Chapter III Stereoselective Total synthesis of Nonenolide ...shodhganga.inflibnet.ac.in/bitstream/10603/21273/9/09_chapter 3.pdf · Chapter III Stereoselective Total synthesis of

Chapter III Stereoselective Total synthesis of Nonenolide

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INTRODUCTION

The field of natural product synthesis has been recognized with the Nobel Prize

in Chemistry with constant periodicity over the entire history of the award. Included

among these prizes are those given to E. Fischer (in 1902; for his work on sugar and

purine syntheses), H. Fischer (in 1930; for his researches into the constitution of

haemin, chlorophyll and especially for his synthesis of haemin), R. Robinson (in 1947;

for his investigations on plant products of biological importance, especially the

alkaloids), R. B. Woodward (in 1965; for his outstanding achievements in the art of

organic synthesis), and E. J. Corey (in 1990; for his development of the theory and

methodology of organic synthesis). These days, the field appears as vigorous as ever,

and its future looks as promising as its past has been rewarding. There are many reasons

why natural product synthesis withstood the test of time as an enabling and rewarding

science and technology, not to mention its attractiveness as an intellectual and creative

endeavor offering opportunities for discovery and invention. Although the theme of

natural product synthesis is attracting a lively interest in research laboratories around the

world today, the reasons for practicing it vary. Generally isolation of natural product is

in minor quantities, but biologically intriguing. So synthesis of natural product in larger

quantities is essential for further extensive biological investigations or medicinal

applications. And the chemical synthesis of a natural product still provides the absolute

proof of the assigned structure, for the recent literature abounds with revisions of

structures of natural products whose originally isolated minute quantities complicated

their characterization. Finally, there are those who will proudly and bravely proclaim

that they enter total synthesis campaigns for the intellectual challenge and sheer

excitement of the endeavor. After this exciting report, we became interested in the

synthesis of macrolides as a part of our research work.

During last thirty years many ten-membered-ring lactones were reported in the

literature. Before 1975, the only described decalactone was the jasmine ketolactone,

identified in Italian jasmine oil in 1942.

Natural products containing a macrolactone framework are found in plants,

insects and bacteria and they may be of terrestrial or marine origin. The useful

properties of macrolides range from perfumery to biological and medicinal activities.


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The new findings in the field of antitumor active and other antibiotic macrolides,

together with pheromones and plant growth regulators with macrolactone framework,

are an inspiration to chemists to study macrolides.

Ten-Membered ring lactones:

According to their structures and biosynthesis, these molecules are classified in

monocyclic polyketides, monocyclic oxylipins and aliphatic bicyclic and aromatic

bicyclic lactones. In each subsection, the lactones are presented in chronological order

of their isolation.

1. Ten-Membered-Ring Lactones:

1. 1. Diplodialides:

Diplodialides (1-4) are the first described group of monocyclic ten-membered-

ring lactones. Diplodialides A, B and C were isolated in 1975, by Ishida and Wada,

from the plant pathogenic fungus Diplodia pinea.1 (+)-Diplodialide A (1) showed

inhibitory activity against steroid 31674 hydroxylase. The isolation of diplodialide D (4)

,2 as well as the full structural elucidation of the four metabolites,

3 were reported by the

same authors, who also established the (R)-configuration for the C9 center. Twenty

years later, Diplodialide B (2) was reported to be found, together with cephalosporolide

G, in Cephalosporium aphidicola.4 This fungus is also responsible for the production of

the closely related ten-membered ring lactones, diplodialides B (2) and C (3).5

1. 2. Phoracanthonolides:

The structurally most simple natural decalactones are the phoracanthonolides I

(5) and J (6), isolated in 1976 from the metasternal gland secretion of the eucalypt

longicorn Phoracantha synonyma.6


103

1. 3. Pyrenolides:

Pyrenolides A, B and C (7–9) were isolated by Nukina et al. in 1980, from

Pyrenophora teres.7,8

In 1992, pyrenolide A was also found in the culture filtrates of

Ascochyta hyalospora.9 These highly functionalized unsaturated keto lactones, which

differ only by the pattern of oxidation at the C7 and C8 positions, exhibit growth

inhibiting and morphogenic activities toward fungi.

1. 4. Curvulides:

Curvulides A-D (10-13) were isolated by Gabriele M. König et al. from Marine-

Derived Fungus Curvularia sp.10

The structures of these new compounds were

characterized on the basis of spectroscopic, MS data and CD spectra and resembled

known ten-membered lactones.

1. 5. Decarestrictines:

In the early 1990s, a series of metabolites produced by different strains of

Penicillium species were isolated, identified and named as decarestrictines. These

compounds were shown to be inhibitors of cholesterol biosynthesis, demonstrated by

both in vitro and in vivo studies.11

The majority of the decarestrictines are ten-membered ring lactones, which

differ in the oxygenation pattern between C3 and C7. Five of them were A1 (14), A2

(15), B (14), E (18), and F (19) bear an epoxide function at C6–C7, eight A1 (14), A2

(15), C1 (17), C2 (18), D (19), F (21), H (23), K (25) possess a double bond, and seven


104

of the decarestrictines B (16), E (20), F (21), G (22), H (23), J (24), K (25) are β-keto

lactones.

The most biologically active among these natural products, decarestrictine D

(19), was simultaneously and independently isolated from the Canadian tuckahoe (the

sclerotium of the fungus Polyporus tuberaster and was named tuckolide by the

authors.12

1. 6. Aspinolides:

Aspinolides A–C (26-28) was reported to be found in the cultures of Aspergillus

ochraceus, in 1997. The structure elucidation and absolute configuration evaluated by

X-ray crystallography as well as Helmchen’s method.13


105

1. 7. Botryolides:

Recently four new decarestrictine analogues botryolides A-D (29-32) were

isolated by Arlene A. Sy et al. from cultures of a fungicolous isolate of Botryotrichum

sp. The structures of these compounds were determined by analysis of 2D NMR and

ESIMS data. The relative configurations were established on the basis of NMR data

and/or X-ray diffraction analysis, while the absolute configuration of botryolide A (29)

was assigned using the modified Mosher method.14

1. 8. Modiolides:

Two new 10-membered macrolides, modiolides A (33) and B (34) were isolated in

2003, by Kobayashi et al. from the cultured broth of fungus Paraphaeosphaeria sp. (N-

119), which was separated from a marine horse mussel, and the structures were

elucidated by spectroscopic data.15

1. 9. Multiplolides:

The epoxy lactones multiplolides A (35) and B (36), isolated from Xylaria

multiplex, are also closely related to the decarestrictine family.16


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Isolation and the structure of nonenolide:

The genus Cordyceps is a rich source of biologically active secondary metabolites.

Cordycepin (3’-deoxyadenosine), possessing antifungal, antivirus, and antitumor

activities, is one of a few secondary metabolites isolated from C. militaris. Nonenolide a

10-membered macrolide (37) isolated from C. militaris BCC 2816,17

it is structurally

similar to decarestrictine C. The initial structural and stereochemical assignment of

nonenolide was established by spectral studies and X-ray analysis. Nonenolide shows

good antimalarial activity.

There are four syntheses reported in literature. A brief introduction of the previous

syntheses of nonenolide is given in the following pages.

PREVIOUS SYNTHETIC APPROACHES

D. K. Mohapatra et al. approach

D. K. Mohapatra et al.18

achieved the first total synthesis of nonenolide.

Synthesis of acid component 40 began with 39 prepared from chiral lactone 38. The

primary hydroxyl group was then oxidized with Dess–Martin periodinane (DMP) to

afford the corresponding aldehyde; further treatment with NaClO2 in the presence of

NaH2PO4 and 2- methyl-2-butene as a scavenger gave the required acid 40 (Scheme 1).

Scheme 1


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Scheme 1: Reagents and conditions: (a) (i) DMP, CH2Cl2, 0 oC-rt, 84%; (ii) NaClO2,

NaH2PO4, 2-methyl-2-butene, 0 oC-rt, 82%.

The alcohol fragment 43 was synthesized in twelve steps from 1,2-O-

isopropylidene D-glyceraldehyde (Scheme 2).19

Scheme 2

Scheme 2: Reagents and conditions: (a) LAH, THF, 0 oC-rt, 88%; (b) 2,4,6-trichloro

benzoyl chloride, 40, CH2Cl2, Et3N, DMAP, rt, 89%; (c) Grubbs 2nd

generation catalyst,

CH2Cl2, reflux, 78%; (d) DDQ, CH2Cl2, H2O, rt, 85%.

Coupling of alcohol 43 and acid 40 using Yamaguchi esterification protocol to

obtained the RCM precursor 44. The RCM of 44 could be conducted by using 10 mol%

of 2nd

generation Grubbs’ catalyst in CH2Cl2 at reflux temperature to produce the

desired lactone 45 as the major product. The PMB deprotection was carried out with

DDQ to afford natural product nonenolide 37 together with small amount of (Z)-isomer

47, which are unseparable (E/Z = 90:10) (Scheme 2).

J. Liu et al. Approach


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J. Liu et al.20

reported a consice synthesis of Nonenolide 45 from (S)-propylene

oxide 52 and known N-acyloxazolidinone 48. The acid fragment was synthesized from

an aldol reaction between the enolate of N-acyloxazolidinone 48 and acrolein under

Crimmins’ conditions gave Evans-syn adduct, followed by protection of hydroxyl group

as its TBS ether 49. The methylsulfenyl group was removed with n-Bu3SnH and AIBN

gave 50. The oxidative removal of the auxiliary by LiOH, H2O2 directly gave the acid

51 (Scheme 3).

Scheme 3

Scheme 3: Reagents and conditions: (a) (i) TiCl4, DIPEA, NMP, acrolein, CH2Cl2, -78

oC; (ii) TBSCl, Imidazole, DMF, 35

oC, overnight, 74%, 2 steps; (b) n-Bu3SnH, AIBN,

benzene, 80 oC, 1h, 95%; (c) LiOH, H2O2 (aq), THF, H2O, 0

oC, 20 min, 97%.

Regioselective ring opening of the epoxide ring by allyl magnesium bromide in

the presence of CuI yielded the alcohol, which was protected as PMB ether 53.

Asymmetric dihydroxylation of 53 with AD-mix-β gave diol 54, which was rapidly

transformed to epoxide 55 using NaH and N-tosylimidazole in THF. Epoxide 55 was

then converted to one carbon homologated allylic alcohol 56 with n-BuLi and

trimethylsulfonium iodide. The compound 56 was protected as MOM ether 57, followed

by PMB deprotection using DDQ, gave alcohol 58. Coupling of alcohol 58 with acid 51

under Mitsunobu reaction conditions gave ester 59. The TBS deprotectin was carried

out with HF-Py in THF afford the diene ester 60. The RCM of 60 could be conducted

by using 2nd

generation Grubbs’ catalyst in CH2Cl2 at reflux temperature. Then

treatment of 61 with Dowex-50W-x8 in MeOH and H2O at reflux finally gave the target

molecule 45 (Scheme 4).


109

Scheme 4

Scheme 4: Reagents and conditions: (a) (i) Allyl magnesium bromide, CuI, THF, -40 oC

to rt; (ii) PMBCl, NaH, TBAI, THF, reflux, 8h, 85%, 2 steps; (b) AD-mix-β, t-

BuOH/H2O = 1:1, 0 oC, 48h, 87%, 67% de; (c) NaH, N-Tosylimidazole, THF, 0

oC-rt,

10h, 83%; (d) n-BuLi, Me3S+I-, THF, -20

oC-rt, 85%; (e) MOMCl, DIPEA, NaI,

CH2Cl2, reflux, 5h, 98%; (f) DDQ, CH2Cl2, Buffer, 0 oC, 3h, 98%; (g) PPh3, DIAD, 51,

benzene, rt, overnight, 87%; (h) HF-Py, THF, rt, 4 days, 79%; (i) Grubbs 2nd

generation

catalyst, CH2Cl2, 1 mM, reflux, 2 days, 50%; (j) Dowex-50Wx8, MeOH, H2O, reflux,

69%.

Jonathan C. killen et al. approach

Jonathan C. killen et al.21

achieved the synthesis of 45, Nozaki-Hiyama-Kishi reaction

(NHK) has been adopted to synthesize the key decanolide ring formation. The synthesis

began with L-Malic acid 62. The compound 63 prepared from L-Malic acid 62,

according to the reported procedure.22

The compound 63 was protected as TIPS ether,


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followed by trityl deprotection using Et3AlCl, gave 64. The primary alcohol 64

oxidized to an aldehyde, followed by Takai olefination gave vinyl iodide, which was

hydrolyzed to acid 65 (Scheme 5).

Scheme 5

Scheme 5: Reagents and conditions: (a) (i) TIPSOTf, imidazole, DMF, rt, 21h, 96%;

(ii) Et3AlCl, CH2Cl2, -78 oC, 7h, 73%; (b) (i) DMP, CH2Cl2, rt, 5h, 88%; (ii) CrCl2,

CHI3, dioxane, THF, 40 oC, 65%; (iii) LiOH(aq), THF:H2O (3:1), rt, 16h, 99%.

The alcohol fragment 67 was synthesized from known tosylate23

66 with KCN

and in situ hydrolysis of the resultant nitrile gave lactone. Reduction of 67 with LiAlH4

followed by selective protection of the primary alcohol as the silyl ether gave 68. The

alcohol 68 coupled with acid 65 under Yamaguchi’s conditions, followed by a selective

deprotection of the primary TBS group in the presence of a secondary TIPS group using

aqueous HCl gave 69. The alcohol 69 was oxidized with DMP gave aldehyde 70. The

aldehyde 70 on treatment with CrCl2 and NiCl2 in DMF, gave a 5:1 mixture of epimers

at C6. The stereochemistry of the major isomer was assigned as 3S, 6R, 9R on the basis

of NOE data. Finally the deprotection of TIPS by TBAT in THF to give Nonenolide 45

(Scheme 6).

Scheme 6


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Scheme 6: Reagents and conditions: (a) (i) KCN, EtOH, H2O, reflux, 16h; (ii) c.HCl(aq),

reflux, 24h, 74%; (b) (i) LAH, Et2O, rt, 3h, 84%; (ii) TBSCl, imidazole, DMAP,

CH2Cl2, rt, 2.5h, 58%; (c) (i) 2,4,6-trichloro benzoyl chloride, Et3N, THF, rt, 24h then

65, DMAP, 6h, 93%; (ii) 1M HCl, EtOH, rt, 0.75h, 47%; (d) DMP, CH2Cl2, rt, 2.5h,

96%; (e) (i) CrCl2 (6.25 equiv), NiCl2 (0.125 equiv), DMF, 0 oC-rt, 14h, 87%; (ii)

TBAT, THF, 5h, 64%.

PRESENT WORK

In this chapter a stereoselective total synthesis of Nonenolide 37 is described.

All three stereogenic centers generated through the MacMillan α-hydroxylation

reaction, intermolecular Steglich esterification and ring-closing metathesis as key steps

for the construction of 10-membered macrolide.

The retrosynthetic analysis of nonenolide 37 is summerized in Scheme 1.

Nonenolide can be achieved from bis-olefin 89 by ring closing metathesis (RCM)

protocol, a key reaction method that has been commonly used for the synthesis of

macrolides. Additionally, this bis-olefin ester 89 in turn can be attained by Steglich-

esterification of acid 88 and alcohol 80. The fragment 80 is envisaged from 1,6-hexane

diol and fragment 88 can be easily synthesized from 1,4-butane diol. Therefore, in the

present strategy the three stereo centers at C-3, C-6 and C-9 in nonenolide 37 (Scheme

7) are constructed by MacMillan α-hydroxylation reaction on 72, 76 and 82

simultaneously.

Scheme 7

Synthesis of alcohol segment 80.


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The 1,6-hexane diol was protected with p-methoxy benzyl bromide in THF (Scheme 8)

to give mono PMB ether 72 in 83% yield. The formation of 72 was established from its

1H NMR spectrum (Fig. 3.01), which displayed signals for PMB proton signals

appeared at δ 7.26 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H) and a singlet 3.80 (s,

3H). The molecular ion peak at m/z 261 [M+Na]+ in its mass spectrum, confirms the

formation of compound 72.

Scheme 8

The primary alcohol 72 was oxidized with IBX in DMSO and CH2Cl2 to afford

aldehyde, which was further subjected to MacMillan α-aminoxylation24

by using

nitrosobenzene and D-Proline in CHCl3, followed by reduction with sodium

borohydride in ethanol to furnish an unstable anilinoxy compound, which was further

treated with AcOH and Zn to provide diol 73 in 65% yield. The formation of diol

product 73 was confirmed from its 1H NMR spectrum (Fig. 3.03) which displays signals

at δ 3.72-3.52 (m, 2H), 3.49-3.32 (m, 3H). Its IR spectrum (Fig. 3.05) showed

absorption band at 3390 cm-1

due to alcohol group. The molecular ion peak at m/z 275

[M+Na]+ in its mass spectrum (Fig. 3.06) indicated the formation of diol product 73

(Scheme 9).

Scheme 9

The primary hydroxyl group in diol 73 was selectively protected with p-

toluenesulfonyl chloride, triethylamine in the presence of catalytic amount of dibutyltin

oxide in dry CH2Cl2 afforded mono tosylate. The monotosylate was treated with LiAlH4

in dry THF to give secondary alcohol 74 in 79% yield (Scheme 10). The formation of

the product 74 was confirmed by 1H NMR spectrum (Fig. 3.07) which displays signal at


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δ 1.18 (d, J = 6.0 Hz, 3H) for terminal methyl group and appearance of molecular ion

peak at m/z 261 [M+Na]+ in mass spectrum (Fig. 3.09) confirms the product 74.

Scheme 10

Protection of hydroxy group in compound 74 with TBSCl, imidazole in CH2Cl2 gave

TBS ether 75 in 92% yield. The 1H NMR spectrum (Fig. 3.10) of compound 75 showed

a signal at δ 0.89 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H) for TBS group protons and

respectively its 13

C NMR spectrum (Fig. 3.11) showed signal at δ 25.9, 19.5, -4.4, -4.9.

Its mass spectrum (Fig. 3.12) shows a molecular ion peak at m/z 353 [M+H]+, further

confirmed the formation of product 75 (Scheme 11).

Scheme 11

The PMB deprotection of compound 75 was carried out with DDQ in

CH2Cl2:H2O, at r.t to give compound 76 in 93% yield (Scheme 12). In 1H NMR (Fig.

3.13), 13

C NMR (Fig. 3.14) the disappearance of signals corresponding to PMB group

and appearance of broad absorption band 3430 cm-1

in IR spectrum confirms the

deprotection of PMB group. The mass spectrum of compound 76 shows a molecular ion

peaks at m/z 255 [M+Na]+ further confirmed the formation of product 76 (Scheme 12).

Scheme 12

The alcohol 76 was oxidized with IBX in CH2Cl2 to afford aldehyde, which was

further subjected to α-aminoxylation25

by using nitrosobenzene and L-Proline in

DMSO, followed by reduction with sodium borohydride in ethanol to furnish an


114

unstable anilinoxy compound, which was further treated with CuSO4.5H2O in methanol

to provide diol 77 in 57% yield (Scheme 13). The formation of compound 77 was

established by 1H NMR spectrum (Fig. 3.15), which displayed signals at δ 3.98-3.90 (m,

1H), 3.71-3.60 (m, 2H), 3.49-3.43 (m, 1H). Its IR spectrum shows absorption band at

3412 cm-1

and mass spectrum shows a molecular ion peak at m/z 271 [M+Na]+ further

confirmed the product 77.

Scheme 13

The diol 77 was protected with anisaldehyde dimethyl acetal in the presence of a

catalytic amount of PPTS in CH2Cl2 to obtain the corresponding cyclic derivative 78a,

which on reductive opening with DIBAL-H in dry CH2Cl2 furnished the alcohol 78 in

87% yield (Scheme 14). The formation of compound 78 was established by 1H NMR

spectrum (Fig. 3.18), which displayed signals at δ 7.27 (d, J = 9.0 Hz, 2H), 6.88 (d, J =

9.0 Hz, 2H), 4.56 (d, J = 10.5 Hz, 1H), 4.45 (d, J = 10.5 Hz, 1H), 3.81 (s, 3H)

corresponding to PMB group. The mass spectrum (Fig. 3.21) showed a peak at m/z 391

[M+Na]+ further confirmed the product 78.

Scheme 14

The primary alcohol 78 was oxidized with IBX in CH2Cl2 to afford aldehyde, which

was subsequently treated with iodomethyltriphenylphosphine in the presence of n-BuLi

to gave the 1-C homologated product 79 in 77% yield. The formation of olefin 79 was

confirmed from its 1H NMR spectrum (Fig. 3.22) which showed signal at δ 5.79-5.66

(m, 1H), 5.24-5.15 (m, 2H) for terminal olefin protons and 13

C NMR spectrum (Fig.

3.23) showed signal at δ 139.2, 116.8 for terminal olefin carbons. The mass spectram


115

shows a molecular ion peak at m/z 387 [M+Na]+ further confirmed the product

(Scheme 15).

Scheme 15

The tert-butyldimethylsilyl ether group in 79 was removed using TBAF in THF

to give allylic alcohol 80 in 92% yields. The formation of product 80 was confirmed

from its spectral data by disappearence of TBS group signals in 1H NMR (Fig. 3.26),

13C NMR (Fig. 3.27) spectrum. Its IR spectrum shows absorption band at 3419 cm

-1 and

mass spectram (Fig. 3.29) shows a molecular ion peak at m/z 273 [M+Na]+ further

confirmed the product 80 (Scheme 16).

Scheme 16

Synthesis of alcohol segment 88.

Second fragment of nonenolide was synthesized from 1,4-butane diol. The 1,4-

butane diol was protected with p-methoxybenzyl bromide in THF (Scheme 17) to give

mono PMB ether 82 in 80% yield. The formation of 82 was established from its 1H

NMR spectrum (Fig. 3.30), which displayed signals for PMB proton signals appeared at

δ 7.27 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 4.35 (s, 2H), 3.81 (s, 3H). The

molecular ion peak at m/z 233 [M+Na]+ in its mass spectrum, confirms the formation of

compound 82.

Scheme 17

The primary alcohol 82 was oxidized with IBX in CH2Cl2 to afford aldehyde, which

was further subjected to α-aminoxylation24

by using nitrosobenzene and D-Proline in


116

DMSO, followed by reduction with sodium borohydride in ethanol to furnish an

unstable anilinoxy compound, which was further treated with AcOH and Zn, provide

diol 83 in 65 % yield. The formation of diol compound 83 was confirmed by its 1H

NMR spectrum (Fig. 3.32) which displays signals at δ 3.90-3.81 (m, 1H), 3.67 (br s,

2H), 3.64-3.53 (m, 3H), 3.48-3.40 (m, 1H) and Its IR spectrum (Fig. 3.34) showed a

band at 3401 cm-1

due to alcohol group. The molecular ion peak at m/z 249 [M+Na]+ in

its mass spectrum (Fig. 3.38), indicated the formation of diol product 83 (Scheme 18).

Scheme 18

The diol 83 was reacted with tosylimidazole in the presence of NaH to give epoxide 84

in 89% yield.26

In 1H NMR (Fig. 3.35) epoxide signals appeared at δ 3.10-3.02 (m, 1H),

2.79 (dd, J = 4.6, 3.8 Hz, 1H), 2.51 (dd, J = 4.6, 3.0 Hz, 1H) ppm and its mass spectrum

shows molecular ion peak at m/z 231 [M++Na] further confirmed the product 84

(Scheme 19).

Scheme 19

The opening of (S)-epoxide 84 with dimethylsulfoniummethylide in the presence of n-

BuLi afforded allylic alcohol 85 in 90% yield (Scheme 20). The formation of compound

85 was established by 1H NMR spectrum (Fig. 3.37), which displayed signals for

olefinic proton signals appeared at δ 5.93-5.81 (m, 1H), 5.27 (d, J = 17.3 Hz, 1H), 5.10

(d, J = 9.8 Hz, 1H). The mass spectrum showed a peak at m/z 231 [M+Na]+.


117

Scheme 20

Protection of hydroxy group in compound 85 with TBSCl, imidazole in CH2Cl2 to give

TBS ether 86 in 88% yield. The 1H NMR spectrum (Fig. 3.40) of compound 86 showed

a signal at δ 0.89 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H) for tertiarybutyldimethyllsilyl group

protons and respectively its 13

C NMR spectrum (Fig. 3.41) showed signal at δ 25.8,

18.2, -4.3, -4.9 indicated the presence of TBS group in 86 (Scheme 21).

Scheme 21

The PMB deprotection of compound 86 was carried out with DDQ in

CH2Cl2:H2O, at r.t to give compound 87 in 93% yield (Scheme 22). The formation of

primary alcohol 87 was confirmed from its spectral data. In the 1H NMR spectrum (Fig.

3.42), devoid of signals at δ 7.26 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H) and a

singlet at δ 3.80 (s, 3H) ppm indicated the absence of PMB group. The mass spectrum

shows a molecular ion peaks at m/z 359 [M+Na]+ further confirmed the structure of 87.

Scheme 22

The primary alcohol 87 was oxidized with bis acetoxy iodobenzene (BAIB) and

a catalytic amount of TEMPO in CH3CN:H2O (2:1) at r.t gave the corresponding acid

88 in 86% yield (Scheme 23). The formation of the acid compound was confirmed by

its spectral data. The 13

C NMR spectrum (Fig. 3.46) showed signal at δ 176.9 due to

presence of carbonyl group and the absorption band at 1714 cm-1

in its IR spectrum

(Fig. 3.47) confirms the formation of acid product 88.

Scheme 23


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After successfully obtaining the alcohol 80 and acid 88 fragments, the coupling reaction

was achieved by employing Steglich esterification27

to give bis olefinic ester 89 with

87% yield. The formation of bis olefinic ester 89 was confirmed by the 1H NMR

spectrum (Fig. 3.48), which showed signals at δ 5.91-5.76 (m, 1H), 5.75-5.63 (m, 1H),

5.27-5.16 (m, 3H), 5.06 (d, J = 10.2 Hz, 1H) due to two terminal double bonds protons

and confirmed by its 13

C NMR (Fig. 3.49) for characteristic ester carbonyl at δ 170.5.

The IR spectrum showed absorption at 1733 cm-1

for the ester carbonyl group and its

mass showed a molecular ion at m/z 485 [M+Na]+ for the compound 62 (Scheme 24).

Scheme 24

The tert-butyldimethylsilyl ether group in 89 was removed using TBAF in THF

to give allylic alcohol 90 in 90% yield. The formation of compound 90 was confirmed

from its spectral data. In the 1H NMR spectrum (Fig. 3.52) of 90, devoid of signals at δ

0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H) indicated the absence of TBS group and its 13

C

NMR spectrum (Fig. 3.53) also devoid of signals for TBS group at δ 25.7, 18.0. -4.4, -

5.0. IR spectrum (Fig. 3.54) of compound 90 shows absorption band at 3447 cm-1 and

in its mass spectrum shows a molecular ion peak at m/z 371 [M+Na]+ (Fig. 3.55) further

confirmed the product 90 (Scheme 25).

Scheme 25

The bis olefinic ester 90 was subjected to ring closure metathesis (RCM) using second

generation Grubbs’ catalyst in CH2Cl2 at reflux to afford the macrolide 91 in 72% yield

(Scheme 26).28

The formation of product 91 was confirmed by its spectral data. In the


119

1H NMR spectrum (Fig. 3.56) devoid of two terminal double bond proton signals at δ

5.87-5.73 (m, 1H), 5.71-5.56 (m, 1H), 5.29-5.03 (m, 4H) and showed signals at δ 5.68

(dd, J = 16.6, 3.0 Hz, 1H), 5.57 (dd, J = 16.6, 8.3 Hz, 1H) due to trans double bond. Its

mass spectrum (Fig. 3.59) showed molecular ion at m/z 343 [M+Na]+ supported the

desired structure.

Scheme 26

Finally deprotection of PMB group in compound 91 with DDQ in CH2Cl2:H2O, at r.t

gave nonenolide 37 in 93% yield (Scheme 27). The formation of 37 was established by

the study of its 1H NMR (Fig. 3.60),

13C NMR (Fig. 3.61), IR (Fig. 3.62), and HRMS

(ESI) (Fig. 3.63) spectral data and optical rotation value found to be identical in all

respects as reported for the natural product, additionally confirmed the structure and

stereochemistry by x-ray crystallography.

Scheme 27


120

X-Ray Crystallography Data

Ortep diagram of Nonenolide 37


121

Table 1. Crystal data and structure refinement for ar64m.

Identification code ar64m

Empirical formula C10 H16 O4

Formula weight 200.23

Temperature 293(2) K

Wavelength 0.71073 Å

Crystal system Monoclinic

Space group P21

Unit cell dimensions a = 5.0183(4) Å = 90°.

b = 7.6545(6) Å = 92.8070(10)°.

c = 13.2425(10) Å = 90°.

Volume 508.07(7) Å3

Z 2

Density (calculated) 1.309 Mg/m3

Absorption coefficient 0.100 mm-1

F(000) 216

Crystal size 0.45 x 0.33 x 0.16 mm3

Theta range for data collection 1.54 to 24.99°.

Index ranges -5


122

To a solution of 1,6-hexanediol 71 (8.0 g, 67.79 mmol) in dry THF (100 mL)

was added NaH (60%, 2.44 g, 45.76 mmol) at 0 oC, the reaction mixture was stirred for

30 min at same temperature. Then p-methoxybenzyl bromide (9.55 g, 61.01 mmol) was

added slowly at 0 oC followed by TBAI (cat.), stirred at rt for 1 h. After completion of

the reaction, the mixture was quenched with cold water at 0 oC and the two layers were

separated, the aqueous phase was extracted with EtOAc (3 X 100 mL). The combined

organic layers were washed with water and brine, dried over anh. Na2SO4 and

concentrated under vacuo. The residue was purified by silica gel column

chromatography using Hexanes/EtOAc (7:3) as eluent to furnish the mono-PMB

protected alcohol 72 (13.08 g, 83%) as colorless oil.

1H NMR (500 MHz, CDCl3) : δ 7.26 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H),

4.43 (s, 2H), 3.80 (s, 3H), 3.62 (t, J = 6.7 Hz, 2H),

3.44 (t, J = 6.5 Hz, 2H), 1.64-1.53 (m, 4H), 1.42-1.32

(m, 4H).

13C NMR (75 MHz, CDCl3) : δ 158.6, 130.5, 129.1, 113.6, 72.4, 69.9, 62.6, 55.1,

32.5, 29.5, 25.8, 25.4.

IR (neat) cm-1

: 3385, 2952,1720,1493,1454,1220,1096.

ESIMS (m/z) : 261 [M+Na]+.

Molecular formula : C14H22O3.

(S)-6-((4-methoxybenzyl)oxy)hexane-1,2-diol (73):

To a stirred solution of IBX (7.05 g, 25.21 mmol) in dry DMSO (7 mL) was

added a solution of 72 (4 g, 16.80 mmol) in dry CH2Cl2 (30 mL) at room temperature

and stirred for 3 h at room temperature. After completion of the reaction, the mixture

was filtered and diluted with water (10 mL) and extracted with CH2Cl2 (2 x 30 mL).

The combined organic extract was washed with brine (20 mL), dried over anh. Na2SO4


123

and concentrated under vacuo to give crude aldehyde, which was directly used for the

next step.

Aldehyde (3.6 g, 15.25 mmol) was added dropwise to a solution of

nitrosobenzene (1.63 g, 15.25 mmol) and D-proline (0.70 g, 6.101 mmol) in chloroform

(9 mL) at 0 oC and the solution was vigorously stirred at 0

oC for 2 h. The reaction

mixture was transferred dropwise to a solution of sodiumborohydride (0.58 g, 15.25

mmol) in ethanol (90 mL) at 0 oC and the solution stirred at 0

oC for 2 h, then

concentrated. Saturated NaHCO3 solution (90 mL) was added and the mixture was

extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were dried

over anh. Na2SO4 and concentrated. The residue was dissolved in 3:1 ethanol:acetic acid

(40 mL) and treated with zinc powder (3.3 g, 50.72 mmol) and the reaction mixture was

stirred at room temperature for 12 h, then filtered through Celite and concentrated. The

crude residue was purified by column chromatography using Hexanes/EtOAc (4:6) as

eluent gave the diol 73 (2.5 g, 65%) as colourless oil. The enantiomeric excess was

determined by chiral HPLC column: (CHIRAL IA: 250 x 4.6mm, 5µ) mobile phase:

15% IPA in Hexane, Flow rate: 1 mL/min, detection: 210 nm, Ret. Time: 17.326 min,

98% ee.

[]D25

: +6.8 (c 1, CHCl3).


4.42 (s, 2H), 3.80 (s, 3H), 3.72-3.52 (m, 2H), 3.49-

3.32 (m, 3H), 2.97 (br s, 1H), 1.70-1.33 (m, 6H).

13C NMR (75 MHz, CDCl3) : δ 159.1, 130.4, 129.2, 113.7, 72.5, 72.0, 69.8, 66.6,

55.2, 32.7, 29.5, 22.2.

IR (neat) cm-1

: 3390, 2934, 2861, 1610, 1513, 1249, 1093, 1033,

821.

ESIMS (m/z) : 275 [M+Na]+.


(R)-6-((4-methoxybenzyl)oxy)hexan-2-ol (74):


124

To a cooled (0 oC) solution of diol 73 (2.4 g, 9.523 mmol), catalytic amount of

dibutyl tin oxide (5 mg) and Et3N (2.64 mL, 21.046 mmol) in CH2Cl2 (15 mL), p-TsCl

(1.81 g, 9.523 mmol) was added portionwise at 0 oC and the mixture was stirred at room

temperature for 4 h. After completion of reaction, the mixture was diluted with water

and extracted into CH2Cl2 (3 x 50 mL). The organic layer was washed with brine

solution and dried over anh. Na2SO4 and concentrated under reduced pressure to get the

crude residue which was purified on a silica gel column, eluting with Hexanes/EtOAc

(75:25) to afford mono tosylated product (3.1 g, 80%) as a viscous liquid.

To a stirred suspension of LiAlH4 (0.56 g, 14.705 mmol) in dry THF (30 mL) a

solution of mono tosylate (3.0 g, 7.35 mmol) in dry THF (30 mL) was added dropwise

at 0 oC under nitrogen atmosphere and the mixture was stirred at reflux temperature for

12 h. The reaction mixture was cooled to 0 oC, treated with saturated aq Na2SO4

solution (25 mL), filtered, and the filtrate was dried over anh. Na2SO4 and concentrated

in vacuo. The crude residue was purified by column chromatography using

Hexanes/EtOAc (8:2) as eluent to give 74 (1.38 g, 79%) as a colorless liquid.

[]D25

: -3.0 (c 2, CHCl3).


4.45 (s, 2H), 3.81 (s, 3H), 3.79-3.68 (m, 1H), 3.47 (t,

J = 6.4 Hz, 2H), 1.70-1.55 (m, 2H), 1.52-1.33 (m,

4H), 1.18 (d, J = 6.0 Hz, 3H).

13C NMR (75 MHz, CDCl3) : δ 158.8, 130.3, 129.0, 113.5, 72.2, 69.7, 67.4, 54.9,

38.7, 29.3, 23.1, 22.2.

IR (neat) cm-1

: 3421, 2934, 2860, 1612, 1513, 1247, 1095, 819.

ESIMS (m/z) : 261 [M+Na]+.


(R)-tert-butyl((6-((4-methoxybenzyl)oxy)hexan-2-yl)oxy)dimethylsilane (75):


125

To a solution of the alcohol 74 (1.3 g, 5.46 mmol) in dry CH2Cl2 (15 mL) was

added imidazole (0.743 g, 10.92 mmol), and the mixture was stirred for 10 min at 0 oC.

To this solution tert-butyldimethylsilyl chloride (0.983 g, 6.55 mmol) was added at 0

oC, and the mixture was stirred at room temperature for 6 h. After completion of the

reaction, the mixture was diluted with water and extracted with CH2Cl2 (3 x 20 mL).

The combined extract was washed with brine, dried over anh. Na2SO4 and concentrated

under reduced pressure. The crude residue was purified by column chromatography

using Hexanes/EtOAc (95:5) as eluent to give pure compound 75 (1.76 g, 92%) as a

colorless liquid.

[]D25

: -5.0 (c 2, CHCl3).


4.42 (s, 2H), 3.78 (s, 3H), 3.77-3.72 (m, 1H), 3.43 (t,

J = 6.4 Hz, 2H), 1.65-1.53 (m, 2H), 1.48-1.29 (m,

4H), 1.11 (d, J = 6.2 Hz, 3H), 0.88 (s, 9H), 0.04 (s,

6H). (Fig. 3.11).

13C NMR (75 MHz, CDCl3) : δ 159.0, 130.7, 129.1, 113.6, 72.4, 70.0, 68.4, 55.1,

39.4, 29.7, 25.8, 23.7, 22.3, 18.0, -4.4, -4.7.

IR (neat) cm-1

: 2932, 2857, 1512, 1248, 1101, 1039, 832, 773.

ESIMS (m/z) : 353 [M+H]+.

Molecular formula : C20H36O3Si.

(R)-5-((tert-butyldimethylsilyl)oxy)hexan-1-ol (76):

To a cooled (0 oC) solution of 75 (1.7 g, 4.83 mmol) in CH2Cl2 (15 mL) and

H2O (1.5 mL) was added DDQ (2.2 g, 9.71 mmol) and stirred at room temperature for 2

h. After completion of the reaction, saturated NaHCO3 solution was added, and the


126

aqueous layer was extracted with CH2Cl2 (2 x 20 mL). The combined organic extract

was dried over anh. Na2SO4 and concentrated in vacuo. The crude residue was purified

by column chromatography using Hexanes/ EtOAc (7:3) as eluent gave product 76

(1.04 g, 93%) as a colorless liquid.

[]D25

: -5.5 (c 1, CHCl3).

1H NMR (300 MHz, CDCl3) : δ 3.83-3.75 (m, 1H), 3.64 (t, J = 6.2 Hz, 2H), 1.60-

1.52 (m, 2H), 1.50-1.30 (m, 4H), 1.12 (d, J = 6.6 Hz,

3H), 0.88 (s, 9H), 0.04 (s, 6H).

13C NMR (75 MHz, CDCl3) : δ 68.5, 62.6, 39.3, 32.6, 25.8, 23.7, 21.8, 18.0, -4.4,

-4.7.

IR (neat) cm-1

: 3430, 1263.

ESIMS (m/z) : 255 [M+Na]+.


(2R,5R)-5-((tert-butyldimethylsilyl)oxy)hexane-1,2-diol (77):


added a solution of 76 (1.0 g, 4.31 mmol) in dry CH2Cl2 (20 mL) at room temperature


was filtered, diluted with water (10 mL) and extracted with CH2Cl2 (2 x 30 mL). The

combined organic extract was washed with brine (20 mL), dried over anh. Na2SO4 and

concentrated in vacuo to give crude aldehyde, which was directly used for next step.


nitrosobenzene (0.372 g, 3.478 mmol) and L-proline (0.16 g, 1.391 mmol) in dry

DMSO (0.5 mL) at room temperature and the solution was vigorously stirred at rt for

0.5 h. The reaction mixture was transferred dropwise to a solution of

sodiumborohydride (0.132 g, 3.478 mmol) in ethanol (15 mL) at 0 oC and the solution

stirred at 0 oC for 2 h, then concentrated. Saturated NaHCO3 solution (10 mL) was

added and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined


127

organic extracts were dried over anh. Na2SO4 and concentrated under vacuo. The

residue was dissolved in methanol (10 mL) and treated with CuSO4.5H2O (0.26 g, 1.043

mmol) and the reaction mixture was stirred at room temperature for 12 h, then filtered

through celite and concentrated. The crude residue was purified by column

chromatography using Hexanes/ EtOAc (6:4) as eluent gave the diol 77 (0.49 g, 57 %)

as colourless oil.

[]D25

: -12.5 (c 1, CHCl3).

1H NMR (300 MHz, CDCl3) : δ 3.98-3.90 (m, 1H), 3.71-3.60 (m, 2H), 3.49-3.43

(m, 1H), 1.68-1.49 (m, 4H), 1.16 (d, J = 5.7 Hz,

3H), 0.90 (s, 9H), 0.07 (s, 6H). (Fig. 3.17).

13C NMR (75 MHz, CDCl3) : δ 72.4, 68.5, 66.9, 35.6, 28.7, 25.8, 22.8, 18.1, -4.5,

-4.8.

IR (neat) cm-1

: 3412, 2930, 2858, 1671, 1251, 1068, 833, 770.

ESIMS (m/z) : 271 [M+Na]+.


tert-butyl(((2R)-4-((4R)-2-(4-methoxyphenyl)-1,3-dioxolan-4-yl)butan-2-yl)oxy)

dimethylsilane (78a):

To a stirred solution of 77 (2.72 g, 10.96 mmol) in CH2Cl2 (30 mL), p-

methoxybenzylidene dimethylacetal (2.5 mL, 15.32 mmol) and catalytic amount of

PPTS were added subsequently. The mixture was stirred at 23 oC for 1 h. After

completion of the reaction, was quenched with Et3N (two drops). The mixture was

concentrated and the residue was purified by column chromatography to afford the

acetal compound 78a (3.4 g, 85%).

[]D25

: +18.3 (c 1.2, CHCl3).



128

5.86 (s, 1H), 4.29-4.15 (m, 2H), 3.88-3.82 (m, 1H),

3.81 (s, 3H), 3.63-3.56 (m, 1H), 1.75-1.55 (m, 4H),

1.15 (d, J = 6.0 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H).

13C NMR (75 MHz, CDCl3) : δ 159.3, 131.9, 130.9, 127.7, 113.6, 103.9, 77.4,

70.7, 68.3, 55.2, 35.6, 29.6, 25.8, 23.7, 18.0, -4.4, -

4.7.

IR (neat) cm-1

: 2937, 1716, 1641, 1615, 1517, 1249, 1171, 1034,

915, 830.

ESIMS (m/z) : 391 [M+Na]+.


(2R,5R)-5-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)oxy)hexan-1-ol (78):

To a stirred solution of compound 78a (2.4 g, 6.56 mmol) in CH2Cl2 (30 mL),

DIBAL–H (13.1 mL, 1 M in Toluene, 13.10 mmol) was added dropwise at -78 oC. The

mixture was stirred at 0 oC for another 1 h. After completion of the reaction, the excess

DIBAL–H was quenched with 10% Roche’s salt solution and the mixture was stirred at

room temperature for 2 h, two layers were separated and the aqueous layer was

extracted with CH2Cl2 (2 x 30 mL). The combined organic layers were dried over anh.

Na2SO4 and concentrated in vacuo. The residue was purified by column

chromatography using Hexanes/ EtOAc (8:2) as eluent to afford the desired compound

78 (2.1 g, 87%) as a colorless liquid.

[]D25

: -38.7 (c 1, CHCl3).


4.56 (d, J = 10.5 Hz, 1H), 4.45 (d, J = 10.5 Hz, 1H),

3.81 (s, 3H), 3.80-3.74 (m, 1H), 3.71-3.60 (m, 1H),

3.57-3.44 (m, 2H), 1.92 (brs, 1H), 1.66-1.53 (m,

2H), 1.51-1.38 (m, 2H), 1.13 (d, J = 6.0 Hz, 3H),

0.89 (s, 9H), 0.05 (s, 6H).


129

13C NMR (75 MHz, CDCl3) : δ 159.1, 129.3, 128.4, 113.7, 79.5, 71.0, 68.5, 64.1,

55.1, 34.9, 26.7, 25.8, 23.6, 18.0, -4.4, -4.8.

IR (neat) cm-1

: 3450, 2931, 2858, 1513, 1249, 1039, 772.

ESIMS (m/z) : 391 [M+Na]+.


tert-butyl(((2R,5R)-5-((4-methoxybenzyl)oxy)hept-6-en-2-yl)oxy)dimethylsilane

(79):

To a stirred solution of IBX (2.074 g, 7.4 mmol) in dry DMSO was added a

solution of 78 (800 mg, 4.92 mmol) in dry CH2Cl2 (20 mL) at room temperature and

stirred for 3 h at room temperature. After completion of the reaction, the mixture was

filtered and diluted with water (10 mL) and extracted with CH2Cl2 (2 x 30 mL). The

combined organic layer was washed with brine (20 mL), dried over anh. Na2SO4 and

concenrated in vacuo to give crude aldehyde, which was directly used for next step.

To a solution of (methylenetriphenyl)phosphonium iodide (3.97 g, 9.83 mmol)

in dry THF (20 mL), n-BuLi (6.14 mL, 9.83 mmol, 1.6 M) was added at 0 oC and the

mixture was stirred for 1 h at room temperature. The reaction mixture was cooled to 0

oC, added aldehyde (1.8 g, 4.91 mmol) in dry THF (5 mL) and the mixture was stirred

for an additional 12 h at rt. The reaction was quenched with saturated NH4Cl (5 mL)

solution and the mixture was extracted with ether (2 x 30 mL). The combined extracts

were washed with brine (20 mL), dried over anh. Na2SO4, concentrated. The crude

residue was purified by column chromatography using Hexanes/EtOAc (95:5) as eluent

to afford 79 (1.37 g, 77%) as a yellow syrup.

[]D25

: +11.14 (c 3.5, CHCl3).


5.79-5.66 (m, 1H), 5.24-5.15 (m, 2H), 5.20 (d, J =

11.3 Hz, 1H), 5.28 (d, J = 11.3 Hz, 1H), 3.80 (s,

3H), 3.78-3.72 (m, 1H), 3.71-3.63 (m, 1H), 1.66-


130

1.36 (m, 4H), 1.11 (d, J = 6.0 Hz, 3H), 0.88 (s, 9H),

0.03 (d, J = 1.5 Hz, 6H).

13C NMR (75 MHz, CDCl3) : δ 159.0, 139.2, 130.9, 129.2, 116.8, 113.7, 80.4,

69.6, 68.6, 55.2, 35.4, 31.7, 25.9, 23.8, 18.1, -4.4, -

4.7.

IR (neat) cm-1

: 2954, 2930, 2856, 1512, 1249, 1040, 831, 773.

ESIMS (m/z) : 387 [M+Na]+.


(2R,5R)-5-((4-methoxybenzyl)oxy)hept-6-en-2-ol (80):

To a solution of 79 (1.0 g, 2.74 mmol) in dry THF (5 mL) was added TBAF (3.3

mL, 1.0 M solution in THF) and stirred for 2 h at room temperature. After completion

of the reaction, the mixture was quenched with saturated NaHCO3 solution and

extracted with EtOAc (2 x 20 mL), the organic layer was washed with brine solution,

dried over anh. Na2SO4 and concentrated under reduced pressure. The crude residue was

purified by silica gel column chromatography using Hexanes/EtOAc (7:3) as eluent to

obtain alcohol 80 (0.63 g, 92%) as a colorless liquid.

[]D25

: +23.2 (c 0.8, CHCl3).


5.83-5.68 (m, 1H), 5.30-5.16 (m, 2H), 4.53 (d, J =

11.3 Hz, 1H), 4.28 (d, J = 11.3 Hz, 1H), 3.84-3.71

(m, 2H), 3.80 (s, 3H), 1.84 (br s, 1H), 1.71-1.60 (m,

2H), 1.58-1.43 (m, 2H), 1.17 (d, J = 6.0 Hz, 3H).

13C NMR (75 MHz, CDCl3) : δ 159.1, 138.7, 129.4, 128.6, 117.2, 113.7, 80.2,

69.8, 67.7, 55.2, 35.0, 31.7, 23.3.

IR (neat) cm-1

: 3419, 2928, 2857, 1612, 1513, 1247, 1035, 821.

ESIMS (m/z) : 273 [M+Na]+.



131

4-((4-methoxybenzyl)oxy)butan-1-ol (82):

To a solution of 1,4-butanediol 81 (2 g, 22.22 mmol) in dry THF (20 mL) was

added NaH (60%, 1.06 g, 44.44 mmol) at 0 oC, the reaction mixture was stirred for 30

min at same temperature. Then p-methoxybenzyl bromide (4.44 g, 22.22 mmol) was

added slowly at 0 oC followed by TBAI (cat.), further stirring for 1 h. After completion

of the reaction, the mixture was quenched with cold water at 0 oC, the two layers were

separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined

organic layers were washed with water and brine, dried over anh. Na2SO4 and

concentrated. The residue was purified by silica gel column chromatography using

Hexanes/EtOAc (7:3) as eluent to furnish the mono-PMB protected alcohol 82 (3.73 g,

80%) as colorless oil.


4.35 (s, 2H), 3.81 (s, 3H), 3.64 (t, J = 6.5 Hz, 2H),

3.45 (t, J = 6.5 Hz, 2H), 1.47-1.36 (m, 4H).

13C NMR (75 MHz, CDCl3) : δ 159.7, 130.9, 129.3, 113.5, 72.7, 69.6, 63.5, 56.1,

33.1, 29.4.

IR (neat) cm-1

: 3395, 2925, 2852, 1609, 1517, 1233, 1092, 820.

ESIMS (m/z) : 233 [M+Na]+.


(S)-4-((4-methoxybenzyl)oxy)butane-1,2-diol (83):


added a solution of 78 (3.0 g, 14.28 mmol) in dry CH2Cl2 (30 mL) at room temperature



132

was filtered and diluted with water (15 mL) and extracted into CH2Cl2 (2 x 30 mL). The

combined organic layer was washed with brine (20 mL), dried over anh. Na2SO4 and

evaporated to give crude aldehyde, which was directly used for next step.


nitrosobenzene (0.977 g, 9.13 mmol) and D-proline (0.42 g, 3.653 mmol) in chloroform

(5 mL) at 0 oC and the solution was vigorously stirred at 0

oC for 2 h. The reaction

mixture was transferred dropwise to a solution of sodiumborohydride (0.347 g, 9.13

mmol) in ethanol (30 mL) at 0 oC and the solution stirred at 0

oC for 2 h, then

concentrated. Saturated aqueous sodium bicarbonate solution (25 mL) was added and

the mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic

extracts were dried over Na2SO4 and concentrated. The residue was dissolved in 3:1

ethanol: acetic acid (20 mL) and treated with zinc powder (1.98 g, 30.32 mmol) and the

reaction mixture was stirred at room temperature for 12 h, then filtered through celite

and concentrated. The crude product was purified by column chromatography using

Hexanes/EtOAc (4:6) as eluent gave the diol 83 (1.42 g, 69 %) as colourless oil. The

enantiomeric excess was determined by chiral HPLC column: (CHIRAL PAK-OD-H:

250 x 4.6mm, 5µ) mobile phase: 8% IPA in Hexane, Flow rate: 1 ml/min, detection:

210 nm, Ret. Time: 16.744 min, 99% ee.

[]D25

: +4.7 (c 1.2, CHCl3).


4.43 (s, 2H), 3.90-3.81 (m, 1H), 3.79 (s, 3H), 3.67

(br s, 2H), 3.64-3.53 (m, 3H), 3.48-3.40 (m, 1H),

1.80-1.65 (m, 2H).

13C NMR (75 MHz, CDCl3) : δ 159.0, 129.8, 129.1, 113.6, 72.6, 70.6, 67.3, 66.3,

55.0, 32.6.

IR (neat) cm-1

: 3401, 2935, 2866, 1612, 1513, 1248, 1089, 1034,

820.

ESIMS (m/z) : 249 [M+Na]+.


(S)-2-(2-((4-methoxybenzyl)oxy)ethyl)oxirane (84):


133

A solution of diol 83 (0.92 g, 4.04 mmol) in THF (10 mL) was added to NaH

(0.392 g, 16.28 mmol) in THF (20 mL) at 0 oC. The resulting mixture was then warmed

to ambient temperature and stirred for 40 min. The mixture was then cooled to 0 oC and

tosylimidazole (1.12 g, 4.88 mmol) was added in one portion. The reaction mixture was

allowed to ambient temperature and stirred for 1 h. The mixture was quenched with

water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was

washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under

reduced pressure. The residue was purified by column chromatography using Hexanes/

EtOAc (95:05) as eluent to give oxirane 84 (0.724 g, 86%) as a colourless oil.

[]D25

: -12.5 (c 1, CHCl3).


4.46 (s, 2H), 3.82 (s, 3H), 3.63-3.57 (m, 2H), 3.10-

3.02 (m, 1H), 2.79 (dd, J = 4.6, 3.8 Hz, 1H), 2.51

(dd, J = 4.6, 3.0 Hz, 1H), 1.93-1.85 (m, 1H), 1.83-

1.75 (m, 1H).

13C NMR (75 MHz, CDCl3) : δ 159.1, 129.9, 129.1, 113.5, 72.6, 66.5, 55.1, 50.0,

45.8, 32.8.

IR (neat) cm-1

: 2928, 2860, 1613, 1514, 1461, 1248, 1094, 755.

ESIMS (m/z) : 231 [M+Na]+.


(S)-5-((4-methoxybenzyl)oxy)pent-1-en-3-ol (85):

A solution of trimethylsulfonium iodide (1.96 g, 9.61 mmol) in THF (30 mL)

was cooled to –20 °C, n-BuLi (2.5 M solution in hexane, 2.9 mL, 7.21 mmol) was

added drop wise and the resulting solution was stirred for 1 h at –20 °C. A solution of


134

the epoxide 84 (0.5 g, 2.40 mmol) in THF (10 mL) was added and a cloudy suspension

was formed. The stirring was continued for another 1 h at –20 °C. The reaction mixture

was warmed to 0 °C and quenched with saturated aqueous NH4Cl (20 mL). The layers

were separated and the aqueous layer was extracted with diethyl ether (2 x 50 mL). The

combined organic layers were dried over anh. Na2SO4 and concentrated under reduced

pressure. The crude product was purified by silica gel column chromatography using

Hexanes/EtOAc (9:1) as eluent gave alcohol 85 (0.48 g, 90%) as a pale yellow oil.

[]D25

: +10.1 (c 0.6, CHCl3).


5.87 (ddd, J = 17.3, 10.5, 6.0 Hz, 1H), 5.27 (dt, J =

17.3, 1.5 Hz, 1H), 5.10 (dt, J = 10.5, 1.5 Hz, 1H),

4.45 (s, 2H), 4.38-4.29 (m, 1H), 3.81 (s, 3H), 3.72-

3.57 (m, 2H), 1.92-1.74 (m, 2H).

13C NMR (75 MHz, CDCl3) : δ 159.3, 140.5, 130.0, 129.3, 114.3, 113.8, 72.9,

71.9, 68.0, 55.2, 36.2.

IR (neat) cm-1

: 3414, 2923, 2858, 1612, 1585, 1513, 1247, 1091,

820.

ESIMS (m/z) : 245 [M+Na]+.


(S)-tert-butyl((5-((4-methoxybenzyl)oxy)pent-1-en-3-yl)oxy)dimethylsilane (86):

To a 0 oC solution of 85 (0.45 g, 2.02 mmol) in CH2Cl2 (8 mL) was added

imidazole (0.48 g, 4.04 mmol) and TBSCl (0.51 g, 2.23 mmol). The mixture was stirred

at 0 oC for 2 h and diluted with CH2Cl2 (15 mL). The organic phase was washed

sequentially with a saturated aqueous solution of NaHCO3 (20 mL) and brine (15 mL),

dried over anh. Na2SO4 and evaporated in vacuo. The residue was purified by column

chromatography using Hexanes/EtOAc (97:03) as eluent to give the 86 (0.6 g, 88%

yield) as colorless oil.

[]D25

: +2.0 (c 1, CHCl3).


135


5.87-5.83 (m, 1H), 5.20-4.97 (m, 2H), 4.41 (q, J =

11.5 Hz, 2H), 4.33-4.24 (m, 1H), 3.80 (s, 3H), 3.60-

3.44 (m, 2H), 1.83-1.72 (m, 2H), 0.89 (s, 9H), 0.04

(d, J = 6.2 Hz, 6H).

13C NMR (75 MHz, CDCl3) : δ 159.1, 141.6, 130.6, 129.2, 113.7, 113.6, 72.6,

70.8, 66.4, 55.2, 38.1, 25.8, 18.2, -4.3, -4.9.

IR (neat) cm-1

: 2953, 2928, 2855, 1513, 1249, 1091, 1036, 836,

775.

ESIMS (m/z) : 359 [M+Na]+.


(S)-3-((tert-butyldimethylsilyl)oxy)pent-4-en-1-ol (87):

To a solution of 86 (0.5 g, 1.50 mmol) in CH2Cl2 (5 mL) and H2O (0.5 mL) was

added DDQ (0.405 g, 1.775 mmol) at 0 oC. The reaction mixture was stirred for 30 min

at rt. After completion of the reaction, saturated NaHCO3 solution was added. The

aqueous phase was extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts

were washed with aqueous NaHCO3 (10 mL), dried over anh. Na2SO4 and concentrated

in vacuo. The crude product was purified by silica gel column chromatography using

Hexanes/EtOAc (8:2) as eluent afforded alcohol 87 (0.3 g, 93%) as a colorless oil.

[]D25

: -3.8 (c 1, CHCl3).

1H NMR (300 MHz, CDCl3) : δ 5.92-5.78 (m, 1H), 5.28-5.06 (m, 2H), 4.48-4.37

(m, 1H), 3.88-3.65 (m, 2H), 2.43 (brs, 1H), 1.92-

1.79 (m, 1H), 1.78-1.65 (m, 1H), 0.91 (s, 9H), 0.09

(s, 3H), 0.06 (s, 3H).

13C NMR (75 MHz, CDCl3) : δ 138.6, 116.4, 74.4, 58.9, 34.6, 25.9, 18.2, -4.1,

-4.7.

IR (neat) cm-1

: 3369, 2955, 2931, 2858, 1254, 1085, 1023, 837,


136

776.

ESIMS (m/z) : 269 [M+Na]+.


(S)-3-((tert-butyldimethylsilyl)oxy)pent-4-enoic acid (88):

To a solution of alcohol 87 (250 mg, 1.16 mmol) in CH2Cl2–H2O (1:1, 4 mL)

were added TEMPO (52 mg, 0.35 mmol) and BAIB (1.12 g, 3.48 mmol). After stirring

at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (5 mL) and

then washed with saturated aqueous Na2S2O3 (10 mL). The organic layer was dried over

Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the

crude carboxylic acid, which was further purified by silica gel column chromatography

Hexanes/EtOAc (6:4) as eluent gave acid 88 (230 mg, 86%) as a colorless oil.

[]D25

: +4.0 (c 1, CHCl3).

1H NMR (300 MHz, CDCl3) : δ 5.92-5.78 (m, 1H), 5.26 (d, J = 17.3 Hz, 1H),

5.11 (d, J = 10.5 Hz, 1H), 4.59 (q, J = 6.0 Hz, 1H),

2.58-2.52 (m, 2H), 0.89 (s, 9H), 0.08 (s, 3H), 0.06

(s, 3H).

13C NMR (75 MHz, CDCl3) : δ 176.9, 139.5, 114.9, 70.4, 43.2, 25.5, 17.9, -4.5,

-5.3.

IR (neat) cm-1

: 2956, 2931, 2858, 1714, 1255, 835, 777.

ESIMS (m/z) : 253 [M+Na]+.


(S)-(2R,5R)-5-((4-methoxybenzyl)oxy)hept-6-en-2-yl 3-((tert-butyldimethylsilyl)

oxy)pent-4-enoate (89):


137

To a cooled (0 oC) solution of acid 88 (200 mg, 0.86 mmol), DCC (180 mg,

0.86 mmol), and DMAP (106 mg, 0.86 mmol) in dry CH2Cl2 (10 mL) was added

alcohol 80 (218 mg, 0.86 mmol) in 5 mL of dry CH2Cl2 and stirred at the same

temperature for 12 h. After completion of the reaction, the mixture was diluted with

water (15 mL) and extracted into CH2Cl2 (3 x 30 mL). The combined organic layer was

dried and concentrated under reduced pressure. The crude product was purified by silica

gel column chromatography using Hexanes/EtOAc (96:4) as eluent to give pure

compound 89 (337 mg, 84%) as a colorless liquid.

[]D25

: +11.3 (c 2.8, CHCl3).


5.91-5.76 (m, 1H), 5.75-5.63 (m, 1H), 5.27-5.16 (m,

3H), 5.06 (d, J = 10.2 Hz, 1H), 4.93-4.81 (m, 1H),

4.62-4.54 (m, 1H), 4.51 (d, J = 11.3 Hz, 1H), 4.27 (d,

J = 11.3 Hz, 1H), 3.80 (s, 3H), 3.74-3.63 (m, 1H),

2.57-2.34 (m, 2H), 1.72-1.46 (m, 4H), 1.19 (d, J =

6.2 Hz, 3H), 0.87 (s, 9H), 0.05 (d, J = 3.7 Hz, 6H).

13C NMR (75 MHz, CDCl3) : δ 170.5, 159.0, 140.2, 138.8, 130.7, 129.2, 117.3,

114.5, 113.7, 80.0, 71.1, 70.7, 69.7, 55.2, 43.8, 31.7,

31.4, 25.7, 19.9, 18.0, -4.4, -5.0.

IR (neat) cm-1

: 2954, 2931, 2857, 1733, 1513, 1249, 1081, 1036,

834, 778.

ESIMS (m/z) : 485 [M+Na]+.


(S)-(2R,5R)-5-((4-methoxybenzyl)oxy)hept-6-en-2-yl 3-hydroxypent-4-enoate (90):


138

A solution of 89 (140 mg, 0.303 mmol) in THF (1 mL) was cooled to 0 °C and

TBAF (0.36 mL, 0.36 mmol, 1.0 M in THF) was added drop wise. The resulting brown

solution was stirred at room temperature for 2 h. The reaction was quenched with

saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (2 x 10 mL). The combined

organic layer was washed with brine (5 mL), dried over Na2SO4 and evaporated under

reduced pressure, which was purified by column chromatography on silica gel using

Hexanes/EtOAc (7:3) as eluent to give alcohol 90 (98 mg, 93%) as a colorless liquid.

[]D25

: +12.77 (c 1.8, CHCl3).


5.87-5.73 (m, 1H), 5.71-5.56 (m, 1H), 5.29-5.03 (m,

4H), 4.93-4.81 (m, 1H), 4.44 (d, J = 11.3 Hz, 1H),

4.19 (d, J = 11.3 Hz, 1H), 3.77-3.68 (m, 1H), 3.73 (s,

3H), 3.66-3.57 (m, 1H), 2.53-2.35 (m, 2H), 1.66-1.39

(m, 4H), 1.14 (d, J = 6.8 Hz, 3H).

13C NMR (75 MHz, CDCl3) : δ 171.8, 159.0, 138.8, 138.7, 130.5, 129.3, 117.3,

115.2, 113.7, 79.8, 71.5, 69.7, 68.9, 55.2, 41.4, 31.6,

31.2, 19.9.

IR (neat) cm-1

: 3447, 2930, 2857, 1727, 1513, 1247, 1175, 1035,

927, 822.

ESIMS (m/z) : 371 [M+Na]+.


(4S,7R,10R,E)-4-hydroxy-7-((4-methoxybenzyl)oxy)-10-methyl-3,4,7,8,9,10-

hexahydro-2H-oxecin-2-one (91):


139

Grubbs’ 2nd

generation catalyst (10.9 mg, 0.013 mmol) was dissolved in dry,

deoxygenated CH2Cl2 (120 mL). After heating the solution to reflux, diene 90 (45 mg,

0.13 mmol) dissolved in dry, deoxygenated CH2Cl2 (30 mL) was added dropwise over

30 min. The mixture was then stirred at reflux for 1 h. After cooling to room

temperature, all volatiles were removed under reduced pressure. The residue was

purified by silica gel column chromatography using Hexanes/EtOAc (85:15) as eluent

to give 91 (29.8 mg, 72%) as a colorless oil.

[]D25

: +7.9 (c 1.2, CHCl3).


5.68 (dd, J = 16.6, 3.0 Hz, 1H), 5.57 (dd, J = 16.6,

8.3 Hz, 1H), 4.92-4.81 (m, 1H), 4.70-4.62 (m, 1H),

4.44 (d, J = 11.3 Hz, 1H), 4.19 (d, J = 11.3 Hz, 1H),

3.87-3.76 (m, 1H), 3.73 (s, 3H), 2.56 (dd, J = 12.0,

3.7 Hz, 1H), 2.46 (dd, J = 12.0, 3.7 Hz, 1H), 1.78-

1.37 (m, 4H), 1.10 (d, J = 6.0 Hz, 3H).

13C NMR (75 MHz, CDCl3) : δ 170.5, 159.0, 134.7, 130.5, 129.6, 129.3, 113.7,

80.2, 73.0, 69.4, 67.6, 55.2, 44.2, 31.9, 29.6, 21.5.

IR (neat) cm-1

: 3447, 2923, 2853, 1715, 1513, 1248, 1167, 1035,

819.

ESIMS (m/z) : 343 [M+Na]+.


(3S,6R,9R,E)-3,6-dihydroxy-9-methylcyclodec-4-enone (37):


140

To a cooled (0 oC) solution of 91 (18 mg, 0.056 mmol) in CH2Cl2 (5 mL) and

H2O (0.5 mL) was added DDQ (25.5 mg, 0.112 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 the CH2Cl2 (2 x 5 mL). The combined organic extract

was dried over anh. Na2SO4 and concentrated to dryness. Column chromatography of

the residue using Hexanes/ EtOAc (6:4) as eluent gave pure compound 37 (10.4 mg,

93%) as a colorless crystal.

[]D25

: -53 (c 0.3, MeOH).

1H NMR (300 MHz, CD3OD) : δ 5.75 (dd, J = 15.9, 2.8 Hz, 1H), 5.63 (ddd, J =

15.9, 8.3, 1.1 Hz, 1H), 4.81-4.71 (m, 1H), 4.65-4.61

(m, 1H), 4.16-4.04 (m, 1H), 2.56-2.43 (m, 2H), 2.02-

1.86 (m, 1H), 1.84-1.69 (m, 1H), 1.66-1.52 (m, 2H),

1.14 (d, J = 6.4 Hz, 3H).

13C NMR (75 MHz, CD3OD) : δ 170.3, 133.0, 130.3, 74.3, 72.9, 66.8, 44.0, 37.0,

31.3, 20.6.

IR (neat) cm-1

: 3353, 2921, 1721, 1459, 1360, 1261, 1170, 1016,

968, 799.

HRMS (ESI) (m/z) : calcd. for C10H16O4Na [M+Na]+

223.0940;

found 223.0938.


References

1. Ishida, T.; Wada, K. J. Chem. Soc., Chem. Commun. 1975, 209.

2. Wada, K.; Ishida, T. J. Chem. Soc., Chem. Commun. 1976, 340.

3. Wada, K.; Ishida, T. J. Chem. Soc., Perkin Trans. 1, 1979, 1154.

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