chapter ii stereoselective total synthesis of...

CHAPTER – II

Stereoselective total synthesis of (+)-Cryptofolione and (-)-Cryptocarya lactone

SECTION – A

Stereoselective total synthesis of (+)-Cryptofolione

• Iodine catalyzed efficient hydrophosphonylation of

N-tosyl aldimines

• Simple, efficient and catalyst-free synthesis of 2-

amino-4H-chromen-4-yl phosphonates in

polyethylene glycol

INTRODUCTION

Human beings have relied on natural products as a resource of

drugs for thousands of years. Plant-based drugs have formed the basis

of traditional medicine systems that have been used for centuries in

many countries such as Egypt, China and India.1

Today plant-based drugs continue to play an essential role in

health care. It has been estimated by the World Health Organization

that 80% of the population of the world rely mainly on traditional

medicines for their primary health care.2 Natural products also play

an important role in the health care of the remaining 20% people of

the world, who mainly reside in developed countries.

The discovery of natural drugs is guided by bioassay. Bioassay

plays a very important role in every step of the discovery program.

First it can be used to detect the bioactivity of the crude extracts and

thus guide the selection of extracts for further study. In the isolation

steps the bioassay will guide the fraction of a crude sample towards

the pure isolated compound. For these purposes, bioassay must be

rapid, simple, reliable, reproducible and most important, predictive. It

should also model a living organism well. Unfortunately, no bioassay

can meet all of the above criteria. In vivo testing (such as on rats) can

provide more valid data than in vitro cellular testing; however, animal

testing is complicated, slow and expensive, and is normally only used

on pure compounds that have demonstrated in vitro activity. Currently

there are a large number of available bioassay systems in the area of

anticancer drugs, divided into two groups; cellular assays and cell-free

assays. Cellular assays utilize intact cells (yeast cells, mammalian

cells, etc.) while cell-free assays utilize isolated systems (enzymes,

DNA fragments, etc.) for bioactivity study. These cell-free assays are

usually mechanism-based, with a key enzyme or other biomolecule as

the target.

Cytotoxicity assays are very commonly used in cellular assays.

Since cytotoxicity is an activity that is consistent with anticancer

activity, the major advantage of cytotoxicity assays is that all potential

mechanisms of cellular proliferation can be monitored simultaneously.

Thus, the search for new anti-cancer reagents in the past has been

primarily focused on extracts showing cytotoxicity to one or two cell

lines. The approach has been fruitful and led to the discovery of

paclitaxel, among many other compounds. Cytotoxicity-based assays

are normally reported as IC50 values (the concentration of a sample

that can inhibit 50% growth of a target cell in a single cell line). The

cell line employed in the cytotoxicity assay of our group is the A2780

human ovarian cancer cell line. The A2780 assay is a general

cytotoxicity assay, which means that in many cases the active

compound will simply be toxic, and thus will not be suitable for drug

use.

The use of cell-free mechanism-based assays is a second approach

to drug discovery. These assays utilize isolated assay systems (cellular

receptor, enzyme, etc.) to test the bioactivity. Basically these assays

are designed to test the unknown extract, fraction, or pure compound

in comparison to known antitumor agents in mechanisms that have

been clearly delineated. Mechanism-based assays are very selective

and sensitive and also reproducible. An important advantage of these

assays is that once a lead compound is discovered, its mechanism of

action is already known, and lead optimization can thus be carried out

more efficiently. Because of these advantages, several mechanism-

based assays are currently employed in the NCDDG project, such as

assays for inhibitors of Akt-kinase, Myt-1 kinase and DNA polymerase

β (pol-β) assay. If a novel compound is found with a similar effect to a

known specific compound, it can be classified to the specific

mechanistic class. This approach can lead to a more systematic

method to discover new anticancer drugs. Thus the original goal of

total synthesis is to confirm structure of a natural product

andexploration and discovery of new chemistry along the pathway to

the target molecule.

ISOLATION AND BIOLOGICAL STUDIES OF CRYPTOCARYA

PYRONES:

In 2000, Cavalheiro and Drewes groups3 reported the isolation of

a group of styryl lactones (1-6) (Figure 1) from the branch and stem

bark of Cryptocarya moschata, Lauraceae, a tree growing up to 30-

40m high, found in the Atlantic Forest, mainly in the Southeastern

Region of Brazil. The structures were established by spectroscopic

studies and these 5, 6-dihydro-α-pyrones contain a styryl group

attached to the C6 side chain. Styryllactones in general are reported to

possess significant cytotoxicity toward several human tumor lines.4

Some of the Cryptocarya pyrones have been identified as highly

efficacious inhibitors of the G2 check point,5 which can enhance

killing of cancer cells by ionizing radiation and DNA-damaging

chemotherapeutic agents, particularly in cells lacking p53 function.5

The highly unique structures and the impressive levels of biological

activities makes them as attractive targets for total synthesis. The

common feature of these pyrones is that they all contain a styryl

group; however they have varying carbon skeletons. The structures of

these compounds were established by spectroscopic studies.

Cryptocarya species showed outstanding equipotent activity towards

COX-1 and COX-2.6

O

O

OH OH O

O

1. Goniothalamin 2. Cryptomoscatone D2

OH OH O

O

OH OH OH O

O

3. Cryptofolione 4. Cryptomoscatone E3

O

OHHO

O

O

O

OHHO

O

O

5. Cryptopyranmoscatone B1 6. Cryptopyranmoscatone B4

Cryptofolione:

Cryptofolione 3 was isolated from the branch, leaves and stem bark

of two species of Cryptocarya (Lauraceae) such as Cryptocarya

latifolia3a and Cryptocarya moschata3b

OH OH O

O

3. Cryptofolione

from South Africa and Brazil by Drews and Cavalheiro coworkers in

1994 and 2000. Cryptofolione showed activity towards Trypanosoma

cruzi trypomastigotes, reducing their number by 77% at 250g mL-1

and moderate cytotoxicity in both macrophages and T. cruzi

amastigotes. It also displayed a mild inhibitory effect on the

promastigote form of Leishmania species. This important activity and

the potential to transfer this application to human beings made 3 as a

challenging target for total synthesis.

PREVIOUS SYNTHETIC APPROACHES OF CRYPTOFOLIONE

As the candidate carried out the synthesis of cryptofolione, it is

relevant to discuss the earlier synthetic approaches.

Tsutomu Katsuki at al. approach7

CHO +

OMe

OTMS

O OMe

O

O OMe

OH

OH OHCO2Et

OR ORCHO

R=TBS

OR OR

R=TBSO

O

OR OR

R=TBSO O

OH OH

O O

O OH

OH

a b

c d

e f

g h

7 8

9 10

11 12

13 14

153

Scheme 1

Reagents and conditions: (a) (R, R- second-generation (salen)

chromium complex), CH2Cl2, MeOH, Et3N, 0 oC, 8h, 82%; (b) (i) LiAlH4,

THF, -78 oC, 1h, 87%; (ii) recrystallization from toluene ,74%; (c) 0.002

M HCl, H2O/MeCN (1:2), 50 oC, 2h, 88%; (d) (Et2O)P(O)CH2COOEt,

NaH, THF, -30 oC, 1h, 84%; (e) (i) TBSCl, imadazole, CH2Cl2, 0 oC, 3h,

91%; (ii) DIBAL-H, CH2Cl2, -78 oC, 15min, 89%; (iii) Ru-selen, O2,

visible light, rt, 12h, 87%; (f) (R, R- second-generation (salen)

chromium complex), CH2Cl2, MeOH, Et3N, TFA, 0 oC, 6h, 77%; (g) (i)

NaBH4, MeOH, CeCl3.7H2O, -78 oC, 3h, 79%; (ii) PPTS, MeOH, rt, 6h,

93%; (iii) Jones oxidation, 0 oC, 3h, 87%; (h) AcOH/H2O/THF (3:1:1),

rt, 3h, 89%.

According to Tsutomu Katsuki procedure, key reaction in the

total synthesis of cryptofolione is an asymmetric hetero Diels-Alder

(AHDA) reaction. The synthesis was started (Scheme 1) with AHDA

reaction of cinnamyl aldehyde 7 with Danishefsky diene 8 using

second-generatoin (salen) chromium complex8 as the catalyst. The

reaction gave 2- methoxy-γ-pyrone 9 of 95% ee, when the reaction was

quenched with methanol in the presence of triethylamine. The product

was reduced with LiAlH4 to give the corresponding cis-alcohol 10, the

recrystallization of which from toluene gave optically pure 10 in 74%

yields.

Compound 10 was hydrolyzed under acidic conditions to give lactol

11 which was subjected to Wittig reaction using (Et2O)P(O)CH2COOEt

to obtaine α,β-unsaturated ester 12. The dihydroxyl groups in

compound 12 was protected with TBSCl to give corresponding t-

butyldimethylsilyl (TBS) ethers and was transformed to aldehyde 13

by following sequence: i) DIBAL-H in DCM at -70 oC for 2h and ii)

subsequently aerobic oxidation using Ru-salen complex.9 Asymmetric

Hetero Dields-Alder (AHDA) reaction of 13 with 8 using R, R- second-

generation (salen) chromium complex catalyst gave γ-pyrone 14, after

the reaction mixture was treated with TFA, γ-pyrone was converted

into corresponding α-pyrone 15 by the following sequence: i) reduction

by Luche’s method, ii) acidic transformation of enol ether to methyl

acetal associated with doublebond migration, and iii) jones oxidation.

Treatment of α-pyrone 15 with acetic acid-water gave 3.

Sabitha et. al. approach10

S

SO

SSOH

SSOMOM

OMOMO OMOMOH OHOH

OOO

O

OO O

O

OHOH O

O

a b

d e

f

g

h

c

16 17 18 19

20 21 22

23

24

25

3

Scheme 2

Reagents and conditions: (a) n-BuLi, BF3.OEt2, THF, -78 oC, 1h,

75%; (b) MOMCl, DIPEA, CH2Cl2, 0 oC, 0.5h, 92%; (c) Hg(ClO4).xH2O,

THF-H2O (5:1), CaCO3, 0 oC, 0.5h, 85%; (d) S-CBS catalyst, toluene,

BH3.DMS, 0 oC, 0.5h, 78%, 98 % de; (e) CeCl3.7H2O, MeCN-MeOH

(1:1), reflux, 6h, 91%; (f) Me2C(OMe)2, PPTS, CH2Cl2, 0 oC, 20 min,

98%; (g) Grubb’s 2nd generation catalyst, CH2Cl2, reflux, 6h, 87%; (h)

aq. 4% HCl, MeCN, 0 oC, 0.5h, 93%.

Sabitha et al reported (Scheme 2) the alternative synthesis of

cryptofolione 3 started with commercially available cinnamaldehyde

which was converted into thioketal 16 using 1, 3 propane thiol and

BF3.OEt2. The 1, 3 dithiane reaction of 16 with 17 using n-BuLi gave

corresponding product 18. The alcohol 18 was protected with MOMCl

using DIPEA to obtained compound 19. Deprotection of 1, 3 thioketal

using mercury (II) perchlorate hydrate produced ketone 20 with high

yield 85%. Diatereoselective reduction of ketone 20 using S-CBS

catalyst with BH3.DMS at 0 oC to give anti product 21 in 78% yield.

The MOM deprotection of compound 21 using CeCl3.7H2O in

MeCN/MeOH gave diol 22. The compound 22 was treated with 2,2-

DMP, PPTS in CH2Cl2 to give acetonide protected diol 23. The anti

relationship of 1, 3 hydroxy groups was determined by using

Rychnovsky’s acetonide method.11Finally cross-metathesis of

compound 23 and compound 24 using Grubb’s 2nd generation at 50

oC produced desired compound 25, which was treated with 2N HCl in

MeCN to give naturally isolated cryptofolione 3.

Kumar et. al. approach12

H

OO

OEt

OTMSTMSOH O

OEt

O

OH OH

OEt

O O O

OEt

O

O O O

H

O O O

OEt

O O OH O O O

O

O O O

O

OH OH O

O

a

b

d e

f g

h i

c

26 27 28

29 30

31 32

33 34

25 3

Scheme 3

Reagents and conditions: (a) (i) Ti(iOPr)4/(R)-BINOL(10 mol%), THF, -

78 °C to rt, 16h; 85% (ii) TFA, CH2Cl2, -78 oC, 30 min, 78%, 1h, 93%;

(b) Me4NBH(OAc)3, MeCN/AcOH (1:1), -40 oC, 5h, 87%; (c) 2,2-DMP,

CSA, CH2Cl2, 0 oC to rt, 2h, 95%; (d) (i) DIBAL-H, THF, 0 oC, 1h, 91%;

(ii) IBX, CH2Cl2/DMSO, 0 oC to rt, 3h, 79%; (e) PPh3=CH2COOEt,

CH2Cl2, 3h, 92%; (f) (i) DIBAL-H, THF, 0 oC, 1h 74%; (ii) Ti(iOPr)4/(R)-

BINOL(10 mol%),Ag2O, allyltributyltin, 4A° MS, CH2Cl2, 0°C, 12 h,

73%; (g) Acryloyl chloride, Et3N, DMAP, 1h, 0°C, CH2Cl2, 85%; (h)

Grubb's 1st generation catalyst, CH2Cl2, reflux, 8h, 59%; (i) CSA,

MeOH, rt, 2h, 91%.

Kumar at al achieved (Scheme 3) the stereoselective synthesis of

cryptofolione 3 starting from cinnamaldehye 26 and Chen’s diene 27

through Mukaiyama aldol reaction using 10 mol % of Ti(OiPr)4/(R)-

BINOL (1:1) to give aldol product 28. The diastereoselective anti

reduction of compound 28 with Me4NBH(OAc)3, 13 in

acetonitrile/acetic acid (1:1) at -40 oC resulted anti exclusive product

29. The diol 29 was protected with 2,2-DMP, PPTS in CH2Cl2 to give

acetonide compound 30. The anti relationship of acetonide compound

30 was determined according to 13C NMR data.11 The ester 30 was

treated with DIBAL-H in THF to give alcohol followed by IBX oxidation

to produce aldehyde. This prepared aldehyde was subjected to Wittig

reaction to give α,β-unsaturated ester 32. Further unsaturated ester

32 was reduced to aldehyde using DIBAL-H in THF, which underwent

Maruoka allylation14 using titanium compex and allyltri-n-butyltin to

obtaine homoallylic alcohol 33. Acrylation followed by ring closing

metathesis using Grubb’s 1st generation catalyst gave desired product

25. Finally deprotection of acetonide using CSA in MeOH gave

cryptofolione 3.

PRESENT WORK

The α,β-unsaturated styryl lactones are important class of natural

products having broad range of biological properties.15 Moreover, it

has been shown that the unsaturated moiety plays an essential role in

the biological activity, due to its potentiality to act as a Michael

acceptor in the presence of protein functional groups. One such

lactone is cryptofolione 3, a class of 6-(w-arylalkenyl)-5,6-dihydro--

pyrones isolated from the branch, leaves and stem bark of two species

of cryptocarya (Lauraceae) such as Cryptocarya moschata3a and

Cryptocarya myrtifolia3b indigenous to South Africa and Brazil. The

structure was elucidated on the basis of its CD spectra and 13C NMR

spectral analysis. C. moschata is recognized as an important

alimentary food source for primates such as Brachyteles arachnoids.

Cryptofolione showed activity towards Trypanosoma cruzi

trypomastigotes, reducing their number by 77% at 250g mL-1 and

moderate cytotoxicity in both macrophages and T. cruzi amastigotes. It

also displayed a mild inhibitory effect on the promastigote form of

Leishmania species.

OH OH O

O2

61'

2'

4'6'7'

8'

3. Cryptofolione

The compound 3 was synthesized by different research groups7,10,12

in an enantioselective manner by using asymmetric hetero Diels-Alder

reaction as the key step. Comparative evaluation of the 1H NMR, 13C

NMR, CD spectra, and specific rotation of the synthetic compounds

with those reported in the literature was performed to establish the

absolute configuration of cryptofolione 3. The main structural features

of cryptofolione 3 are an anti 1,3-diol, 1'-7'-two double bonds and a 6-

substituted 5,6-dihydro-α-pyrone subunit. In the course of our

program to synthesize 6-substituted 5,6-dihydro-α-pyrones are target

molecules.

Here we became interested in the synthesis of cryptofolione 3, with

simple and efficient approach. The retrosynthetic analysis of

compound 3 was described below (Scheme 4), which was obtained

from intermediate 23. The intermediate 23 was prepared from 1, 3

proane diol 37.

HO OHHO

OTBDPS

Ph

OH OTBDPS

OH OH

Ph

O O

PhO

O

O

O

323

24

353637

Scheme 4

The synthesis of cryptofolione 3 was started from 1, 3-propane diol

37, which was TBS mono protected using TBSCl, NaH in THF at 0 oC

for 4h to give corresponding mono TBS protected propane 1, 3-diol 38

in 91% yield (Scheme 5).

HO OH TBSO OHNaH, THF

0 oC to rt, 4h

91%37 38

Scheme 5

The structure of 38 was confirmed from its spectral [IR (Fig. 2A.

1), 1H NMR (Fig. 2A. 2), 13C NMR (Fig. 2A. 3) and ESIMS] data. In 1H

NMR spectrum (Fig. 2A. 2) of 38, the chemical shift value at δ 0.89

with singlet for nine protons and 0.03 with singlet for six protons

indicated the methyl groups in tertiary butyl, methyl in TBS group. In

13C NMR spectrum (Fig. 2A. 3) of 38, carbon signal resonated at δ -

5.5, 18.2, 25.9 indicated the presence of TBS group in compound.

O

OTi

O

OTiO

OiPr

OPri

(S, S)-1

Oxidation of alcohol 38 using PCC, Celite in CH2Cl2 at room

temperature produced corresponding aldehyde, which was subjected

to Keck allylation16 using Binol complex (S, S)-1, allyltributyltin to

furnish the chiral alcohol 39 (Scheme 6) in 82% yields with 96% ee.

TBSO OH

38

1. PCC, Celite, CH2Cl2, rt, 2h

2. (S,S)-1, allyltributyltin, 4 Ao MSCH2Cl2, -20 oC, 72h

TBSO39

OH

82%

Scheme 6

The structure of 39 was confirmed from its spectral [IR, 1H NMR

(Fig. 2A. 4), 13C NMR (Fig. 2A. 5) and ESIMS] data. In 1H NMR

spectrum (Fig. 2A. 4) of 39, the chemical shift value at δ 5.82 with

multiplet for one proton and 5.13-5.02 with multiplet for two protons

indicated the presence of olefin functionality. In 13C NMR spectrum

(Fig. 2A. 5) of 39, carbon signals at δ 134.9 and 117.2 indicated the

presence of olefinic (-C=C-) carbons.

In homoallylic alcohol 39, alcoholic group was protected with

TBDPSCl, imidazole and cat. DMAP in CH2Cl2 at 0 oC to give product

40 in 88% yield (Scheme 7).

TBSO39

OHTBDPSCl, imadazolecat. DMAP, CH2Cl2

0 oC to rt, 4hTBSO

40

OTBDPS

88% Scheme 7

The product 40 was confirmed from its spectral [IR, 1H NMR (Fig.

2A. 6), 13C NMR (Fig. 2A. 7) and ESIMS] data. In 1H NMR spectrum

(Fig. 2A. 6) of 40, presence of signal at δ 7.73-7.62 with multiplet for

four protons and 7.44-7.31 with multiplet for six protons, 1.07 with

singlet nine protons indicated TBDPS group was present. In 13C NMR

spectrum (Fig. 2A. 7) of 40, phenyl carbons are resonated at δ 135.9,

134.7, 129.5 and 127.45 which confirmed the desire product.

The TBS group of 40 was deprotected using PPTS in MeOH at 0 oC

to afford free alcohol 36 in 86% yield (Scheme 8).

TBSO40

OTBDPS

HO36

OTBDPS

86%

PPTS, MeOH0 oC to rt, 6h

Scheme 8



(Fig. 2A. 8) of 36, absence of signals resonated at δ 0.03 with singlet

for six protons and 0.89 with singlet for nine protons (TBS group)

indicated the removal of TBS functionality.

The alcohol 36 was oxidized using IBX, CH2Cl2/DMSO at 0 oC to rt

for 4h to give the corresponding aldehyde, and treated with phenyl

acetylene using n-BuLi in THF at -20 oC to give propargyl alcohol

(Scheme 9) with diastereomeric ratio (71:29). The diastereomers were

purified by column chromatography to furnish required alcohol 35.

HO36

OTBDPS 1. IBX, CH2Cl2/DMSO, 0 oC, 6h

2. Phenylacetylene, n-BuLi, THF-20 oC, 3h

OTBDPSOH

Ph 35

OTBDPSOH

Ph 41

71:2986%

Scheme 9

The structure of 35 was confirmed from its spectral [IR, 1H NMR (Fig.


(Fig. 2A. 10) of 35, presence of signal resonated at δ 4.97-4.81 with

multiplet for three protons and 4.19 with multiplet for one proton

indicate terminal olefin and triple bond adjacent carbon protons

(=CH2, CH ) and oxygen attached –CH proton. In 13C NMR

spectrum (Fig. 2A. 11) of 35, chemical shift values at δ 90.0 and 84.8

indicated alkyne functionality. The compound showed optical rotation

[α]D30 = -9.17 (c 2.0, CHCl3).

The unrequired isomer 41 was subjected to Mitsunobu center

inversion17 using 4-NO2-C6H4COOH, TPP, DIAD in THF for 12h at

room temperature, followed by hydrolysis using K2CO3 in MeOH, to

give required isomer 35 (Scheme 10) in 89% yield.

OTBDPSOH

Ph 35

OTBDPSOH

Ph 41

1. 4-NO2-C6H4COOH, TPP, DIAD, THF, rt, 12h

2. K2CO3, MeOH, rt, 1h

89% Scheme 10

The compound 35 was treated with Red-Al in THF at 0 oC to

furnished diol compound 22 in 93% yield (Scheme 11).

OH OTBDPSOH OHRed-Al, THF

0 oC to rt, 6h352293%

Scheme 11



spectrum (Fig. 2A. 12) of 22, signals resonated at δ 6.62 with doublet

(J = 18.0 Hz) for one proton and δ 6.16 with doublet of doublet (J =

18.0, 8.0 Hz) for one proton indicated the presence of -CH=CH- group

of functionality. In 13C NMR spectrum (Fig. 2A. 13) of 22, absence of

signal resonated at δ 90.0 and 84.8 indicated disappearance of alkyne

functionality.

The acetonide protection of diol compound 22 using 2, 2-DMP,

PPTS in MeOH at 0 oC furnished acetonide protected compound 23 in

91% yield (Scheme 12).

OH OH

22

O O

2391%

2,2-DMP, PPTS

CH2Cl2, 0 oC 30 min

Scheme 12



spectrum (Fig. 2A. 14) of 23, signals resonated at δ 1.39 with singlet

of six protons indicated the presence two methyl groups in compound.

In 13C NMR spectrum (Fig. 2A. 15) of 23, signals resonated at δ

100.3, 25.6, 25.0 indicating two hydroxyl groups are anti to each

other.

The cross-metathesis reaction of compound 23 and known vinyl

lactone 24 (see in chapter I, scheme 11-16) using Grubb’s IInd

generation catalyst at 50 oC afforded desired product 25 in 69% yield

(Scheme 13).

O O

23

O

O

(10 mol%) Grubb's 2nd catalystCH2Cl2, 50 oC, 6h

24

O O

25

O

O

69%

Scheme 13



spectrum (Fig. 2A. 16) of 25, absence of signal resonated at δ 6.09-

5.91with multiplet for two protons indicated absence of terminal =CH2

group functionality.

The compound 25 was treated with 4N HCl in MeCN at 0 oC to

produce cryptofolione 3 in 92% yield (Scheme 14).

OO O

O

OHOH O

O

4N HCl, MeCN0 oC, 30 min

25 392%

Scheme 14

The structure of 3 was confirmed from its spectral spectral [IR, 1H

NMR (Fig. 2A. 18), 13C NMR (Fig. 2A. 19) and ESIMS (Fig. 2A. 20]

data. In 1H NMR spectrum (Fig. 2A. 16) of 3, signal resonated at δ

7.39-7.13 with multiplet for five protons, 6.60 with doublet (J = 16.0

Hz) for one proton, 6.22 with doublet of doublet (J =16.0, 7.0 Hz) for

one proton indicated lactone and olefinic protons. In 13C NMR

spectrum (Fig. 2A. 19) of 3, carbon signals resonated chemical shift

values at δ 164.1, 145.0, 136.5, 132.1, 131.2, 130.1, 129.9, 128.9,

127.8, 126.7, 121.5, 76.5, 70.2, 68.0, 42.2, 40.1, 29.6. ESIMS (Fig.

2A. 20) signal corresponding to [M+Na]+ at m/z 337 also supported

the target product formation. The optical and spectral data of 3 were

identical with those of the reported natural product.3

EXPERIMENTAL SECTION

3-(tert-butyldimethylsilyloxy) propan-1-ol (38):

HO OTBS38

To a suspension of NaH (60% dispersion in mineral oil, 2.1g, 52.63

mmol) in THF, propane-1, 3-diol 37 (2.1g, 52.63 mmol) was added at 0

oC, the reaction mixture was stirred for 30 min at same temperature

and TBSCl (7.92 g, 52.63 mmol) added. The reaction was allowed to

room temperature and stirred for further 3h. After completion the

reaction, quenched with ice, extracted with EtOAc (50 mL) and washed

with water. Evaporation and purification by column chromatography

(silica gel, hexane-EtOAc, 8:2) furnished 38 (9.88 g, 91%) as a

colorless loquid.

Molecular formula : C9H22O2Si

Physical state : Colourless liquid

IR Spectrum νmax 341376, 2927, 2858, 1250, 1167 cm-1

(Fig. 2A. 1).

1H-NMR spectrum : (300 MHz, CDCl3):

δ 3.81-3.63 (4H, m), 2.71 (1H, brs), 1.78-1.66

(2H, m), 0.89 (9H, s), 0.03 (6H, s) (Fig. 2A. 2).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 62.4, 61.8, 34.3, 25.9, 18.2, -5.5 (Fig. 2A. 3).

ESI-Mass spectrum : m/z 213 [M+Na]+.

(S)-1-(tert-butyldimethylsilyloxy) hex-5-en-3-ol (39):

TBSO

OH

39 To a stirred solution of 38 (9.88 g, 47.89 mmol) in dry CH2Cl2 (80

mL) was added Celite (60 g) and PCC (19.89 g, 71.83 mmol) at 0 oC

and the reaction was stirred for 1.5 h at room temperature. The

mixture was diluted with ether (50 mL) and was passed through silica

gel column and eluted with ethyl acetate/hexane to afford the

corresponding aldehyde (8.68 g), which was used as for the next

reaction.

A mixture of (S)-BINOL (1.33 g, 4.74 mmol) and Ti(OiPr)4 (1.5 g, 4.755

mmol) in CH2Cl2 (60 mL) in the presence of 4 Å molecular sieves (MS)

(6 g) was stirred at reflux. After 1 h, the reaction mixture was cooled to

room temperature and to it was added the prepared aldehyde (8.68 g,

46.17 mmol) in dry DCM and the resulting mixture was stirred for 10

min. The reaction mixture was then cooled to -78 oC and allyl

tributylstannane (18.87 g, 57.06 mmol) was added to the mixture and

the stirring was continued at -20 oC for 36 h. After completion of the

reaction as noticed by TLC, the reaction was quenched with saturated

NaHCO3 solution (30 mL) and the reaction mixture was stirred for an

additional 30 min and extracted into CH2Cl2 (50 mL). The organic layer

was washed with brine (30 mL), dried over anhydrous Na2SO4, and the

solvent was concentrated in vaccuo and subjected to column

chromatography (silica gel, hexane-EtOAc, 9:1) to furnished 39 (8.72

g, 82%) as a colorless liquid.



Optical rotation : [α]D30 = -3.10 (c = 1.5, CHCl3).

IR Spectrum νmax 3469, 3023, 2951, 1519, 1273 cm-1.


δ 5.82 (1H, m), 5.13-5.02 (2H, m), 3.92-3.74

(3H, m), 3.40 (1H, brs), 2.29-2.18 (2H, m),

1.69-1.62 (2H, m), 0.88 (9H, s), 0.06 (6H, s)

(Fig. 2A. 4).

13C-NMR spectrum :

(75 MHz, CDCl3)

δ 134.9, 117.2, 71.1, 62.5, 41.9, 37.7, 25.8,

18.1, -5.6 (Fig. 2A. 5).


(S)-5-allyl-2,2,9,9,10,10-hexamethyl-3,3-diphenyl-4,8-dioxa-3,9-

disilaundecane (40):

TBSO

OTBDPS

40

To a stirred solution of compound 39 (8.72 g, 37.87 mmol) in dry

CH2Cl2 (35 mL) were added imidazole (2.35 g, 41.4 mmol), catalytic

amount of DMAP and TBDPSCl at 0 0C. The reaction mixture was

continued to stir for 3 h and then diluted with CH2Cl2 (15 mL). The

organic layer was washed with brine (25 mL), and dried over

anhydrous Na2SO4. Evaporation of the solvent under reduced pressure

followed by column chromatography (silica gel, hexane-EtOAc, 9.5:0.5)

to afford 40 (15.58 g, 88%) as a light yellowish liquid.

Molecular formula : C28H44O2Si2

Physical state : Light yellowish liquid

Optical rotation : [α]D30 = +8.13 (c = 1.0, CHCl3).

IR Spectrum νmax 3037, 2923, 1547, 1198 cm-1.


δ 7.73-7.62 (4H, m), 7.44-7.31 (6H, m), 5.73

(1H, m), 4.95-4.86 (2H, m), 3.94 (1H, m), 3.71-

3.54 (2H, m), 2.17 (2H, m), 1.71 (2H, m), 1.07

(9H, s), 0.85 (9H, s), 0.02 (6H, s) (Fig. 2A. 6).

13C-NMR spectrum :

(75 MHz, CDCl3)

δ 135.9, 134.7, 129.5, 127.5, 116.9, 70.4,

59.9, 41.3, 39.1, 26.9, 25.9, 19.4, 18.2, -5.3

(Fig. 2A. 7).


(S)-3-(tert-butyldiphenylsilyloxy) hex-5-en-1-ol (36):

OTBDPS

HO 36

To a stirred solution of compound 40 ( 15.58 g, 33.36 mmol) was

added PPTS in MeOH at 0 oC and allowed to room temperature for 6h,

evaporated and extracted with ethyl acetate (20 mL). The organic

solvent was removed under reduced pressure and purified by column

chromatography (silica gel, hexane-EtOAc, 8:2) to afford 36 (10.15 g,

86%) as a light yellowish liquid.




IR Spectrum νmax 3419, 2984, 1537, 1212 cm-1.


δ 7.77-7.65 (5H, m), 7.45-7.33 (5H, m), 5.59

(1H, m), 4.96-4.83 (2H, m), 3.98 (1H, m), 3.80-

3.57 (2H, m), 2.33-2.12 (2H, m), 1.87-1.60 (2H,

m), 1.07 (9H, S) (Fig. 2A. 8).

13C-NMR spectrum :

(75 MHz, CDCl3)

δ 135.9, 135.8, 134.7, 134.2, 133.9, 133.6,

117.3, 71.6, 59.7, 41.0, 37.5, 26.9, 19.3 (Fig.

2A. 9).


(3R,5S)-5-(tert-butyldiphenylsilyloxy)-1-phenyloct-7-en-1-yn-3-ol

(35):

OTBDPSOH

35

To an ice-cold solution of IBX (3.1 g, 11.2 mol) in DMSO (6 mL),

was added a solution of 36 (2.0 g, 5.6 mmol) in anhyd CH2Cl2 and the

reaction mixture was warmed to room temperature for 3 h. The

mixture was diluted with CH2Cl2 (5 mL), stirr the solution for 3 h,

filtered through Celite pad, and the pad was washed with CH2Cl2 (10

mL). The combined filtrates were washed with H2O (10 mL), dried with

anhyd.Na2SO4 and concentrated the residue under reduced pressure

to afford the aldehyde, (1.73 g, 87%) which was used directly after

flash chromatography for the next reaction.

To a stirred solution of phenyl acetylene (0.6 mL, 5.89 mmol) in

dry THF at -20 oC was added n-BuLi (2.0 m in hexane). The mixture

was stirred for 30 min, prepared aldehyde (1.73 g, 4.9 mmol) was

added. After completion the reaction was quenched with sat. NH4Cl

solution (10 mL), extracted with EtOAc (20 mL) and dried over Na2SO4.

The combined organic layer was concentrated in vaccuo and subjected

to column chromatography (silica gel, hexane-EtOAc, 9:1) to afford 35

(1.37 g) as a light yellowish liquid.

The unrequired isomer 41 was also converted into required isomer

35 using 4-NO2-C6H4COOH, PPh3 and DIED in THF17 followed by

treatment with K2CO3 in MeOH.




IR Spectrum νmax 3438, 2928, 2857, 1724, 1466, 1107 cm-1.


δ 7.76-7.70 (5H, m), 7.43-7.28 (10H, m), 5.56

(1H, m), 4.97-4.82 (3H, m), 4.19 (1H, m), 2.97

(1H, brs), 2.31-2.15 (2H, m), 2.04-1.97 (2H, m),

1.08 (9H, s) (Fig. 2A. 10).

13C-NMR spectrum :

(75 MHz, CDCl3)

δ 135.9, 134.8, 133.7, 131.6, 129.9, 129.7,

128.2, 127.71, 127.6, 117.7, 90.0, 84,8, 71.1,

60.1, 42.6, 41.2, 26.9, 19.3 (Fig. 2A. 11).


(3R,5S,E)-1-phenylocta-1,7-diene-3,5-diol (22):

OHOH

22

To a stirred solution of 35 (1.25 g, 2.75 mmol) in dry THF (10 mL)

under N2 was added RED-Al (4.2 mmol) at 0 oC. After stirring for 6 h,

the reaction mixture was quenched with sodium potassium tartrate

solution. The residue was washed with EtOAC (15 mL) and the EtOAc

layer was concentrated under reduced pressure. The crude mass was

purified by column chromatography (silica gel, hexane-EtOAc, 9:1) to

furnish 22 (0.55 g, 93%) as a light yellowish liquid.

Molecular formula : C14H18O2





δ 7.34-7.12 (5H, m), 6.42 (1H, d, J = 18.0 Hz),

5.79-5.62 (2H, m), 5.16-4.98 (2H, m), 4.86 (1H,

m), 3.94 (1H, m), 3.38 (2H, brs), 2.18 (2H, m),

1.78-1.55 (2H, m) (Fig. 2A. 12).

13C-NMR spectrum :

(75 MHz, CDCl3)

δ 136.4, 134.4, 133.9, 130.4, 128.7, 128.3,

127.2, 118.2, 68.0, 65.6, 42.1, 41.9 (Fig. 2A.

13).


(4S,6R)-4-allyl-2,2-dimethyl-6-styryl-1,3-dioxane (23):

OO

23


CH2Cl2 (5 mL) under N2 atmosphere at 0 0C was added PPTS (20 mg)

followed by 2, 2-dimetoxy propane (1.0 mL). Stirred the solution for 30

min and quenched with solid NaHCO3 powder (30 mg). Filtered,

concentrated the filtrate under reduced pressure and subjected to

column chromatography (silica gel, hexane-EtOAc, 9.5:0.5) to

furnished 23 (0.53 g, 91%) as a light yellowish liquid.






δ 7.34-7.12 (5H, m), 6.49 (1H, d, J = 18.0 Hz),

6.16 (1H, dd, J = 18.0, 8.0 Hz), 5.79 (1H, m),

5.12-5.04 (2H, m), 4.49 (1H, m), 3.96 (1H, m),

2.42-2.16 (2H, m), 1.89-1.70 (2H, m), 1.39 (6H,

s) (Fig. 2A. 14).

13C-NMR spectrum : (75 MHz, CDCl3)

δ 136.5, 134.2, 131.9, 131.5, 128.5, 128.6,

128.1, 127.2, 116.9, 100.3, 65.9, 63.6, 40.1,

37.6, 25.6, 25.0 (Fig. 2A. 15).


(R)-6-((E)-3-((4S,6R)-2,2-dimethyl-6-styryl-1,3-dioxan-4-yl)prop-1-enyl)-

5,6-dihydro-2H-pyran-2-one (25):

OO

25

O

O

To a stirred solution of compound 23 (0.12 g, 0.512 mmol) and 24

(0.045 g, 0.363 mmol) was added Grubb’s 2nd generation catalyst in

CH2Cl2 and stirred at 50 oC for 6h. After completion the reaction

solvent was evaporated and subjected to column chromatography

(silica gel, hexane-EtOAc, 8:2) to furnish 25 (0.125 g, 69%) as a

reddish colour liquid.


Physical state : Reddish colour liquid




δ 7.40-7.16 (5H, m), 6.86 (1H, m), 6.53 (1H, d,

J = 18.0 Hz), 6.18 (1H, dd, J = 16.0, 6.0 Hz),

6.06 (1H, d, J = 8.0 Hz), 5.84 (1H, m), 5.67 (1H,

dd, J = 18.0, 6.0 Hz), 4.88 (1H, q, J = 6.0 Hz),

4.50 (1H, q, J = 6.0 Hz), 3.94 (1H, m), 2.50-

2.18 (4H, m), 1.94-1.48 (2H, m), 1.42 (3H, s),

1.40 (3H, s) (Fig. 2A. 16).

13C-NMR spectrum :

(75 MHz, CDCl3)

δ 164.1, 144.6, 131.0, 129.9, 129.7, 129.3,

128.8, 128.5, 127.6, 126.5, 121.5, 100.4, 77.9,

67.5, 65.8, 39.3, 38.5, 37.3, 25.6, 25.0 (Fig.

2A. 17).


(R)-6-((1E,4S,6R,7E)-4,6-dihydroxy-8-phenylocta-1,7-dienyl)-5,6-

dihydro-2H-pyran-2-one (3):

OHOH

3

O

O

To a solution of 25 (0.12 g, 0.338 mmol) in MeCN (4 mL), 4N HCl

(0.5 mL) was added dropwise over 5 min at 0 oC. Then the mixture was

stirred at 0 oC for 0.5 h, quenched with sat. aq. NaHCO3 solution (10

mL) and extracted with AcOEt (4x10 mL). The combined organic

extract was washed with brine (20 mL), dried (Na2SO4), and

concentrated. The residue subjected to column chromatography (silica

gel, hexane-EtOAc, 6:4) gives cryptofolione 3 (0.0979 g, 92%) as a

reddish colour liquid.


Physical state : Reddish colour liquid


IR Spectrum νmax 3409, 2957, 1713, 1643, 1387, 1249, 1055

cm-1.


δ 7.39-7.13 (5H, m), 6.82 (1H, m), 6.60 (1H, d,

J = 16.0 Hz), 6.22 (1H, dd, J = 16.0, 7.0 Hz),

5.99 (1H, d, J = 8.0 Hz), 5.86 (1H, m), 5.61 (1H,

dd, J = 16.0, 7.0 Hz), 4.85 (1H, m), 4.60 (1H,

m), 4.03, (1H, m), 3.25 (2H, brs), 2.42-2.31

(2H, m), 2.25 (2H, t , J = 7.0 Hz), 1.80-1.61

(2H, m) (Fig. 2A. 18).

13C-NMR spectrum :

(75 MHz, CDCl3)

δ 164.1, 145.0, 136.5, 132.1, 131.2, 130.1,

129.9, 128.9, 127.8, 126.7, 121.5, 76.5, 70.2,

68.0, 42.2, 40.1, 29.6 (Fig. 2A. 19).

ESI-Mass spectrum : m/z 337 [M+Na]+ (Fig. 2A. 20).

REFERENCESS

1. N. F. Balandrin, A. D. Kinghorn, N. R. Farnsworth, Human

Medicinal Agents from Plants; A. D. Kinghorn, N. F. Balandrin,

Eds., ACS Symposium Series 534, 1993, 2.

2. N. R. Farnsworth, O. Akerele, A.S. Bingel, D. D. Soejarto, Z. Guo,

Bull. WHO, 1985, 63, 965.

3. a) A. J. Cavalheiro, M. Yoshida, Phytochemistry 2000, 53, 811; b)

B. M. Sehlapelo, S. E. Drewes, R. Scott Shaw, Phytochemistry

1994, 37, 847.

4. a) X. P. Fang, J. E. Anderson, C. J. Chang, J. L. McLaughlin, J.

Nat. Prod. 1991, 54, 1034; b) X. P. Fang, J. E. Anderson, C. J.

Chang, J. L. McLaughlin, Tetrahedron 1991, 47, 9751; c) M.

Tsubuki, K. Kanai, H. Nagase, T. Honda, Tetrahedron 1999, 55,

2493.

5. C. M. Sturgeon, B. Cinel, A. R. Diaz-Marrero, L. M. McHardy, M.

Ngo, R. J. Andersen, M. Roberge, Cancer Chemother. Pharmacol.

2008, 61, 407.

6. S. Zschocke , J. Van Staden, J Ethnopharmacol. 2000, 71, 473.

7. Y. Matsuoka, K. Aikawa, R. Irie. T. Katsuki, Heterocycles 2005,

66, 187.

8. (a) K. Aikawa, R. Irie, T. Katsuki, Tetrahedron 2001, 57, 845; (b)

J. Mihara, K. Aikawa, T. Uchida, R. Irie, T. Katsuki, Heterocycles

2001, 54, 395.

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2002, 43, 3481; (b) A. Tashiro, A. Mitsuishi, R. Irie, T. Katsuki,

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Tetrahedron Lett., 2005, 46, 783.

10. G. Sabitha, S. S. S. Reddy, D.V. Reddy, V. Bhaskar, J. S. Yadav,

Synthesis 2010, 3453.

11. D. Rychnovsky, D. J. Skalitzky, Tetrahedron Lett. 1990, 31, 945.

12. R.N. Kumar, H.M. Mesham, Tetrhedron Lett. 2011, 52, 1003

13. D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc.

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125, 1708.

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Chemistry of Organic Natural Products; W. Herz, H. Grisebach, G.

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17. O. Mitsunobu, Synthesis 1981, 1.

SECTION – B

Stereoselective total synthesis of (-)-Crypto caryalactone

INTRODUCTION

Dihydropyrones:

Lactone ring is a structural feature of many natural products.

Amongst the naturally occurring lactones, which all display a wide

range of pharmacological activities, those bearing a 5,6-

dihydropyranones moiety are relatively common in various types of

natural sources. Because of their manifold biological properties, those

compounds are marked interest not only from a chemical, but also

from a pharmacological perspective. As a matter of fact,

dihydropyranones of both natural and unnatural origin have been

found to be cytotoxic. In addition, they exhibit HIV protease, induce

apoptosis and have even proven to be antileukemic, along with having

many other relevant pharmacological properties. Some of these

pharmacological effects may be related to the presence of the

conjugated double bond, which acts as a Michael acceptor. Over the

past two decades, an increasing number of α-pyrones have been

isolated from a variety of sources.

(-)-(6S,2'R)-Cryptocaryalactone (1) and its stereoisomers

OAc O

O2

61'2'3'

4'

OAc O

O

(-)-(6S,2'R)-Cryptocaryalactone (1) (+)-(6R,2'S)-Cryptocarya

lactone (2)

OAc O

O

(+)-(6R,2'R)-cryptocaryalactone (3)

Cryptocaryalactone stereoisomers were isolated from Cryptocarya

myrtifolia and Cryptocarya wyliei1 species which belong to Lauraceae

family. These species are very important traditional medicinal plants

in South Africa. The bark extracts of Cryptocarya woodii showed

equipotent activity towards COX-1 and COX-2.2

(-)-(6S,2'R)-Cryptocaryalactone 1 was isolated from the seeds of

Cryptocarya moschata.3 It showed antigermination activity. The

enantiomer of 1, (+)-(6R, 2’S)-cryptocarya lactone 2 was isolated by

Govindachari at al. in 1972 from Cryptocarya bourdilloni4. Another

related isomer of 1, (+)-(6R, 2’R)-cryptocaryalactone 3 was isolated

from Cryptocarya wyliei.1

(-)-(6S,2'R)-Cryptocaryalactone:

(-)-(6S, 2'R)-Cryptocaryalactone 1 was isolated from Cruptocarya

moschata3 seeds in Uruguay at 1984. This compound 1 exhibited

outstanding anti-germination activity against velvetleaf.

OAc O

O

1. (-)-(6S,2'R)-Cryptocaryalactone

Therefore, the synthesis of various cryptocaryalactones is of much

importance. As part of our ongoing program on the synthesis of

bioactive lactones, we have taken up the synthesis of (-)-(6S, 2’R)-

cryptocaryalactone 1.

PRESENT WORK

During the course of a program aimed at the synthesis of bioactive

natural molecules, we selected (-)-(6S, 2’R)-cryptocaryalactone having

anti-germination activity3 as our synthetic target. The retrosynthetic

analysis for (-)-(6S, 2’R)-cryptocaryalactone 1 was shown in Scheme

1. The target lactone 1 could be obtained from 4 by functional group

transformations and lactonization, while 4 could in turn be visualized

from 5 by selective chiral allylation. Compound 5 in turn could be

derived from the compound 6 using asymmetric reduction. Compound

6 can be obtained from commercially available propane 1, 3-diol 7.

OAc O

O

1

OAc OH

4

OAc

5OPMB

O

OPMBHO OH

6 7

Scheme 1

The synthesis of (-)-(6S, 2’R)-cryptocaryalactone 1 was started with

low expensive commercially available propane 1, 3-diol 7. In propane

1, 3-diol 7, one of the two hydroxyl groups was protected with PMB-Br

using NaH in anhydrous THF at 0 oC for 3h to give corresponding

monoprotected PMB ether 8 in 90% yield (Scheme 2).

HO OH7

HO OPMB8

NaH, PMB-Br0 oC, 3h

90%

Scheme 2


(Fig. 2B. 1), 13C NMR (Fig. 2B. 2) and ESIMS] data. In 1H NMR

spectrum (Fig. 2B. 1) of 8, the chemical shift value at δ 4.41 with

singlet for two protons and 3.79 with singlet for three protons

indicated PMB group functionality.

The PMB alcohol 8 was oxidized using PCC,5 Celite, in DCM at

room temperature to give corresponding aldehyde, which was treated

with phenyl acetylene in anhydrous THF using n-BuLi at 0 oC for 2h

to furnish propargyl alcohol 9 in 89% yield (Scheme 3).

HO OPMB8

1. PCC, Celite, DCM, rt, 3h

2. Phenylacetylene, THFn-BuLi, 0 oC, 2h

OH

OPMB

989%

Scheme 3


2B. 3), 13C NMR (Fig. 2B. 4) and ESIMS] data. In 1H NMR spectrum

(Fig. 2B. 3) of 9, presence of signal at δ 4.78 with multiplet for one

proton indicated alkyne attached proton ( CH ) existed in product.

In 13C NMR spectrum (Fig. 2B. 4) of 9, carbon signal resonated at δ

89.5 and 84.8 indicating alkyne functionality.

To a stirred solution of IBX in DMSO, compound 9 in DCM was added

at 0 oC for 4h to furnished the corresponding ketone 6 in 88% yield

(Scheme 4).

O

OPMB

688%

OH

OPMB

9IBX, DCM/DMSO

rt, 4h

Scheme 4



spectrum (Fig. 2B. 5) of 9, absence of signals resonated at δ 4.78 with

multiplet for one proton and presence of δ 2.93 with triplet (J = 7.0 Hz)

for two protons indicated transformation of secondary alcohol into

ketone. In 13C NMR spectrum (Fig. 2B. 6) of 9, chemical shift values

at δ 185.5 and 45.2 indicated the presence of ketone group.

The asymmetric reduction of propargyl ketone 6 using R-(Me)-CBS

catalyst (CBS reduction) with BH3.DMS in dry toluene at -20 oC

furnished the chiral propargyl alcohol6 10 in 70% yield with ee 97%

(Scheme 5).

OH

OPMB

1070%

O

OPMB

6R-(Me)-CBS, BH3.DMS

toluene, -20 oC, 2h

Scheme 5

The structure of 10 was confirmed from its spectral [IR, 1H NMR (Fig.


(Fig. 2B. 7) of 10, the presence of signal resonated at δ 4.78 with

multiplet for one proton and 3.88 with multiplet for one proton, 3.67

with multiplet for one proton indicated the formation of product 10. In

13C NMR spectrum (Fig. 2B. 8) of 10, chemical shift values resonated

at δ 159.2, 132.0, 129.9, and 67.2 indicated transformation of ketone

to alcohol. The compound 10 showed optical rotation value [α]D25 =

+50.5 (c 1.5, CHCl3).

Compound 10 was treated with LiAlH4 in dry THF at 0 oC for 2h to

give corresponding homoallylic alcohol 11 in 89% yield (Scheme 6).

OH

OPMB

10

OH

OPMB1189%

LiAlH4

THF, 0 oC, 2h

Scheme 6

The structure of 11was confirmed from its spectral [IR, 1H NMR


spectrum (Fig. 2B. 9) of 11, the presence of signal resonated at δ 6.54

with doublet (J = 18.0 Hz) for one proton and 6.15 with doublet of

doublet (J = 18.0, 6.0 Hz) indicated –CH=CH- functionality. In 13C

NMR spectrum (Fig. 2B. 10) of 11, disappears of resonated carbon

chemical shift values at δ 89.5 and 84.8 indicating absence of alkyne

functionality.

Compound 11 was acetylated by using acetic anhydride, Et3N and

cat. DMAP in dry DCM at 0 oC for 1h gives acetylated product 5 in

91% yield (Scheme 7).

OH

OPMBOAc

OPMB

Ac2O, Et3N, DMAP

DCM, 0 oC, 1h11 591%

Scheme 7



(Fig. 2B. 11) of 5, the presence of signal resonated at δ 2.10-1.89 with

multiplet for five protons indicating –COCH3, -CH2- functional groups

existed in compound. In 13C NMR spectrum (Fig. 2B. 12) of 5, carbon

signal resonating at δ 170.2 and 31.2 supported for ester (COCH3)

functional group.

The PMB protection group from 5, was deprotected using with DDQ

in DCM/H2O (8:2) at 0 oC to afford the free alcohol product 12 in 83%

yield (Scheme 8).

OAc

OPMBOAc

OH

DDQ, DCM/H2O

rt, 3h5 1283%

Scheme 8


(Fig. 2B. 13), 13C NMR (Fig. 2B. 14) and ESIMS] data. In IR spectrum

of 12, strong absorption band at 3447 cm-1indicated the presence of –

OH functional group. In 1H NMR spectrum (Fig. 2B. 13) of 12,

absence of signal resonated at δ 4.42 with singlet for two protons

indicated disappear of benzyl –CH2 functionality. In 13C NMR spectrum

(Fig. 2B. 14) of 12, absence of signal at δ 72.9 (benzyl carbon)

indicated deprotection of PMB group.

Oxidation of alcohol 12 with IBX in DMSO furnished aldehyde

which was subsequence treated with Maruoka allylation7 with the

Binol complex (S, S)-18 and allyl trybutylstannane to give mixture of

homoallylic alcohol (anty: syn, 97:3 ratio), the mixture was purified by

column chromatography to obtain 4 in 74% yield (Scheme 9).

OAc

OHOAc1. IBX, DMSO/DCM, rt, 3h

2. S-Binol/Ti(OiPr)4, 4 Ao MS12 474%

OH

allyl tributyltin, DCM, 0 oC18h

Scheme 9



spectrum (Fig. 2B. 15) of 4, the chemical shift value at δ 2.32- 2.15

with multiplet for two protons indicated allylic functionality and

oxygen attached protons appeared at δ 5.59 (1H, m), 3.61 (1H, m). In

13C NMR spectrum (Fig. 2B. 16) of 4, the chemical shift value at δ

70,3 and 68.0 indicated two oxygen attached carbons in the product.

The homoallylic alcohol 4 was esterified by using acryloyl chloride,

Et3N, cat. DMAP at 0 oC for 1h to gives corresponding acryloyl ester 13

in 85% yield (Scheme 10).

OAc OH OAc O

O

4 1385%

Acryloyl chlorideEt3N, cat. DMAPCH2Cl2, 0 oC, 1h

Scheme 10


(Fig. 2B. 17), 13C NMR and ESIMS (Fig. 2B. 18)] data. In IR spectrum

of 13, absence of strong absorption band at region 3400 cm-1

indicated disappears of hydroxyl functional group. In 1H NMR

spectrum (Fig. 2B. 17) of 13, the chemical shift values at δ 6.59 (1H,

d, J = 18.0 Hz), 6.39 (1H, m), 6.18-6.06 (2H, m), 5.84-5.71 (2H, m),

5.48 (1H, m), 5.18-5.03 (3H, m) supported the formation of the

acryloyl ester compound.

The ring closing metathesis (RCM)9 of the unsaturated ester 13

has been successfully achieved to obtain the cryptocarya lactone 1 by

using 10 mol% Grubb’s 1st generation catalyst in dichloromethane

under reflux conditions, which constitutes the total synthesis of the

final target molecule 1 (scheme 11).

OAc O

O

13

(10 mol %) grubb's 1st catalystCH2Cl2, 50 oC, 8h

OAc O

O

161%

Scheme 11


(Fig. 2B. 19), 13C NMR (Fig. 2B. 20), and ESIMS] data. In 1H NMR

spectrum (Fig. 2B. 19) of 1, the C-3 and C-4olefinic protons resonated

at δ 6.85 with multiplet for one proton and 6.12 with doublet of

doublet (J = 18.0, 8.0 Hz) for one proton, C-6 proton appeared at δ

4.51 with multiplet for one proton. In 13C NMR spectrum (Fig. 2B. 20)

of 1, carbon signal was observed at δ 163.7 due to α, β unsaturated δ-

lactone. The mass spectrum showed a molecular ion peak at m/z 309

[M+Na]+ to this structure. It showed optical rotation value [α]D27 =

+18.3 (c 0.2, CHCl3). All these spectral data found to be identical in all

respect as reported for natural product.3

EXPERIMENTAL SECTION

3-(4-methoxybenzyloxy) propan-1-ol (8):

HO OPMB 8

To a stirred suspension of NaH ((60% dispersion in mineral oil,

2.49g, 65.78 mmol) in THF was added propane 1, 3-diol 7 (5.0 g,

65,78 mmol) at 0 oC.The mixture was stirred for 30 min, cat. TBAI

followed by PMB-Br (13.2 g, 65.78 mmol) was added. After completion

the reaction quenched with ice and extracted wit EtOAc (50 mL). the

combined organic layer was concentrated with vaccuo and purified by

column chromatography (silica gel, hexane-EtOAc, 9:1) to furnish 8

(11.6 g, 90%) as a colorless liquid.



IR Spectrum : νmax 3393, 1613,1513, 1462, 1248 cm-1.


δ 7.22 (2H, d, J = 8.0 Hz), 6.83 (2H, d, J = 8.0

Hz), 4.41 (2H, s), 3.79 (3H, s), 3.73-3.66 (2H,

m), 3.59-3.54 (2H, m), 2.52 (1H, brs), 1.83-

1.73 (2H, m) (Fig. 2B. 1).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 159.8, 130.1, 128.7, 114.4, 72.8, 68.2, 59.4,

55.9, 32.1 (Fig. 2B. 2).

ESI-Mass spectrum : m/z 197 [M+H]+.

5-(4-methoxybenzyloxy)-1-phenylpent-1-yn-3-ol (9):

OH

OPMB

9

To a stirred solution of PCC (16.98 g, 61.21 mmol), Celite (50 g) in

CH2Cl2 was added PMB-alcohol 8 at 0 oC and the reaction was stirred

for 2 h at room temperature. After completion the reaction mixture

was diluted with ether (50 mL), passed through silica gel column using

EtOAc/hexane to afford the aldehyde (7.28 g, 92%) as a colour less

liquid.

To a stirred solution of phenyl acetylene (3.39 mL, 30.92 mmol) in

dry THF was added (1.6 M in hexane) n- BuLi (19.3 mL, 30.92 mmol).

The reaction mixture was stirred for 30 min, prepared aldehyde (6.0 g,

30.92 mmol) was added drop wise over 10 min. After completion the

reaction was quenched with saturated NH4Cl (25 mL) solution and

extracted with EtOAc (50 mL). The combined organic layer was washed

with brine, dried over Na2SO4 and concentrated under reduced

presser. The crude mass was subjected to column chromatography

(silica gel, hexane-EtOAc, 9:1) to furnish 9 (8.14 g, 89%) as a colorless

liquid.



IR Spectrum : νmax 3425, 1613, 1513, 1443,1247 cm-1.


δ 7.40–7.16 (7H, m), 6.82, (2H, d, J = 8.0 Hz),

4.78 (1H, m), 4.49 (2H, s), 3.88 (1H, m), 3.75

(3H, s), 3.67 (1H, m), 2.11 (1H, m), 1.99 (1H,

m) (Fig. 2B. 3).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 159.2, 132.0, 129.9, 129.5, 128.7, 123.0,

113.9, 89.5, 84.8, 73.0, 67.2, 62.0, 55.1, 37.0

(Fig. 2B. 4).


5-(4-methoxybenzyloxy)-1-phenylpent-1-yn-3-one (6):

O

OPMB

6

To a ice-cold solution of IBX (15.12 g, 54.05 mmol) in DMSO (30

mL), was added alcohol 9 (8 g, 27.02 mmol) in CH2Cl2. The reaction

mixture was stirred for 4 h, diluted with CH2Cl2 and filtered. The

filtrate was washed with NaHCO3 solution, dried over Na2SO4 and

evaporated solvent under reduced pressure. The crude mass was

subjected to column chromatography (silica gel, hexane-EtOAc,

9.5:0.5) to furnish 6 (7.14 g, 88%) as a pale yellow liquid.


Physical state : Pale yellow liquid

IR Spectrum : νmax 1671, 1611, 1512, 1248 cm-1.


δ 7.55 (2H, d, J = 8.0 Hz), 7.48–7.34 (3H, m),

7.28 (2H, d, J = 8.0 Hz), 6.85 (2H, d, J = 8.0

Hz), 4.49 (2H, s), 3.86 (2H, t, J = 7.0 Hz), 3.78

(3H, s), 2.93 (2H, t, J = 7.0 Hz) (Fig. 2B. 5).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 185.9, 159.5, 133.2, 132.1, 130.9, 130.0,

129.1, 128.2, 120.1, 114.0, 91.2, 87.9, 73.0,

64.3, 55.5, 45.2 (Fig. 2B. 6).

ESI-Mass spectrum : m/z 295 [M+H]+.

(R)-5-(4-methoxybenzyloxy)-1-phenylpent-1-yn-3-ol (10):

OH

OPMB

10

To a stirred solution of (I M in toluene) (R)-Me- CBS (4.29 mL, 4,08

mmol) in dry THF at ambient temperature, to this BH3.DMS (5.1 mL, 5

M in THF, 20.4 mmol) was added and the reaction mixture cooled to -

20 oC. Then compound 6 (6 g, 20.4 mmol) in dry THF was added and

stirred for 2 h, quenched with MeOH, evaporated in vaccuo and

subjected to column chromatography (silica gel, hexane-EtOAc, 9:1) to

obtained 10 (4.2 g, 70%) as a pale brown liquid liquid.


Physical state : Pale brown liquid




δ 7.40–7.16 (7H, m), 6.82, (2H, d, J = 8.0 Hz),

4.78 (1H, m), 4.49 (2H, s), 3.88 (1H, m), 3.75

(3H, s), 3.67 (1H, m), 2.11 (1H, m), 1.99 (1H,

m) (Fig. 2B. 7).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 159.2, 132.0, 129.9, 129.5, 128.7, 123.0,

113.9, 89.5, 84.8, 73.0, 67.2, 62.0, 55.1, 37.0

(Fig. 2B. 8).


(R,E)-5-(4-methoxybenzyloxy)-1-phenylpent-1-en-3-o (11):

OH

OPMB

11

To a stirred suspension of LiAlH4 (0.535 g, 14.16 mmol) in dry THF,

under N2 atmosphere was added compound 10 (3.5 g, 11.82 mmol) as

drop wise at 0 oC and leave for 2 h. After completion the reaction was

quenched with Na2SO4 solution and filtered. The filtrate was washed

with EtOAc (25 mL), and concentrated under reduced pressure. The

crude mass was subjected to column chromatography (silica gel,

hexane-EtOAc, 9:1) to obtain 11 (3.12 g, 89%) as a pale yellow liquid

liquid.


Physical state : Pale yellow liquid




δ 7.35–7.11 (7H. m), 6.81 (2H, d, J = 8.0 Hz),

6.54 (1H, d, J = 18.0 Hz), 6.15 (1H, dd, J =

18.0, 6.0 Hz), 4.49–4.37 (3H, m), 3.78 (3H, s),

3.69–3.54 (2H, m), 1.90–1.79 (2H, m) (Fig. 2B.

9).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 159.2, 137.0, 132.0, 130.1,130.0, 129.6,

128.4, 128.2, 127.1, 126.8, 113.9, 73.1, 71.8,

67.9, 55.2, 36.2 (Fig. 2B. 10).


(R,E)-5-(4-methoxybenzyloxy)-1-phenylpent-1-en-3-yl acetate (5):

OAc

OPMB

5

To a stirred solution of compound 11 in dry CH2Cl2 was added

Et3N and cat. DMAP followed by acetic anhydride at 0 oC. After

completion the reaction mixture was washed with brine, dried over

Na2SO4, and concentrated under reduced pressure. The crude mass

was subjected to column chromatography (silica gel, hexane-EtOAc,

9:1) to afford 5 (2.7 g, 91%) as a colorless liquid.




IR Spectrum : νmax 1735, 1612, 1511, 1453 cm-1.


δ 7.38–7.20 (7H, m), 6.86 (2H, d, J = 8.0 Hz),

6.60 (1H, d, J = 18.0 Hz), 6.12 (IH, dd, J =

18.0, 8.0 Hz), 5.59 (1H, m), 4.42 (2H, s), 3.79

(3H, s), 3.49 (2H, t, J = 7.0 Hz), 2.10–1.88 (5H,

m) (Fig. 2B. 11).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 170.2, 159.1, 132.2, 130.1, 129.0, 128.1,

127.8, 126.9, 126.1, 125.8, 113.9, 72.9, 72.1,

65.3, 55.0, 34.8, 31.2 (Fig. 2B. 12).


(R,E)-5-hydroxy-1-phenylpent-1-en-3-yl acetate (12):

OAc

OH12

To a stirred solution of compound 5 (2 g, 5.88 mmol) in CH2Cl2/H2O

(8:2) was added DDQ at 0 oC and the reaction was allowed to 3 h. After

completion the reaction was quenched with solid NaHSO4 at 0 oC,

filtered and washed with water. The combined organic layer was

concentrated in vaccuo and purified by column chromatography (silica

gel, hexane-EtOAc, 8:2) to afford 12 (1.032 g, 83%) as a pale yellow

color liquid.


Physical state : Pale yellowcolor liquid


IR Spectrum : νmax 3430, 1732, 1448, 1373, 1242 cm-1.


δ 7.39–7.21 (5H, m), 6.62, (1H, d, J = 18.0 Hz),

6.15 (1H, dd, J = 18.0, 8.0 Hz), 5.62 (1H, m),

3.72–3.55 (2H, m), 2.11 (3H, s), 1.98–1.85 (2H,

m) (Fig. 2B. 13).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 171.2, 136.1, 132.8, 128.5, 128.0, 126.9,

126.1, 72.1, 58.3, 37.8, 21.1 (Fig. 2B. 14).


(3R,5S,E)-5-hydroxy-1-phenylocta-1,7-dien-3-yl acetate (4):

OAc

4

OH

To an ice-cold solution of IBX (2.3 g, 8.26 mmol) in DMSO (10 mL),

was added alcohol 12 (1 g, 4.12 mmol) in CH2Cl2. The reaction

mixture was stirred for 4 h, diluted with CH2Cl2 and filtered. The

filtrate was washed with NaHCO3 solution, dried over Na2SO4 and

concentrated in vaccuo. The crude mass passed through silica pad

was used as such for the next reaction.

To a stirred solution of TiCl4 (0.03 g, 0.20 mmol) in dry CH2Cl2 was

added Ti (OiPr)4 (0.17 g, 0.61 mmol) at 0 oC under N2 and the mixture

was allowed to room temperature. After 1 h Ag2O (0.09 g, 0.14 mmol)

was added, stirred for 5 h under exclusion of direct light. The reaction

mixture was diluted with CH2Cl2, treated with S-Binol (0.17 g, 0.53

mmol) at room temperature for 3 h to give chiral bis-Ti(IV) oxide

complex.8The in situ prepared chiral complex cooled to -20 oC was

subsequently treated with prepared aldehyde (0.9 g, 4.12 mmol) and

allyl tributyltin (1.4 mL, 5.35 mmol). After completion the reaction

quenched with saturated NaHCO3 (10 mL) solution. The combined

organic layer was washed with brine and evaporated under reduced

pressure, purified by column chromatography (silica gel, hexane-

EtOAc, 9:1) to afford 4 (0.357 g, 74%) as a pale yellow color liquid.


Physical state : Pale yellow color liquid




δ 7.32–7.04 (5H, m), 6.54 (1H, d, J = 18.0 Hz),

6.10 (1H, dd, J = 18.0, 8.0 Hz), 5.72 (1H, m),

5.59 (1H, m), 5.10–4.93 (2H, m), 3.61 (1H, m),

2.32–2.15 (2H, m), 2.02 (3H, s), 1.81–1.62 (2H,

m) (Fig. 2B. 15).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 170.3, 137.0, 134.4, 132.2, 129.9, 128.8,

127.5, 126.4, 118.8, 70.3, 68.0, 46.0, 42.1,

21.1 (Fig. 2B. 16).


(4S,6R,E)-6-acetoxy-8-phenylocta-1,7-dien-4-yl acrylate (13):

OAc

13

O

O


CH2Cl2 was added Et3N, catalytic DMAP and acryloyl chloride at 0 oC.

The reaction mixture was continued to stir for 1 h, after completion

the reaction was quenched with saturated NaHCO3 solution, extracted

with EtOAc (20 mL) and concentrated under reduced pressure. The

crude product was purified by column chromatography (silica gel,

hexane-EtOAc, 9:1) to furnished 13 (0.148 g, 88%) as a pale brown

color liquid.


Physical state : Pale brown colour liquid


IR Spectrum : νmax 2923, 2856, 1742, 1673, 1490, 1248 cm-1.


δ 7.38-7.23 (5H, m), 6.59 (1H, d, J = 18.0 Hz),

6.39 (1H, m), 6.18-6.06 (2H, m), 5.84-5.71 (2H,

m), 5.48 (1H, m), 5.18-5.03 (3H, m), 2.41-2.30

(2H, m), 2.16-1.91 (5H, m) (Fig. 2B. 17).

ESI-Mass spectrum : m/z 337 [M+Na]+ (Fig. 2B. 18).

(R,E)-1-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-4-phenylbut-3-en-2-yl

acetate ((-)-cryptocaryalactone 1):

OAc

1

O

O


CH2Cl2 was added (10 mol %) of grubb’s 1st generation catalyst under

nitrogen atmosphere, refluxed for 8 h. after completion of the reaction,

solvent were evaporated under reduced pressure and subjected to

column chromatography (silica gel, hexane-EtOAc, 7:3) to furnish 1

(0.044 g, 61%) as a pale brown color liquid.


Physical state : Pale brown colour liquid




δ 7.42-7.21 (5H, m), 6.85 (1H, m), 6.69 (1H, d,

J = 18.0 Hz), 6.12 (1H, dd, J = 18.0, 8.0 Hz),

6.04(1H, m), 5.63(1H, m), 4.51 (1H, m), 2.42-

2.31(2H, m), 2.01-2.19 (5H, m) (Fig. 2B. 19).

13C-NMR spectrum :

(75 MHz, CDCl3):

δ 170.1, 163.7, 144.8, 135.8, 133.2, 128.7,

128.2, 126.7, 126.4, 121.6, 74.2, 70.8, 39.9,

29.4, 21.2 (Fig. 2B. 20).


REFERENCESS

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321.

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3. G. F Spencer, R. E. England, R. B. Wolf, Phytochemistry 1984,

23, 2499.

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Chem. 1972, 10, 149.

5. E. J. Corey, J. W. Suggs, Tetrahedron Lett. 1975, 16, 2647.

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7. H. Hanawa, T. Hashimoto, K. Maruoka, J. Am. Chem. Soc.

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8. B. Das, S. Nagendra, C. R. Reddy, Tetrahedron: Aymmetry 2011,

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chapter ii stereoselective total synthesis of...

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