CHAPTER-II First stereoselective total synthesis of ...shodhganga.inflibnet.ac.in/bitstream/10603/19732/10/10_chapter 2.pdf · explain an efficient and simple approach for the stereoselective

CHAPTER-II

First stereoselective total synthesis of Pectinolide H

INTRODUCTION

Five membered ring lactone containing a substitution at the γ-

position is a significant structural subunit in various bio-active

compounds.1 Natural products, which containing a γ-lactone moiety

known to display a variety of biological properties,2 including anti-fungal,

anti-bacterial,3 anti tumor,4 cytotoxic,5 cyclooxygenase or phospholipase

A2 inihibition.6 Pectinolide H (8) is a structurally characteristic γ-lactone

that has been isolated from the chloroform extract of the aerial parts of a

Mexican terrestrial plant Hyptis pectinata,7 which is used in traditional

mexican medicines for a multipurpose therapies in the treatment of

fevers, skin infections, gastric disturbances,8 and lung congestion.9

R. P. -Miranda et al. isolated pectinolides A–C10 (1-3) in 1993 and

pectinolide H7 (8) in 2005 and W. F. Tinto et al. isolated pectinolides D–G

(4-7) in 2003.11 All pectinolides A-H (1-8) were isolated from the same

plant Hyptis pectinata. Pectinolides A-E (1-5) are 5,6-dihydro-α-pyrones,

pectinolide F (6) is tetrahydropyran derivative and pectinolides G and H

(7 and 8) are furanones.

Pectinolides A-C (1-3) known to exhibit antimicrobial and cytotoxic

properties.10 Especially, pectinolide H (8) displayed strong antimicrobial

activity against a panel of multidrug-resistant strains of Staphylococcus

aureus.7 The structure and stereo chemistry of 8 was determined on the

basis of spectral, chiroptical data and chemical evidence.

OR2 O

OR1

O

Pectinolide A; R1 = R2 = Ac (1)

Pectinolide B; R1 = Ac, R2 = H (2)

Pectinolide C; R1 = H, R2 = Ac (3)

OAc O

R1

O

Pectinolide D; R1= OH, R2=H (4)

Pectinolide E; R1= OAc, R2= Ac (5)

OR2

OAc

OAc O

OAc

O

Pectinolide F (6)

OAc

OAc

OMe

OAc

Pectinolide G (7)

OAc

OAc

OO

Pectinolide H (8)

OAc OH

OO

54' 1' 1

PRESENT WORK

In continuation of our interest in the total synthesis of biologically

active natural products,12 accompanied by important biological activities

and significant structural features of pectinolide H (8) encouraged us to

explore the synthesis of this molecule. To the best of our knowledge,

there is no report on the synthesis of pectinolide H (8). Here in, we

explain an efficient and simple approach for the stereoselective total

synthesis of 8.

The retro synthetic analysis of 8 is described in Scheme 1. The

target molecule 8 can be easily envisaged from the cis olefinic ester (19)

by one pot acetonide deprotection and lactonization followed by Lindlar’s

reaction. The intermediate 19 in turn can be achieved from the Still-

Gennari olefination and other chronological reactions of diol (14).

Scheme 1

OAc OH

O

O

OTBS

OH

OH

OPMB

OTBS

+ I OH

8

O

1411

9

21

OAc

O

O

O

O

19

The intermediate 14 was prepared from the Sonogashira cross coupling

of alkyne (11) and iodoallylic alcohol (21). In addition, compound 11 was

prepared from the acetylenic ketone (9) by stereoselective asymmetric

reduction (Scheme 1).

The synthesis of pectinolide H 8 was commenced from the

acetylenic ketone (9)13 and the first stereogenic centre was generated by

the enantioselective reduction of 9 with (S)-alpine borane (22) in THF at

r.t. for 8 h provided the chiral propargyl alcohol (10) in 75% yield (ee

75% ).14 (Scheme 2).

O OH

109

(S)-Alpine borane (22),

THF, 8 h, r.t., 75%

B

(S)-22

Scheme 2

The formation of product propargylic alcohol 10 was confirmed from

its spectral data. In 1H NMR spectrum (Fig. 2.1) of 10, by the presence of

signal at \ 4.31 (dt, J = 6.4, 1.5 Hz, 1 H) due to methine proton bearing

hydroxyl group and a deuterium exchangeable proton due to hydroxyl

group at \ 1.90 (brs, 1 H). The IR spectrum showed absorption band at

3308 cm-1 for hydroxyl group. The 13C NMR spectrum (Fig. 2.2) of 10

showed a signal at \ 62.1 due to methine bearing hydroxy group in 10.

The secondary alcohol in 10 was protected with tert-butyl

dimethylsilyl chloride (TBSCl), imidazole in CH2Cl2 at r.t. for 3 h to give

TBS ether (11) in 94% yield. (Scheme 3).

OH OTBS

1011

Imidazole, TBSCl,

CH2Cl2, r.t., 3 h

Scheme 3

The formation of TBS ether (11) was confirmed from its spectral data.

The 1H NMR spectrum (Fig. 2.4) of 11 showed signals due to tert-butyl

dimethylsilyl group at \ 0.91 (s, 9 H), 0.13 (s, 3 H) and 0.10 (s, 3 H). The

13C NMR spectrum (Fig. 2.5) showed signals at \ 25.8, 18.2, -4.5, -5.0

indicated the presence of TBS group in 11.

The terminal alkyne in 11 was subjected to Sonogashira cross

coupling with (E)-3-iodoprop-2-en-1-ol (21)15,16a in the presence of

[Pd(PPh3)4], CuI, iPr2NH in dry benzene at r.t. for 2 h to afford allylic

alcohol 1216 in 88% yield (Scheme 4).

OTBS

1211

OTBS

OH

(E)-3-Iodoprop-2-en-1-ol

(21), iPr2NH, Pd(PPh3)4,

CuI, dry benzene, r.t., 2 h,88%

Scheme 4

The formation of product 12 was confirmed from its spectral data. Its

1H NMR spectrum (Fig. 2.7) showed signals at \ 6.21 (td, J = 15.8, 5.2

Hz, 1 H) and 5.80-5.72 (m, 1 H) indicated the presence of conjugated

double bond. In 13C NMR spectrum (Fig. 2.8) of 12, double bond carbons

resonated at \ 141.3 and 110.2. IR spectrum showed absorption band at

3387 cm-1 for hydroxyl group which confirmed the required product.

The primary alcohol in 12 was protected with p-methoxybenzyl

chloride using NaH in dry THF at r.t for 4 h to afford compound 13 in

93% yield. (Scheme 5).

12

OTBS

OH

OTBS

OPMB13

NaH, PMBCl, THF,

0 oC to r.t., 4 h, 93%

Scheme 5

The formation of PMB protected compound 13 was confirmed from

the 1H NMR spectrum (Fig. 2.10) of 13 which showed signals due to p-

methoxybenzyl group at \ 7.20 (d, J = 8.3 Hz, 2 H), 6.82 (d, J = 8.3 Hz, 2

H), 3.79 (s, 3 H) and confirmed by the 13C NMR spectrum (Fig. 2.11) and

its mass spectrum showed molecular ion peak m/z 425 [M+Na] (Fig.

2.12).

Sharpless dihydroxylation of 13 with AD-mix-α in t-Butanol/H2O

(1:1) at 0 oC furnished diol 1417 in 82% yield (de 96%, Chiral HPLC)

(Scheme 6).

OTBS

OH

OH

OPMB

OTBS

OPMB13 14

AD-mix-α, MeSO2NH2,t-BuOH/H2O (1:1),

0 oC, 24 h, 82%

Scheme 6

The structure of 14 was confirmed from its spectral data. The 1H

NMR spectrum (Fig. 2.13) of 14 showed disappearance of signals due to

double bond at \ 6.10 (td, J = 15.8, 5.2 Hz, 1 H), 5.72 (dd, J = 15.8, 1.5

Hz, 1 H) and presence of signals at \ 4.35-4.30 (m, 1 H), 3.78-3.72 (m, 1

H) due to methines bearing hydroxyl groups and further corroboration by

the 13C NMR spectrum (Fig. 2.14) of 14, which showed signals at \ 73.1

and 62.7. Its mass spectrum displayed molecular ion peak at m/z 459

[M+Na] (Fig. 2.16).

The diol (14) was protected with 2,2-dimethoxy propane in the

presence of a catalytic amount of PTSA in CH2Cl2 to obtain 15 with 90%

yield (Scheme 7)

OTBS

OH

OH

OPMB

14

2,2-dimethoxypropane,PTSA,

CH2Cl2, r.t., 12 h, 90%

OTBS

O

O

OPMB15

Scheme 7

The formation of acetonide protected compound 15 was established

from the 1H NMR spectrum (Fig. 2.17), which showed signals for two

acetonide methyl protons at \ 1.45 (s, 3 H), 1.40 (s, 3 H). The 13C NMR

spectrum (Fig. 2.18) of 15 showed signals at \ 110.5, 26.9 and 26.1 due

to acetonide group and molecular ion peak at m/z 499 [M++Na] in its

mass spectrum (Fig. 2.19), confirms the formation of acetonide protected

compound 15.

The tert-butyldimethylsilyl ether group in 15 was removed using TBAF

in THF to give secondary alcohol 16 in 97% yield (Scheme 8).

16

TBAF, THF, r.t.,

2 h, 97%

OTBS

O

O

OPMB15

OH

O

O

OPMB

Scheme 8

The formation of compound 16 was confirmed from its spectral data.

In 1H NMR spectrum (Fig. 2.20) of 16 the absence of signals due to TBS

group at \ 0.89 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H). In 13C NMR spectrum

(Fig. 2.21) of 16, disappearance of signals at \ 25.7, 18.2, -4.5, -5.0 and

futher confirmed by molecular ion peak at 385 [M+Na] (Fig. 2.23) and IR

(Fig. 2.22) spectrum absorption band at 3449 cm-1.

The secondary alcohol 16 was acetylated using acetic anhydride in

pyridine to afford compound 17 in 96% yield (Scheme 9).

Ac2O, pyridine,

r.t., 4 h, 96%

OH

O

O

OPMB16

OAc

O

O

OPMB17

Scheme 9

The formation of acetylated product 17 was confirmed from its

spectral data. The 1H NMR spectrum (Fig. 2.24) of 17 showed signal at \

2.06 (s, 3 H) due to acetyl group and 13C NMR spectrum (Fig. 2.25) of 17

showed signal at \ 169.7, 20.8 due to acetyl group and molecular ion

peak at m/z 422 [M+NH4] (Fig. 2.27) in its mass spectrum and a IR

absorption band at 1743 cm-1 (Fig. 2.26) indicated the presence of acetyl

group in 17.

Now, the p-methoxybenzyl group in 17 was removed employing DDQ

in CH2Cl2/H2O (10:1) at r.t. for 2 h to give primary alcohol 18 in 95%

yield (Scheme 10).

DDQ, CH2Cl2/H2O(10:1),

r.t., 2 h, 95%

OAc

O

O

OH18

OAc

O

O

OPMB17

Scheme 10

The formation of primary alcohol 18 was confirmed from its 1H NMR

spectrum (Fig. 2.28) with the conspicuous disappearance of signals in

the aromatic region due to PMB group. Its IR spectrum (Fig. 2.30)

showed a band at 3466 cm-1 indicates the formation of hydroxyl

functional group and the molecular ion peak at m/z 302 [M+NH4] in its

mass spectrum (Fig. 2.31) indicated the formation of primary alcohol 18.

The primary alcohol 18 was oxidized with dess-martin periodinane

(DMP) in CH2Cl2 to afford aldehyde, which was further subjected to Z-

selective still-gennari olefination18 by employing bis((2,2,2-

trifluoroethyl)(methoxycarbonyl-ethyl phosphonate)), 18-crown ether,

KHMDS in THF to afford cis-olefinic ester (19) in 86% yield (Scheme 11).

i) Dess-martin periodinane,

CH2Cl2, 0 oC to r.t., 2 h, 94%

ii) (F3CCH2O)2POCH2COOMe,

18-crown ether, KHMDS,

THF, -78 oC, 4 h, 86%

OAc

O

O

OH18

OAc

O

O

O

O

19

Scheme 11

The structure of cis olefinic ester 19 was confirmed from its spectral

data. The 1H NMR spectrum (Fig. 2.32) of 19, showed signals at \ 6.18-

6.08 (m, 1 H), 5.95 (d, J = 11.3 Hz, 1 H) indicated the presence of double

bond and the signal at \ 2.07 (s, 3 H) due to methyl group in ester. In 13C

NMR spectrum (Fig. 2.33) of 19, the double bond carbons resonated at \

144.3 and 123.3. The mass spectrum showed molecular ion peak at m/z

356 [M+NH4] (Fig. 2.35) which confirmed the desire product.

Deprotection of acetonide group in 19 and lactonization were

achieved in one pot using 80% AcOH to give acetylenic lactone 20 with

96% yield. (Scheme 12).

20

OAc

OH

O

O

80% AcOH, r.t.,

20 h, 96%

OAc

O

O

O

O

19

Scheme 12

The formation of lactone product 20 was confirmed from its 1H

NMR spectrum (Fig. 2.36) with the conspicuous disappearance of signals

due to the acetonide group protons, and appearance of a signal at \ 5.11

(td, J = 6.2, 1.5 Hz, 1 H) due to lactone center proton. Its IR spectrum

(Fig. 2.38) showed a band at 3438 cm-1 indicates the presence of

hydroxyl functional group and absorption band at 1750 cm-1 due to

lactone carbonyl group. The molecular ion peak at m/z 284 [M+NH4] in

its mass spectrum (Fig. 2.39), indicated the formation of lactone product

20.

Finally, partial hydrogenation of triple bond in 20 over Lindlar’s

catalyst, quinoline in ethylacetate furnished the target natural product,

pectinolide H (8) in 88% yield (Scheme 13).19

20

OAc OH

OO

OAc

OH

O

O

8

Lindlar's catalyst,quinoline,

ethyl acetate, r.t.,2 h, 88%.

Scheme 13

The formation of product (pectinolide H) 8 was established by the study

of its 1H (Fig. 2.40), 13C (Fig. 2.41), IR (Fig. 2.42) and mass (Fig. 2.43)

spectral data and optical rotation value found to be identical in all

respects as reported for the natural product. 7

Ref. 19. Ramesh, D.; Shekhar, V.; Chantibabu, D.; Rajaram, S.; Ramulu,

U.; Venkateswarlu, Y. Tetrahedron Lett. 2012, 53, 1258–1260.

EXPERIMENTAL SECTION

(S)-Hept-1-yn-3-ol (10):

OH

10

Hept-1-yn-3-one (9) (2.0 g, 18.18 mmol) was added to neat S-Alpine-

borane (22) (36.36 mmol) under inert atmosphere and stirred at room

temperature for 8 h. After completion of the reaction, the reaction

mixture was cooled to 0 °C, and then freshly distilled acetaldehyde (1.59

g, 36.40 mmol) was added and stirred for 1 h to quench the excess

reagent. The reaction mixture diluted with diethyl ether and BBN was

removed by adding ethanolamine (2.22 g, 36.50 mmol) and filtaration.

The precipitate was washed (2 x 25 mL) with cold ether, the combined

filtrate and washings were dried over anhydrous sodium sulfate, and

concentrated under reduced pressure. The crude product was purified by

column chromatography using hexane / ethyl acetate (9.6:0.4) as eluent

to obtain 10 (1.52 g, 75% yield, ee 75%)14 as color less liquid.

Molecular formula : C7H12O

Physical state : Colorless liquid

Optical rotation : [α]D25 = - 18.4 (c = 0.9, CHCl3).

1H-NMR spectrum : 4.31 (dt, J = 6.4, 1.5 Hz, 1 H), 2.38 (d, J = 2.1

Hz, 1 H), 1.90 (brs, 1 H), 1.75-1.64 (m, 2 H),

1.50-1.28 (m, 4 H), 0.93 (t, J = 6.9 Hz, 3 H)

(Fig. 2.1).

13C-NMR spectrum :

85.1, 72.6, 62.1, 37.2, 27.1, 22.2, 13.9 (Fig.

2.2).

IR Spectrum : 3308, 2958, 2867, 1021, 655 (Fig. 2.3).

ESI-Mass spectrum : 135 [M + Na]

(S)-tert-Butyl(hept-1-yn-3-yoloxy)dimethylsilane (11):

OTBS

11

To a cooled solution (0 oC) of 10 (1.2 g, 10.71 mmol) in dry CH2Cl2

(15 mL) was added imidazole (1.45 g, 21.42 mmol) and stirred for 10

minutes and to this solution, tert-butyldimethylsilyl chloride (1.93 g,

12.85 mmol) was added and stirred at room temperature for 3 h. After

completion of the reaction, the reaction was diluted with water and

extracted into CH2Cl2 (2 x 20 mL), organic layer was dried over

anhydrous Na2SO4 and concentrated under reduced pressure. The crude

residue was purified by column chromatography using hexane / ethyl

acetate (9.9:0.1) as eluent to obtain pure 11 (2.27 g, 94% yield) as pale

yellow liquid.

Molecular formula : C13H26OSi

Physical state : Pale yellow liquid

Optical rotation : [α]D25 = -13.6 (c = 2.6, CHCl3).

1H-NMR spectrum : 4.31 (dt, J = 6.4, 2.0 Hz, 1 H), 2.30 (d, J = 2.1

Hz, 1 H), 1.71-1.62 (m, 2 H), 1.49-1.26 (m, 4

H), 0.93 (t, J = 6.9 Hz, 3 H), 0.91 (s, 9 H), 0.13

(s, 3 H), 0.10 (s, 3 H) (Fig. 2.4).

13C-NMR spectrum :

85.8, 71.8, 62.7, 38.3, 27.3, 25.8, 22.3, 18.2,

14.0, -4.5, -5.0 (Fig. 2.5).

IR Spectrum : 3312, 2958, 2860, 1255, 1088, 666 (Fig. 2.6).


(S,E)-6-(tert-Butyldimethylsilyloxy)dec-2-en-4-yn-1-ol (12):

12

OTBS

OH

To a solution of alkyne 11 (2.0 g, 8.85 mmol) and iodo allylic alcohol

21 (1.79 g, 9.73 mmol) in dry benzene (20 mL), was added iPr2NH (5 mL)

followed by Pd(PPh3)4 (0.2 g, 0.17 mmol) and CuI (0.067 g, 0.35 mmol)

and stirred for 2 h at room temperature. After completion of the

reaction, saturated aqueous solution of NH4Cl was added and the

mixture was extracted into EtOAc (3 x 25 mL). The combined organic

layers was washed with brine and dried over anhydrous Na2SO4, and the

solvent was evaporated. The residue was purified by column

chromatography using hexane / ethyl acetate (9.2:0.8) as eluent to

obtain pure 12 (2.19 g, 88% yield) as colorless liquid.

Molecular formula : C16H30O2Si



1H-NMR spectrum : 6.21 (td, J = 15.8, 5.2 Hz, 1 H), 5.80-5.72 (m,

1 H), 4.44 (dt, J = 6.4, 1.1 Hz, 1 H), 4.23-4.16

(m, 2 H), 1.72-1.62 (m, 2 H), 1.53 (brs, 1 H),

1.46-1.26 (m, 4 H), 0.91 (t, J = 6.9 Hz, 3 H),

0.90 (s, 9 H), 0.13 (s, 3 H), 0.10 (s, 3 H) (Fig.

2.7).

13C-NMR spectrum :

141.3, 110.2, 91.9, 81.9, 63.4, 62.7, 38.3,

27.4, 25.8, 22.3, 18.2, 14.0, -4.5, -5.0 (Fig.

2.8).

IR Spectrum : 3387, 2956, 2859, 2210, 1466, 1254, 1085,

837, 777 (Fig. 2.9).


(S,E)-tert-Butyl(10-(4-methoxybenzyloxy)dec-8-en-6-yn-5-yloxy)

dimethylsilane (13):

OTBS

OPMB13

To a cooled (0 oC) solution of 12 (2 g, 7.09 mmol) in dry THF (25 mL)

was added sodium hydride (0.56 g, 14.18 mmol) and stirred for 10

minutes, followed by p-methoxybenzyl chloride (1.15 mL, 8.51 mmol) was

added to the reaction mixture was allowed to warm to room temperature

and stirring was continued for 4 h. After completion of the reaction, the

reaction was diluted with water and extracted with EtOAc (2 x 30 mL),

dried over anhydrous Na2SO4 and concentrated under reduced pressure.

The crude residue was purified by column chromatography using hexane

/ ethyl acetate (9.8:0.2) as eluent to obtain pure 13 (2.65 g, 93% yield) as

colorless liquid.




1H-NMR spectrum : 7.20 (d, J = 8.3 Hz, 2 H), 6.82 (d, J = 8.3 Hz, 2

H), 6.10 (td, J = 15.8, 5.2 Hz, 1 H), 5.72 (dd, J

= 15.8, 1.5 Hz, 1 H), 4.42 (s, 2 H), 4.41 (dt, J =

6.4, 1.5 Hz, 1 H), 3.99 (dd, J = 5.3, 1.5 Hz, 2

H), 3.79 (s, 3 H), 1.72-1.60 (m, 2 H), 1.45-1.29

(m, 4 H), 0.92 (t, J = 6.8 Hz, 3 H), 0.90 (s, 9 H),

0.12 (s, 3 H), 0.10 (s, 3 H) (Fig. 2.10).

13C-NMR spectrum :

159.2, 139.0, 130.0, 129.3, 113.8, 111.5,

91.9, 81.9, 71.9, 69.5, 63.4, 55.2, 38.3, 27.4,

25.8, 22.3, 18.2, 14.0, -4.5, -5.0 (Fig. 2.11).

IR Spectrum : 2953, 2859, 1513, 1250, 1081, 838, 775

ESIMS spectrum : 425 [M + Na] (Fig. 2.12).

(2S,3S,6S)-6-(tert-Butyldimethylsilyloxy)-1-(4-methoxybenzyloxy)

dec-4-yne-2,3-diol (14):

OTBS

OH

OH

OPMB14

To a solution of AD-mix-α (5.22 g) in t-BuOH/H2O 1:1 (60 mL) was

added methanesulfonamide (0.35 g, 3.73 mmol) at room temperature

and stirred for 10 min and cooled to 0 oC, and added the olefin 13 (3.73

mmol) and the entire reaction mixture was stirred vigorously at this

temperature for 24 h. After completion of the reaction (as noticed by

TLC), the reaction was quenched with sodium sulfite (6.6 g, 52.2 mmol)

and stirring was continued for another 30 min and the reaction mixture

was brought to room temperature. The product was extracted into EtOAc

(3 x 50 mL). The combined organic layer was dried over Na2SO4 and

concentrated. The residue was purified by silica gel column

chromatography using hexane / ethyl acetate (8:2) as eluent to obtain

diol 14 (1.48 g, 82% yield, 96% de, Chiral HPLC) as colorless viscous

liquid


Physical state : Colorless viscous liquid



H), 4.47 (s, 2 H), 4.39-4.30 (m, 2 H), 3.79 (s, 3

H), 3.78-3.72 (m, 1 H) 3.67-3.50 (m, 2 H), 2.62

(brs, 2 H), 1.69-1.56 (m, 2 H), 1.44-1.26 (m, 4

H), 0.91 (t, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.10

(s, 3 H), 0.08 (s, 3 H), (Fig. 2.13).

13C-NMR spectrum :

159.2, 129.6, 129.3, 113.7, 88.0, 81.4, 73.3,

73.1, 70.2, 63.5, 62.7, 55.1, 38.1, 27.2, 25.6,

22.2, 18.1, 13.9, -4.6, -5.1 (Fig. 2.14).

IR Spectrum : 3413, 2932, 2860, 1613, 1249, 1083, 838, 777

(Fig. 2.15).


tert-Butyl((S)-1-((4S,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-

dimethyl-1,3-dioxolan-4-yl)hept-1-yn-3-yoloxy)dimethylsilane (15):

OTBS

O

O

OPMB15

To a cooled (0 oC) solution of 14 (0.48 g, 1.10 mmol) in CH2Cl2 (5 mL)

was added 2,2-dimethoxypropane (0.34 mL, 2.75 mmol) and a catalytic

amount of PTSA. The resulting mixture was brought to room temperature

and stirred for 12 h. After completion the reaction, the reaction was

quenched with saturated NaHCO3 solution and extracted into CH2Cl2 (2 x

20 mL). The organic layer was dried over anhydrous Na2SO4 and

concentrated under reduced pressure. The crude residue was purified by

column chromatography using hexane / ethyl acetate (9.5:0.5) as eluent

to obtain pure compound 15 (0.46 g, 90% yield) as color less liquid.


Physical state : Color less liquid.



H), 4.51 (s, 2 H), 4.50-4.44 (m, 1 H), 4.34 (dt, J

= 6.8, 1.5 Hz, 1 H), 4.18-4.10 (m, 1 H), 3.79 (s,

3H), 3.60-3.46 (m, 2 H), 1.70-1.57 (m, 2 H),

1.45 (s, 3 H), 1.40 (s, 3 H), 1.39-1.26 (m, 4 H),

0.91 (t, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.10 (s, 3

H), 0.08 (s, 3 H) (Fig. 2.17).

13C-NMR spectrum :

159.2, 129.9, 129.3, 113.7, 110.5, 88.4, 80.9,

80.5, 73.2, 68.9, 67.4, 62.9, 55.2, 38.1, 27.3,

26.9, 26.1, 25.7, 22.2, 18.2, 14.0, -4.5, -5.0

(Fig. 2.18).

IR Spectrum 2932, 1612, 1513, 1250, 1085, 838, 777


(S)-1-((4S,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)hept-1-yn-3-ol (16):

OH

O

O

OPMB16

To a solution of 15 (0.36 g, 0.75 mmol) in dry THF (4 mL) was added

TBAF (1 M in THF, 0.83 mL) and stirred for 2 h at room temperature.

After completion of the reaction, the reaction mixture was quenched with

saturated NaHCO3 solution, and extracted into EtOAc (2 x 20 mL), the

organic layer was washed with brine solution, dried over anhydrous

Na2SO4 and concentrated under reduced pressure. The crude residue was

purified by silica gel column chromatography using hexane / ethyl

acetate (8.4:1.6) as eluent to obtain pure compound 16 (0.26 g, 97%

yield) as colorless liquid.

Molecular formula : C21H30O5


Optical rotation : [α]D25 = -48.6 (c = 1.29, CHCl3)


H), 4.56-4.51 (m, 3 H), 4.44-4.34 (m, 1 H),

4.25-4.17 (m, 1 H), 3.81 (s, 3 H), 3.66-3.53 (m,

2 H), 1.81-1.60 (m, 3 H), 1.51-1.24 (m, 10 H),

0.90 (t, J = 6.9 Hz, 3 H) (Fig. 2.20).

13C-NMR spectrum :

159.2, 129.8, 129.3, 113.7, 110.5, 87.7, 81.3,

80.8, 73.2, 68.7, 67.4, 62.3, 55.2, 37.2, 27.2,

26.9, 26.2, 22.2, 13.9 (Fig. 2.21).

IR Spectrum : 3449, 2932, 2862, 1612, 1513, 1247, 1033

(Fig. 2.22).


(S)-1-((4S,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)hept-1-yn-3-yl acetate (17):

OAc

O

O

OPMB17

To a cooled (0 oC) solution of secondary alcohol 16 (0.2 g,

0.552mmol) in pyridine (1 mL) was added Ac2O (0.5 mL) and stirred at

room temperature for 4 h. After completion of the reaction, the reaction

was diluted with aqueous CuSO4 (5 mL) and extracted into ethyl acetate

(2 x 15 mL), the combined organic phase was washed with brine, dried

over Na2SO4. After evaporation of the solvent, the crude residue was

purified by column chromatography using hexane / ethyl acetate

(8.8:1.2) as eluent to afford the desired product 17 (0.22 g, 96% yield) as

colorless liquid.





H), 5.39 (dt, J = 6.8, 1.5 Hz, 1 H), 4.56-4.51 (m,

3 H), 4.26-4.19 (m, 1 H), 3.81 (s, 3 H), 3.64-

3.52 (m, 2 H), 2.06 (s, 3 H), 1.79-1.70 (m, 2 H),

1.50-1.24 (m, 10 H), 0.90 (t, J = 6.9 Hz, 3 H)

(Fig. 2.24).

13C-NMR spectrum :

169.7, 159.1, 129.7, 129.2, 113.6, 110.6, 83.9,

82.1, 80.7, 73.1, 68.7, 67.2, 63.7, 55.1, 34.1,

26.9, 26.8, 26.0, 22.0, 20.8, 13.8 (Fig. 2.25).

IR Spectrum : 2931, 2864, 1743, 1513, 1373, 1234, 1033

(Fig. 2.26).

ESIMS spectrum : 422 [M+NH4] (Fig. 2.27).

(S)-1-((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)hept-

1-yn-3-yl acetate (18):

OAc

O

O

OH18

To a cooled (0 oC) solution of 17 (155 mg, 0.38 mmol) in DCM (5 mL)

and water (0.5 mL) was added DDQ (174 mg, 0.76 mmol) and stirred at

room temperature for 2 h. After completion of the reaction, saturated

NaHCO3 solution was added, and the aqueous layer was extracted with

DCM (2 X 10 mL). The combined organic extract was dried over

anhydrous Na2SO4 and concentrated to dryness. Column

chromatography of the residue using hexane / ethyl acetate (8.2:1.8)

gave 18 (109 mg, 95%) as colorless liquid.




1H-NMR spectrum : 5.39 (t, J = 7.0 Hz, 1 H), 4.61 (d, J = 8.0 Hz, 1

H), 4.16-4.12 (m, 1 H), 3.90-3.85 (m, 1 H),

3.70-3.63 (m, 1 H), 2.06 (s, 3 H), 1.87 (brs, 1

H), 1.79-1.72 (m, 2 H), 1.51-1.29 (m, 10 H),

0.90 (t, J = 7.0 Hz, 3 H) (Fig. 2.28).

13C-NMR spectrum :

170.0, 110.6, 84.3, 82.0, 81.9, 66.3, 63.9,

60.8, 34.2, 27.1, 26.8, 26.0, 22.2, 21.0, 13.9

(Fig. 2.29).

IR Spectrum : 3466, 2934, 2869, 1742, 1375, 1233, 1047

(Fig. 2.30).


(Z)-Methyl 3-((4S,5S)-5-((S)-3-acetoxyhept-1-ynyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)acrylate (19):

OAc

O

O

O

O

19

To a cooled (0 oC) solution of alcohol 18 (60 mg, 0.21 mmol) in dry

CH2Cl2 (3 mL) was added Dess-Martin reagent (116 mg, 0.27 mmol) and

stirred at room temperature for 2 h. After completion of the reaction,

saturated Na2S2O3 solution was added and stirring continued for 10

minutes. The reaction mixture was diluted with saturated NaHCO3

solution and aqueous layer was extracted into CH2Cl2 (2 x 10 mL), dried

over anhydrous Na2SO4 and concentrated under reduced pressure to

afford crude aldehyde (56 mg, 94% yield), which was used as such for

further reaction. To cooled (-78 oC) solution of (F3CCH2O)2POCH2COOMe

(0.06 mL, 0.292 mmol), 18-crown-6 (258 mg, 0.975 mmol) in anhydrous

THF (4 mL) was added KHMDS (0.23 mL, 0.23 mmol) and the reaction

mixture was stirred for 30 min. To this reaction mixture, the aldehyde

(55 mg, 0.195 mmol) in dry THF (2 mL) was added and stirred for 4 h at

the same temperature. After completion of the reaction, the reaction was

quenched with saturated NH4Cl, and extracted into ethyl acetate. The

combined organic layer was washed with brine, dried over Na2SO4, and

concentrated. The residue was purified by column chromatography using

hexane / ethyl acetate (9.2:0.8) to give the product 19 (56.6 mg, 86%

yield) as colorless liquid.




1H-NMR spectrum : 6.18-6.08 (m, 1 H), 5.95 (d, J = 11.3 Hz, 1 H),

5.65 (t, J = 6.8 Hz, 1 H), 5.39 (t, J = 6.8 Hz, 1

H), 4.42 (d, J = 6.0 Hz, 1 H), 3.76 (s, 3 H), 2.07

(s, 3 H), 1.81-1.71 (m, 2 H), 1.55-1.24 (m, 10

H), 0.91 (t, J = 6.8 Hz, 3 H) (Fig. 2.32).

13C-NMR spectrum :

169.8, 165.4, 144.3, 123.3, 111.4, 84.1, 81.6,

77.1, 70.8, 63.8, 51.5, 34.2, 27.2, 26.9, 26.4,

22.1, 20.9, 13.8 (Fig. 2.33).

IR Spectrum : 2956, 2867, 1731, 1374, 1230, 1054 (Fig.

2.34).


(1S,4S)-1-Hydroxy-1-((S)-5-oxo-2,5-dihydrofuran-2-yl)oct-2-yn-4-yl

acetate (20):

20

OAc

OH

O

O

To a cooled (0 oC) solution of the cis olefinic ester 19 (52 mg, 0.153

mmol) was added 80% AcOH (2 ml) and stirred for 20 h. After completion

of the reaction, the reaction was quenched with saturated NaHCO3

solution at 0 oC and extracted into ethyl acetate (2 x 10 mL). The

combined organic layer was washed with brine, dried over anhydrous

Na2SO4 and concentrated under reduced pressure. The crude residue

was purified by silica gel column chromatography using hexane / ethyl

acetate (7.2:2.8) as eluent to obtain pure compound 20 (39 mg, 96%

yield) as color less liquid.




1H-NMR spectrum : 7.53 (dd, J = 5.6, 1.5 Hz, 1 H), 6.25 (dd, J =

5.6, 1.5 Hz, 1 H), 5.30 (t, J = 6.2 Hz, 1 H), 5.11

(td, J = 6.2, 1.5 Hz, 1 H), 4.58 (d, J = 5.6 Hz, 1

H), 2.09 (s, 3 H), 1.82-1.69 (m, 2 H), 1.46-1.29

(m, 4 H), 0.92 (t, J = 6.8 Hz, 3 H) (Fig. 2.36).

13C-NMR spectrum :

172.3, 170.2, 152.8, 123.3, 85.5, 84.4, 80.6,

63.8, 63.3, 34.0, 27.0, 22.1, 20.9, 13.8 (Fig.

2.37).

IR Spectrum : 3438, 2923, 2857, 1750, 1237, 1052, 759 (Fig.

2.38).

ESIMS spectrum : 284 [M + NH4] (Fig. 2.39).

Pectinolide H (8):

OAc OH

OO

8

A solution of acetylenic lactone 20 (30 mg, 0.112 mmol) in ethyl

acetate was hydrogenated with the Pd-BaSO4 (5 mg) and quinoline (2 µL)

with vigorous stirring for 2 h. After completion of the reaction, the

catalyst was removed by filtration and washed with ethyl acetate. The

filtrate was washed with 0.5 N HCl and saturated NaHCO3 solution dried

over anhydrous Na2SO4 and concentrated under reduced pressure. The

crude residue was purified by silica gel column chromatography using

hexane / ethyl acetate (7.1:2.9) as eluent to obtain pure compound 8 (26

mg, 88% yield) as color less liquid.




1H-NMR spectrum : 7.55 (dd, J = 6.1, 1.8 Hz, 1 H), 6.22 (dd, J =

6.1, 1.8 Hz, 1 H), 5.56-5.33 (m, 3 H), 5.16 (dt,

J = 6.1, 1.8 Hz, 1 H), 4.96 (dd, J = 7.8, 6.1 Hz,

1 H), 3.70 (d, J = 3.8 Hz, 1 H), 2.05 (s, 3 H),

1.79-1.48 (m, 2 H), 1.44-1.18 (m, 4 H), 0.92 (t,

J = 7.0 Hz, 3 H) (Fig. 2.40).

13C-NMR spectrum :

172.5, 171.8, 153.3, 133.1, 129.3, 123.2, 84.1,

71.0, 67.1, 33.6, 27.1, 22.4, 21.3, 13.9 (Fig.

2.41).

IR Spectrum : 3444, 2924, 2855, 1752, 1243, 1044 (Fig.

2.42).


REFERENCES

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Senda, S.; Nakazono, Y.; Omata, T. Tetrahedron 1991, 47, 6223-

6230; (c) Mori, K. Tetrahedron 1989, 45, 3233-3298;

2. (a) Gunasekera, S. P.; Mc Carthy, P. J.; Kelly-Borges, M.;

Lobkovsky, E.; Clardy, J. J. Am. Chem. Soc. 1996, 118, 8759–760;

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Givskov, M.; Nielsen, J. Bioorg. Med. Chem. 2003, 11, 3261-3271;

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Carcia, V. Eur. J. Med.Chem. 2006, 41, 192-200; (b) Brohm, D.;

Philippe, N.; Metzger, S.; Bhargava, A.; Muller, O.; Lieb, F.;

Waldmann, H. J. Am. Chem. Soc. 2002, 124, 13171–13178.

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Arch. Pharm. Res. 2006, 29, 624-626.

6. Ma, S.; Shi, Z.; Yu, Z. Tetrahedron 1999, 55, 12137-12148.

7. Fragoso-Serrano, M.; Gibbons, S.; Perda-Miranda, R. Planta Med.

2005, 71, 278-280.

8. Mattinez, M. Las Plantas Medicinales de Mexico, Editorial Botas,

mexico, 1989, p. 508.

9. Malan, K.; Pelissier, Y.; Marion, C.; Blaise, A.; Blessiere, J. Planta

Med. 1988, 54, 531-532.

10. Perda-Miranda, R.; Hernandez, L.; Villavicencio, M. J.; Novelo, M.;

Ibarra, P. J. Nat. Prod. 1993, 56, 583-593.

11. Boalino, D. M.; Connolly, J. D.; McLean, S.; Reynolds, W. F.; Tinto,

W. F. Phytochemistry 2003, 64, 1303–1307.

12. (a) Reddy, D. K.; Shekhar, V.; Prabhakar, P.; Chanti Babu, D.;

Ramesh, D.; Siddhardha, B.; Murthy, U.S.N.; Venkateswarlu, Y.

Bioorg. Med. Chem. Lett. 2011, 21, 997-1000. (b) Ramesh, D.;

Rajaram, S.; Prabhakar, P.; Ramulu, U.; Reddy, D. K. Helv. Chim.

Acta 2011, 94, 1226-1233; (c) Shekhar, V.; Reddy, D. K.; Suresh,

V.; Chanti Babu, D.; Venkateswarlu, Y. Tetrahedron Lett. 2010, 51,

946-948.

13. (a) Colobert, F.; Genet, J-P. Tetrahedron Lett. 1985, 26, 2779-

2782; (b) Babudri, F.; Fiandanese, V.; Hasan, O.; Punzi, A.; Naso,

F. Tetrahedron 1998, 54, 4327-4336.

14. (a) Reddy, M. V. R.; Rearick, J. P.; Hoch, N.; Ramachandran, P. V.

Org. Lett. 2001, 3, 19-20; (b) Midland, M. M.; McDowell, D. C.;

Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867-

869; (c) Stille, J. K.; Sweet, M. P. Tetrahedron Lett. 1989, 30, 3645-

3648.

15. Rossi, R.; Bellina, F.; Catanese, A.; Manninab, L.; Valensinc, D.

Tetrahedron, 2000, 56, 479–487.

16. (a) Vaz, B.; Pereira, R.; Perez, M.; Alvarez, R.; de Lera, A. R. J. Org.

Chem. 2008, 73, 6534–6541; (b) Andreini, B. P.; Carpita, A.; Rossi,

R.; Scamuzzi, B. Tetrahedron 1989, 45, 5621-5640.

17. (a) Caddick, S.; Shanmugathasan, S.; Brasseur, D.; Delisser, V. M.

Tetrahedron Lett. 1997, 38, 5735-5736; (b) Somfai, P.; Marchand,

P.; Torsell, S.; Lindstrom, U. M. Tetrahedron 2003, 59, 1293–1299.

18. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408. b)

Horita, K.; Sakurai, Y.; Nagasawa, M.; Yonemitsu, O. Chem. Pharm.

Bull. 1997, 45, 1558-1572; c) Krishna, P. R.; Reddy P. S.

Tetrahedron 2007, 63, 3995–3999.

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U.; Venkateswarlu, Y. Tetrahedron Lett. 2012, 53, 1258–1260.

Fig. 2.1: 1H NMR Spectrum of 10

Fig. 2.2: 13

C NMR Spectrum of 10

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

OH

10

00101020203030404050506060707080809090100100

OH

5.55.56.06.06.56.57.07.07.57.5

Fig. 2. 3: IR spectrum of compound 10


1.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.5

OTBS

OH

0.00.00.50.51.01.0

80809090100100

Fig. 2.5: 13


Fig. 2.6: IR spectrum of compound 11

202030304040505060607070

OTBS

11

OTBS

001010


Fig. 2.8: 13


0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

12

OTBS

OH

-10-1000101020203030404050506060707080809090100100110110120120130130140140150150160160

12

OTBS

OH

5.55.56.06.06.56.57.07.07.57.5



1.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.5

OTBS

OP MB 1 3

OTBS

OH

0.00.00.50.51.01.0

Fig.

120120130130140140150150160160170170

Fig. 2.11: 13


Fig. 2.12: Mass spectrum of compound 13

3030404050506060707080809090100100110110120120

OTBS

OPMB13

OTBS

OPMB

-10-100010102020


Fig. 2.14: 13


0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

OTBS

OH

OH

OPMB

14

00101020203030404050506060707080809090100100110110120120130130140140150150160160

OTBS

OH

OH

OPMB

14

Fig.



OTBS

OH

OH

OPMB

OTBS

OH

OH

OPMB


Fig. 2.18: 13


0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.0

00101020203030404050506060707080809090100100110110120120130130140140150150160160170170

OTBS

O

O

OPMB

OTBS

O

O

OPMB



0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

OTBS

O

O

OPMB

OH

O

O

OPMB

Fig. 2.21: 13



00101020203030404050506060707080809090100100110110120120130130140140150150160160170170

OH

O

O

OPMB

OH

O

O

OPMB



0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

OH

O

O

OPMB

OAc

O

O

OPMB

Fig. 2.25: 13



00101020203030404050506060707080809090100100110110120120130130140140150150160160170170

OAc

O

O

OPMB

OAc

O

O

OPMB



0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

OAc

O

O

OPMB

OAc

O

O

OH

Fig. 2.29: 13



00101020203030404050506060707080809090100100110110120120130130140140150150160160170170

OAc

O

O

OH

OAc

O

O

OH



0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

OAc

O

O

OH

OAc

O

O

O

O

Fig. 2.33: 13



00101020203030404050506060707080809090100100110110120120130130140140150150160160170170

OAc

O

O

O

O

OAc

O

O

O

O



0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

OAc

OH

O

O

OAc

O

O

O

O

Fig. 2.37: 13



00101020203030404050506060707080809090100100110110120120130130140140150150160160170170180180

OAc

OH

O

O

OAc

OH

O

O



0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.08.58.5

OAc OH

OO

OAc

OH

O

O

Fig. 2.41: 13

C NMR Spectrum of 8


00101020203030404050506060707080809090100100110110120120130130140140150150160160170170180180

OAc OH

OO

OAc OH

OO


OAc OH

OO

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CHAPTER-II First stereoselective total synthesis of ...shodhganga.inflibnet.ac.in/bitstream/10603/19732/10/10_chapter 2.pdf · explain an efficient and simple approach for the stereoselective