.1, 124.0; 31P NMR (162 MHz, CDCl3) δ 31.3.

33

1,2-Bis(diphenylphosphie oxide)xylene. A solution of 1,4-bis(diphenyl-

phosphino)xylene (0.15 g, 0.38 mmol) in anhydrous THF (4 mL) was treated with 33%

H2O2 (1.1 mL) added via syringe. The reaction was stirred at rt for 2 h as the reaction

mixture turned from opaque to a clear solution upon completion. THF was removed by

rotary evaporator and the precipitated solid was filtered, washed with cold H2O, and dried

overnight under high vacuum: 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.31 (m, 2H), 7.11

(dd, J = 5.6, 3.4 Hz, 2H), 3.82 (d, J = 11.4 Hz, 4H), 1.20 (d, J = 13.2 Hz, 33H); 13C NMR

(101 MHz, CDCl3) δ 134.6, 134.6, 134.5, 132.5, 126.5, 36.8, 36.2, 29.6, 29.1, 27.1, 26.1.

IR (ATR) 3056, 2960, 2926, 2855, 1439, 1194, 1115 cm-1; 31P NMR (162 MHz, CDCl3)

δ 63.5. HRMS (ESI) m/z calc for C24H44O2P2 (M+H+) 427.2895; found, 427.2895.

1,1’Bis(diphenylphosphine oxide)ferrocene. A solution of 1,1’-

bis(diphenylphosphino)ferrocene (0.408 g, 0.736 mmol) in anhydrous THF (10 mL) was

treated with 33% H2O2 (4 mL) added via syringe. The reaction was stirred at rt for 2 h,

THF was removed by rotary evaporator and DPPFO2 partially precipitated in the

remaining aqueous layer. The remaining water was removed under high vacuum

overnight at 50 °C. After overnight drying, DPPFO2 formed an orange powder: 1H NMR

(400 MHz, CDCl3) δ 7.69 – 7.21 (m, 20H), 4.68 (s, 4H), 4.27 (s, 4H); 13C NMR (101

MHz, CDCl3) δ 131.6, 131.3, 131.2, 128.3, 128.2, 128.1, 74.1, 74.0, 73.5, 73.4; 31P NMR

(162 MHz, CDCl3) δ 28.6; IR (ATR) 3484, 3098, 3052, 1439, 1168, 1123 cm-1; HRMS

(ESI) m/z calc for C34H28FeO2P2 (M+Li+), 593.1075, found 593.1073.

34

2,2'-Bis(diphenylphosphine oxide)-1,1'-binaphthyl. A solution of 1, (2,2'-

bis(diphenylphosphino)-1,1'-binaphthyl) (0.255 g, 0.410 mmol) in anhydrous THF (20

mL) was treated with 33% H2O2 (3 mL) added slowly via syringe. The reaction was inc.

at rt. for 2 hr. Excess THF was removed by rotary evaporator. The remaining water was

removed from BINAPO2 under high vacuum overnight. After overnight drying,

BINAPO2 formed a white powder spectra matching reported data44: 1H NMR (300 MHz,

CDCl3) δ 7.89 – 7.79 (m, 1H), 7.71 (ddd, J = 12.2, 8.3, 1.4 Hz, 1H), 7.49 – 7.32 (m, 5H),

7.30 – 7.19 (m, 4H), 6.83 – 6.78 (m, 1H). 31P NMR (122 MHz, CDCl3) δ 28.4.

(-)-2,2-Dimethyl-4,5-(Bis(diphenylphosphine oxide)dimethyl)dioxolane. A solution

of (R,R)-DIOP (0.166 g, 0.333 mmol) in anhydrous THF (4 mL) was treated with 33%

H2O2 (1 mL) added via syringe. The reaction was stirred at rt for 2 h, and THF was

removed by rotary evaporator. The partially precipitated (R,R)-DIOPO2 in the remaining

aqueous was dried under high vacuum overnight at 50 °C giving a white powder spectra

matching reported data50: 1H NMR (300 MHz, CD2Cl2) δ 7.86 – 7.69 (m, 8H), 7.57 –

7.42 (m, 12H), 4.17 (q, J = 5.5, 4.9 Hz, 2H), 2.93 (td, J = 15.0, 4.6 Hz, 2H), 2.61 (ddd, J

= 15.2, 8.8, 6.2 Hz, 2H); 31P NMR (122 MHz, CD2Cl2) δ 29.3.

Phosphonium salt 6. In an NMR tube a solution of 1,2-Bis(diphenylphosphine

oxide)ethane (7.5 mg, 0.017 mmol, 1 equiv.) in anhydrous CD2Cl2 (0.5 mL) was treated

with distilled triflic anhydride (10 µL, 0.060 mmol, 3.5 equiv.) under inert nitrogen

atmosphere of a glovebox. The solution was vortexed, stirred at 0 °C for 30 min, and

characterized by NMR: 1H NMR (400 MHz, CD2Cl2) δ 8.10 – 7.54 (m, 20H), 4.46 (d, J =

35

7.2 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 140.0, 135.6, 135.5, 135.4, 132.7, 132.6,

132.5, 123.5, 122.2, 119.3, 118.3, 117.9, 117.0, 24.9, 24.8, 24.1, 24.0; 31P NMR (122

MHz, CD2Cl2) δ 60.2.


oxide)propane (23.8 mg, 0.054 mmol, 1 equiv.) in anhydrous CD2Cl2 (0.5 mL) was

treated with distilled triflic anhydride (10.8 µL, 0.064 mmol, 1.2 equiv.) under inert

nitrogen atmosphere of a glovebox. The solution was vortexed, stirred at 0 °C for 30 min,

and was characterized by NMR: 1H NMR (300 MHz, CD2Cl2) δ 7.89 – 7.61 (m, 20H),

3.12 (dt, J = 11.2, 7.9 Hz, 4H), 2.04 (dt, J = 16.0, 7.9 Hz, 2H); 13C NMR (75 MHz,

CD2Cl2) δ 135.4, 135.4, 135.4, 131.5, 131.4, 131.4, 131.3, 130.1, 130.1, 130.0, 129.9,

129.9, 125.8, 122.2, 121.6, 120.8, 117.3, 113.1, 27.0, 26.8, 26.1, 25.9, 14.1, 14.0, 14.0;

31P NMR (122 MHz, CD2Cl2) δ 85.4.

Phosphonium salt 8. In an NMR tube a solution of 1,4-Bis(diphenylphosphie

oxide)butane (11.3 mg, 0.025 mmol, 1 equiv.) in anhydrous CD2Cl2 (0.5 mL) was treated

with distilled triflic anhydride (4.5 µL, 0.024 mmol, 1.1 equiv.) under inert nitrogen


analyzed by NMR: 1H NMR (300 MHz, CD2Cl2) δ 8.03 – 7.61 (m, 20H), 3.84 (q, J = 5.7

Hz, 4H), 2.61 – 2.38 (m, 4H); 13C NMR (75 MHz, CD2Cl2) δ 139.9, 135.0, 134.9, 134.8,

132.9, 132.8, 132.8, 130.0, 128.4, 124.1, 122.2, 120.0, 119.4, 119.3, 118.6, 117.9, 117.8,

23.4, 23.1, 22.7, 19.2; 31P NMR (122 MHz, CD2Cl2) δ 90.6.

36


oxide)pentane (12.6 mg, 0.027 mmol, 1 equiv.) in anhydrous CD2Cl2 (0.5 mL) was

treated with distilled triflic anhydride (5 µL, 0.029 mmol, 1.1 equiv.) under inert nitrogen


analyzed by NMR: 1H NMR (400 MHz, CD2Cl2) δ 7.91 – 7.52 (m, 20H), 2.90 – 2.64 (m,

4H), 1.69 (d, J = 4.5 Hz, 6H); 13C NMR (75 MHz, CD2Cl2) δ 135.1, 135.1, 131.4, 131.3,

129.9, 129.7, 125.8, 123.0, 121.6, 117.4, 113.2, 30.4, 26.0, 25.2, 19.9, 19.9; 31P NMR

(122 MHz, CD2Cl2) δ 62.0.

Phosphonium salt 10. In an NMR tube a solution of 1,1'-(1,2-phenylene)bis(1,1-diphenyl-

phosphine oxide (17.0 mg, 0.036 mmol, 1.5 equiv.) in anhydrous CD2Cl2 (0.4 mL) was


nitrogen atmosphere of a glovebox. The solution was vortexed, and inc. at 0 °C for 30

min. After 30 min. the reaction was characterized by 1H NMR (300 MHz, CD2Cl2) δ 7.91

– 7.80 (m, 2H), 7.72 – 7.63 (m, 4H), 7.60 – 7.38 (m, 18H).31P NMR (122 MHz, CD2Cl2)

δ 51.81. 13C NMR (101 MHz, CD2Cl2) δ 139.3, 134.8, 134.3, 134.3, 134.2, 131.3, 125.7,

125.6, 124.7, 124.6, 121.3, 119.7, 118.1, 116.5, 115.4, 114.3.


oxide)naphthalene (25.3 mg, 0.048 mmol, 1 equiv.) in anhydrous CD2Cl2 (0.5 mL) was



37

and analyzed by NMR: 1H NMR (400 MHz, CD2Cl2) δ 8.92 – 8.73 (m, 2H), 8.15 (dq, J =

26.6, 8.8, 8.3 Hz, 4H), 8.01 – 7.42 (m, 20H); 31P NMR (162 MHz, CD2Cl2) δ 68.7.


oxide)xylene (26.7 mg, 0.063 mmol, 1 equiv.) in anhydrous CD2Cl2 (0.5 mL) was treated

with distilled triflic anhydride (12.6 µL, 0.075 mmol, 1.2 equiv) under inert nitrogen


analyzed by NMR: 1H NMR (300 MHz, CD2Cl2) δ 7.49 – 7.35 (m, 4H), 3.97 (d, J = 10.8

Hz, 2H), 1.35 (d, J = 15.6 Hz, 32H); 13C NMR (75 MHz, CD2Cl2) δ 135.8, 131.3, 127.9,

123.6, 119.4, 115.2, 39.2, 38.6, 28.0; 31P NMR (122 MHz, CD2Cl2) δ 95.8.

Phosphonium salt 13. In an NMR tube a solution of 1,1’Bis(diphenylphosphine

oxide)ferrocene (43.9 mg, 0.075 mmol, 1 equiv) in anhydrous CD2Cl2 (0.5 mL) was

treated with distilled triflic anhydride (15.1 µL, 0.09 mmol, 1.2 equiv) under inert


and analyzed by NMR: 1H NMR (400 MHz, CD2Cl2) δ 10.12 – 9.59 (m, 4H), 7.27 (s,

2H); 13C NMR (75 MHz, CD2Cl2) δ 140.2, 134.9, 134.8, 134.7, 133.3, 133.2, 133.1,

119.2, 119.0, 118.2, 117.9, 117.4, 117.2, 82.6, 82.5, 82.4, 80.1, 80.0, 80.0; 31P NMR (122

MHz, CD2Cl2) δ 79.2.

Phosphonium salt (R)-14. In an NMR tube a solution of (R)-2,2'-Bis(diphenylphosphine

oxide)-1,1'-binaphthyl (29 mg, 0.044 mmol, 1.5 equiv) in anhydrous CD2Cl2 (0.5 mL)

was treated with distilled triflic anhydride (7.0 µL, 0.037 mmol, 1.25 equiv) under inert

38

nitrogen atmosphere of a glovebox. The solution was vortexed and immediately

characterized by 1H NMR (300 MHz, CD2Cl2) δ 8.00 – 7.90 (m), 7.86 – 7.68 (m), 7.65

(d, J = 1.7 Hz), 7.51 – 7.41 (m), 7.38 – 7.04 (m), 7.02 – 6.87 (m). 31P NMR (122 MHz,

CD2Cl2) δ 40.85. 13C NMR (101 MHz, CD2Cl2) δ 134.9, 134.4, 133.1, 132.3, 132.2,

130.6, 130.5, 130.3, 130.1, 129.8, 129.7, 129.5, 128.6, 128.5, 128.2, 128.1, 127.8, 127.6,

126.8, 121.0, 120.7, 117.8, 117.6.

Phosphonium salt (R)-15. In an NMR tube a solution of (-)-2,2-Dimethyl-4,5-

(Bis(diphenylphosphine oxide)dimethyl)dioxolane (11.5 mg, 0.022 mmol, 1 equiv) in

anhydrous CD2Cl2 (0.4 mL) was treated with distilled triflic anhydride (4.4 µL, 0.026

mmol, 1.2 equiv.) under inert nitrogen atmosphere of a glovebox. The solution was

vortexed, stirred at 0 °C for 30 min, and analyzed by NMR: 1H NMR (300 MHz, CD2Cl2)

δ 8.07 – 7.73 (m, 13H), 7.73 – 7.50 (m, 7H), 4.36 – 4.21 (m, 2H), 3.96 (d, J = 12.3 Hz,

1H), 3.48 (td, J = 16.6, 16.2, 1.8 Hz, 2H), 2.98 (ddd, J = 15.5, 9.0, 6.2 Hz, 1H), 1.07 (s,

6H); 13C NMR (101 MHz, CD2Cl2) δ 137.6, 137.4, 136.2, 135.3, 135.0, 132.8, 132.6,

131.8, 131.6, 131.5, 129.8, 129.7, 129.4, 129.3, 74.6, 74.5, 74.4, 74.3, 25.9; 31P NMR

(122 MHz, CD2Cl2) δ 58.4.

2.4.2: Mechanistic studies of glycosyl donor and cyclic phosphonium interaction

In an NMR tube a solution of DPPBO2 (60.0 mg, 0.131 mmol, 1 equiv) and

2,4,6-tri-tert-butylpyridine (97.1 mg, 0.393 mmol, 3 equiv) in anhydrous CD2Cl2 (0.3

mL) was treated with distilled Tf2O (33.0 µL, 0.197 mmol, 1.5 equiv) under inert

39

nitrogen atmosphere of a glove box. The solution was vortexed and reacted at rt for 5

min. After 10 minutes the mixture was characterized by 1H and 31P NMR. A solution of

2,3,4,6-tetra-O-benzyl-D-glucopyranoside (70.8 mg, 0.131 mmol, 1 equiv) in anhydrous

DCM (0.3mL) was added to the prepared cyclic phosphonium 10 and vortexed to mix

before immediate characterization by 1H and 31P NMR. For full characterization see

Appendix 2.

2.4.3 General dehydrative glycosylation procedure

A typical dehydrative glycosylation procedure: A mixture of diphenyl[4-

(diphenylphosphinyl)butyl]phosphine oxide (0.105 g, 0.230 mmol) and 2,4,6-tri-tert-

butylpyridine (0.170 g, 0.690 mmol) was azeotropically dried with PhMe (2 x 3 mL) and

under high vacuum for 1 h. Freshly activated 4 Å MS (0.10 g) were added to the above

mixture and further dried under high vacuum for 1 h. Anhydrous dichloromethane (3.0

mL) was added, the mixture was cooled to 0 °C, Tf2O (64.9 µL, 0.230 mmol) was added

and stirred at 0 °C for 30 min. 2,3,4,6-Tetra-O-benzyl-D-glucopyranoside (0.083 g, 0.153

mmol) in anhydrous dichloromethane (0.8 mL) was added, stirred for 15 min at 0 °C,

followed by cyclohexanol (32.1 µL, 0.307 mmol). This mixture was stirred at 0 °C for 2

h, quenched with Et3N. The crude product was extracted into additional DCM and

worked up with sat. NaHCO3, brine, dried (Mg2SO4), filtered, and concentrated. The

crude compound was purified by chromatography on SiO2 (Hexanes:EtOAc, 10:1) to

afforded cyclohexyl 2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside 10 (0.950 g, 83%, α/β =

35/65) as a white solid matching reported data38.

40

2.4.4 General dehydrative glycosylation procedure with TBAI modification

A typical dehydrative glycosylation procedure with TBAI: A mixture of

diphenyl[4-(diphenylphosphinyl)butyl]phosphine oxide (0.105 g, 0.230 mmol) and 2,4,6-

tri-tert-butylpyridine (0.170 g, 0.690 mmol) was azeotropically dried with PhMe (2 x 3

mL) and under high vacuum for 1 h. Freshly activated 4 Å MS (0.10 g) were added to the

above mixture and further dried under high vacuum for 1 h. Anhydrous dichloromethane

(3.0 mL) was added, the mixture was cooled to 0 °C, Tf2O (64.9 µL, 0.230 mmol) was

added and stirred at 0 °C for 30 min. 2,3,4,6-Tetra-O-benzyl-D-glucopyranoside (0.083 g,

0.153 mmol) in anhydrous dichloromethane (0.8 mL) was added, stirred for 15 min at 0

°C. A solution of TBAI (0.113 g, 0.306 mmol) and benzyl alcohol (15.9 µL, 0.153 mmol)

in DCM (3 mL) was then added to the reaction at a race of 3.7mL/hr for approximately

45 minutes. After TLF had indicated the reaction was complete (1hr) the crude product

was extracted into additional DCM and worked up with 1x sat. NaHCO3, 1x brine, dried

over Mg2SO4, filtered, and concentrated. The crude compound was purified by

chromatography on SiO2 (Hexanes:EtOAc, 10:1) afforded benzyl 2,3,4,6-tetra-O-benzyl-

β-D-glucopyranoside (0.048 g, 50%, only α) as a colorless oil matching reported data41.

Cyclohexyl 2,3,4-tri-O-benzyl-6-deoxy-β-L-fucopyranose. A mixture of diphenyl[4-

(diphenylphosphinyl)butyl]phosphine oxide (0.105 g, 0.230 mmol) and 2,4,6-tri-tert-

butylpyridine (0.170 g, 0.690 mmol) was azeotropically dried with PhMe (2 x 3 mL) and

under high vacuum for 1 h. Freshly activated 4 Å MS (0.10 g) were added to the above

41

mixture and further dried under high vacuum for 1 h. Anhydrous dichloromethane (3.0

mL) was added, the mixture was cooled to 0 °C, Tf2O (23.2 µL, 0.138 mmol) was added

and stirred at 0 °C for 30 min. 2,3,4-tri-O-benzyl-6-deoxy-β-L-fucopyranose (0.040 g,


°C. A solution of TBAI (0.070 g, 0.184 mmol) and cyclohexanol (4.6 µL, 0.046 mmol) in

DCM (3 mL) was then added to the reaction at a race of 3.7mL/hr for approximately 45

minutes. After TLC had indicated the reaction was complete (1hr) the crude product was

extracted into additional DCM and worked up with 1x sat. NaHCO3, 1x brine, dried over

Mg2SO4, filtered, and concentrated. The crude compound was purified by

chromatography on SiO2 (Hexanes:EtOAc, 10:1) afforded cyclohexyl 2,3,4-tri-O-benzyl-

6-deoxy-β-L-fucopyranose (0.030 g, 64%, only 71:29 α:β) as a colorless oil. [α]D23 -0.3 (c

0.6, CHCl3); IR (ATR) 2944, 2859, 1455, 1366, 1071, 1030 cm-1; 1H NMR (500 MHz,

CDCl3) δ 7.39 – 7.27 (m, 15 H), 4.98 (dd, J = 11.3, 5.0 Hz, 1H), 4.80 – 4.69 (m, 4H),

4.42 (d, J = 7.7 Hz, 1H), 3.78 (dd, J = 9.7, 7.7 Hz, 1H), 3.70 – 3.63 (m, 1H), 3.54 (dd, J =

3.0, 1.0 Hz, 1H), 3.49 (dd, J = 9.7, 3.0 Hz, 1H), 3.44-3.40 (m, 1H), 1.97 – 1.90 (m, 2H),

1.76 – 1.72 (m, 2H), 1.52 – 1.20 (m, 7H), 1.15 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz,

CDCl3) δ 139.0, 138.8, 138.7, 128.6, 128.3, 128.2(2), 128.1, 127.5(2), 127.4, 101.8, 82.8,

79.5, 76.3, 75.1, 74.4, 73.2, 70.2, 33.6, 31.8, 25.7, 24.1, 24.0, 17.0; HRMS (ESI) m/z calc

for C33H40O5Li (M+Li+) 523.3036, found 523.3037.

Cyclohexyl 2,3,5-tri-O-benzyl-α-D-ribofuranoside. A mixture of diphenyl[4-

(diphenylphosphinyl)butyl]phosphine oxide (0.40.8 g, 0.089 mmol) and 2,4,6-tri-tert-

butylpyridine (0.52.9 g, 0.089 mmol) was azeotropically dried with PhMe (2 x 3 mL)

42

and under high vacuum for 1 h. Freshly activated 4 Å MS (0.10 g) were added to the



added and stirred at 0 °C for 30 min. 2,3,5-tri-O-benzyl-α-D-ribofuranoside (0.030 g,


°C. A solution of TBAI (0.053 g, 0.143 mmol) and cyclo58hexanol (2.2 µL, 0.021 mmol)


45 minutes. After TLC had indicated the reaction was complete (1hr) the crude product



chromatography on SiO2 (Hexanes:EtOAc, 10:1) afforded Cyclohexyl 2,3,5-tri-O-benzyl-

α-D-ribofuranoside (0.011 g, 76%, only α) as a white foam. [α]D23 +103.6 (c 0.5, CHCl3);

IR (ATR) 2937, 1455, 1221, 1030 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.21 (m,

15H), 5.18 (d, J = 4.2 Hz, 1H), 4.72 (d, J = 13.2 Hz, 2H), 4.62 (d, J = 12.3 Hz, 1H), 4.54

– 4.41 (m, 3H), 4.24 (q, J = 3.9 Hz, 1H), 3.84 – 3.82 (m, 1H), 3.77 – 3.75 (m, 1H), 3.62 –

3.58 (m, 1H), 3.46 (dd, J = 10.6, 3.7 Hz, 1H), 3.37 (dd, J = 10.5, 4.2 Hz, 1H), 1.98 – 1.92

(m, 2H), 1.77 – 1.75 (m, 2H), 1.56 -1.17 (m, 7H); 13C NMR (75 MHz, CDCl3) δ 138.6,

138.2, 138.0, 128.3 (2), 128.2, 128.0 (2), 127.7, 127.6 (2), 127.5, 99.6, 80.9, 76.2, 75.5,

73.4, 72.3, 72.1, 69.9, 33.8, 31.9, 25.7, 24.6, 24.5; HRMS (ESI) m/z calc for C32H38O5Li

(M+Li+) 509.2880, found 509.2880.

Cyclohexyl 2,3-bis-O-(phenylmethyl)-4,6-O-[(R)-phenylmethylene]-β-D-

mannopyranoside. A mixture of diphenyl[4-(diphenylphosphinyl)butyl]phosphine oxide

43

(0.077 g, 0.167 mmol) and 2,4,6-tri-tert-butylpyridine (0.099 g, 0.400 mmol) was

azeotropically dried with PhMe (2 x 3 mL) and under high vacuum for 1 h. Freshly

activated 4 Å MS (0.10 g) were added to the above mixture and further dried under high

vacuum for 1 h. Anhydrous dichloromethane (1.5 mL) and 1,2-dichloroethane (1.5 mL)

was added, the mixture was cooled to 0 °C, Tf2O (34.0 µL, 0.200 mmol) was added and

stirred at 0 °C for 30 min. 2,3-bis-O-(phenylmethyl)-4,6-O-[(R)-phenylmethylene]-β-D-

mannopyranoside (0.050 g, 0.111 mmol) in anhydrous dichloromethane (1.5 mL) and

1,2-dichloroethane (1.5 mL) with TBAI (0.098g, 0.266) was added via syringe pump at a

rate of 3.7mL/hr. at 0 °C. After TLC had indicated the reaction was complete (1hr) the

crude product was extracted into additional DCM and worked up with 1x sat. NaHCO3,

1x brine, dried over Mg2SO4, filtered, and concentrated. The crude compound was

purified by chromatography on SiO2 (Hexanes:EtOAc, 10:1) afforded cyclohexyl 2,3-bis-

O-(phenylmethyl)-4,6-O-[(R)-phenylmethylene]-β-D-mannopyranoside (0.010 g, 56%,

67:33 α:β) as a colorless oil. [α]D23 -73 (c 0.45, CHCl3); IR (ATR) 2937, 2863, 1459,

1221, 1093 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.51 – 7.28 (m, 15 H), 5.62 (s, 1H), 5.02

(d, J = 12.5 Hz, 1H), 4.91 (d, J = 12.5 Hz, 1H), 4.66 (d, J = 12.5 Hz, 1H), 4.59 – 4.57 (m,

2H), 4.30 (dd, J = 10.4, 4.8 Hz, 1H), 4.22 (t, J = 9.6 Hz, 1H), 3.95 (t, J = 10.3 Hz, 1H),

3.88 (d, J = 3.2 Hz, 1H), 3.73-3.68 (m, 1H), 3.58 (dd, J = 9.9, 3.2 Hz, 1H), 3.32 (td, J =

9.7, 4.8 Hz, 1H), 1.92 – 1.70 (m, 4H), 1.56 – 1.26 (m, 7H); 13C NMR (75 MHz, CDCl3) δ

138.5, 138.4, 137.6, 128.8, 128.7, 128.3, 128.2, 128.1, 127.5, 126.0, 101.4, 100.0, 78.6,

78.1, 76.2, 74.6, 72.3, 68.7, 67.5, 33.4, 31.4, 25.6, 23.7, 23.6 ; HRMS (ESI) m/z calc for

C33H38O6Li (M+Li+) 537.2829, found 537.2842.

44

Methyl 6-O-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)- 2,3,4-tri-O-benzyl-α-D-

glucopyranoside. A mixture of diphenyl[4-(diphenylphosphinyl)butyl]phosphine oxide

(0.105 g, 0.230 mmol) and 2,4,6-tri-tert-butylpyridine (0.170 g, 0.690 mmol) was

azeotropically dried with PhMe (2 x 3 mL) and under high vacuum for 1 h. Freshly

activated 4 Å MS (0.10 g) were added to the above mixture and further dried under high

vacuum for 1 h. Anhydrous dichloromethane (1.5 mL) and 1,2-dichloroethane (1.5 mL)

was added, the mixture was cooled to 0 °C, Tf2O (25.5 µL, 0.152 mmol) was added and

stirred at 0 °C for 30 min. 2,3,4-tri-O-benzyl-α-D-glucopyranoside (0.055 g, 0.101 mmol)

in anhydrous dichloromethane (0.8 mL) and 1,2-dichloroethane (0.8 mL) was added,

stirred for 15 min at 0 °C. A solution of Methyl 6-O-(2,3,4,6-tetra-O-benzyl-α-D-

glucopyranose (0.016, 0.034 mmol) in DCM (1 mL) was then added to the reaction. After

TLC had indicated the reaction was complete (1hr) the crude product was extracted into

additional DCM and worked up with 1x sat. NaHCO3, 1x brine, dried over Mg2SO4,

filtered, and concentrated. The crude compound was purified by chromatography on SiO2

(Hexanes:EtOAc, 10:1) afforded Methyl 6-O-(2,3,4,6-tetra-O-benzyl-α-D-

glucopyranosyl)- 2,3,4-tri-O-benzyl-α-D-glucopyranoside (0.030 g, 89%, 85:15 α:β) as a

colorless oil as a clear oil: [α]D23 +7.7 (c 2, CHCl3); IR (ATR) 2930, 1731, 1264, 1072,

1031 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.09 (dd, J = 8.3, 1.4 Hz, 2H), 8.05 (dd, J =

8.3, 1.4 Hz, 2H), 7.90 – 7.92 (m, 2H), 7.84 (dd, J = 8.4, 1.4 Hz, 2H), 7.61 – 7.26 (m,

27H), 6.08 (t, J = 10.1 Hz, 1H), 5.89 (dd, J = 10.1, 3.3 Hz, 1H), 5.74 (dd, J = 3.4, 1.8 Hz,

1H), 5.17 (d, J = 1.8 Hz, 1H), 5.03 (dd, J = 11.1, 2.7 Hz, 2H), 4.85 – 4.80 (m, 2H), 4.70

(dd, J = 11.7, 3.1 Hz, 2H), 4.66 – 4.63 (m, 2H), 4.43 – 4.40 (m, 1H), 4.35 (dd, J = 12.1,

4.4 Hz, 1H), 4.05 (t, J = 9.2 Hz, 1H), 3.95 (dd, J = 11.0, 5.1 Hz, 1H), 3.89 – 3.86 (m,

45

1H), 3.82 (dd, J = 11.0, 1.8 Hz, 1H), 3.60 – 3.52 (m, 2H), 3.46 (s, 3H); 13C NMR (75

MHz, CDCl3) δ 166.1, 165.4(2), 165.3, 138.7, 138.2(2), 133.4, 133.2, 133.1, 129.9(2),

129.7(2), 129.4, 129.1, 129.0, 128.6, 128.5(2), 128.4, 128.3, 128.1, 128.0, 127.9, 127.8,

127.6(2), 97.9, 97.8, 82.1, 80.2, 77.7, 75.7, 75.0, 73.5, 70.3, 70.0, 69.9, 68.9, 66.9, 66.7,

62.7, 55.2; HRMS (ESI) m/z calc for C62H58O15Li (M+Li+) 1049.3937, found 1049.3922.

(3β)-cholest-5-en-3-ol 2,3,4,6-tetra-O-benzyl-D-galactopyranose. A mixture of

diphenyl[4-(diphenylphosphinyl)butyl]phosphine oxide (0.014 g, 0.032 mmol) and 2,4,6-

tri-tert-butylpyridine (0.093 g, 0.078 mmol) was azeotropically dried with PhMe (2 x 3

mL) and under high vacuum for 1 h. Freshly activated 4 Å MS (0.10 g) were added to the



added and stirred at 0 °C for 30 min. 2,3,4,6-tetra-O-benzyl-D-galactopyranose (0.014 g,


°C. A solution of TBAI (0.019 g, 0.052 mmol) and benzyl alcohol (0.004g, 0.010 mmol)


45 minutes. After TLC had indicated the reaction was complete (1hr) the crude product



chromatography on SiO2 (Hexanes:EtOAc, 10:1) afforded (3β)-cholest-5-en-3-ol 2,3,4,6-

tetra-O-benzyl-D-galactopyranose (0.009 g, 88%, 64:36 α:β) as a colorless oil matching

reported data32.

46

2.4.5: Mechanistic studies of TFE and cyclic phosphonium interaction

In an NMR tube a solution of DPPBO2 (60.0 mg, 0.131 mmol, 1 equiv.) and

2,4,6-tri-tert-butylpyridine (97.1 mg, 0.393 mmol, 3 equiv) in anhydrous CD2Cl2 (0.35

mL) was treated with distilled Tf2O (33.0 µL, 0.197 mmol, 1.5 equiv.) under inert

nitrogen atmosphere of a glovebox. The solution was vortexed and reacted at 0°C for 30

min. After 30 minutes this mixture was characterized by NMR: 1H NMR (400 MHz,

CD2Cl2) 7.89 (dq, J = 13.8, 7.6 Hz, 12H), 7.70 (dt, J = 10.8, 5.2 Hz, 4H), 3.86 (d, J = 7.3

Hz, 4H), 2.47 (dt, J = 16.0, 5.8 Hz, 4H); 31P NMR (162 MHz, CD2Cl2) δ 91.7. To this

solution was added freshly distilled 2,2,2-triflouroethanol (60.0 mg, 0.131 mmol, 1

equiv.) under inert atmosphere. This was repeated with 0.5, 1.0, and 2.0 equiv. The new

solution was votrexed and characterized by 1D NMR: 1H NMR (400 MHz, CD2Cl2); 31P

NMR; and 2D NOESY experiments.

Chapter 3: α-Selective Glycosylation of Glycosyl Phosphinites

3.1: α-selective glycosylation reactions

The use of in situ anomerization in highly α-selective glycosylations has been

well reported by Lemieux34 and Mukaiyama37-39 with anomeric bromides but with limited

substrate scope. In the case of the work by Lemieux, α-glycosyl halides were reacted

with quaternary ammonium halide salts. Addition of excess of halide salt promoted in

47

situ anomerization between the stable α-halide and the more reactive β-halide. Once the

reactive β-halide forms, it undergoes glycosylation to give the α-anomer (Scheme 3.1).

The method used by Lemieux was limited by the necessity to prepare unstable anomeric

bromides as glycosyl donors.

Later work by Mukaiyama37 relied primarily upon the preparation of the more

stable glycosyl phosphinites but under harsh conditions and with limited ribofuranose

substrates. Typical conditions for preparation of glycosyl phosphinites relied upon the use

of n-butyl lithium with a suitable glycosyl donor in the presence of

chlorodiphenylphosphine. The corresponding glycosyl phosphinites were then reacted

with TBAI in the presence of a glycosyl acceptor. While the yields and selectivities of

this reaction were high, application of this method to more complicated glycosyl donors

would be problematic while using strongly basic reagents such as n-butyl lithium. It was

envisioned that development of a new method to prepare glycosyl phosphinites under

mild conditions with a wide range of functional groups would allow for an expanded

reaction scope to this method and also allow for application to more complicated

molecules with a high degree of α-glycosidic linkages.

The work described herein shows how a library of glycosyl phosphinites were

prepared under mildly basic conditions from the corresponding chlorophosphines and

characterized. The optimized reaction conditions were then used in a number of

glycosylation examples demonstrating high α-selectivity and good yields. A series of

mechanistic 1H and 31P NMR studies were performed to better understand the mechanism

of this glycosylation reaction. Development of highly α-selective glycosylation methods

is highly useful because inherently α-selective reactions with wide functional group

48

tolerances and substrate scope are still uncommon. While β-selective glycosylations are

relatively easy with the use of protecting groups, exploration of anomeric in situ

anomerization as a route to α-selective glycosylations could possibly represent an

analogous method to C-2 neighboring group participation, enabling the practical

synthesis of practical α-glycosides, especially carbohydrate-containing natural products

with numerous α-glycosidic linkages such as Axinelloside A42.

3.2: Preparation of glycosyl phosphinites

It was known based on work by Mukaiyama that preparation of ribose glycosyl

phosphinites from 2,3,5-tri-O-benzyl-D-ribose preceded smoothly with n-butyl lithium in

the presence of a suitable chlorophosphine (ClPR2). In an effort to expand this method to

a range of substrates and with wide functional group compatibility, a series of mild bases

were first evaluated with commercially available chlorodiphenylphosphine (Table 3.1).

The base optimization experiments indicated that 1,8-Diazabicycloundec-7-ene (DBU)

resulted in the highest yield and the shortest reaction time as well as giving minimal

elimination product of all bases tested. An excess of DBU (3 equiv) was also found to be

optimal. It was notable that DBU had similar efficiency for the preparation of glycosyl

phosphinite 27 than the reported Mukaiyama procedure using n-butyllithium however,

under more mild conditions.

OOH

ClPR2, Base

CH2Cl2 rt

OBn

BnOBnO

OBn

OOPPh2

OBn

BnOBnO

OBn

2726

49

Entry Base Time (min) Yield α:β

1 nBuLi 5 85% 21:79

2 nBuLi >5 <5% N.D.

3 Et3N 5 32% 58:42

4 Et3N 30 45% 58:42

5 Et3N 60 70% 56:44

6 pyridine 30 30% 18:82

7 DABCO 30 65% 10:90

8 DBU 30 89% 45:55

9 DBU 60 71% 45:55

10 DIPEA 12 hr <5% 49:51

Table 3.1 Base optimizations for the preparation of glycosyl phosphinites.

With these conditions in place, a collection of various glycosyl phosphinites were

prepared from a number of commercially available chlorophosphines. These

chlorophosphines were then screened in glycosylation reactions with cyclohexanol in the

presence of iodomethane as an electrophile in methylene chloride over the course of

several days (Table 3.2). Ultimately chlorophosphines (ClPR2) where R = phenyl, 4-

methoxyphenyl (PMP), and aminodiisopropyl (N(iPr)2) had the highest yields however,

only the glycosyl phosphinite prepared from ClPPh2 gave the desired α-selective product

(Table 3.2). The glycosylation was also tested in DMF, toluene, MeCN, and THF

however, in each case the yield and selectivities observed were inferior to conditions with

DCM.

50

Entry R Solvent Yield α:β Time 1 N(iPr)2 CH2Cl2 55% 52:48 3 d 2 iPr CH2Cl2 no rxn. - - 3 PMP CH2Cl2 75% 52:48 3 d 4 Ph DMF 64% 58:42 2.5 d 5 Ph PhMe 32% 76:24 2.5 d 6 Ph MeCN 62% 62:38 3 d 7 Ph THF no rxn. - - 8 Ph DCM 69% 99:5 3 d

Table

3.2 Optimization of glycosyl phosphinites in α-selective glycosylations.

3.3.1: Substrate scope

In order to test the scope of this method with more complex molecules, various

glycosyl donors were prepared and subjected to the conditions described above for the

preparation of glycosyl phosphinites followed by reaction with iodomethane and a

suitable glycosyl acceptor (Table 3.3). Glycosylation of 2,3,4,6-tetra-O-benzyl glucose

and galactose with 1,2:3,4-Di-O-isopropylidene-α-galactose yielded the glycosylation

products in 80% and 60% yields, respectively with excellent α:β selectivities of 92:8-

>99:1. Glycosylation with 3,4-di-O-benzoyl-2-O-benzyl-arabinose and the same acceptor

gave the corresponding product in 73% yield with only the α-anomer observed.

Donor Acceptor Yield α:β

OOH

1. ClPR2, DBU

CH2Cl2 rt

OBn

BnOBnO

OBn

OOCy

OBn

BnOBnO

OBn

2. MeI, CyOH

51

26

28

80% 92:8

29

28

60% >99:1

30

28

73% only α

Table 3.3 Reaction scope of glycosylation with anomeric phosphinites.

examples using the reported optimized conditions for preparation of glycosyl

phosphinites and corresponding glycosylation.

This method was also used with a number of other glycosyl donors and acceptors

by Dr. Jie Guang demonstrating similar yields and selectivities. Taken together these

results show that glycosyl phosphinites can be prepared under mild basic conditions from

a number of glycosyl donors and used in glycosylation reaction that give highly α-

selective and high yielding products.

3.4: Mechanistic studies

A number of mechanistic NMR studies were undertaken to better understand

OOH

OBnOBn

BnOOBn

OO

OHO

OO

OBnO OBn

BnOBnO

OH

OO

OHO

OO

OOHBzO

OBz OBnO

O

OHO

OO

52

the observed high α-selectivity of these reactions and the significant time (3d) required

for the reaction to go to completion. It was predicted that glycosylation with glycosyl

phosphinites proceeds through in situ anomerization of the glycosyl iodide (Scheme 3.1).

The glycosyl phosphinite 31 with iodomethane electrophile was observed every hour by

31P NMR for 13 hours (Figure 3.1) during conversion via pathway 32.

Scheme 3.1 Proposed mechanism of α-selective glycosylation with glycosyl

phosphinites.

O(BnO)n

OPPh2

MeI O(BnO)n

O PPh2Me

O(BnO)n

O PPh2Me

O(BnO)n

I

OPPhPh

Me

ROH O(BnO)n

OR

3231

53

Figure 3.1 glycosyl phosphinite 31 reacted with iodomethane observed via 31P NMR

each hour over the course of 12 hours.

The α/β glycosyl phosphinites (31P NMR δ =155.9, 114.2) were slowly consumed over

the course of the experiment (14h). After approximately 14 hours almost none of the

glycosyl phosphinite remained. At this point cyclohexanol was added and the reaction

was observed every 12 hours an additional 72 hours (Figure 3.2). After 72 hours no

further change was observed in the 31P NMR spectra. The reaction progress was

monitored via TLC, indicating that the glycosylation to give product 20 was complete.

Over the course of the glycosylation the 31P shift of the corresponding

methyldiphenylphosphine oxide (prepared and observed independently) peak can be

1520253035404550556065707580859095100105110115120125 ppm

13 hr

0 hr

54

explained by the anomeric iodide existing as an iodine-phosphine oxide complex with the

shift corresponding to the consumption of anomeric iodide as the reaction progresses.

Figure 3.2 31P NMR of glycosyl intermediate 32 reacted with cyclohexanol over the

course of 3 days.

Given these observations, conversion to the anomeric iodide is relatively fast (13

hours) compared to the glycosylation (72 hours). Under these conditions the more

reactive β-iodide reacts readily once formed to give the α-glycosylation product whereas

slow conversion of anomeric-effect-stabilized α-iodide to the reactive β-intermediate

5101520253035404550556065707580859095100105110115120125 ppm

0 hr

72 hr

55

explains the extended reaction times and the nature of observed high α-selectivity.

3.5: Methods

General: All chemicals used were reagent grade without further purification, unless

otherwise noted. DCM, THF, Et2O, PhME, and DMF were filtered through a column of

activated alumina prior to use. All reactions were carried out under dry N2 atmosphere.

Glassware used was dried in an oven. Trifluoromethanesulfonic anhydride was distilled

from phosphorus pentoxide. MeCN, pyridine, DIPEA, and Et3N were distilled from

CaH2. TLC analyses were performed on Merck TLC plates and visualizations were

performed with Hanessian stain. Column chromatography was performed on silica gel

(230-400 mesh). 1H and 13C NMR spectra were recorded on Bruker/Varian/Varian

300/400/500 MHz instruments are reported as follows: chemical shift (δ), multiplicity (s

= singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling

constants (Hz), and integration. NMR experiments carried out under inert N2 atmosphere

were performed within a glovebox. The residual solvent reference peaks were used from

published literature.43 2D NMR experiments were performed using standard parameters

(200 and More NMR Experiments, S. Berger, S. Braun, Wiley-VCH, 2004). IR

measurements were performed on Agilent Cary 630 FT/IR instrument and optical

rotations were measured on JASCO P-1030 and are reported as an average of ten data

points.

56

3.5.1: General preparation of glycosyl phosphinites

2,3,4,6-tetra-O-benzyl-D-glucose 19 was evaporated 2x azeotropically from

PhMe and then dried under high vacuum for 30 min. Under N2 atm. at rt 19 was dissolved

in anhydrous CH2Cl2 and stirred. To this stirring solution was added DBU followed by

ClP(R)2 via microsyringe. For ClP(PMP)2 and ClP(N(iPr)2)2, chlorophosphines were dried

under high vacuum in a 10 mL rbf before dissolving in 1 mL anhydrous CH2Cl2 and

adding to the stirred solution via syringe after addition of DBU. DBU, nBuLi, Et3N, or

pyridine bases were via microsyringe. DABCO was dissolved with the initial

glucopyranoside 19 and dried azeotropically from PhMe, dried under high vacuum and

dissolved in anhydrous CH2Cl2 before stirred as described above. Chlorophosphines were

directly added as described above. Glycosyl phosphinites were purified via flash

chromatography over SiO2 (Hexanes:EtOAc) over SiO2.and characterized by 1H, 31P, 13C,

and HSQC (see Appendix 4).

2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl diphenylphosphinite (27).

248.0 mg (0..459 mmol) of 2,3,4,6-tetra-O-benzyl glucopyranoside 19 was evaporated 2x

azeotropically from PhMe and then dried under high vacuum for 30 min. Under N2 atm.

at rt 19 was dissolved in anhydrous CH2Cl2 (12 mL) and stirred. To this stirring solution

was added 1,8-Diazabicycloundec-7-ene (194.0 µL, 1.377 mmol) followed by

chlorodiphenylphosphine (98.9.0 µL, 0.551 mmol) via microsyringe. This reaction was

stirred for 35 minutes at rt before TLC indicated the reaction was complete. The reaction

57

mixture was evaporated under reduced pressure and purified via flash chromatography

over SiO2 to give 296.0 mg of the title compound as a white solid in 89% yield (45:55

α:β) matching data reported in literature.51 1H NMR (300 MHz, Methylene Chloride-d2)

7.58 - 7.39 (m, 8H), 7.35 - 7.01 (m, 21H), 6.99 - 6.91 (m, 1H), 5.40 (dd, J = 8.3, 3.5 Hz,

1H), 4.86 (d, J = 11.0 Hz, 1H), 4.80 - 4.73 (m, 2H), 4.72 - 4.68 (m, 1H), 4.66 - 4.54 (m,

3H), 4.48 (d, J = 26.3 Hz, 1H), 4.41 - 4.36 (m, 1H), 4.32 (d, J = 15.4 Hz, 1H), 3.98 - 3.88

(m, 0H), 3.64 ? 3.45 (m, 7H). 13C NMR (75 MHz, CD2Cl2) 142.0, 141.7, 141.6, 141.4,

139.1, 138.8, 138.5, 138.4, 138.3, 138.3, 131.5, 131.2, 130.5, 130.2, 130.1, 129.8, 129.8,

129.1, 129.0, 128.4, 128.3 (2), 128.2, 128.2, 128.1, 128.1 (2), 27.8, 127.7, 127.6, 127.5,

127.5, 127.4, 127.4, 103.4, 103.2, 98.6, 98.3, 84.6, 81.6, 80.9, 80.8, 77.7, 77.5, 75.5, 75.4,

75.3, 74.9, 74.8, 74.8, 73.4, 73.1, 72.7, 71.4, 68.7, 68.3, 54.1, 53.8, 53.4, 53.1, 52.7. 31P

NMR (122 MHz, CD2Cl2) 115.9, 114.2.

3.5.2: Optimization of glycosylation conditions with glycosyl phosphinites

2,3,4,6-tetra-O-benzyl-D-glucose 26 (71.8 mg, 0.099 mmol, 1 equiv.) was

evaporated 2x azeotropically from PhMe and then dried under high vacuum for 30 min.

Under N2 atm. at rt 26 was then dissolved in anhydrous CH2Cl2 (5 mL) and stirred. To

this stirring solution was added 1,8-Diazabicycloundec-7-ene (44.4 µL, 0.297 mmol, 3

equiv.) followed by chlorodiphenylphosphine (21.3 µL, 0.119 mmol, 1.2 equiv.) via

microsyringe. This reaction was stirred for 35 minutes at rt before TLC indicated the

reaction was complete. The reaction mixture was evaporated under reduced pressure and

filtered through a small plug of SiO2 to remove excess base (2:1 Hexanes:EtOAc) to give

58

the crude glycosyl phosphinite 27 as a white solid in quantitative yield. The filtered

product was dried under high vacuum for 30 min. Under N2 atm. and at rt 27 was

dissolved in anhydrous CH2Cl2 and stirred. To this stirring solution was added

iodomethane (10.2 µL, 0.163 mmol, 1.6 equiv.) followed by a solution of distilled

cyclohexanol (11.4 mg, .109 mmol 1.1 equiv.) in 0.5 mL anhydrous CH2Cl2. The reaction

mixture was allowed to stir at rt for 3 d. before TLC indicated the reaction was complete.

The reaction was then concentrated under reduced pressure, dissolved in EtOAc and

worked up with 1x75mL sat. NaHCO3, 50 mL dH2O, and 50 mL sat. NaCl solution. The

organic layer was then dried over MgSO4, filtered, and concentrated under reduced

pressure. The crude product was purified over SiO2 (4:1 Hexanes:EtOAc) to give 45.0

mg of cyclohexyl 2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside as a colorless oil in 69%

yield (95:5 α:β): matching data previously reported in literature.41

3.5.3: Glycosylations with glycosyl phosphinites

1,2,3,4-di-O-isipropylidine galactopyranoside-(2-O-benzyl-3,4-O-di-benzoyl-α-D-

arabinopyranoside) A typical glycosylation using glycosyl phosphinites follows as

such: 2-O-benzyl-3,4-O-di-benzoyl-α-D-arabinopyranoside (53.0 mg, 0.118 mmol, 1

equiv) was evaporated 2x azeotropically from PhMe and then dried under high vacuum

for 30 min. Under N2 atm. at rt 30 was dissolved in anhydrous CH2Cl2 (5 mL) and stirred.

To this stirring solution was added 1,8-Diazabicycloundec-7-ene (50.0 µL, 0.355 mmol, 3

equiv) followed by chlorodiphenylphosphine (26.0 µL, 0.143 mmol, 1.2 equiv) via

microsyringe. This reaction was stirred for 35 minutes at rt before TLC indicated the

59

reaction was complete. The reaction mixture was evaporated under reduced pressure and

filtered through a small plug of SiO2 to remove excess base (2:1 hexanes:EtOAc) to give

the crude arabinosyl phosphinite as a white solid. The filtered product was dried under

high vacuum for 30 min. Under N2 atm. and at rt the white solid was dissolved in

anhydrous CH2Cl2 and stirred. To this stirring solution was added iodomethane (22.0 µL,

0.089 mmol) followed by a solution of 1,2,3,4-di-isopropylidine-D-galactopyranoside (23

mg, 0.075mmol) in 0.5 mL anhydrous CH2Cl2. The reaction mixture was allowed to stir at

rt for 3 d. before TLC indicated the reaction was complete. The reaction was then

concentrated under reduced pressure, dissolved in EtOAc and worked up with 75mL sat.

NaHCO3, 50 mL dH2O, and 50 mL sat. NaCl solution. The organic layer was then dried

over MgSO4, filtered, and concentrated under reduced pressure. The crude product was

purified over SiO2 (2:1 Hexanes:EtOAc) to give 36.1 mg of the title compound as a

colorless oil in 73% yield (only α). 1H, 13C, and HSQC NMR characterization data can be

found in Appendix 10. 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 8.1 Hz, 2H), 7.89 (d, J

= 8.1 Hz, 2H), 7.60 (t, J = 7.0 Hz, 1H), 7.52 (t, J = 7.0 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H),

7.39 – 7.24 (m, 7H), 5.73 (dd, J = 10.2, 3.2 Hz, 1H), 5.66 (s, 1H), 5.58 (d, J = 5.0 Hz,

1H), 5.23 (d, J = 3.1 Hz, 1H), 4.73 (q, J = 12.4 Hz, 2H), 4.64 (d, J = 7.9 Hz, 1H), 4.39 –

4.33 (m, 2H), 4.25 (d, J = 13.1 Hz, 1H), 4.20 – 4.09 (m, 5H), 3.92 (dd, J = 10.5, 6.2 Hz,

1H), 3.87 – 3.75 (m, 2H), 1.53 (s, 3H), 1.47 (s, 3H), 1.36 (d, J = 15.9 Hz, 6H). 13C NMR

(75 MHz, CDCl3) δ 165.7, 165.5, 161.3, 137.9, 133.2, 133.0, 129.9, 129.8, 129.7, 129.7,

128.40, 128.3, 128.3, 127.9, 127.7, 109.3, 108.6, 97.7, 96.3, 73.5, 72.3, 71.0, 70.6, 70.5,

69.6, 67.0, 66.3, 60.9, 60.4, 30.9, 26.1, 26.0, 24.9, 24.6, 21.1, 14.2.

60

1,2,3,4-di-O-isipropylidine galactopyranoside-(2,3,4,6-tetra-O-benzyl

mannopyranoside). 86.0 mg (0.159 mmol) of 2,3,4,6-tetra-O-benzyl mannopyranoside

29 was evaporated 2x azeotropically from PhMe and then dried under high vacuum for

30 min. Under N2 atm. at rt 29 was dissolved in anhydrous CH2Cl2 (7 mL) and stirred. To

this stirring solution was added 1,8-Diazabicycloundec-7-ene (28.0 µL, 0..239 mmol)

followed by chlorodiphenylphosphine (34.3 µL, 0.191 mmol) via microsyringe. This

reaction was stirred for 35 minutes at rt before TLC indicated the reaction was complete.

The reaction mixture was evaporated under reduced pressure and filtered through a small

plug of SiO2 to remove excess base (2:1 Hexanes:EtOAc) to give the crude arabinosyl

phisphinte as a white solid. The filtered product was dried under high vacuum for 30 min.

Under N2 atm. and at rt the white solid was dissolved in anhydrous CH2Cl2 and stirred.

To this stirring solution was added iodomethane (20.0 µL, 0.318 mmol) followed by a

solution of 1,2,3,4-di-isopropylidine-D-galactopyranoside (19 mg, 0..075) in 0.5 mL

anhydrous CH2Cl2. The reaction mixture was allowed to stir at rt for 3 d. before TLC

indicated the reaction was complete. The reaction was then concentrated under reduced

pressure, dissolved in EtOAc and worked up with 1x75mL sat. NaHCO3, 1x 50 mL

dH2O, and 1x50 mL sat. NaCl solution. The organic layer was then dried over MgSO4,

filtered, and concentrated under reduced pressure. The crude product was purified over

SiO2 (2:1 Hexanes:EtOAc) to give 36.1 mg of the title compound as a colorless oil in

60% yield (>99:1 α:β). 1H, 13C, and HSQC NMR characterization data can be found in

Appendix 11. 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.2 Hz, 1H), 7.33 (m, 16H),

7.21 – 7.16 (m, 4H), 5.55 (d, J = 5.0 Hz, 1H), 4.89 (d, J = 10.6 Hz, 1H), 4.76 (d, J = 5.5

Hz, 2H), 4.74 – 4.69 (m, 1H), 4.66 – 4.58 (m, 5H), 4.54 (dd, J = 15.3, 9.6 Hz, 4H), 4.38 –

61

4.32 (m, 2H), 4.18 (dd, J = 7.9, 1.4 Hz, 2H), 4.08 – 4.02 (m, 2H), 4.02 – 3.90 (m, 3H),

3.87 – 3.78 (m, 6H), 3.74 (qd, J = 10.4, 6.4 Hz, 3H), 1.53 (s, 3H), 1.46 (s, 3H), 1.35 (s,

6H). 13C NMR (75 MHz, CDCl3) 138.6, 138.5, 138.5, 138.4, 128.7, 128.3, 128.2, 128.1,

128.0, 127.9, 127.8, 127.6, 127.56, 127.5, 127.5, 127.4, 109.5, 109.4, 108.8, 108.6, 102.4,

97.3, 96.4, 96.4, 81.9, 80.1, 77.5, 77.0, 76.6, 75.1, 74.9, 74.6, 73.3, 72.3, 72.1, 70.9, 70.7,

70.6, 69.1, 68.1, 65.4, 65.3, 29.7, 26.2, 26.0, 25.1, 24.9, 24.6, 24.4.

1,2,3,4-di-O-isipropylidine galactopyranoside-(2,3,4,6-tetra-O-benzyl

galactopyranoside). 71.0 mg (0.131 mmol) of 2,3,4,6-tetra-O-benzyl galactopyranoside

(26) was evaporated 2x azeotropically from PhMe and then dried under high vacuum for

30 min. Under N2 atm. at rt 26 was dissolved in anhydrous CH2Cl2 (7 mL) and stirred. To

this stirring solution was added 1,8-Diazabicycloundec-7-ene (28.0 µL, 0..197 mmol)

followed by chlorodiphenylphosphine (28.3 µL, 0.158 mmol) via microsyringe. This

reaction was stirred for 35 minutes at rt before TLC indicated the reaction was complete.

The reaction mixture was evaporated under reduced pressure and filtered through a small

plug of SiO2 to remove excess base (2:1 Hexanes:EtOAc) to give the crude arabinosyl

phisphinte as a white solid. The filtered product was dried under high vacuum for 30 min.

Under N2 atm. and at rt the white solid was dissolved in anhydrous CH2Cl2 and stirred.

To this stirring solution was added iodomethane (16.0 µL, 0.263 mmol) followed by a

solution of 1,2,3,4-di-isopropylidine-D-galactopyranoside (17.0 mg, 0.066 mmol) in 0.5

mL anhydrous CH2Cl2. The reaction mixture was allowed to stir at rt for 3 d. before TLC

indicated the reaction was complete. The reaction was then concentrated under reduced

pressure, dissolved in EtOAc and worked up with 1x75mL sat. NaHCO3, 1x 50 mL

62

dH2O, and 1x50 mL sat. NaCl solution. The organic layer was then dried over MgSO4,

filtered, and concentrated under reduced pressure. The crude product was purified over

SiO2 (2:1 Hexanes:EtOAc) to give 36.1 mg of the title compound as a colorless oil in

80% yield (92:8 α:β): 1H, 13C, and HSQC NMR characterization data can be found in

Appendix 12. 1H NMR (300 MHz, CD2Cl2) δ 7.58 – 7.39 (m, 8H), 7.35 – 7.01 (m, 12H),

6.99 – 6.91 (m, 1H), 5.40 (dd, J = 8.3, 3.5 Hz, 1H), 4.86 (d, J = 11.0 Hz, 1H), 4.80 – 4.73

(m, 2H), 4.72 – 4.68 (m, 1H), 4.66 – 4.54 (m, 3H), 4.48 (d, J = 26.3 Hz, 1H), 4.41 – 4.36

(m, 1H), 4.32 (d, J = 15.4 Hz, 1H), 3.98 – 3.88 (m, 1H), 3.64 – 3.45 (m, 6H). 13C NMR

(75 MHz, CD2Cl2) δ 142.0, 141.7, 141.6, 141.4, 139.1, 138.8, 138.5, 138.4, 138.3,

138.3, 131.5, 131.2, 130.5, 130.2, 130.1, 129.8, 129.8, 129.1, 129.0, 128.4, 128.3, 128.3,

128.2, 128.2, 128.1, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.5, 127.4, 127.4, 103.4,

103.2, 98.6, 98.3, 84.6, 81.6, 80.9, 80.8, 77.7, 77.5, 75.5, 75.4, 75.3, 74.9, 74.8, 74.8,

73.4, 73.1, 72.7, 71.4, 68.7, 68.4, 54.1, 53.8, 53.4, 53.1, 52.7.

Chapter 4: Conclusions

4.1: Cyclic phosphonium anhydrides as reagents for dehydrative glycosylations

A library of cyclic phosphonium anhydrides have been prepared from their

corresponding bis-phosphine oxides and evaluated for their potential as dehydrating

agents in a series of dehydrative glycosylations. Of these cyclic phosphoniums, 1,1,3,3-

diphenylphenyl-2-oxa-1,3-phosphepane ditriflate (3) consistently gave the highest

glycosylation yields and was the easiest to prepare from the corresponding bis-oxide.

63

Optimizations with cyclic phosphonium 3 and a number of conditions for dehydrative

glycosylations (solvent, temperature, reactions times) eventually afforded a standard

protocol for dehydrative glycosylation in good yields and selectivities.

In order to better understand the mechanism of this reaction and explain the

differences in this methodology compared to similar dehydrative glycosylation reactions

with Hendrickson’s POP reagent, a series of mechanistic studies were performed. Cyclic

phosphonium 3 reacts readily with glycosyl donors (e.g. 2,3,4,6-tetra-O-benzyl-D-

glucose) to form the presumed intermediate 10 (Scheme 2.1). The overall stability of this

intermediate would explain the lack of observed homocoupling product between two

molecules of the glycosyl donor in this dehydrative glycosylation methodology, a

common problem with similar methods. Support for the proposed mechanism comes

from a series of 1D and 2D experiments including long range 1H-31P coupling observed

between the anomeric proton and the nearby phosphorus in the proposed intermediate 10.

4.2: Glycosyl phosphinites yield highly α-selective glycosylation products

Glycosyl phosphinites represent a powerful tool for highly α-selective

glycosylations via in situ anomerization of the corresponding anomeric iodide. In this

thesis a library of glycosyl phosphinites was prepared in mild conditions (DBU) and

evaluated in glycosylation reactions promoted by the presence of iodomethane and a

suitable glycosyl acceptor. Glycosyl phosphinites prepared from

chlorodiphenylphosphine were ultimately chosen as the model system to test the scope of

64

this method. Various glycosyl phosphinites were demonstrated with a variety of glycosyl

donors and acceptors to give highly α-selective glycosylations in good yields (Table 3.3).

To gain a better understanding of the high α-selectivity of these reactions a

number of 1H and 31P NMR experiments were performed to observe the reaction progress

from start to completion. The presumed mechanism (Scheme 3.1) is supported by 31P

experiments showing addition of the methyl electrophile to the glycosyl phosphinite, a

reaction that proceeds relatively rapidly. Subsequent addition of the acceptor and the

corresponding glycosylation proceed slowly, supporting that the less prevalent but highly

reactive β-iodide affords the product in high α-selectivity.

References

1. Thibodeaux, C. J.; Melançon, C. E. ; Liu, H. Unusual sugar biosynthesis and

natural product glycodiversification. Nature 446, 1008-1016 (2007).

2. Thibodeaux, C. J.; Melançon, C. E. ; Liu, H. Natural-Product Sugar Biosynthesis

and Enzymatic Glycodiversification. Angew. Chem. Int. Ed. 47, 9814-59 (2008).

3. Zhu, X. & Schmidt, R. R. New principles for glycoside-bond formation. Angew.

Chem. Int. Ed. Engl. 48, 1900–34 (2009).

4. A. Michael, Am. Chem. J. 1879, 1, 305 – 312.

5. Fischer, E. Ueber die Glucoside der Alkohole. Ber. Dtsch. Chem. Ges. 26, 2400–

2412 (1893).

6. Fischer, E.; Beensch, L. Ueber einige synthetische Glucoside. Ber. Dtsch. Chem.

Ges. 27, 2478–2486 (1894).

65

7. Fischer, E. "Ueber die Verbindungen der Zucker mit den Alkoholen und

Ketonen". Ber. Dtsch. Chem. Ges. 28, 1145–1167 (1985)

8. Helferich, B. Schmitz, E. Eine neue Methode zur Synthese von Glykosiden der

Phenole. Ber. Dtsch. Chem. Ges. 66, 321 - 462 (1933)

9. Koenigs, W.; Knorr, E. Ueber einige Derivate des Traubenzuckers und der

Galactose. Ber. Dtsch. Chem. Ges. 34, 957–981 (1901)

10. Schmidt, R.R. Reichrath, M. Facile, Highly Selective Synthesis of α- and β-

Disaccharides from 1-O-Metalated D-Ribofuranoses. Angew. Chem. Int. Ed. 18,

466 – 467 (1979)

11. Klotz, W.; Schmidt, R. R. Anomeric O-Alkylation of O-Acetyl-Protected Sugars.

J. Carb. Chem. 13, 1093-1101 (1994).

12. Schmidt, R.R. New Methods for the Synthesis of Glycosides and

Oligosaccharides—Are There Alternatives to the Koenigs-Knorr Method? Angew.

Chem. Int. Ed. Engl. 25, 212 – 235 (1986).

13. Schmidt, R.R.; Jung, K.-H. “Oligosaccharide Synthesis via

Trichloroacetimidates” in Preparative Carbohydrate Chemistry (Ed.: Hannessian,

S.), Wiley-VCH,Weinheim, (1997).

14. Schmidt, R.R.; Jung, K.-H. “Trichloroacetimidates” in Carbohydrates in

Chemistry and Biology, Part I: Chemistry of Saccharides, 1 (Eds.: Ernst, B.; Hart,

G.W.; Sina, P.), Wiley-VCH,Weinheim, (2000).

15. Goodman, L. Advances in Carbohydrate Chemistry and Biochemistry. 22, 109–

175. (1967)

66

16. Fife, T.H.; Bembi, R.; Natarajan, R. Neighboring Carboxyl Group Participation in

the Hydrolysis of Acetals. Hydrolysis of o-Carboxybenzaldehyde cis- and trans-

1,2-Cyclohexanediyl Acetals J. Am. Chem. Soc. 118, 12956–12963. (1996)

17. Nukada, T.; Berces, A.; Zgierski, M.Z.; Whitfield, D.M. Exploring the

Mechanism of Neighboring Group Assisted Glycosylation Reactions J. Am.

Chem. Soc. 120, 13291– 13295. (1998)

18. Demchenko, A. V. “General Aspects of Glycoside Formation” in Handbook of

Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic

Relevance, Wiley-VCH,Weinheim, (2008)

19. Koto, S.; Morishima, N.; Zen, S. A Stereoselective One-stage α-Glucosylation

with 2,3,4,6-Tetra-O-benzyl-α-D-glucopyranose and a Mixture of

Methanesulfonic Acid, Cobalt(II) Bromide, and Tetraethylammonium Perchlorate

Bull. Chem. Soc. Jpn. 55, 1543-1547 (1982).

20. Koto, S.; Morishima, N.; Kusuhara, C.; Sekido, S.; Yoshida, T.; Zen, S.

Stereoselective α-Glucosylation with Tetra-O-benzyl-α-D-glucose and a Mixture

of Trimethylsilyl Bromide, Cobalt(II) Bromide, Tetrabutylammonium Bromide,

and a Molecular Sieve. A Synthesis of 3,6-Di-O-(α-D-glucopyranosyl)-D-glucose

Bull. Chem. Soc. Jpn. 55, 2995- 2999 (1982).

21. Leroux, J.; Perlin, A. S. Synthesis of glycosyl halides and glycosides via 1-O-

sulfonyl derivatives. Carbohydr. Res. 67, 163-178 (1978)

22. Inanaga, J.; Yokoyama, Y.; Hanamoto, T. Catalytic O- and S-glycosylation of 1-

hydroxy sugars J. Chem. Soc., Chem. Commun. 1090-1091 (1993).

67

23. Mukaiyama, T.; Matsubara, K.; Hora, M. An Efficient Glycosylation Reaction of

1-Hydroxy Sugars with Various Nucleophiles Using A Catalytic Amount of

Activator and Hexamethyldisiloxane Synthesis. 1368-1373 (1994).

24. Grochowski, E.; Jurczak, J. Carbohydr. Res. 1976, 50, C15-C16.

25. Smith, A. B. III; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. Phyllanthoside-

phyllanthostatin synthetic studies. 8. Total synthesis of (+)-phyllanthoside.

Development of the Mitsunobu glycosyl ester protocol J. Am. Chem. Soc. 113,

2092-2112 (1990).

26. Nicolaou, K. C.; Groneberg, R. D. Novel strategy for the construction of the

oligosaccharide fragment of calichemicin γ1αI. Synthesis of the ABC skeleton J.

Am. Chem. Soc. 112, 4085- 4086 (1990).

27. Roush, W. R.; Lin, X.-F. Studies on the Synthesis of Aureolic Acid Antibiotics:

Highly Stereoselective Synthesis of Aryl 2-Deoxy-β-glycosides via the

Mitsunobu Reaction and Synthesis of the Olivomycin A-B Disaccharide J. Am.

Chem. Soc. 117, 2236-2250 (1995).

28. Garcia, B.; Gin, D. Dehydrative Glycosylation with Activated Diphenyl

Sulfonium Reagents . Scope , Mode of C (1)-Hemiacetal Activation, and

Detection of Reactive Glycosyl Intermediates. J. Am. Chem. Soc. 122, 4269–4279

(2000)

29. Mukaiyama, T.; Suda, S. Diphosphonium Salts as Effective Reagents for

Stereoselective Synthesis of 1,2-cis-Ribofuranosides. Chem. Lett. 52, 1143-1146

(1990).

68

30. Hendrickson J.B.; Schartzman S.M. Triphenyl phosphine ditriflate: A general

oxygen activator. Tetrahedron Lett. 16: 277 (1975).

31. Hendrickson J.B.; Hussoin, M.S. Seeking the ideal dehydrating reagent. J. Org.

Chem. 52, 413 (1987).

32. Mossotti, M.; Panza, L. Dehydrative Glycosylation with the Hendrickson

Reagent. J. Org. Chem. 76, 9122–9126 (2011).

33. Walvoort, M. T. C.; Dinkelaar, J.; van den Bos, L. J.; Lodder, G.; Overkleeft, H.

S.; Codée, J. D. C.; van der Marel G. A.; Carb. Res. 2010, 345, 1252-1263

34. Lemieux, R.U.; Hendriks, K.B.; Stick, R.V.; James, K. Halide ion catalyzed

glycosidation reactions. Syntheses of α-linked disaccharides. J. Am. Chem. Soc.

97, 4056–4062 (1975).

35. Paulsen, H.; Paal, M. Synthese der tetra- und trisaccharid-sequenzen von asialo-

GM1 und -GM2. Lenkung der regioselektivität der glycosidierung von lactose.

Carb. Res. 137, 39-62 (1985).

36. Paulsen, H.; Steiger, K. M. Regioselektive glycosylierung an stellungen 3′ und 4′

von lactose-derivaten. Carb. Res. 169, 105-25 (1987).

37. Mukaiyama, T; Kobashi, Y.; Shintou, T. A New Method for α-Selective

Glycosylation Using a Donor, Glycosyl Methyldiphenylphosphonium Iodide,

without Any Assistance of Acid Promoters. Chem. Lett. 32, 900-901 (2003).

38. Mukaiyama, T; Kobashi, Y. Highly α-Selective Synthesis of Disaccharide Using

Glycosyl Bromide by the Promotion of Phosphine Oxide. Chem. Lett. 33, 10-11

(2004).

69

39. Mukaiyama, T; Kobashi, Y. Highly α-Selective Glycosylation with Glycosyl

Acetate via Glycosyl Phosphonium Iodide. Chem. Lett. 33, 874-875 (2004).

40. Elson, K.E.; Jenkins, I.D.; Loughlin, W.A. Novel Cyclic Analouges of

Hendrickson’s ‘POP’ Reagent. Aust. J. Chem. 57, 371-376 (2004).

41. Hotha, S.; Kashyap, S. Propargyl Glycosides as Stable Glycosyl Donors:

Anomeric Activation and Glycoside Syntheses J. Am. Chem. Soc. 128, 9620–

9621 (2006).

42. Warabi, K.; Hamada, T.; Nakao, Y.; Matsunaga, S.; Hirota, H.; van Soest, R. W.

M.; Fusetani, N. Axinelloside A, an Unprecedented Highly Sulfated

Lipopolysaccharide Inhibiting Telomerase, from the Marine Sponge, Axinella

infundibula. J. Am. Chem. Soc. 127, 13262–13270 (2005).

43. Fulmer, G.R.; Miller, A.J.M.; Sherden, N.H.; Gottlieb, H.E.; Nudelman, A.;

Stoltz, B.N.; Bercaw, J.E.; Goldberg, K.I. NMR Chemical Shifts of Trace

Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated

Solvents Relevant to the Organometallic Chemist. Organometallics. 29, 2176–

2179 (2009).

44. Petersson, M. J.; Loughlin, W. A.; Jenkins, I. D. Selective mono reduction of bis-

phosphine oxides under mild conditions. Chemical Communications. 4493-4494

(2008).

45. Lin, Y.; Bernardi, D.; Doris, E.; Taran, F. Phosphine-Catalyzed Synthesis of

Unsymmetrical 1,3-Bis- and Trisphosphorus Ligands. Synlett. 9, 1466-1470

(2009).

70

46. Calcagno, P.; Kariuki, B. M.; Kitchin, S. J.; Robinson, J. M. A.; Philp, D.; Harris,

K. D. M., Understanding the Structural Properties of a Homologous Series of Bis-

diphenylphosphine Oxides. Chem. Eur. J. 6, 2338-2349 (2000).

47. Bew, S.P.; Brimage, R.A.; Hughes, D.L.; Legentil, L.; Sharma, S.V.; Wilson,

M.A. Expedient Synthesis of Substituted (Diphenylphosphinoylmethyl)benzenes.

J. Org. Chem., 72, 2655–2658 (2007).

48. Xu, H.; Xie, G.; Han, C.; Zhang, Z.; Deng, Z.; Zhao, Y.; Yan, P.; Liu, S.

Influence of molecular configuration and functional substituents on excited state

energy levels in two naphthyl-based phosphine oxide hosts. Organic Electronics.

13, 1516-1525 (2012).

49. Petersson, M. J.; Loughlin, W. A.; Jenkins, I. D., Chemical Communications.

4493-4494 (2012).

50. Yamamoto, K.; Ur-Rehman, S., Chem. Lett. 13, 1603-1606 (1984).

51. Watanabe, Y.; Nakamoto, C.; Yamamoto, T.; Ozaki, S. Glycosylation using

glycosyl phosphite as a glycosyl donor. Tetrahedron. 50, 6523-6536 (1994).

71

Appendix

Appendix 1: 1H 13C, and 31P NMR spectra for 1,1,3,3-diphenylphenyl-2-oxa-1,3-

phosphepane ditriflate.

Appendix 2: 1H, 13C, and HSQC NMR spectra for cyclohexyl 2,3,4-tri-O-benzyl-6-

deoxy-D-fucopyranose.

Appendix 3: 1H, 13C, and HSQC NMR spectra for cyclohexyl 2,3-bis-O-(phenylmethyl)-

4,6-O-[(R)-phenylmethylene]-D-mannopyranoside.

Appendix 4: 1H, 13C, and HSQC NMR spectra for phenyl 2,3,4,6-tetra-O-benzyl-D-

glucopyranoside.

Appendix 5: 1H, 13C, and HSQC NMR spectra for methyl 6-O-(2,3,4,6-tetra-O-benzyl-α-

D-glucopyranosyl)-2,3,4-tri-O-benzyl-D-glucopyranoside.

Appendix 6: 1H, 13C, and HSQC NMR spectra for (3β)-cholest-5-en-3-ol-2,3,4,6-tetra-

O-benzyl-D-glucopyranoside.

Appendix 7: 31P, 31P selective decoupling, 31P broadband decoupling, and 1H-31P HMBC

NMR spectra for dehydrative glycosylation mechanistic experiments.

Appendix 8: NOESY NMR spectra for dehydrative glycosylation mechanistic

experiments with acceptor 2,2,2-triflouroethanol.

Appendix 9: 1H, 31P, 13C, and HSQC NMR spectra for 2,3,4,6-tetra-O-benzyl-D-glycosyl

phosphinite.

Appendix 10: 1H, 13C, and HSQC NMR data for 1,2,3,4-di-O-isipropylidine

galactopyranoside-(2-O-benzyl-3,4-O-di-benzoyl-α-D-arabinopyranoside).

72

Appendix 11: 1H, 13C, and HSQC NMR data for 1,2,3,4-di-O-isipropylidine

galactopyranoside-(2,3,4,6-tetra-O-benzyl-D-mannopyranoside).

Appendix 12: 1H, 13C, and HSQC NMR data for 1,2,3,4-di-O-isopropylidene-D-

galactopyranoside-(2,3,4,6-tetra-O-benzyl-D-galactopyranoside).

73

Appendix 1.1: 1H NMR spectra for 1,1,3,3-diphenylphenyl-2-oxa-1,3-phosphepane

ditriflate (8).

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

3.8

6

3.8

5

8.1

2

12.4

6

B (q)3.8435

C (m)2.4947

D (dq)7.8971

E (dq)7.7195

2.4

496

2.4

606

2.4

697

2.4

807

2.5

047

2.5

369

2.5

487

2.5

608

3.8

157

3.8

346

3.8

523

3.8

714

7.6

870

7.6

982

7.7

136

7.7

198

7.7

257

7.7

400

7.7

527

7.8

234

7.8

479

7.8

687

7.8

945

7.9

233

7.9

482

7.9

737

1H NMR (300 MHz, CD2Cl2)

74

Appendix 1.2: 13C NMR spectra for 1,1,3,3-diphenylphenyl-2-oxa-1,3-phosphepane

ditriflate.

102030405060708090100110120130140150160f1 (ppm)

19

.17

21

22

.71

60

23

.04

81

23

.38

12

11

7.7

75

011

7.9

17

211

8.6

04

411

9.2

88

511

9.4

30

411

9.8

88

41

22

.17

76

12

4.1

20

91

28

.35

29

12

9.9

85

91

32

.74

59

13

2.8

41

81

32

.93

55

13

4.7

84

61

34

.87

03

13

4.9

56

91

39

.92

79

13C NMR (75 MHz, CD2Cl2)

75

Appendix 1.3: 31P NMR spectra for 1,1,3,3-diphenylphenyl-2-oxa-1,3-phosphepane

ditriflate.

798081828384858687888990919293949596979899100101102103f1 (ppm)

90

.58

43

31P NMR (162 MHz, CD2Cl2)

76

Appendix 2: 1H, 13C, and HSQC NMR spectra for cyclohexyl 2,3,4-tri-O-benzyl-6-

deoxy-D-fucopyranose.

Appendix 2.1: 1H NMR spectra for cyclohexyl 2,3,4-tri-O-benzyl-6-deoxy-D-

fucopyranose.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

3.0

9

7.5

6

2.1

6

2.0

8

1.0

11.2

21.0

51.0

81.0

1

1.0

0

4.2

3

2.1

7

15.2

0

1.2

11.2

11.2

21.2

31.2

31.2

41.2

41.2

41.2

51.2

61.2

71.2

71.2

81.2

91.2

91.3

81.3

91.4

01.4

11.4

21.4

41.4

51.4

61.4

71.4

91.5

01.5

11.5

21.5

21.5

91.7

21.7

31.7

41.7

51.7

61.7

61.9

01.9

31.9

41.9

73.4

03.4

13.4

13.4

23.4

33.4

43.4

83.4

93.5

03.5

13.5

33.5

33.5

43.5

43.6

53.6

63.6

73.6

83.6

83.6

93.7

73.7

83.7

93.8

04.4

14.4

34.6

94.7

04.7

14.7

24.7

44.7

64.7

84.8

04.9

64.9

74.9

84.9

97.2

67.2

77.2

77.2

87.2

97.2

97.3

07.3

07.3

17.3

17.3

27.3

27.3

27.3

37.3

37.3

47.3

47.3

57.3

57.3

57.3

67.3

67.3

67.3

77.3

77.3

77.3

87.3

9

77

Appendix 2.2: 13C NMR spectra for cyclohexyl 2,3,4-tri-O-benzyl-6-deoxy-D-

fucopyranose.

101520253035404550556065707580859095100105110115120125130135140145f1 (ppm)

17.0

0

23.9

724.1

025.7

3

31.7

8

33.6

4

70.1

7

73.2

574.4

575.1

176.3

2

79.5

0

82.7

7

101.7

6

127.4

4127.4

9127.5

4128.0

8128.2

1128.2

4128.3

3128.5

8

138.6

6138.7

6138.9

6

78

Appendix 2.3: HSQC NMR spectra for cyclohexyl 2,3,4-tri-O-benzyl-6-deoxy-D-

fucopyranose.

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5(ppm)

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)

79

Appendix 3: 1H, 13C, and HSQC NMR spectra for cyclohexyl 2,3-bis-O-(phenylmethyl)-

4,6-O-[(R)-phenylmethylene]-D-mannopyranoside.

Appendix 3.1: 1H NMR spectra for cyclohexyl 2,3-bis-O-(phenylmethyl)-4,6-O-[(R)-

phenylmethylene]-D-mannopyranoside.

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm

0.9

4

0.9

5

0.9

9

1.9

7

0.9

31.0

2

2.9

5

1.9

8

0.8

8

11.7

9

3.9

6

3.3

03.3

13.3

33.3

43.3

63.3

83.5

83.5

93.6

13.6

23.6

93.7

13.7

23.7

33.7

53.8

93.9

03.9

33.9

74.0

04.2

14.2

44.2

74.3

04.3

14.3

34.3

54.5

84.6

14.6

24.6

74.7

14.9

14.9

55.0

25.0

6

5.6

4

7.2

87.3

07.3

17.3

27.3

37.3

47.3

67.3

77.3

87.3

87.3

97.4

07.5

17.5

17.5

27.5

37.5

37.5

4

80

Appendix 3.2: 13C NMR spectra for cyclohexyl 2,3-bis-O-(phenylmethyl)-4,6-O-[(R)-

phenylmethylene]-D-mannopyranoside.

0102030405060708090100110120130140 ppm

23.6

023.7

525.6

5

31.4

5

33.3

6

67.5

568.7

0

72.2

774.5

876.1

678.1

178.6

3

99.9

9101.3

6

126.0

5127.4

6127.5

1128.0

7128.1

7128.2

8128.7

3128.8

1

137.6

5138.4

0138.5

5

81

Appendix 3.3: HSQC NMR spectra for cyclohexyl cyclohexyl 2,3-bis-O-

(phenylmethyl)-4,6-O-[(R)-phenylmethylene]-D-mannopyranoside.

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)

82

Appendix 4: 1H, and HSQC NMR spectra for phenyl 2,3,4,6-tetra-O-benzyl-D-

glucopyranoside.

Appendix 4.1: 1H NMR spectra for phenyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

0.8

3

3.3

3

0.9

9

0.8

1

0.8

30.9

71.7

11.2

11.8

61.2

3

1.1

2

0.8

1

5.0

1

23.7

2

3.5

93.6

23.6

33.6

83.7

53.7

53.7

83.7

93.8

33.8

63.9

13.9

44.2

24.2

54.2

84.3

14.4

24.4

64.5

14.5

54.5

94.6

14.6

34.6

54.6

74.7

04.7

44.7

74.7

84.8

24.8

54.8

64.8

84.9

14.9

24.9

54.9

85.0

15.0

45.0

85.1

25.5

25.5

3

7.0

47.0

67.0

97.1

17.1

47.1

67.1

67.1

87.1

97.2

27.2

47.2

87.2

97.3

07.3

27.3

47.3

57.3

57.3

97.4

17.4

4

83

Appendix 4.3: HSQC NMR spectra for prepared phenyl 2,3,4,6-tetra-O-benzyl-D-

glucopyranoside.

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)

84

Appendix 5: 1H, 13C, and HSQC NMR spectra for methyl 6-O-(2,3,4,6-tetra-O-benzyl-α-

D-glucopyranosyl)-2,3,4-tri-O-benzyl-D-glucopyranoside.

Appendix 5.1: 1H NMR spectra for methyl 6-O-(2,3,4,6-tetra-O-benzyl-α-D-

glucopyranosyl)-2,3,4-tri-O-benzyl-D-glucopyranoside.

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

2.7

8

2.0

9

0.9

50.9

41.0

20.9

4

0.9

90.9

6

2.0

51.9

61.9

5

1.9

4

0.9

5

0.9

8

1.0

1

1.0

0

24.5

8

3.2

7

1.9

72.0

21.9

61.9

6

3.4

63.5

43.5

43.5

63.5

83.5

83.6

03.6

03.8

33.8

33.9

44.0

34.0

54.3

64.6

34.6

34.6

54.6

54.6

64.6

94.6

94.7

14.7

24.8

04.8

34.8

34.8

55.0

25.0

25.0

45.0

45.1

75.1

75.7

45.7

45.7

45.7

55.8

85.9

05.9

06.0

66.0

87.2

67.2

77.2

87.2

87.2

87.2

87.2

97.2

97.2

97.3

07.3

07.3

17.3

17.3

17.3

27.3

27.3

27.3

37.3

47.3

47.3

57.3

57.3

67.3

67.3

77.3

77.3

87.3

87.3

87.3

97.3

97.4

07.4

07.4

17.4

17.4

17.4

27.4

27.4

37.4

47.5

07.5

27.5

67.5

87.5

87.5

87.6

07.6

07.8

37.8

37.8

57.8

57.9

07.9

07.9

27.9

28.0

48.0

58.0

68.0

68.0

88.0

98.1

08.1

0

85

Appendix 5.2: 13C NMR spectra for methyl 6-O-(2,3,4,6-tetra-O-benzyl-α-D-


0102030405060708090100110120130140150160170180190200f1 (ppm)

55.2

5

62.7

166.6

666.8

968.9

069.8

969.9

870.2

873.4

775.0

575.7

377.7

480.2

382.1

3

97.7

597.9

2127.6

0127.6

4127.7

8127.8

9127.9

7128.1

2128.3

1128.4

0128.4

5128.4

8128.5

7129.0

0129.1

1129.3

6129.7

2129.7

4129.8

6129.9

5133.0

5133.1

5133.4

3138.1

8138.2

1138.7

4

165.2

7165.4

3165.4

4166.1

1

86

Appendix 5.3: HSQC NMR spectra for methyl 6-O-(2,3,4,6-tetra-O-benzyl-α-D-


0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)

87

Appendix 6: 1H, 13C, and HSQC NMR spectra for (3β)-cholest-5-en-3-ol-2,3,4,6-tetra-

O-benzyl-D-glucopyranoside.

Appendix 6.1: 1H NMR spectra for (3β)-cholest-5-en-3-ol-2,3,4,6-tetra-O-benzyl-D-

glucopyranoside.

0.40.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.44.64.85.05.25.45.65.86.06.26.46.66.87.07.27.4 ppm

8.49

1.00

1.12

1.96

5.13

1.62

0.93

4.20

0.51

0.44

3.19

0.53

0.42

1.09

45.75

3.4

73.4

83.4

83.4

93.4

93.5

03.5

13.5

13.5

23.5

33.5

33.5

43.5

53.5

63.5

63.5

73.5

83.5

93.6

03.6

03.6

03.6

53.7

33.8

03.8

13.8

13.8

33.8

53.8

83.8

93.9

43.9

43.9

63.9

63.9

83.9

83.9

94.0

04.0

04.0

24.0

34.0

44.0

54.0

64.0

74.0

84.1

04.4

04.4

34.4

34.4

44.4

64.4

84.5

04.5

84.6

04.6

24.6

54.6

84.7

04.7

34.7

44.7

64.7

64.7

84.8

04.8

04.8

34.8

64.8

84.9

34.9

44.9

54.9

64.9

64.9

74.9

85.0

05.0

05.2

75.2

75.2

75.2

85.2

85.2

85.3

35.3

35.3

45.3

4

88

Appendix 6.2: 13C NMR spectra for (3β)-cholest-5-en-3-ol-2,3,4,6-tetra-O-benzyl-D-

glucopyranoside.

05101520253035404550556065707580859095100105110115120125130135f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

11.85

14.13

18.72

19.41

21.04

22.56

22.82

23.82

24.27

28.01

28.23

29.37

29.70

30.17

31.93

35.78

36.19

36.77

38.24

39.51

42.32

56.15

102.47

127.51

127.70

127.83

127.97

128.12

128.26

128.38

89

Appendix 6.3: HSQC NMR spectra for (3β)-cholest-5-en-3-ol-2,3,4,6-tetra-O-benzyl-D-

glucopyranoside.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 ppm

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

f1 (

ppm

)

90

Appendix 7.1: 31P NMR spectra for dehydrative glycosylation mechanistic experiments.

152025303540455055606570758085f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

32

.61

42

.73

43

.14

73

.16

73

.67

75

.27

15202530354045505560657075808590f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

32

.58

42

.73

43

.14

73

.15

73

.20

73

.66

75

.27

0 min

40 min

91

Appendix 7.2: 1H NMR with 31P selective decoupling NMR spectra for dehydrative

glycosylation mechanistic experiments.

Appendix 7.2.1: 1H NMR without 31P decoupling.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200

210

5.505.555.605.655.705.755.805.855.905.956.006.05f1 (ppm)

0

1

2

3

4

5

5.3

1

1.0

0

5.7

15

.72

5.7

35

.74

5.8

95

.90

5.9

15

.92

92

Appendix 7.2.1: 31P selective decoupling at 73.2 ppm

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-5

0

5

10

15

20

25

30

35

40

45

50

55

60

65

5.65.75.85.96.0f1 (ppm)

0

1

2

5.7

15

.72

5.7

3

5.9

05

.91

93

Appendix 7.2.2: 31P selective decoupling at 73.7 ppm

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

-5

0

5

10

15

20

25

30

35

40

45

50

5.55.65.75.85.96.06.1f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

5.7

25

.72

5.9

05

.91

94

Appendix 7.3: 31P broadband decoupling NMR spectra for dehydrative glycosylation

mechanistic experiments.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

5.605.655.705.755.805.855.905.956.006.05f1 (ppm)

0

10

20

30

5.7

75

.78

5.9

55

.96

95

Appendix 7.4: 1H-31P HMBC NMR spectra for dehydrative glycosylation mechanistic

experiments.

2.02.53.03.54.04.55.05.56.06.57.07.58.0f2 (ppm)

35

40

45

50

55

60

65

70

75

f1 (

ppm

)

96

Appendix 8: NOESY NMR spectra for dehydrative glycosylation mechanistic

experiments with 2,2,2-triflouroethanol.

Solution 4 NOESY (300 MHz, CD2Cl2)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f2 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

f1 (

ppm

)

97

Appendix 9: 1H, 31P, 13C, and HSQC NMR spectra for 2,3,4,6-tetra-O-benzyl-D-glycosyl

diphenylphosphinite.

Appendix 9.1: 1H NMR spectra for 2,3,4,6-tetra-O-benzyl-D-glycosyl


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm

0.7

0

1.0

9

4.2

5

1.0

00.7

71.3

10.9

61.2

20.8

1

0.6

9

0.5

33.9

431.2

2

5.4

3

3.2

23.2

53.4

43.4

53.4

93.5

23.5

33.5

33.5

43.5

53.5

53.5

63.5

63.5

73.6

03.6

13.9

03.9

34.2

64.3

04.3

54.3

84.3

94.4

04.4

44.5

24.5

74.5

94.6

14.7

04.7

04.7

14.7

34.7

44.7

54.7

94.8

44.8

85.3

85.3

95.4

15.4

26.9

66.9

67.0

57.0

67.0

77.0

87.0

97.1

07.1

17.1

27.1

37.1

47.1

47.1

57.1

67.1

67.1

77.1

87.1

87.1

97.2

07.2

17.2

17.2

17.2

27.2

37.2

37.2

47.2

47.2

47.2

57.2

57.2

67.2

77.2

77.2

87.4

17.4

17.4

17.4

27.4

27.4

37.4

47.4

57.4

57.4

67.4

67.4

67.4

77.4

77.4

87.4

87.4

97.4

97.5

07.5

07.5

0

benzyl glucose glycosyl

phosphinite

1H NMR (300MHz)

98

Appendix 9.2: 31P NMR spectra for 2,3,4,6-tetra-O-benzyl-D-glycosyl


-80-70-60-50-40-30-20-100102030405060708090100110120130140150160170180 ppm

114.1

7115.8

5

31P NMR 122MHz)

99

Appendix 9.3: 13C NMR spectra for 2,3,4,6-tetra-O-benzyl-D-glycosyl


404550556065707580859095100105110115120125130135140145150155 ppm

52.7

053.0

653.4

253.7

854.1

4

68.3

568.7

471.4

372.7

473.1

473.4

474.7

674.8

274.9

475.3

375.4

475.5

477.5

277.7

280.7

980.8

881.5

9

84.6

2

98.2

598.5

5

103.1

7103.4

3

127.4

1127.4

4127.5

2127.5

4127.6

2127.7

4127.7

8127.9

0128.0

9128.1

3128.2

0128.2

2128.2

5128.2

9128.3

8128.9

7129.1

0129.8

0129.8

4130.1

2130.1

8130.4

6131.1

8131.4

9138.2

8138.3

1138.4

2138.5

3138.8

1139.0

5141.4

1141.5

9141.7

3141.9

8

13C NMR (75MHz)

100

Appendix 9.4: Decoupled HSQC NMR spectra for 2,3,4,6-tetra-O-benzyl-D-glycosyl


0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)

HSQC decoupled (300 MHz)

101

Appendix 9.5: Coupled HSQC NMR spectra for 2,3,4,6-tetra-O-benzyl-D-glycosyl


0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)

HSQC coupled (300 MHz)

102



Appendix 10.1: 1H NMR data for 1,2,3,4-di-O-isopropylidene-D-galactopyranoside-(2-

O-benzyl-3,4-O-di-benzoyl-α-D-arabinopyranoside).

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

2.9

32.6

72.7

32.5

2

2.0

5

1.1

5

5.2

90.9

61.6

3

0.8

01.8

2

1.0

0

0.9

81.0

41.1

3

8.0

12.4

12.1

01.1

81.1

7

4.0

0

1.3

11.3

51.3

81.4

01.4

31.4

41.4

71.5

3

3.7

73.7

83.7

93.8

03.8

33.8

53.8

93.9

03.9

23.9

23.9

44.1

14.1

34.1

44.1

64.1

74.1

84.1

84.2

34.2

64.3

54.3

64.3

74.6

34.6

44.6

94.7

24.7

44.7

6

5.2

35.2

3

5.5

85.5

95.6

65.7

25.7

35.7

45.7

5

7.2

67.2

77.2

87.3

17.3

17.3

47.3

57.3

77.4

37.4

57.4

67.5

17.5

27.5

47.5

87.6

07.6

17.8

87.8

97.9

57.9

7

1H NMR (500MHz)

103

Appendix 10.2: 13C NMR data for 1,2,3,4-di-O-isopropylidene-D-galactopyranoside-(2-

O-benzyl-3,4-O-di-benzoyl-α-D-arabinopyranoside).

-100102030405060708090100110120130140150160170180190200210 ppm

14.2

0

21.0

524.5

824.9

126.0

426.0

630.9

3

60.3

960.7

866.3

067.0

169.6

270.5

270.6

071.0

372.2

773.4

9

96.2

897.6

8

108.6

2109.2

7

127.7

0127.9

0128.2

5128.3

0128.4

0129.6

7129.7

2129.8

4129.9

0132.9

7133.1

5137.9

2

161.3

0165.5

3165.7

0

13C NMR (75MHz)

104

Appendix 10.3: Decoupled HSQC NMR data for 1,2,3,4-di-O-isopropylidene-D-


0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)


105

Appendix 10.4: Coupled HSQC NMR data for 1,2,3,4-di-O-isopropylidene-D-


0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)


106



Appendix 11.1: 1H NMR data for 1,2,3,4-di-O-isopropylidene-D-galactopyranoside-

(2,3,4,6-tetra-O-benzyl-D-mannopyranoside).

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

7.483.002.973.696.513.181.531.772.183.545.121.471.901.191.073.6138.940.63

1.3

51.4

61.5

33.7

13.7

23.7

33.7

43.7

43.7

63.7

63.7

83.7

93.8

13.8

13.8

33.8

63.8

63.9

13.9

23.9

33.9

43.9

53.9

83.9

94.0

14.0

34.0

54.0

74.1

54.1

74.1

84.1

94.1

94.3

34.3

44.3

44.3

54.3

64.3

64.3

74.5

24.5

44.5

54.5

74.5

94.6

04.6

14.6

34.6

34.6

54.7

04.7

34.7

34.7

64.7

74.8

84.9

0

5.5

55.5

6

7.1

77.1

87.1

97.2

57.2

87.2

97.3

07.3

17.3

37.3

47.3

57.3

77.3

97.4

07.4

17.5

37.5

5

1H NMR 500MHz)

107

Appendix 11.2: 13C NMR data for 1,2,3,4-di-O-isopropylidene-D-galactopyranoside-

(2,3,4,6-tetra-O-benzyl-D-mannopyranoside).

0102030405060708090100110120130140 ppm

24.4

324.5

924.9

325.1

026.0

026.1

529.7

2

65.2

765.3

768.0

769.1

370.6

170.6

870.9

272.0

872.3

373.3

374.5

974.8

775.1

076.6

177.0

377.4

680.0

681.8

8

96.3

596.4

397.2

8

102.3

7

108.5

6108.7

5109.3

5109.4

8

127.4

1127.4

7127.5

2127.5

5127.6

1127.7

9127.9

2128.0

1128.1

1128.1

6128.2

9128.7

1138.3

9138.4

6138.5

1138.6

0

13C NMR 75MHz)

108



0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)

HSQC NMR decoupled

109



Appendix 12.1: 1H NMR data for 1,2,3,4-di-O-isopropylidene-D-galactopyranoside-

(2,3,4,6-tetra-O-benzyl-D-galactopyranoside).

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 ppm

3.4

72.8

02.8

22.6

4

3.0

4

2.6

3

1.4

05.7

6

2.9

81.2

30.9

72.6

1

3.5

80.9

60.9

41.0

0

1.0

7

19.9

715.3

7

1.2

91.3

21.3

41.4

51.5

11.5

4

3.5

13.5

33.5

33.5

43.5

73.5

83.6

03.7

43.7

53.7

63.7

73.7

93.8

03.8

13.8

23.9

63.9

63.9

83.9

84.0

24.0

34.0

44.0

64.0

74.0

84.3

14.3

14.3

24.3

24.3

44.4

14.4

24.4

44.4

84.5

04.5

84.5

94.6

04.6

14.7

44.7

64.7

74.7

94.8

44.8

64.9

44.9

65.0

35.0

35.5

25.5

3

7.2

67.2

87.3

07.3

07.3

17.3

27.3

37.3

57.3

77.3

97.3

9

1H NMR (500MHz)

110

Appendix 12.2: 13C NMR data for 1,2,3,4-di-O-isopropylidene-D-galactopyranoside-

(2,3,4,6-tetra-O-benzyl-D-galactopyranoside).

102030405060708090100110120130140150160170 ppm

24.6

024.9

426.0

526.1

629.7

130.9

4

65.8

166.3

268.6

769.1

570.6

370.6

670.8

772.6

673.0

573.3

874.7

774.9

478.9

9

96.3

297.5

6

108.5

1109.1

7

127.3

8127.4

1127.4

6127.4

8127.6

5127.7

2127.8

1128.1

8128.2

1128.2

3128.3

0128.3

7128.5

9138.0

7138.7

6138.9

3

13C NMR 75MHz)

111



0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)


112

Appendix 12.4: Coupled HSQC NMR data for 1,2,3,4-di-O-isopropylidene-D-


0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0 ppm

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

f1 (

ppm

)

galactose product


Documents

NEW METHODS IN CARBOHYDRATE CHEMISTRY: DEHYDRATIVE