Approaches to a synthesis of galbonolide B

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Peter M. Smith and Eric J. Thomas*

The Department of Chemistry, The University of Manchester, Manchester, UK M13 9PL

Received (in Cambridge) 27th July 1998, Accepted 7th September 1998

An approach to the C(7)–C(15) fragment of galbonolide B 2 has been completed in which the diene fragment 51

was assembled from (R)-3-tert-butyldimethylsilyloxypentan-2-one 29 by conversion into the unsaturated ester 30,

acylation of the sulfone 47 using this ester, reductive desulfurisation, methylenation using a Wittig reaction and

deprotection. Following model studies, the aldehyde 62, prepared by oxidation of the alcohol 51, was converted

into a mixture of the epimeric alcohols 63 and these were converted into the di(methylene)tridecadienoic acid 65

using a phosphine catalysed Ireland–Claisen rearrangement. Sharpless epoxidations of the alcohol 67 using either

-(ϩ)- or -(Ϫ)-diethyl tartrate were highly stereoselective and gave the epoxides 68 and 69 which were clearly

distinguishable. Model studies using the heptadiene monoepoxide 70 led to a synthesis of the monoprotected

dihydroxy aldehyde 76 so establishing a protocol for the introduction into the vicinal diol of the galbonolides.

Finally, aldol addition of tert-butyl acetate to the aldehyde 78 followed by selective protection, deprotection and

cyclisation completed a synthesis of the macrolide 85.

The galbonolides are 14-membered macrolides which exhibit a

the (4R,13R)-diastereoisomer 1. Nevertheless, the chemistry

broad range of antifungal activity.¹The structure 1 originally

should be applicable for a synthesis of the natural product.

At the onset of our work, it was intended to prepare the

α,β-unsaturated ketone 8 by means of a Wittig condensation

between the keto ylid 9 and the 3-alkoxypentan-2-one 10, and

to convert the ketone into the diene 7, corresponding to

the C(7)–C(15) fragment of galbonolide B, by methylenation

(Scheme 1).

Scheme 1

Results and discussion

assigned to galbonolide B by reference to the Celmer model¹

was subsequently revised to the (4S,13S)-diastereoisomer 2 on

the basis of an X-ray structure determination and a total

synthesis in which a key step was the stereoselective alkylation

of an enolate anion derived from dioxolane 3 using the iodide

4.²In addition an ingenious stereoselective synthesis of the

C(7)–C(15) fragment 6 has been described based on the

Ireland–Claisen rearrangement of the propanoate 5 followed by

1,4-elimination to introduce the conjugated diene.³We here

report an approach to the C(7)–C(15) fragment and studies

into strategies for completion of a synthesis of galbonolide B 2.

This work was carried out before the structure of the natural

product was revised and was directed towards the synthesis of

The diene 18 was synthesized to gain familiarity with the pro-

posed chemistry, see Scheme 2. The racemic 3-alkoxypentan-2-

one 14 was prepared in three steps from 2-methyl-1,3-dithiane

11, with better results for the lithiation of the dithiane being

obtained using sec-butyllithium. Although condensations of

the ketone 14 with either the keto phosphorane 19 or the keto

phosphonate 20 were unsuccessful (the reactants were generally

recovered unchanged), the ketone 14 reacted cleanly with tri-

ethyl phosphonoacetate to give the unsaturated ester 15 as a

10:1 mixture of (E)- and (Z)-isomers (NOE). Ester 15 was

converted into the Weinreb amide 16 which gave the ketone 17

on treatment with butyllithium, and a Wittig reaction of

this enone with methylene(triphenyl)phosphorane gave the

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Scheme 3 Reagents and conditions: i, BnOCH₂Cl, Hunig’s base (72%);

ii, diisobutylaluminium hydride, Ϫ78 ЊC (75%); iii, ethylmagnesium

bromide, zinc bromide, 0 ЊC (65%); iv, (R)- or (S)-O-acetylmandelic

acid, 4-N,N-dimethylaminopyridine, dicyclohexylcarbodiimide (56%);

v, tert-butyldimethylsilyl chloride, imidazole (94%); vi, hydrogen, Pd/C,

60 psi (94%); vii, dimethyl sulfoxide, oxalyl chloride, Ϫ50 ЊC, triethyl-

amine (98%); viii, triethyl phosphonoacetate, sodium hydride (89%);

ix, Bu₄NF (92%); x, (R)- or (S)-Mosher’s acid chloride, triethylamine,

4-N,N-dimethylaminopyridine (90%).

Scheme 2 Reagents and conditions: i, sec-Butyllithium, Ϫ20 ЊC then

propanal, Ϫ78 ЊC (66%); ii, sodium hydride, 0 ЊC, then p-methoxy-

benzyl chloride, NBu₄I, DMF (77%); iii, mercuric chloride, calcium

carbonate (85%); iv, triethyl phosphonoacetate, sodium hydride (79%);

v, trimethylaluminium, N,O-dimethylhydroxylamine hydrochloride

(62%); vi, n-butyllithium (46%); vii, Ph₃PMeBr, n-butyllithium (74%).

conjugated diene 18. The diﬃculties in reacting the keto phos-

phorane 19 or keto phosphonate 20 with the ketone 14 have

precedent⁴and may be due, at least in part, to the steric

hindrance to attack on the 2-substituted ketone. However, the

preparation of the ester 15 using triethyl phosphonoacetate,

followed by conversion of the ester functionality into the

ketone by addition of the organometallic reagent, provided a

useful alternative synthesis of the α,β-unsaturated ketone. It

was now necessary to prepare the enantiomerically enriched

ester 15 for reaction with a chiral organometallic reagent to

achieve a synthesis of the target fragment 7.

Commercially available isobutyl (R)-lactate 21 was converted

into its benzyloxymethyl ester 22⁵which was reduced to (2R)-

2-(benzyloxymethoxy)propanal 23 (Scheme 3). Chelation

controlled addition⁶of ethylmagnesium bromide to 23 was

enhanced by the presence of zinc bromide⁷and gave predomin-

antly the syn-alcohol 24 with syn:anti-stereoselectivities within

the range syn:anti = 97:3 to 94:6, better stereoselectivity being

obtained for smaller scale reactions. The conﬁguration of the

Scheme 4 Reagents and conditions: i, p-methoxybenzyl trichloro-

acetimidate, chlorosulfonic acid (78%); ii, lithium aluminium hydride

(98%); iii, N-bromosuccinimide, triphenylphosphine (93%); iv, thio-

phenol, DBU (96%); v, oxone (86%); vi, n-butyllithium, MgBr₂ؒEt₂O,

then 30 (96%); vii, lithium naphthalenide, Ϫ78 ЊC (82%); viii, Ph₃-

PMeBr, n-butyllithium (76%).

1

syn-alcohol 24 at C(3) was checked by comparison of the H

NMR chemical shifts of its O-acetylmandelates 25 and 26.⁸

Protection–deprotection and oxidation then gave the 3-silyl-

oxyketone 29 which was condensed with triethyl phosphono-

acetate to give the (R)-ester 30. The optical purity of this ester

was checked by desilylation and conversion of the hydroxy

ester 31 into its (R)- and (S)-Mosher’s derivatives 32 and 33.

Comparison of the ¹⁹F NMR spectra of these indicated that

the optical purity of the hydroxy ester 31 was in the region of

84–96%, with better enantiomeric excesses being obtained for

smaller scale preparations.

to the addition of the ester.⁹Reductive desulfurisation¹⁰then

gave the ketone 41 which was converted into the diene 42 using

a Wittig reaction. It remained to deprotect the primary alcohol

of 42 to complete a synthesis of the C(7)–C(15) fragment of the

galbonolides. However, attempts to remove the p-methoxy-

benzyl group oxidatively using dichlorodicyanoquinone¹¹or

ceric ammonium nitrate¹²resulted in decomposition, and the

use of other procedures¹³for removal of the p-methoxybenzyl

group resulted in either decomposition, perhaps because of

instability of the alcohol (vide infra) or recovery of starting

material.

It was necessary to investigate the use of other protecting

groups for the primary alcohol. Attempted deprotection of the

SEM-ether 43,¹⁴prepared following the route used to prepare

the p-methoxybenzyl ether 42, gave rise to a complex mixture of

products even when buﬀered conditions were used. However,

The bromide 37 was prepared from methyl (R)-3-hydroxy-2-

methylpropanoate 34, see Scheme 4, but preliminary attempts

to convert this into either an organolithium or Grignard

reagent for reaction with the Weinreb amide derived from the

ester 30 resulted only in decomposition. The bromide was there-

fore converted, via sulﬁde 38, into the sulfone 39 and conditions

developed for the acylation of the lithiated sulfone by the ester

30 to yield ketone 40. Signiﬁcant improvements in the yield of

this acylation were obtained when a solution of magnesium

bromide–diethyl ether was added to the lithiated sulfone prior

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monodesilylation¹⁵of the bis-tert-butyldimethylsilyl ether 50,

prepared as outlined in Scheme 5, gave the required primary

Scheme 6 Reagents and conditions: i, 2-bromopropene, sec-butyl-

lithium (80%); ii, acryloyl chloride (57%); iii, tricyclohexylphosphine

(cat.), trimethylsilyl chloride, DBU, acetonitrile, 75 ЊC, 17 h (75%);

iv, diazomethane (82%); v, diisobutylaluminium hydride (72%).

Scheme 5 Reagents and conditions: i, diphenyl disulﬁde, Bu₃P (96%);

ii, lithium aluminium hydride (91%); iii, m-chloroperoxybenzoic acid

(97%); iv, tert-butyldimethylsilyl chloride, imidazole (93%); v, butyl-

lithium, magnesium bromide diethyl etherate, then 30 (90%); vi, lithium

naphthalenide, Ϫ78 ЊC (70%); vii, methyl(triphenyl)phosphonium

bromide, n-butyllithium (78%); viii, Bu₄NF (87%).

alcohol 51 in excellent yield (87%). This alcohol was found to be

very sensitive to acid with cyclisation to the epimeric tetra-

hydrofurans 52 being observed on standing in chloroform.

This phase of the work completed a convergent synthesis of

the alcohol 51 which corresponds to the C(7)–C(15) fragment

7 of the galbonolides. At this point, the recently reported

phosphine catalysed Ireland–Claisen rearrangement of α,β-

unsaturated esters¹⁶was identiﬁed as a useful procedure for

the preparation of advanced intermediates for a synthesis

of galbonolide B 2. To gain familiarity with this chemistry,

model studies were carried out starting with (racemic) 2-phenyl-

propanal 53.

Addition of prop-2-enyllithium to 2-phenylpropanal 53 gave

a mixture of the secondary alcohols 54¹⁷which were acyl-

ated with acryloyl chloride to give the esters 55 (Scheme 6).

Rearrangement of these was achieved by heating a solution

with tricyclohexylphosphine, trimethylsilyl chloride and 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile at 75 ЊC

for 17 h, and gave a good yield of the dienyl acid 57 via the in

situ generation and rearrangement of the silylated conjugate

addition product 56.¹⁶The use of trimethylsilyl chloride rather

than triethylsilyl chloride was preferred because of the faster

hydrolysis of the trimethylsilyl ester 58 compared with its

triethylsilyl analogue 59. Esteriﬁcation of the acid 57 using

diazomethane gave the methyl ester 60 which was reduced using

diisobutylaluminium hydride to give the alcohol 61.

The same procedures were used to convert the aldehyde 62,

prepared by oxidation of alcohol 51, into the chain extended

allylic alcohol 67, see Scheme 7. Thus treatment of the aldehyde

with 2-lithiopropene, generated in this case from 2-bromo-

propene by halogen–metal exchange using tert-butyllithium,

gave the epimeric alcohols 63. Alternatively, on a small

Scheme 7 Reagents and conditions: i, dimethyl sulfoxide, oxalyl

chloride, Ϫ50 ЊC, then triethylamine; ii, 2-bromopropene, tert-

butyllithium (75% from 51); iii, acryloyl chloride, triethylamine (83%);

iv, tricyclohexylphosphine (cat.), trimethylsilyl chloride, DBU,

acetonitrile, 75 ЊC (96%); v, diazomethane (85%); vi, diisobutyl-

aluminium hydride (90%).

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scale, the aldehyde was reacted with 2-bromopropene and

chromium() chloride.¹⁸Esteriﬁcation of the alcohols 63 with

acryloyl chloride gave the esters 64 which on treatment with

tricyclohexylphosphine, trimethylsilyl chloride, and DBU in

acetonitrile at 75 ЊC, gave the rearranged acid 65 in excellent

yield (96%). Reduction of the corresponding methyl ester 66

gave the allylic alcohol 67. The ester 66 and alcohol 67 have

the same carbon skeleton as the C(3)–C(15) fragment of gal-

bonolide B 2 and are promising advanced intermediates for

incorporation into a synthesis of the natural product.

Two problems have to be addressed for a conversion of either

the ester 66 or alcohol 67 into galbonolide B; the stereoselective

introduction of the vicinal diol unit, and the chain extension to

compete the assembly of the carbon framework. Moreover the

sensitivity of the natural product to both acid and base¹will

determine the conditions allowable for any ﬁnal deprotection.

It was considered that stereoselective epoxidation–epoxide-

opening could be used for the introduction of the vicinal diol

moiety and this approach was shown to be feasible by Sharpless

epoxidation of the allylic alcohol 67.¹⁹The use of -(ϩ)- and

-(Ϫ)-diethyl tartrate gave rise to the (S)- and (R)-epoxides 68

1

and 69 which were distinguishable by H NMR spectroscopy.

Scheme 8 Reagents and conditions: i, titanium tetraisopropoxide, 3 Å

sieves, tert-butyl hydroperoxide, D-(Ϫ)-diethyl tartrate (62%); ii,

PhNCO (71, 73%); iii, benzyl chloroformate (72, 90%); iv, 5% aq.

HClO₄(45% from 71) or aluminium trichloride, dichloromethane

(76% from 72); v, (2-trimethylsilylethoxy)methyl chloride, Hunig’s

base (52%); vi, lithium hydroxide, dimethoxyethane, water (81%);

vii, dimethyl sulfoxide, oxalyl chloride then triethylamine (46%).

Excellent stereoselectivities were observed in these epoxidations

with only traces of the minor diastereoisomer being obtained in

each case. As preliminary studies into the ring-opening of these

epoxides using oxygen nucleophiles were not successful, model

studies were carried out at this juncture using the epoxides 70

prepared from the allylic alcohol 61, see Scheme 8. As the start-

ing alcohol was racemic, these epoxides were obtained as a 1:1

mixture of epimers at C(6), which could not be separated, but

this mixture was used since it was felt that the remote chiral

centre would have little eﬀect on the chemistry of the epoxide.

The epoxides 70 were converted into the carbamate 71²⁰and

the carbonate 72.²¹The Lewis acid induced ring-opening reac-

tions of these were then studied as a route to the dioxolanone

73. The choice of solvent was found to be important in these

reactions. Aluminium trichloride, boron triﬂuoride–diethyl

ether and diethylaluminum chloride all gave the dioxolanone 73

in yields of 40–45% from the benzyl carbonate 72 if ether was

used as the solvent, a similar yield being obtained from the

carbamate 71 using perchloric acid in acetonitrile. However

better yields were obtained in dichloromethane, for example a

76% yield of the dioxolanone 73 was obtained from the benzyl

carbonate 72 using aluminium chloride in this solvent and 69%

was obtained using boron triﬂuoride–diethyl ether. The struc-

ture of the dioxolanone 73 was assigned on the basis of its

spectroscopic data with the conﬁguration at the tertiary centre

being assigned by analogy with literature reactions.^20,21Protec-

tion of the hydroxymethyldioxolanone gave the (2-trimethylsilyl-

ethoxy)methyl ether 74 which was hydrolysed to the diol 75.

This in turn was oxidized to the aldehyde 76 which structur-

ally corresponds to the vicinal diol containing the C(3)–C(8)

fragment of galbonolide B.

ammonium perruthenate (TPAP)²²gave the aldehyde 78 and

addition of the lithium enolate generated from tert-butyl acet-

ate using lithium hexamethyldisilazide gave the aldol adducts

79 as a mixture of epimers at C(3) (Scheme 9). These were

protected as their tert-butyldiphenylsilyl ethers 80 as it was

expected that removal of the tert-butyldimethylsilyl ether from

C(13) would be faster than removal of the tert-butyldiphenyl-

silyl ether from C(3) so providing access to cyclisation pre-

cursors. However, this was not found to be the case. After

cleavage of the tert-butyl ester, deprotection of the hydroxy

group at C(3) by cleavage of the tert-butyldiphenylsilyl ether

was faster than deprotection at C(13). Indeed deprotection of

the tert-butyldimethylsilyl ether from C(13) required prolonged

treatment with an excess of tetrabutylammonium ﬂuoride.

Other protecting groups were screened for protection of the

C(3)-hydroxy group. The alcohol 79 was converted into its (2-

trimethylsilylethoxy)methyl ether 81, but subsequent cleavage

of the tert-butyl ester using trimethylsilyl triﬂate and tri-

ethylamine to obtain the free acid, was accompanied by elimin-

ation of the 3-substituent and gave the α,β-unsaturated acid 86

(68%) as the major product. However, after protection of the 3-

hydroxy group as its p-methoxyphenoxymethyl ether 82,²³

cleavage of the tert-butyl ester gave some of the required bis-

protected dihydroxy acid 83 (35%), although the elimination

product 86 was still obtained as a signiﬁcant by-product (30%).

Selective mono-deprotection of the tert-butyldimethylsilyl ether

83 by treatment with tetrabutylammonium ﬂuoride then gave

the hydroxy acid 84 which was cyclised to the macrolide 85

using the modiﬁed Yamaguchi method²⁴in a yield of 43%.

At this stage, it was decided to investigate procedures for the

addition of the three remaining carbons to complete the syn-

thesis of the carbon skeleton of galbonolide B. Preliminary

attempts to eﬀect stereoselective aldol reactions of the alde-

hydes 76 or 77, prepared by oxidation of the hydroxy epoxide

70, using enol borinates gave rise to complex mixtures of prod-

ucts. However, oxidation of the alcohol 67 using tetrapropyl-

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on Bruker AC300 (300 MHz), Varian XL300 (300 MHz) and

Varian Gemini 200 (200 MHz) spectrometers, carbon nuclear

magnetic resonance spectra were recorded on Bruker AC300

(75 MHz) and Varian Gemini 200 (50 MHz) spectrometers, and

ﬂuorine nuclear magnetic resonance spectra were recorded on a

Varian Unity 500 (470 MHz) spectrometer, respectively, in

chloroform-d₁, unless otherwise stated. Mass spectra were

recorded on Kratos MS25, Kratos Concept and Fisons VG Trio

2000 mass spectrometers using electron impact (E.I.), chemical

ionisation (C.I.), fast atom bombardment (FAB) and electro-

spray (ESP) techniques. Infrared spectra were recorded on a

Perkin-Elmer 1710 FTIR spectrometer as either an evaporated

ﬁlm or liquid ﬁlm on sodium chloride plates unless otherwise

stated.

Flash column chromatography was carried out using Merck

silica gel 60H (40–60 µm, 230–300 mesh) or May and Baker

sorbsil C60 silica gel as the stationary phase. Analytical high

pressure liquid chromatography (HPLC) was performed using a

C18 Novapak cartridge (8 mm × 10 cm) with a Perkin-Elmer

diode array system for detection. Melting points were recorded

on a Köﬂer heated stage microscope and are uncorrected.

Optical rotations were measured on an Optical Activity AA-

100 polarimeter operating at 589 nm.

Light petroleum refers to the fraction with bp 40–60 ЊC

and was redistilled before use. Ether refers to diethyl ether. All

solvents were distilled and puriﬁed by standard procedures.

2-Methyl-2-(1-hydroxypropyl)-1,3-dithiane 12²⁵(2.4 g, 66%)

was prepared from 2-methyl-1,3-dithiane (2.5 g, 18.6 mmol)

using s-butyllithium (1.3 M in cyclohexane; 17 cm³, 22.3 mmol)

as base (Ϫ20 ЊC; 2 h). Methyl (R)-3-(4-methoxybenzyloxy)-

2-methylpropanoate 35²⁶(5.5 g, 78%) was prepared from

4-methoxybenzyl 2,2,2-trichloroacetimidate (16 g, 59.1 mmol)

and methyl (R)-3-hydroxy-2-methylpropanoate (3.5 g, 29.6

mmol) in hexane–dichloromethane (6:1) at 0 ЊC and had

[α]_D²⁰Ϫ9.8 (c 1.0, CHCl₃). Methyl (2R)-2-methyl-3-phenyl-

thiopropanoate 44 (22.3 g, 96%) prepared according to the

published procedure²⁷had [α]_D²²66.6 (c 1, CHCl₃) {lit.,²⁷

[α]_D²²64.3 (c 1.59, CHCl₃)} and was reduced using lithium

aluminium hydride to (2R)-2-methyl-3-phenylthiopropan-1-ol

45²⁸(17.6 g, 91%) with [α]_D²³Ϫ13 (c 2.2, CHCl₃) {lit.,²⁸[α]_D

Ϫ18.9 (c 3.9, CH₂Cl₂)}. 2-Methyl-4-phenylpent-1-en-3-ol 54¹⁷

(9.76 g, 80%) was prepared as a 4.9:1 mixture of diastereo-

isomers by the addition of prop-2-enyllithium, from s-butyl-

Scheme 9 Reagents and conditions: i, TPAP, N-morpholine N-oxide,

3 Å sieves (81%); ii, lithium hexamethyldisilazide–tert-butyl acetate,

Ϫ78 ЊC (88%); iii, tert-butyldiphenylsilyl chloride, imidazole (93%);

iv, (2-trimethylsilylethoxy)methyl chloride, Hunig’s base (87%); v,

p-MeOC₆H₄OCH₂Cl, Hunig’s base (66%), vi, trimethylsilyl triﬂate,

triethylamine (83, 35%; 86, 30%); vii, Bu₄NF (69%); viii, 2,6-dichloro-

benzoyl chloride, triethylamine, then 4-N,N-dimethylaminopyridine,

toluene, 95 ЊC (43%).

lithium (1.3

M

in cyclohexane; 63.6 cm³, 82.7 mmol)

Conclusions

and 2-bromopropene (10 g, 82.7 mmol) in tetrahydrofuran

(500 cm³) at Ϫ78 ЊC, to 2-phenylpropanal 53 (9.1 cm³, 68.9

mmol).

The work outlined in this paper provides a basis for a proposed

synthesis of galbonolide B. Aspects of general interest include

the development of the highly stereoselective chelation con-

trolled addition of ethylmagnesium bromide to the aldehyde 23,

the completion of the convergent synthesis of the diene 51, the

use of the phosphine promoted Ireland–Claisen rearrangement

for the eﬃcient synthesis of the tetraene 67, the development of

the ring-opening of the hydroxy epoxide 70 leading to the

mono-protected dihydroxy aldehyde 76, and the completion of

the synthesis of the macrocyclic analogue 85 of galbonolide B.

The convergent synthesis of the C(7)–C(15) fragment 51 makes

this intermediate available in signiﬁcant quantities. The phos-

phine induced Ireland–Claisen rearrangement provides a swift

access to the tetraene 67 and modiﬁcation of the epoxide 68

following the chemistry used in the synthesis should give access

to the fully functionalised C(3)–C(15) part of galbonolide B

including the vicinal diol containing component. Conditions

have been found for the ﬁnal stages of a synthesis including

assembly of the macrocyclic ring. Further work in this area

would concentrate on improvements to the protecting group

strategy and completion of the synthesis.

2-Methyl-2-[1-(4-methoxybenzoyloxy)propyl]-1,3-dithiane 13

Sodium hydride (60% w/w in mineral oil; 624 mg, 15.6 mmol)

was washed twice with dry hexane under an inert atmosphere

and the remainder of the hexane removed with a stream of

argon. Tetrahydrofuran (40 cm³) and alcohol 12 (2.0 g, 10.4

mmol) in tetrahydrofuran (2 cm³) were added. After stirring for

2 h the reaction mixture was cooled to 0 ЊC and 4-methoxy-

benzyl chloride (1.7 cm³, 12.5 mmol), tetrabutylammonium

iodide (770 mg, 2.08 mmol) and N,N-dimethylformamide

(1 cm³) were added and the mixture stirred for 24 h. Water and

ether were added, the two phases separated and the organic

phase washed with brine. The aqueous phases were extracted

with ether and the organic phases dried (MgSO₄). Concen-

tration under reduced pressure and ﬂash chromatography of

the residue [light petroleum:ether (10:1)] gave the title com-

pound 13 (2.5 g, 77%) as a colourless oil (Found: M^ϩϩ H,

313.1309. C₁₆H₂₅O₂S₂requires M, 313.1296); ν_max/cm^Ϫ11613,

1587, 1515, 1250, 1077 and 1036; δ_H1.06 (3 H, t, J 8, CH₂CH₃),

1.61 (4 H, m, 2-CH₃, CHHCH₃), 1.99 (3 H, m, 5-H₂,

CHHCH₃), 2.86 (4 H, m, 4-H₂, 6-H₂), 3.63 (1 H, dd, J 9.5, 2.5,

CHO), 3.81 (3 H, s, OCH₃), 4.59 and 4.89 (each 1 H, d, J 10,

Experimental

Proton nuclear magnetic resonance spectra were recorded

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

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ArCHH) and 6.88 and 7.36 (each 2 H, d, J 8.5, ArH); m/z (C.I.)

313 (M^ϩϩ 1, 40%), 133 (100) and 121 (99).

4.48 (each 1 H, d, J 11.5, ArCHH), 6.32 (1 H, s, 2-H) and 6.88

and 7.27 (each 2 H, d, J 8.5, ArH); m/z (C.I.) 308 (M^ϩϩ 1,

23%), 280 (56), 263 (40) and 121 (100).

3-(4-Methoxybenzyloxy)pentan-2-one 14

(6E)-8-(4-Methoxybenzyloxy)-7-methyldec-6-en-5-one 17

Calcium carbonate (60 mg, 0.64 mmol) and mercury() chlor-

ide (350 mg, 1.28 mmol) were added to the dithiane 13 (200 mg,

0.64 mmol) in 80% aqueous methanol (10 cm³) and the reaction

mixture heated under reﬂux for 4 h. After cooling to room tem-

perature, the white solids were ﬁltered oﬀ and the solvent

removed under reduced pressure. The residue was dissolved in

ether and washed with brine, saturated aqueous ammonium

chloride and water, and dried (MgSO₄). The solvent was

removed under reduced pressure to give the title compound

14 (121 mg, 85%) as a colourless oil (Found: M^ϩ, 222.1255.

C₁₃H₁₈O₃requires M, 222.1256); ν_max/cm^Ϫ11714, 1613, 1514,

1249 and 1034; δ_H0.94 (3 H, t, J 7.5, 5-H₃), 1.70 (2 H, m, 4-H₂),

2.16 (3 H, s, 1-H₃), 3.68 (1 H, t, J 6.5, 3-H), 3.81 (3 H, s, OCH₃),

4.38 and 4.51 (each 1 H, d, J 11.5, ArCHH) and 6.89 and 7.27

(each 2 H, d, J 8.5, ArH); m/z (E.I.) 222 (M^ϩ, 9%), 221 (10), 137

(32) and 121 (100).

n-Butyllithium (1.6 M in hexanes; 0.56 cm³, 0.9 mmol) was

added slowly to the amide 16 (230 mg, 0.748 mmol) in tetra-

hydrofuran (10 cm³) at 0 ЊC. The reaction mixture was stirred

for 0.5 h and then poured into ethanolic hydrogen chloride (5%;

10cm³).Themixturewaspartitionedbetweenbrineanddichloro-

methane–ether (1:1). The organic phase was dried (MgSO₄)

and concentrated under reduced pressure. Flash chromato-

graphy of the residue [light petroleum:ether (8:1)] gave the

title compound 17 (114 mg, 50%) as a colourless oil (Found:

M^ϩϩ H, 305.2129. C₁₉H₂₉O₃requires M, 305.2117); ν_max/cm^Ϫ1

1690, 1616, 1514, 1249, 1070 and 1036; δ_H0.91 (6 H, m, 1-H₃,

10-H₃), 1.33 (2 H, m, 9-H₂), 1.56 (4 H, m, 2-H₂, 3-H₂), 2.07

(3 H, d, J 1, 7-CH₃), 2.47 (2 H, t, J 7.5, 4-H₂), 3.60 (1 H, t, J 6.5,

8-H), 3.81 (3 H, s, OCH₃), 4.20 and 4.44 (each 1 H, d, J 11.5,

ArCHH), 6.23 (1 H, s, 6-H) and 6.88 and 7.24 (each 2 H, d,

J 8.5, ArH); m/z (C.I.) 305 (M^ϩϩ 1, 18%), 227 (6), 185 (10), 167

(28), 137 (38) and 121 (100).

Ethyl (2E)-4-(4-methoxybenzyloxy)-3-methylhex-2-enoate 15

Sodium hydride (60% w/w in mineral oil; 72 mg, 1.8 mmol) was

washed with dry hexane under an inert atmosphere and the

remainder of the solvent removed with a stream of argon. Ben-

zene (7.5 cm³) was added and then triethyl phosphonoacetate

(0.36 cm³, 1.80 mmol) and the reaction mixture stirred for 1 h.

Ketone 14 (400 mg, 1.80 mmol) in benzene (2 cm³) was added

and the reaction mixture heated to 60 ЊC for 2 h. The mixture

was cooled to room temperature, saturated aqueous ammo-

nium chloride was added and the mixture was extracted twice

with dichloromethane. The extracts were washed with brine,

dried (MgSO₄) and concentrated under reduced pressure. Flash

chromatography of the residue [light petroleum: ether (8:1)]

gave the title compound 15 (413 mg, 79%) as a colourless

oil containing ca. 10% of its (Z)-isomer (Found: M^ϩϩ NH₄,

310.2031. C₁₇H₂₈NO₄requires M, 310.2018); ν_max/cm^Ϫ11718,

1650, 1613, 1515, 1250, 1218, 1173 and 1037; δ_H0.88 (3 H, t,

J 8, 6-H₃), 1.31 (3 H, t, J 7.5, CH₃CH₂O), 1.62 (2 H, m, 5-H₂),

2.11 (3 H, d, J 1, 3-CH₃), 3.63 (1 H, t, J 7, 4-H), 3.81 (3 H, s,

OCH₃), 4.19 (3 H, m, CH₃CH₂O, ArCHH), 4.43 (1 H, d, J 11.5,

ArCHH), 5.85 (1 H, s, 2-H) and 6.87 and 7.24 (each 2 H, d,

J 7.5, ArH); δ_C10.1, 14.0, 14.3, 26.8, 55.3, 59.8, 70.4, 85.3,

113.8, 117.4, 129.4, 130.4, 158.2, 159.2, 166.5; m/z (C.I.) 310

(M^ϩϩ 18, 76%), 293 (M^ϩϩ 1, 10) and 121 (100). Selected

peaks for the minor (Z)-isomer; δ_H0.94 (3 H, t, J 8, 6-H₃), 12.6

(3 H, t, J 7.5, CH₃CH₂O), 1.88 (3 H, s, 3-CH₃), 3.79 (3 H, s,

OCH₃). Unchanged starting material 14 (84 mg, 21%) was also

recovered.

(4E)-3-(4-Methoxybenzyloxy)-4-methyl-6-methylenedec-4-ene

18

n-Butyllithium (1.6 M in hexanes; 0.308 cm³, 0.493 mmol) was

added to methyl(triphenyl)phosphonium bromide (176 mg,

0.492 mmol) suspended in ether (1 cm³) at 0 ЊC. The reaction

mixture was stirred for 1 h and then the ketone 17 (30 mg, 98.7

µmol) in ether (0.2 cm³) was added. The reaction mixture was

stirred for 2 h then water was added and the mixture extracted

with pentane. The extract was washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. Flash

chromatography of the residue [light petroleum:ether (20:1)]

gave the title compound 18 (22 mg, 74%) as a colourless oil

(Found: M^ϩϩ H, 303.2336. C₂₀H₃₁O₂requires M, 303.2324);

ν_max/cm^Ϫ11613, 1514, 1248, 1069 and 1038; δ_H0.91 (6 H, m,

1-H₃, 10-H₃), 1.20–1.70 (6 H, m, 2-H₂, 8-H₂, 9-H₂), 1.74 (3 H, d,

J 1, 4-CH₃), 2.13 (2 H, t, J 6.5, 7-H₂), 3.57 (1 H, t, J 7, 3-H), 3.81

(3 H, s, OCH₃), 4.19 and 4.43 (each 1 H, d, J 11.5, ArCHH),

4.87 and 5.04 (each 1 H, m, 1Ј-H), 5.77 (1 H, s, 5-H) and 6.88

and 7.26 (each 2 H, d, J 8.5, ArH); m/z (E.I) 303 (M^ϩϩ 1, 6%),

302 (M^ϩ, 7) and 244 (7).

2-Methylpropyl (R)-2-(benzyloxymethoxy)propanoate 22

Benzyl chloromethyl ether (120 g, 0.769 mol), distilled before

use, was slowly added to 2-methylpropyl (R)-(ϩ)-lactate (75 g,

0.513 mol) and diisopropylethylamine (274 cm³, 1.54 mol)

cooled to 0 ЊC. The reaction mixture was allowed to warm to

room temperature, stirred for 18 h, then diluted with dichloro-

methane and washed with aqueous hydrogen chloride (3 M)

and dried (MgSO₄). Concentration under reduced pressure

gave the title compound 22 (143 g) as a colourless oil. For

large scale synthesis this material was used without further

puriﬁcation. Flash chromatography for characterisation [light

petroleum:ether (10:1)] gave the title compound 22 (typically

72%) as a colourless oil, [α]_D²⁰69 (c 1.4, CHCl₃) (Found: M^ϩ,

266.1519. C₁₅H₂₂O₄requires M, 266.1518); ν_max/cm^Ϫ11750,

1498, 1176, 1122, 1083, 1050 and 1026; δ_H0.93 [6 H, d, J 6.5,

HC(CH₃)₂], 1.45 (3 H, d, J 6.5, 3-H₃), 1.94 (1 H, m, 2Ј-H), 3.91

(2 H, m, 1Ј-H₂), 4.33 (1 H, q, J 6.5, 2-H), 4.65 (2 H, s, ArCH₂),

4.84 (2 H, s, OCH₂O) and 7.34 (5 H, m, ArH); δ_C19.1, 19.5,

28.2, 70.4, 71.4, 72.0, 94.4, 128.2, 128.4, 128.9, 138.2 and 173.6;

m/z (C.I.) 284 (M^ϩϩ 18, 88%), 267 (M^ϩϩ 1, 22), 254 (23), 159

(73) and 91 (100).

(2E)-N-Methoxy-N-methyl-4-(4-methoxybenzyloxy)-3-methyl-

hex-2-enamide 16

Trimethylaluminium (2 M in toluene; 1.5 cm³, 3 mmol) was

added slowly to N,O-dimethylhydroxylamine hydrochloride

(300 mg, 3 mmol) suspended in benzene (3 cm³) at ca. 5 ЊC. The

reaction was stirred for 1 h until no further gas was evolved.

This solution (3.0 cm³, 2.01 mmol) was added to the ester

15 (300 mg, 1.02 mmol) in benzene (10 cm³) and the mixture

heated under reﬂux for 1 h then cooled to 0 ЊC and aqueous

hydrogen chloride (5%) was added carefully. The mixture was

extracted with ether and the extracts dried (MgSO₄). Concen-

tration under reduced pressure and ﬂash chromatography of

the residue [light petroleum:ether (8:1)] gave the title com-

pound 16 (190 mg, 62%) as a colourless oil (Found: M^ϩϩ H,

308.1857. C₁₇H₂₆NO₄requires M, 308.1862); ν_max/cm^Ϫ11658,

1638, 1613, 1514, 1249 and 1035; δ_H0.90 (3 H, t, J 8, 6-H₃), 1.63

(2 H, m, 5-H₂), 2.10 (3 H, d, J 1, 3-CH₃), 3.24 (3 H, s, N-CH₃),

3.68 (4 H, m, N-OCH₃, 4-H), 3.80 (3 H, s, ArOCH₃), 4.22 and

Diisobutylaluminium hydride (1 M in hexane; 29.3 cm³, 29.3

mmol) was added dropwise over 45 min to the ester 22 (6.5 g,

24.4 mmol) in hexane (210 cm³) at Ϫ78 ЊC. The reaction

3546

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

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mixture was stirred for 1.5 h then water (10 cm³) was added.

The reaction mixture was warmed to room temperature and the

two layers separated. The organic layer was dried (MgSO₄) and

the solvent removed under reduced pressure. Flash chroma-

tography of the residue [light petroleum:ether (8:1–4:1)] gave

(R)-2-benzyloxymethoxy)propanal 23²⁶(3.55 g, 75%) as a

colourless oil, [α]_D²⁰15.0 (c 0.86, CHCl₃) {lit.,²⁹for the (S)-

enantiomer, [α]_D²⁰Ϫ22.7 (c 2.3 in tetrahydrofuran)} (Found:

5.96 (1 H, s, 2-H) and 7.42 (10 H, m, ArH); δ_C9.7, 16.2, 20.7,

23.1, 69.4, 73.8, 74.7, 79.0, 93.8, 127.7, 127.8, 127.9, 128.4,

128.8, 129.3, 133.9, 137.8, 168.7 and 170.4; m/z (C.I.) 418

(M^ϩϩ 18, 63%), 360 (19), 326 (30), 298 (45) and 106 (100).

(2R,3R)-2-(Benzyloxymethoxy)-3-tert-butyldimethylsilyloxy-

pentane 27

tert-Butyldimethylsilyl chloride (42 g, 0.278 mol) was added to

a solution of imidazole (39.5 g, 0.58 mol) and the alcohol 24 (52

g, 0.232 mol) in N,N-dimethylformamide (180 cm³) at 0 ЊC. The

reaction mixture was stirred for 36 h then diluted with hexane,

washed with brine and dried (MgSO₄). Concentration under

reduced pressure and ﬂash chromatography of the residue [light

petroleum:ether (50:1)] gave the title compound 27 (73.5 g,

94%) as a colourless oil, [α]_D²⁰18.9 (c 1.88, CHCl₃) (Found:

M^ϩϩ NH₄, 212.1277. C₁₁H₁₈NO₃requires M, 212.1287); ν_max

/

cm^Ϫ11736, 1381, 1179 and 1041; δ_H1.34 (3 H, d, J 7, 3-H₃), 4.12

(1 H, qd, J 7, 1, 2-H), 4.65 and 4.75 (each 1 H, d, J 11.5,

ArCHH), 4.88 (2 H, s, OCH₂O), 7.32 (5 H, m, ArH) and 9.65

(1 H, d, J 1, 1-H); m/z (C.I.) 212 (M^ϩϩ 18, 100%), 184 (32), 108

(77) and 91 (91).

M^ϩϩ H, 339.2358. C₁₉H₃₅O₃Si requires M, 339.2355); ν_max

/

(2R,3R)-2-(Benzyloxymethoxy)pentan-3-ol 24

cm^Ϫ11463, 1256, 1154, 1115, 1044, 836 and 775; δ_H0.05 [6 H, s,

Si(CH₃)₂], 0.89 [12 H, m, SiC(CH₃)₃, 5-H₃], 1.35 (3 H, d, J 6.5,

1-H₃), 1.50 (2 H, m, 4-H₂), 3.59 (1 H, m, 3-H), 3.73 (1 H, m,

2-H), 4.62 (2 H, s, ArCH₂), 4.81 (2 H, s, OCH₂O) and 7.35 (5 H,

m, ArH); δ_CϪ4.6, Ϫ4.4, 10.6, 15.4, 18.6, 24.7, 26.2, 26.4, 69.9,

76.3, 76.7, 94.6, 128.1, 128.3, 128.9, 138.5; m/z (C.I.) 339

(M^ϩϩ 1, 10%) and 231 (52).

Zinc bromide (44 g, 0.196 mol) was suspended in ether (350

cm³) and the mixture cooled to 0 ЊC. Ethylmagnesium bromide

(3 M in ether; 65.3 cm³, 0.196 mol) was added and the reaction

mixture stirred for 0.5 h before being added via cannula to the

aldehyde 23 (19 g, 97.9 mmol) in ether (350 cm³) cooled to 0 ЊC.

A white precipitate formed on addition. After 25 min, an excess

of ethylmagnesium bromide (3 M in ether, 130.7 cm³, 0.392 mol)

was added and the reaction mixture stirred for 4 h. After cool-

ing to Ϫ40 ЊC, water (70 cm³) was added and the reaction mix-

ture was allowed to warm slowly to room temperature over a

period of several hours. The white solids were ﬁltered oﬀ and

the ﬁltrate concentrated under reduced pressure. HPLC indi-

cated that the ratio of syn:anti-products was 94:6. Distillation

of the residue through a Vigreux column (10 cm) gave the title

compound 24 (14.3 g, 65%) as a colourless oil, bp 92–96 ЊC (0.1

mmHg) [α]_D²⁰Ϫ34.2 (c 1.12, CHCl₃) (Found: M^ϩϩ H, 225.1502.

C₁₃H₂₁O₃requires M, 225.1491); ν_max/cm^Ϫ13459, 1454, 1151,

1106 and 1043; δ_H1.01 (3 H, t, J 7.5, 5-H₃), 1.21 (3 H, d, J 6.5,

1-H₃), 1.52 (2 H, m, 4-H₂), 2.61 (1 H, d, J 4, OH), 3.37 (1 H, m,

3-H), 3.64 (1 H, m, 2-H), 4.62 and 4.69 (each 1 H, d, J 11.5,

ArCHH), 4.82 and 4.88 (each 1 H, d, J 7, OCHHO) and 7.34

(5 H, m, ArH); δ_C10.4, 17.3, 26.4, 70.3, 76.7, 78.0, 94.3, 128.3,

128.4, 129.0 and 138.0; m/z (C.I.) 242 (M^ϩϩ 18, 9%).

(S)-(ϩ)-Acetylmandelic acid (21 mg, 0.107 mmol), 4-

(dimethylamino)pyridine (1 mg) and 1,3-dicyclohexylcarbo-

diimide (20 mg, 96.9 µmol) were added to the alcohol 24

(20 mg, 89.3 µmol) in dichloromethane (1 cm³) cooled to 0 ЊC.

The reaction mixture was allowed to warm to room temper-

ature, stirred for 17 h, then ﬁltered and washed with aqueous

hydrochloric acid (3 M), saturated aqueous sodium hydro-

gen carbonate and dried (MgSO₄). Concentration under

reduced pressure and ﬂash chromatography of the residue [light

petroleum:ether (3:1)] gave (2R,3R)-2-(benzyloxymethoxy)-

pentan-3-yl (S)-2-acetylmandelate 25 (15 mg, 42%) as a colour-

less oil (Found: M^ϩϩ NH₄, 418.2237. C₂₃H₃₂NO₆requires M,

418.2230); ν_max/cm^Ϫ11746, 1628, 1234, 1180 and 1045; δ_H0.59

(3 H, t, J 7.5, 5Ј-H₃), 1.23 (3 H, d, J 6.5, 1Ј-H₃), 1.57 (2 H, m,

4Ј-H₂), 2.24 (3 H, s, CH₃CO), 3.91 (1 H, m, 2Ј-H), 4.68 (2 H, s,

ArCH₂), 4.82 and 4.86 (each 1 H, d, J 7, OCHHO), 4.93 (1 H,

m, 3Ј-H), 5.95 (1 H, s, 2-H) and 7.42 (10 H, m, ArH); δ_C9.2,

16.2, 20.7, 22.9, 69.6, 73.4, 74.7, 79.0, 93.7, 127.7, 127.8, 128.4,

128.7, 129.2, 133.9, 138.0, 168.9 and 170.3; m/z (C.I.) 418

(M^ϩϩ 18, 100%), 326 (18) and 298 (29).

(2R,3R)-3-tert-Butyldimethylsilyloxypentan-2-ol 28

A mixture of the benzyloxymethyl ether 27 (14 g, 41.4 mmol)

and palladium on carbon (10%; 2.1 g) in acetic acid–ethanol

(95%) (200 cm³; 15:85) was shaken under an atmosphere of

hydrogen at 60 psi for 24 h. The reaction mixture was then

ﬁltered through a small pad of charcoal on top of a pad of

Celite,^washing the reaction vessel three times with ethanol

(95%). The ﬁltrate was concentrated under reduced pressure

and the residue dissolved in ether, washed with saturated

aqueous sodium hydrogen carbonate and dried (MgSO₄). The

solvent was removed under reduced pressure and ﬂash chrom-

atography of the residue [light petroleum:ether (10:1)] gave the

title compound 28 (8.45 g, 94%) as a colourless oil, [α]_D²⁰Ϫ21.2

(c 1.28, CHCl₃) (Found: M^ϩϩ H, 219.1774. C₁₁H₂₇O₂Si

requires M, 219.1780); ν_max/cm^Ϫ13425, 1464, 1362, 1256, 1094,

1065, 1013, 940, 895, 863, 838 and 775; δ_H0.09 [6 H, s,

Si(CH₃)₂], 0.88 (3 H, t, J 7.5, 5-H₃), 0.91 [9 H, s, SiC(CH₃)₃],

1.13 (3 H, d, J 6.5, 1-H₃), 1.58 (2 H, m, 4-H₂), 2.11 (1 H, br s,

OH), 3.38 (1 H, dt, J 6, 5, 3-H) and 3.67 (1 H, dq, J 6.5, 5, 2-H);

δ_CϪ4.6, Ϫ4.2, 9.5, 15.8, 18.6, 20.1, 26.4, 26.8, 69.0 and 78.2;

m/z (C.I.) 236 (M^ϩϩ 18, 8%) and 219 (9).

(3R)-3-tert-Butyldimethylsilyloxypentan-2-one 29

Dimethyl sulfoxide (3.4 cm³, 48 mmol) in dichloromethane (10

cm³) was added dropwise to oxalyl chloride (2.1 cm³, 24 mmol)

in dichloromethane (45 cm³) cooled to below Ϫ50 ЊC. The reac-

tion mixture was stirred for 2 min and then the alcohol 28 (3.5

g, 16 mmol) in dichloromethane (20 cm³) was added slowly. The

reaction mixture was stirred for 15 min, triethylamine (8.1 cm³,

100 mmol) was added and the reaction mixture was allowed to

warm to room temperature before water (25 cm³) was added.

The organic layer was washed with brine, dried (MgSO₄) and

concentrated under reduced pressure to give the title compound

29 (3.38 g, 98%) as a pale yellow liquid, [α]_D²⁰39.8 (c 0.72, CHCl₃)

(Found: M^ϩϩ H, 217.1626. C₁₁H₂₅O₂Si requires M, 217.1624);

ν_max/cm^Ϫ11719, 1464, 1390, 1255, 1131, 1019, 839 and 778;

δ_H0.06 and 0.07 (each 3 H, s, SiCH₃), 0.91 (3 H, t, J 7.5, 5-H₃),

0.93 [9 H, s, SiC(CH₃)₃], 1.63 (2 H, m, 4-H₂), 2.16 (3 H, s, 1-H₃)

and 3.93 (1 H, t, J 6.5, 3-H); m/z (C.I.) 234 (M^ϩϩ 18, 82%) and

217 (M^ϩϩ 1, 100).

Following this procedure, the alcohol 24 (20 mg, 89.3

µmol) and (R)-(Ϫ)-acetylmandelic acid (21 mg, 0.107 mmol),

4-(dimethylamino)pyridine (1 mg) and 1,3-dicyclohexycarbo-

diimide (20 mg, 96.9 µmol) gave (2R,3R)-2-(benzyloxy-

methoxy)pentan-3-yl (R)-2-acetylmandelate 26 (20 mg, 56%) as

a colourless oil (Found: M^ϩϩ NH₄, 418.2225. C₂₃H₃₂NO₆

requires M, 418.2230); ν_max/cm^Ϫ11744, 1232, 1211, 1178 and

1042; δ_H0.99 (6 H, m, 1Ј-H₃, 5Ј-H₃), 1.70 (2 H, m, 4Ј-H₂), 2.24

(3 H, s, CH₃CO), 3.69 (1 H, m, 2Ј-H), 4.44 (2 H, s, ArCH₂), 4.45

and 4.53 (each 1 H, d, J 11.5, OCHHO), 4.91 (1 H, m, 3Ј-H),

Ethyl (2E,4R)-4-tert-butyldimethylsilyloxy-3-methylhex-2-

enoate 30

Sodium hydride (60% w/w in mineral oil; 277 mg, 6.93 mmol)

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

3547

View Article Online

was washed with hexane under an inert atmosphere and the

remainder of the solvent removed with a stream of argon.

Benzene (30 cm³) and triethyl phosphonoacetate (1.4 cm³, 6.93

mmol) were added. The reaction mixture was stirred for 1 h and

then the ketone 29 (1.0 g, 4.62 mmol) in benzene (10 cm³) was

added. After stirring at 60 ЊC for 3 h, the reaction was cooled

and quenched with saturated aqueous ammonium chloride.

The product was extracted with dichloromethane, dried

(MgSO₄) and concentrated under reduced pressure. Flash

chromatography of the residue [light petroleum:ether (50:1)]

gave the title compound 30 (1.18 g, 89%) as a colourless oil, [α]_D²⁰

13.6 (c 0.91, CHCl₃) (Found: M^ϩϩ NH₄, 304.2302. C₁₅H₃₄-

NO₃Si requires M, 304.2308); ν_max/cm^Ϫ11720, 1656, 1464, 1257,

1217, 1156, 1104, 1045, 1018, 837 and 777; δ_H0.04 and 0.08

(each 3 H, s, SiCH₃), 0.88 (3 H, t, J 7.5, 6-H₃), 0.94 [9 H, s,

SiC(CH₃)₃], 1.32 (3 H, t, J 7, CH₃CH₂O), 1.58 (2 H, m, 5-H₂),

2.10 (3 H, d, J 1, 3-CH₃), 4.00 (1 H, t, J 5.5, 4-H), 4.19 (2 H, q,

J 7, CH₃CH₂O) and 5.88 (1 H, s, 2-H); δ_CϪ5.0, Ϫ4.7, 9.5, 14.3,

14.7, 18.2, 25.8, 28.9, 59.6, 78.4, 115.1, 160.8 and 197.0; m/z

(C.I.) 304 (M^ϩϩ 18, 100%) and 287 (M^ϩϩ 1, 24).

406.1841); ν_max/cm^Ϫ11752, 1719, 1655, 1224 and 1123; δ_H0.96

(3 H, t, J 7.5, 6-H₃), 1.32 (3 H, t, J 7, CH₃CH₂O), 1.67 (2 H, m,

5-H₂), 2.07 (3 H, d, J 1, 3-CH₃), 3.61 (3 H, s, OCH₃), 4.19 (2 H,

q, J 7, CH₃CH₂O), 5.28 (1 H, t, J 6.5, 4-H), 5.77 (1 H, s, 2-H)

and 7.37–7.55 (5 H, m, ArH); δ_FϪ72.7 (minor), Ϫ73.0 (major);

m/z (C.I.) 406 (M^ϩϩ 18, 100%).

(S)-3-(4-Methoxybenzyloxy)-2-methylpropan-1-ol 36

Lithium aluminium hydride (2.3 g, 60.6 mmol) was suspended

in ether (120 cm³) and the mixture cooled to 0 ЊC. The methyl

ester 35 (6.9 g, 29.7 mmol) in ether (100 cm³) was added slowly

then the reaction mixture was stirred for 1 h at room temper-

ature. After cooling to 0 ЊC, water (6.3 cm³) and aqueous

sodium hydroxide (10%; 4.8 cm³) were added and the mixture

stirred for 20 min. The white solid was ﬁltered oﬀ and the

ﬁltrate concentrated under reduced pressure to give the title

compound 36 (6.1 g, 98%) as a colourless oil, [α]_D²²Ϫ18.7 (c 1.14,

CHCl₃) (Found: M^ϩϩ NH₄, 228.1599. C₁₂H₁₂NO₃requires M,

228.1600); ν_max/cm^Ϫ13413, 1613, 1587, 1514, 1248, 1090 and

1036; δ_H0.91 (3 H, d, J 7, 2-CH₃), 2.06 (1 H, m, 2-H), 2.78 (1 H,

br s, OH), 3.43 (1 H, m, 3-H), 3.53 (1 H, dd, J 9, 5, 3-HЈ), 3.61

(2 H, m, 1-H₂), 3.83 (3 H, s, OCH₃), 4.48 (2 H, s, ArCH₂) and

6.91 and 7.27 (each 2 H, d, J 8.5, ArH); δ_C14.0, 36.1, 55.7, 68.2,

73.5, 75.5, 114.3, 129.7, 130.6 and 159.7; m/z (C.I.) 228

(M^ϩϩ 18, 11%), 210 (M^ϩ, 5) and 121 (100).

Ethyl (2E,4R)-4-hydroxy-3-methylhex-2-enoate 31 and

conversion to Mosher’s esters 32 and 33

Tetrabutylammonium ﬂuoride (1 M in tetrahydrofuran; 3.5

cm³, 3.49 mmol) was added to the ester 30 (500 mg, 1.75 mmol)

and the reaction mixture stirred for 1.5 h. Water was added and

the two layers separated. The aqueous layer was extracted with

ether and the combined organic phases dried (MgSO₄) and

concentrated under reduced pressure. Flash chromatography

of the residue [light petroleum:ether (5:1)] gave the title

compound 31 (577 mg, 92%) as a colourless oil, [α]_D²⁰Ϫ2.9 (c 1.27,

CHCl₃) (Found: M^ϩϩ H, 173.1182. C₉H₁₇O₃requires M,

173.1178); ν_max/cm^Ϫ13436, 1718, 1654, 1219 and 1157; δ_H0.87

(3 H, t, J 7.5, 6-H₃), 1.24 (3 H, t, J 7, CH₃CH₂O), 1.59 (2 H, m,

5-H₂), 2.05 (3 H, d, J 1, 3-CH₃), 2.58 (1 H, br s, OH), 3.97 (1 H,

t, J 6, 4-H), 4.11 (2 H, q, J 7, CH₃CH₂O) and 5.86 (1 H, s, 2-H);

δ_C10.1, 14.7, 15.2, 28.2, 60.2, 78.2, 115.6, 160.7 and 167.4; m/z

(C.I.) 173 (M^ϩϩ 1, 100%).

(R)-1-Bromo-3-(4-methoxybenzyloxy)-2-methylpropane 37

The alcohol 36 (1.4 g, 6.67 mmol) and triphenylphosphine (1.9

g, 7.24 mmol) in dichloromethane (5 cm³) were cooled to 0 ЊC.

N-Bromosuccinimide (1.3 g, 7.24 mmol) was added portion-

wise, keeping the reaction temperature below 5 ЊC. The reaction

mixture was then warmed to room temperature and stirred for 1

h before being ﬁltered through a column of silica and con-

centrated under reduced pressure. Flash chromatography of the

residue [light petroleum:ether (30:1)] on base washed silica

gave the title compound 37 (1.7 g, 93%) as a colourless oil, [α]_D²²

Ϫ10.6 (c 1.33, CHCl₃) (Found: M^ϩ, 272.0417. C₁₂H₁₇O₂⁷⁹Br

requires M, 272.0412); ν_max/cm^Ϫ11613, 1586, 1514, 1249, 1174,

1094, 1037 and 820; δ_H1.07 (3 H, d, J 7, 2-CH₃), 2.13 (1 H, m,

2-H), 3.37 and 3.52 (each 2 H, m), 3.85 (3 H, s, OCH₃), 4.49

(2 H, s, ArCH₂) and 6.93 and 7.31 (each 2 H, d, J 8.5, ArH);

δ_C16.4, 36.1, 38.8, 55.8, 73.0, 73.4, 114.3, 129.7, 130.9 and

159.9; m/z (E.I.) 274 [M(⁸¹Br)^ϩ, 10%], 272 [M(⁷⁹Br)^ϩ, 10] and

121 (100).

Oxalyl chloride (0.053 cm³, 0.61 mmol) was added to (R)-

(ϩ)-Mosher’s acid (30 mg, 0.128 mmol) and N,N-dimethyl-

formamide (0.015 cm³, 0.19 mmol) in hexane (2.5 cm³) and the

mixture stirred for 1 h. The precipitate was ﬁltered oﬀ and the

ﬁltrate concentrated under reduced pressure to give the (ϩ)-

Mosher’s acid chloride (29 mg, 90%) as a colourless oil; ν_max

/

cm^Ϫ11791, 1452, 1263 and 1133. The alcohol 31 (10 mg, 58.1

µmol), triethylamine (0.04 cm³, 0.172 mmol) and 4-dimethyl-

aminopyridine (<1 mg) in dichloromethane (0.5 cm³) were

added to the (ϩ)-Mosher’s acid chloride (29 mg, 0.125 mmol)

and the mixture was stirred for 3 h. The reaction mixture was

diluted with ether and washed with aqueous hydrogen chloride

(1 M), saturated aqueous sodium hydrogen carbonate, brine,

and dried (MgSO₄). Concentration under reduced pressure gave

the (R)-(ϩ)-Mosher’s ester 32 (29 mg, 90%) as a pale yellow

oil (Found: M^ϩϩ NH₄, 406.1831. C₁₉H₂₇F₃NO₅requires M,

406.1841); ν_max/cm^Ϫ11751, 1719, 1657, 1225, 1163 and 1018;

δ_H0.85 (3 H, t, J 7.5, 6-H₃), 1.32 (3 H, t, J 7, CH₃CH₂O), 1.77 (2

H, m, 5-H₂), 2.16 (3 H, s, 3-CH₃), 3.56 (3 H, s, OCH₃), 4.20 (2

H, q, J 7, CH₃CH₂O), 5.34 (1 H, t, J 6.5, 4-H), 5.89 (1 H, s, 2-H)

and 7.42–7.55 (5 H, m, ArH); δ_FϪ72.7 (major), Ϫ73.0 (minor);

m/z (C.I.) 406 (M^ϩϩ 18, 100%). Alternatively, pyridine (0.009

cm³, 0.116 mmol) was added to the alcohol 31 (10 mg, 58.1

µmol) and (ϩ)-Mosher’s acid chloride (29 mg, 0.116 mmol) in

dichloromethane (0.5 cm³) and the mixture stirred for 1 h.

Work-up as above gave the (R)-(ϩ)-Mosher’s ester 32 (20 mg,

90%).

(R)-1-(4-Methoxybenzyloxy)-2-methyl-3-phenylthiopropane 38

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.72 cm³, 4.83

mmol) and thiophenol (0.5 cm³, 4.83 mmol) were added to

benzene (10 cm³) cooled in an ice–water bath. The bromide

37 (1.1 g, 4.03 mmol) was added dropwise and the reaction

mixture was allowed to warm to room temperature. After

stirring for 2 h the mixture was ﬁltered and the ﬁltrate diluted

with ether, washed with aqueous sodium hydroxide (10%),

aqueous hydrogen chloride (3 M), brine and dried (MgSO₄).

Flash chromatography of the residue [light petroleum:ether

(25:1)] gave the title compound 38 (1.2 g, 96%) as a colourless

oil, [α]_D²³12.5 (c 1.62, CHCl₃) (Found: M^ϩ, 302.1343. C₁₈H₂₂O₂S

requires M, 302.1341); ν_max/cm^Ϫ11612, 1584, 1512, 1246, 1088

and 1033; δ_H1.06 (3 H, d, J 7, 2-CH₃), 2.07 (1 H, m, 2-H), 2.78

(1 H, dd, J 13, 7.5, 3-H), 3.15 (1 H, dd, J 13, 5.5, 3-HЈ), 3.41

(2 H, d, J 6, 1-H₂), 3.81 (3 H, s, OCH₃), 4.42 (2 H, s, ArCH₂),

6.88 (2 H, d, J 8.7, ArH) and 7.33 (7 H, m, ArH); m/z (E.I.) 302

(M^ϩ, 30%), 181 (29) and 121 (100).

(R)-1-(4-Methoxybenzyloxy)-2-methyl-3-phenylsulfonylpropane

39

The alcohol 31 (22 mg, 0.128 mmol) was similarly reacted

with the (Ϫ)-Mosher’s acid chloride (65 mg, 2.57 mmol) to

give the (S)-(Ϫ)-Mosher’s ester 33 (46 mg, 93%) as a colourless

oil (Found: M^ϩϩ NH₄, 406.1831. C₁₉H₂₇F₃NO₅requires M,

The sulﬁde 38 (3.9 g, 12.9 mmol) in methanol (50 cm³) was

cooled to 0 ЊC and oxone^(12 g, 38.7 mmol of active oxidant)

3548

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

View Article Online

in water (50 cm³) was added slowly. The mixture was allowed to

warm to room temperature and stirred for 16 h then concen-

trated under reduced pressure and the resulting slurry diluted

with water and extracted with dichloromethane (×3). The

organic extracts were dried (MgSO₄) and concentrated under

reduced pressure. Flash chromatography of the residue [light

petroleum:ether (3:1)] gave the title compound 39 (3.7 g, 85%)

as a colourless oil, [α]_D¹⁷Ϫ3.4 (c 1.2, CHCl₃) (Found: M^ϩ,

334.1235. C₁₈H₂₂O₄S requires M, 334.1239); ν_max/cm^Ϫ11612,

1586, 1514, 1304, 1247, 1148 and 1085; δ_H1.11 (3 H, d, J 7,

2-CH₃), 2.38 (1 H, m, 2-H), 2.91 (1 H, dd, J 14, 8, 3-H), 3.27

(1 H, dd, J 9.5, 6.5, 1-H), 3.40 (2 H, m, 1-HЈ, 3-HЈ), 3.81 (3 H, s,

OCH₃), 4.35 (2 H, s, ArCH₂), 6.86 and 7.18 (each 2 H, d, J 8.5,

ArH), 7.57 (3 H, m, ArH) and 7.90 (2 H, m, ArH); m/z (E.I.).

334 (M^ϩ, 3%).

as a colourless oil, [α]_D²²10.5 (c 2.18, CHCl₃) (Found: M^ϩϩ H,

435.2926. C₂₅H₄₃O₄Si requires M, 435.2931); ν_max/cm^Ϫ11688,

1617, 1514, 1362, 1249, 1097, 837 and 777; δ_H0.04 and 0.09

(each 3 H, s, SiCH₃), 0.89 (3 H, t, J 7, 9-H₃), 0.95 [12 H, m,

SiC(CH₃)₃, 2-CH₃], 1.40 (2 H, m, 8-H₂), 2.07 (3 H, s, 6-CH₃),

2.34 (2 H, m, 3-H, 2-H), 2.66 (1 H, dd, J 15, 5, 3-HЈ), 3.34 (2 H,

m, 1-H₂), 3.84 (3 H, s, OCH₃), 3.97 (1 H, t, J 5.5, 7-H), 4.46

(2 H, s, ArCH₂), 6.30 (1 H, s, 5-H) and 6.91 and 7.28 (each 2 H,

d, J 8.5, ArH); m/z (C.I.) 435 (M^ϩϩ 1, 1%), 303 (4) and 121

(100).

(2R,5E,7R)-7-tert-Butyldimethylsilyloxy-2,6-dimethyl-1-(4-

methoxybenzyloxy)-4-methylenenon-5-ene 42

n-Butyllithium (1.5 M in hexanes; 4.6 cm³, 6.90 mmol) was

added to methyl(triphenyl)phosphonium bromide (2.5 g, 6.90

mmol) in tetrahydrofuran (56 cm³) at 0 ЊC. The solution was

stirred for 20 min then the enone 41 (1.5 g, 3.45 mmol) in tetra-

hydrofuran (10 cm³) was added. The mixture was allowed to

warm to room temperature and stirred for 3 h then quenched

with water, extracted with pentane, and the organic extracts

dried (MgSO₄) and concentrated under reduced pressure. Flash

chromatography of the residue [light petroleum:ether (50:1)]

gave the title compound 42 (1.14 g, 76%) as a colourless oil, [α]_D²³

37.4 (c 1.09, CHCl₃) (Found: M^ϩϩ H, 433.3106. C₂₆H₄₅O₃Si

requires M, 433.3138); ν_max/cm^Ϫ11613, 1514, 1249, 1040 and

835; δ_H0.04 and 0.08 (each 3 H, s, SiCH₃), 0.86 (3 H, t, J 7,

9-H₃), 0.92 [12 H, m, SiC(CH₃)₃, 2-CH₃], 1.56 (2 H, m, 8-H₂),

1.74 (3 H, d, J 1, 6-CH₃), 1.91 (2 H, m, 2-H, 3-H), 2.30 (1 H, m,

3-HЈ), 3.25 (1 H, dd, J 9, 6, 1-H), 3.33 (1 H, dd, J 9, 5, 1-HЈ),

3.85 (3 H, s, OCH₃), 3.93 (1 H, t, J 6.5, 7-H), 4.46 (2 H, s,

ArCH₂), 4.88 and 5.01 (each 1 H, s, 1Ј-H), 5.74 (1 H, s, 5-H) and

6.91 and 7.30 (each 2 H, d, J 8.5, ArH); δ_CϪ5.0, Ϫ4.6, 10.2,

13.2, 17.0, 18.3, 25.9, 29.2, 32.3, 42.2, 55.3, 72.6, 75.2, 80.1,

113.7, 114.6, 126.0, 129.1, 131.0, 140.4, 144.1 and 159.1; m/z

(C.I.) 433 (M^ϩϩ 1, 2%), 301 (17) and 121 (100).

(2R,5E,7R)-7-tert-Butyldimethylsilyloxy-1-(4-methoxybenz-

yloxy)-2,6-dimethyl-3-phenylsulfonylnon-5-en-4-one 40

1,2-Dibromoethane (1.1 cm³, 12.5 mmol) in benzene (1.5 cm³)

was added to magnesium turnings (365 mg, 15 mmol) in ether

(11 cm³) at a rate to maintain reﬂux, then the reaction mixture

was heated under reﬂux for 1 h to give a solution of magnesium

bromide–diethyl ether (ca. 1 M).

n-Butyllithium (1.2 M in hexanes; 2.5 cm³, 3 mmol) was

added to sulfone 39 (1.0 g, 2.99 mmol) in tetrahydrofuran (21

cm³) at Ϫ78 ЊC. After 10 min, freshly prepared magnesium

bromide–diethyl ether (3.0 cm³, 1 M in ether, 3 mmol) was

added resulting in the formation of a white precipitate. The

reaction mixture was stirred at Ϫ78 ЊC for 45 min and 15 min at

0 ЊC then cooled to Ϫ78 ЊC before addition of the ester 30 (390

mg, 1.36 mmol) in tetrahydrofuran (4 cm³). The reaction

mixture was allowed to warm slowly to room temperature

and stirred for 1 h. Saturated aqueous ammonium chloride

was added and the reaction mixture extracted with ether (×2).

The organic extracts were dried (MgSO₄) and concentrated

under reduced pressure. Flash chromatography of the residue

[light petroleum:ether (3:1)] gave the title compound 40 (749

mg, 96%) as a pale yellow oil, a 1:1 mixture of epimers at

C(3) (Found: M^ϩϩ H, 575.2857. C₃₁H₄₇O₆SSi requires M,

575.2863); ν_max/cm^Ϫ11684, 1614, 1514, 1308, 1250, 1150 and

1084; δ_H0.00, 0.02, 0.08 and 0.1 (each 1.5 H, s, SiCH₃), 0.80 and

0.87 (each 1.5 H, t, J 8, 9-H₃), 0.92 and 0.94 [each 4.5 H, s,

SiC(CH₃)₃], 1.06 (1.5 H, d, J 7, 2-CH₃), 1.43 (3.5 H, m, 2-CH₃,

8-H₂), 1.88 and 1.96 (each 1.5 H, s, 6-CH₃), 2.75 (1 H, m, 2-H),

3.30 (0.5 H, dd, J 9.5, 5, 1-H), 3.39 (0.5 H, dd, J 9.5, 4, 1-H),

3.50 (0.5 H, dd, J 9.5, 5.5, 1-HЈ), 3.66 (0.5 H, dd, J 9.5, 5, 1-HЈ),

3.83 and 3.85 (each 1.5 H, s, OCH₃), 3.93 (1 H, m, 7-H), 4.20–

4.46 (3 H, m, ArCH₂, 3-H), 6.26 and 6.43 (each 0.5 H, s, 5-H),

6.89, 7.23 and 7.52 (each 2 H, m, ArH), 7.64 (1 H, m, ArH) and

7.86 (2 H, m, ArH); m/z (C.I.) 593 (M^ϩϩ 18, 0.4%), 575

(M^ϩϩ 1, 2) and 121 (100).

(2R)-2-Methyl-3-phenylsulfonylpropan-1-ol 46³⁰

m-Chloroperoxybenzoic acid (ca. 50% by mass; 44.6 g, 121

mmol) was suspended in dichloromethane (250 cm³) and cooled

to 0 ЊC. The sulﬁde 45 (11 g, 60.4 mmol) in dichloromethane (50

cm³) was added slowly, keeping the reaction temperature below

25 ЊC. When the addition was complete, the reaction mixture

was stirred for 1 h then aqueous sodium sulﬁte (5%; 60 cm³) was

added and the mixture stirred for 0.5 h. The white solids were

ﬁltered oﬀ and washed with dichloromethane. The organic ﬁl-

trate was washed with aqueous sodium hydroxide (2 M), brine

and dried (MgSO₄). Removal of the solvent under reduced

pressure gave the title compound 46³⁰(12.5 g, 97%) as a viscous

colourless oil, [α]_D²⁰Ϫ8.8 (c 1.17, CHCl₃) (Found: M^ϩϩ NH₄,

232.1007. C₁₀H₁₈NO₃S requires M, 232.1007); ν_max/cm^Ϫ13529,

1585, 1302, 1147 and 1085; δ_H1.10 (3 H, d, J 7, 2-CH₃), 1.74

(1 H, br s, OH), 2.34 (1 H, m, 2-H), 2.97 (1 H, dd, J 14, 6.5,

3-H), 3.36 (1 H, dd, J 14, 6, 3-HЈ), 3.51 (1 H, dd, J 11, 6.5, 1-H),

3.75 (1 H, dd, J 11, 5, 1-HЈ), 7.61 (3 H, m, Ar-H) and 7.90 (2 H,

m, Ar-H); δ_C17.5, 31.9, 59.7, 66.6, 128.3, 129.9, 134.2 and

140.3; m/z (C.I.) 232 (M^ϩϩ 18, 100%).

(2R,5E,7R)-7-tert-Butyldimethylsilyloxy-1-(4-methoxy-

benzyloxy)-2,6-dimethylnon-5-en-4-one 41

Lithium wire (135 mg, 19.2 mmol) was added in small pieces to

naphthalene (1.2 g, 9.4 mmol) in tetrahydrofuran (11.6 cm³)

and the mixture sonicated in an ultrasound bath under an inert

atmosphere for 1 h, to produce a dark green solution of lithium

naphthalenide (ca. 0.8 M).

Lithium naphthalenide in tetrahydrofuran was added drop-

wise to the keto sulfone 40 (2.5 g, 4.35 mmol) in tetrahydro-

furan (70 cm³) at Ϫ78 ЊC until the starting material had just

been consumed (TLC). The reaction mixture became a brown–

orange colour during the addition. Saturated aqueous ammo-

nium chloride was added and the reaction mixture warmed to

room temperature and diluted with ether. The organic layer was

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Flash chromatography of the residue [light

petroleum:ether (10:1)] gave the title compound 41 (1.6 g, 82%)

(R)-1-tert-Butyldimethylsilyloxy-2-methyl-3-phenylsulfonyl-

propane 47³¹

tert-Butyldimethylsilyl chloride (13.9 g, 92.4 mmol) and then

imidazole (13.1 g, 193 mmol) were added to the hydroxy sulfone

46 (16.5 g, 77.1 mmol) in N,N-dimethylformamide (40 cm³)

at 0 ЊC. The reaction mixture was allowed to warm to room

temperature and stirred for 17 h then diluted with hexane,

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Flash chromatography of the residue

(dichloromethane) gave the title compound 47³¹(23.4 g, 93%)

as a viscous colourless oil, [α]_D¹⁸Ϫ6.8 (c 1.14, CHCl₃) {lit.,³¹for

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

3549

View Article Online

(S)-enantiomer [α]_D8.2 (c 5, CHCl₃)} (Found: M^ϩϩ H,

329.1609. C₁₆H₂₉O₃SSi requires M, 329.1607); ν_max/cm^Ϫ11473,

1307, 1252, 1151, 1086, 839 and 779; δ_HϪ0.03 and 0.01 (each

3 H, s, SiCH₃), 0.83 [9 H, s, SiC(CH₃)₃], 1.07 (3 H, d, J 7,

2-CH₃), 2.18 (1 H, m, 2-H), 2.86 (1 H, dd, J 14, 8, 3-H), 3.35

(1 H, dd, J 10, 6.5, 1-H), 3.41 (1 H, dd, J 14, 4.5, 3-HЈ), 3.55

(1 H, dd, J 10, 5, 1-HЈ), 7.59 (3 H, m, ArH) and 7.90 (2 H, m,

ArH); δ_CϪ5.5, Ϫ5.4, 17.2, 26.3, 59.4, 66.9, 128.3, 129.7, 133.9

and 140.5; m/z (C.I.) 330 (M^ϩϩ 1, 100%) and 272 (49).

Ϫ4.6, 10.2, 13.2, 16.5, 18.2, 18.3, 25.9, 26.0, 29.2, 34.5, 41.8,

67.9, 80.1, 114.5, 126.1, 140.2 and 144.4; m/z (C.I.) 427

(M^ϩϩ 1, 15%), 369 (15), 295 (46) and 163 (100).

(2R,5E,7R)-7-tert-Butyldimethylsilyloxy-2,6-dimethyl-4-

methylenenon-5-en-1-ol 51

Tetrabutylammonium ﬂuoride (TBAF; 1 M in tetrahydrofuran;

11.0 cm³, 11.0 mmol) was added slowly to the diene 50 (4.25 g,

9.96 mmol) in tetrahydrofuran (50 cm³) at 0 ЊC. After 1 h, add-

itional TBAF (5.5 cm³, 5.5 mmol) was added and the mixture

stirred a further 1 h. Saturated aqueous ammonium chloride

was added, the aqueous phase was extracted with ether and

the organic extracts dried (MgSO₄) and concentrated under

reduced pressure. Flash chromatography of the residue [light

petroleum:ether (5:1)] gave the title compound 51 (2.72 g, 87%)

as a colourless oil, [α]_D²⁰20.4 (c 1.03, CHCl₃) (Found: M^ϩϩ H,

313.2565. C₁₈H₃₇O₂Si requires M, 313.2563); ν_max/cm^Ϫ13342,

1627, 1467, 1253, 1067, 1038, 837 and 775; δ_H(C₆D₆) 0.15 and

0.17 (each 3 H, s, SiCH₃), 0.77 (1 H, br s, OH), 0.95 (6 H, m,

2-CH₃, 9-H₃), 1.08 [9 H, s, SiC(CH₃)₃], 1.62 (2 H, m, 8-H₂), 1.84

(5 H, m, 2-H, 3-H, 6-CH₃), 2.33 (1 H, dd, J 13, 6, 3-HЈ), 3.32

(2 H, m, 1-H₂), 3.98 (1 H, t, J 6.5, 7-H), 5.03 and 5.11 (each 1 H,

s, 4-CHH) and 5.89 (1 H, s, 5-H); δ_C(C₆D₆) Ϫ4.8, Ϫ4.5, 10.3,

13.4, 16.6, 18.4, 26.1, 29.5, 34.8, 42.2, 67.7, 80.4, 115.0, 126.6,

140.6 and 144.5; m/z (C.I.) 313 (M^ϩϩ 1, 8%), 198 (15) and 181

(100).

It was found that under acidic conditions, for example on

standing in solution in chloroform, that the alcohol 51 gave the

(4S)-2-[(1E,3R)-3-tert-butyldimethylsilyloxy-2-methylpent-1-

enyl]-2,4-dimethyltetrahydrofuran 52 as a mixture of epimers at

C(2) (Found: M^ϩϩ H, 313.2569. C₁₈H₃₇O₂Si requires M,

313.2563); ν_max/cm^Ϫ11455, 1217, 1107 and 1046; δ_H0.03, 0.04,

0.06 and 0.07 (each 1.5 H, s, SiCH₃), 0.83 and 0.84 (each 1.5 H,

t, J 7.5, 5Ј-H₃), 0.92 [9 H, s, SiC(CH₃)₃], 1.03 and 1.07 (each

1.5 H, d, J 6.5, 4-CH₃), 1.34 and 1.41 (each 1.5 H, s, 2-CH₃),

1.54 (3 H, m, 4Ј-H₂, 3-H), 1.68 and 1.71 (each 1.5 H, d, J 1,

2Ј-CH₃), 2.15 (1 H, m, 3-HЈ), 2.37 (1 H, m, 4-H), 3.31 (0.5 H, t,

J 8.5, 5-H), 3.39 (0.5 H, t, J 8, 5-H), 3.83 (1 H, m, 3Ј-H), 3.96

(1 H, m, 5-HЈ) and 5.43 and 5.59 (each 0.5 H, s, 1Ј-H); δ_CϪ5.0,

Ϫ4.9, Ϫ4.6, Ϫ4.5, 10.2, 10.3, 11.5, 11.7, 17.4, 18.1, 18.3, 25.7,

25.8, 25.9, 27.2, 27.5, 29.1, 33.9, 34.1, 47.6, 48.2, 73.5, 73.7,

80.3, 80.5, 83.0, 83.3, 132.6, 134.1, 136.7 and 137.7; m/z (C.I.)

313 (M^ϩϩ 1, 25%), 198 (31) and 181 (100).

(2R,5E,7R)-1,7-Bis(tert-butyldimethylsilyloxy)-2,6-dimethyl-3-

phenylsulfonylnon-5-en-4-one 48

Following the procedure outlined for the synthesis of the keto

sulfone 40, the sulfone 47 (54 g, 0.165 mol) was treated with

n-butyllithium (1.6 M in hexanes; 108 cm³, 0.173 mol) and

magnesium bromide etherate (1 M in ether; 173 cm³, 0.173

mol), and acylated using the ester 30 (23.5 g, 82.3 mmol) to give,

after ﬂash chromatography [light petroleum:ethyl acetate

(30:1)], the title compound 48 (42.1 g, 90%) as a viscous pale

yellow oil, a 1:1 mixture of epimers at C(3) (Found: M^ϩϩ H,

569.3144. C₂₉H₅₃O₅SSi₂requires M, 569.3152); ν_max/cm^Ϫ11685,

1615, 1472, 1322, 1257, 1151, 1085, 837 and 778; δ_H0.03 (12 H,

m, 4 × SiCH₃), 0.91 [21 H, m, 2 × SiC(CH₃)₃, 9-H₃], 1.03 and

1.39 (each 1.5 H, d, J 7, 2-CH₃), 1.52 (2 H, m, 8-H₂) 1.91 and

1.97 (each 1.5 H, d, J 1, 6-CH₃), 2.58 (1 H, m, 2-H), 3.38 (0.5 H,

dd, J 10, 5, 1-H), 3.52 (1 H, m, 1-H), 3.73 (0.5 H, dd, J 10, 5,

1-HЈ), 3.96 (1 H, m, 7-H), 4.18 (0.5 H, d, J 9, 3-H), 4.38 (0.5 H,

d, J 7, 3-H), 6.31 and 6.45 (each 0.5 H, s, 5-H), 7.52 (2 H, m,

ArH), 7.64 (1 H, m, ArH) and 7.86 (2 H, m, ArH); δ_C9.82, 14.7,

16.1, 16.5, 16.6, 18.6, 18.7, 18.8, 26.3, 26.4, 29.4, 36.1, 36.5,

65.5, 66.0, 76.6, 78.4, 78.5, 79.3, 122.6, 129.3, 129.4, 129.5,

129.6, 134.2, 134.3, 139.4, 139.7, 164.0, 164.3, 192.3 and 192.5;

m/z (FAB) 569 (M^ϩ, 20%), 511 (100) and 437 (99).

(2R,5E,7R)-1,7-Bis(tert-butyldimethylsilyloxy)-2,6-dimethyl-

non-5-en-4-one 49

Following the procedure outlined for the synthesis of the

ketone 41, the keto sulfone 48 (42 g, 71.7 mmol) gave, after ﬂash

chromatography [light petroleum:ether (50:1)], the title com-

pound 49 (21.5 g, 70%) as a colourless oil, [α]_D¹⁷30.8 (c 1.45,

CHCl₃) (Found: M^ϩϩ H, 429.3219. C₂₃H₄₉O₃Si₂requires M,

429.3220); ν_max/cm^Ϫ11690, 1626, 1473, 1258, 1099, 838 and 776;

δ_H0.05 (3 H, s, SiCH₃), 0.07 (6 H, s, 2 × SiCH₃), 0.1 (3 H, s,

SiCH₃), 0.89 (3 H, t, J 7, 9-H₃), 0.91 [9 H, s, SiC(CH₃)₃], 0.93

(3 H, d, J 8, 2-CH₃), and 0.95 [9 H, s, SiC(CH₃)₃], 1.58 (2 H, m,

8-H₂), 2.08 (3 H, d, J 1, 6-CH₃), 2.22 (2 H, m, 2-H, 3-H), 2.67

(1 H, dd, J 19, 8.5, 3-HЈ), 3.43 (1 H, dd, J 10, 6, 1-H), 3.51 (1 H,

dd, J 10, 5, 1-HЈ), 3.98 (1 H, t, J 5.5, 7-H) and 6.31 (1 H, s, 5-H);

δ_CϪ5.4, Ϫ5.0, 9.5, 15.6, 16.7, 18.2, 18.3, 25.8, 25.9, 29.0, 32.5,

48.4, 67.6, 77.2, 78.2, 122.2, 158.5 and 201.5; m/z (FAB) 429

(M^ϩϩ 1, 70%), 371 (65) and 239 (100).

3-Propenoyloxy-2-methyl-4-phenylpent-1-ene 55

Propenoyl chloride (10 cm³, 0.123 mol) was added to the alco-

hol 54 (18 g, 0.102 mol) and diisopropylethylamine (21.9 cm³,

0.123 mol) in dichloromethane (500 cm³) at Ϫ10 ЊC. The reac-

tion was stirred for 1 h, water was added, and the organic phase

washed with saturated aqueous sodium hydrogen carbonate,

aqueous hydrogen chloride (1 M) and dried (MgSO₄). Con-

centration under reduced pressure and ﬂash chromatography

of the residue [light petroleum:ether (20:1)] gave the title

compound 55 (13.45 g, 57%), a colourless oil, as a mixture of

diastereoisomers (Found: M^ϩϩ NH₄, 248.1647. C₁₅H₂₂NO₂

requires M, 248.1651); ν_max/cm^Ϫ13030, 1724, 1635, 1406, 1266,

1190, 1045, 984, 962, 903, 809, 764 and 701; δ_H(major isomer)

1.32 (3 H, d, J 7, 5-H₃), 1.63 (3 H, s, 2-CH₃), 3.10 (1 H, m, 4-H),

4.81–6.49 (6 H, m) and 7.23 (5 H, m, ArH); (minor isomer) 1.23

(3 H, d, J 7, 5-H₃) and 1.74 (3 H, s, 2-CH₃); m/z (C.I.) 248

(M^ϩϩ 18, 100%), 176 (35) and 159 (11).

(2R,5E,7R)-1,7-Bis(tert-butyldimethylsilyloxy)-2,6-dimethyl-

4-methylenenon-5-ene 50

Following the procedure outlined for the synthesis of the diene

42, the enone 49 (4.59 g, 10.7 mmol) was reacted with the

ylid generated from methyl(triphenyl)phosphonium bromide

(11.5 g, 32.1 mmol) and n-butyllithium (1.6 M in hexanes; 20

cm³, 32.1 mmol) to give, after ﬂash chromatography [light

petroleum:ether (40:1)], the title compound 50 (3.57 g, 78%) as

a colourless oil, [α]_D¹⁷30.8 (c 1.45, CHCl₃) (Found: M^ϩϩ H,

427.3454. C₂₄H₅₁O₂Si₂requires M, 427.3428); ν_max/cm^Ϫ1

1627, 1428, 1254, 1093, 837 and 775; δ_H0.04 (3 H, s, SiCH₃),

0.08 (6 H, s, 2 × SiCH₃), 0.09 (3 H, s, SiCH₃), 0.86 (3 H, t,

J 7, 9-H₃), 0.93 [21 H, m, 2 × SiC(CH₃)₃, 2-CH₃], 1.55 (2 H, m,

8-H₂), 1.79 (5 H, m, 6-CH₃, 2-H, 3-H), 2.31 (1 H, dd, J 12, 5,

3-HЈ), 3.43 (2 H, m, 1-H₂), 3.93 (1 H, t, J 6.5, 7-H), 4.89 and

5.02 (each 1 H, s, 1Ј-H) and 5.75 (1 H, s, 5-H); δ_CϪ5.4, Ϫ5.0,

4-Methyl-2-methylene-6-phenylhept-4-enoic acid 57

Tricyclohexylphosphine (195 mg, 0.695 mmol) in toluene (0.9

cm³) was added to the ester 55 (1.6 g, 6.95 mmol), trimethylsilyl

chloride (4.8 cm³, 38.2 mmol) and 1,8-diazabicyclo[5.4.0]undec-

7-ene (2.6 cm³, 17.4 mmol) in acetonitrile (80 cm³). The mixture

was heated at 75 ЊC for 17 h then cooled and concentrated

3550

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

View Article Online

under reduced pressure. The residue was dissolved in ether and

washed with aqueous hydrogen chloride (3 M), brine and dried

(MgSO₄). Concentration under reduced pressure and chrom-

atography of the residue [light petroleum:ether (4:1)] gave the

title compound 57 (1.2 g, 75%) as a colourless oil (Found:

29.1, 38.9, 45.0, 79.6, 115.7, 124.8, 141.8, 142.3 and 204.6;

m/z (C.I.) 328 (M^ϩϩ 18, 14%), 311 (M^ϩϩ 1, 7), 196 (24) and

179 (100).

(4S,7E,9R)-9-tert-Butyldimethylsilyloxy-2,4,8-trimethyl-6-

methyleneundeca-1,7-dien-3-ol 63

M^ϩϩ NH₄, 248.1642. C₁₅H₂₂NO₂requires M, 248.1651); ν_max

/

cm^Ϫ13200, 1694, 1627, 1494, 1294, 1228, 1156 and 1025; δ_H1.35

(3 H, d, J 7, 7-H₃), 1.68 (3 H, d, J 1.5, 4-CH₃), 3.02 (2 H, s,

3-H₂), 3.72 (1 H, dq, J 9, 7, 6-H), 5.44 (1 H, d, J 9, 5-H), 5.64

and 6.37 (each 1 H, d, J 1.5, 2-CH), 7.26 (5 H, m, ArH) and

10.45 (1 H, br s, OH); m/z (C.I.) 248 (M^ϩϩ 18, 100%).

tert-Butyllithium (1.7 M in pentane; 20 cm³, 1.29 mmol) was

added to 2-bromopropene (0.057 cm³, 0.644 mmol) in tetra-

hydrofuran (4 cm³) at Ϫ78 ЊC. The reaction mixture was stirred

for 0.5 h then the aldehyde 62 (100 mg, 0.322 mmol) in tetra-

hydrofuran (0.5 cm³) was added. The reaction was stirred at

Ϫ78 ЊC for 1 h and then at 0 ЊC for 2 h. Water was added, the

mixture extracted with ether, and the ether extracts dried

(MgSO₄) and concentrated under reduced pressure. Flash

chromatography of the residue gave the title compounds 63 (85

mg, 75%) as a colourless oil (Found: M^ϩ, 352.2796. C₂₁H₄₀O₂Si

requires M, 352.2798); ν_max/cm^Ϫ13425, 3076, 1651, 1463, 1257,

1066, 1016, 898, 838 and 775; δ_H(C₆D₆) 0.17 [6 H, m, Si(CH₃)₂],

0.51 (1 H, br s, OH), 0.91–1.10 [15 H, m, SiC(CH₃)₃, 11-H₃,

4-CH₃], 1.66 (5 H, m, 10-H₂, 2-CH₃), 1.90 (4.3 H, m, 8-CH₃,

4-H, 5-H₂), 2.06 (0.7 H, dd, J 13, 8.5, 5-H), 2.41 (0.7 H, dd,

J 13, 6, 5-HЈ), 2.84 (0.3 H, m, 4-H), 3.63 (0.3 H, d, J 6.5, 3-H),

3.82 (0.7 H, d, J 4, 3-H), 3.99 (1 H, t, J 6.5, 9-H), 4.87–5.18

(4 H, m, 1-H₂, 6-CH₂) and 5.91 (1 H, m, 7-H); m/z (C.I.) 353

(M^ϩ5%), 238 (52), 221 (100) and 203 (51).

Methyl 4-methyl-2-methylene-6-phenylhept-4-enoate 60

Ethereal diazomethane was added dropwise to the acid 57 (3.95

g, 17.2 mmol) in ether (39 cm³) at 0 ЊC until the reaction

mixture remained a pale yellow colour. A few drops of glacial

acetic acid were added to destroy the excess of diazomethane

and the reaction mixture was washed with saturated sodium

hydrogen carbonate, dried (MgSO₄) and concentrated under

reduced pressure. Flash chromatography of the residue [light

petroleum:ether (30:1)] gave the title compound 60 (3.16 g,

82%) as a colourless oil (Found: M^ϩϩ NH₄, 262.1801.

C₁₆H₂₄NO₂requires M, 262.1807); ν_max/cm^Ϫ11724, 1631, 1439

and 1142; δ_H1.33 (3 H, d, J 7, 7-H₃), 1.66 (3 H, s, 4-CH₃), 3.00

(2 H, br s, 3-H₂), 3.72 (4 H, m, OCH₃, 6-H), 5.39 (1 H, d, J 9.5,

5-H), 5.50 and 6.19 (each 1 H, s, 2-CH) and 7.26 (5 H, m, ArH);

m/z (C.I.) 262 (M^ϩϩ 18, 100%) and 245 (M^ϩϩ 1, 18).

Alternatively, 2-bromopropene (0.086 cm³, 0.966 mmol) was

added to the aldehyde 62 (100 mg, 0.322 mmol) in N,N-

dimethylformamide (2 cm³) which had been degassed by pass-

ing nitrogen through it for 40 min. Chromium() chloride (237

mg, 1.93 mmol) and nickel() bromide (<1 mg) were added and

the mixture stirred for 48 h. Saturated aqueous ammonium

chloride and chloroform were added and stirred for 20 min. The

mixture was extracted with ethyl acetate (×3) and the extracts

washed with brine and dried (MgSO₄). Concentration under

reduced pressure and ﬂash chromatography of the residue gave

the alcohols 63 (107 mg, 95%).

4-Methyl-2-methylene-6-phenylhept-4-en-1-ol 61

Diisobutylaluminium hydride (1 M in hexane; 56.8 cm³, 56.8

mmol) was added slowly to the ester 60 (6.3 g, 25.8 mmol) in

tetrahydrofuran (150 cm³) at Ϫ78 ЊC. The reaction was stirred

for 1 h then saturated aqueous ammonium chloride (25 cm³)

was added. After warming to room temperature, Celite^was

added and the mixture stirred for 20 min before being ﬁltered

and washed with ether. The ﬁltrate was concentrated under

reduced pressure and ﬂash chromatography of the residue [light

petroleum:ether (4:1)] gave the title compound 61 (4 g, 72%)

as a colourless oil (Found: M^ϩϩ NH₄, 234.1855. C₁₅H₂₄NO

requires M, 234.1858); ν_max/cm^Ϫ13323, 3026, 1651, 1602, 1494,

1451, 1060, 1024 and 899; δ_H1.37 (3 H, d, J 7, 7-H₃), 1.54 (1 H,

s, OH), 1.68 (3 H, d, J 1.5, 4-CH₃), 2.81 (2 H, s, 3-H₂), 3.23 (1 H,

m, 6-H), 4.05 (2 H, s, 1-H₂), 4.93 and 5.11 (each 1 H, d, J 1,

2-CH), 5.44 (1 H, dq, J 9.5, 1.5, 5-H) and 7.26 (5 H, m, ArH);

m/z (C.I.) 234 (M^ϩϩ 18, 100%), 217 (M^ϩϩ 1, 24), 199 (30) and

145 (29).

(4S,7E,9R)-3-Propenoyloxy-9-tert-butyldimethylsilyloxy-2,4,8-

trimethyl-6-methyleneundeca-1,7-diene 64

Acryloyl chloride (0.537 cm³, 6.61 mmol) was added slowly to

the alcohol 63 (1.55 g, 4.4 mmol) and triethylamine (0.92 cm³,

6.61 mmol) in dichloromethane (45 cm³) at 0 ЊC. The reaction

was stirred for 1 h then saturated aqueous sodium hydrogen

carbonate was added. The organic phase was dried (MgSO₄)

and concentrated under reduced pressure. Flash chrom-

atography of the residue [light petroleum:ether (15:1)] gave the

title compound 64 (1.48 g, 83%) as a colourless oil, a 1:1 mix-

ture of epimers at C(3) (Found: M^ϩ, 406.2906. C₂₄H₄₂O₃Si

requires M, 406.2903); ν_max/cm^Ϫ13081, 1730, 1635, 1463, 1405,

1261, 1189, 1066, 900, 837 and 776; δ_H0.06 [6 H, m, Si(CH₃)₂],

0.92 [15 H, m, SiC(CH₃)₃, 11-H₃, 4-CH₃], 1.57 (2 H, m, 10-H₂),

1.76 (6 H, m, 2-CH₃, 8-CH₃), 1.95 (2 H, m, 5-H₂), 2.21 and

2.44 (each 0.5 H, m, 4-H), 3.96 (1 H, m, 9-H), 4.90–5.22 (5 H,

m, 3-H, 1-H₂, 6-CH₂), 5.74 (1 H, s, 7-H), 5.85 (1 H, m, 3Ј-H),

6.18 (1 H, m, 2Ј-H), 6.46 (1 H, m, 3Ј-HЈ); m/z (C.I.) 424

(M^ϩϩ 18, 8%), 407 (M^ϩϩ 1, 4), 292 (20), 275 (100) and 203 (27).

(2S,5E,7R)-7-tert-Butyldimethylsilyloxy-2,6-dimethyl-4-

methylenenon-5-enal 62

Dimethyl sulfoxide (0.384 cm³, 5.42 mmol) in dichloromethane

(1.1 cm³) was added dropwise to oxalyl chloride (0.237 cm³,

2.71 mmol) in dichloromethane (4.4 cm³) cooled to Ϫ50 ЊC.

The reaction was stirred for 5 min then the alcohol 51 (0.7 g,

2.26 mmol) in dichloromethane (2.1 cm³) was added. After stir-

ring for 15 min, triethylamine (0.919 cm³, 11.3 mmol) was

added and the mixture warmed to room temperature. Water

was added and the two layers were separated. The organic

phase was washed with brine, dried (MgSO₄) and concentrated

under reduced pressure to give the title compound 62 (0.655 g,

94%) as a pale yellow oil, [α]_D²⁰55.1 (c, 1.06, CHCl₃) (Found:

(4E,6S,9E,11R)-11-tert-Butyldimethylsilyloxy-4,6,10-trimethyl-

2,8-dimethylenetrideca-4,9-dienoic acid 65

Tricyclohexylphosphine (64 mg, 0.228 mmol) in toluene (0.5

cm³) was added to the ester 64 (930 mg, 2.29 mmol), trimethyl-

silyl chloride (1.6 cm³, 12.6 mmol) and 1,8-diazabicyclo-

[5.4.0]undec-7-ene (0.856 cm³, 5.72 mmol) in acetonitrile (23

cm³). The mixture was heated to 70 ЊC and stirred for 16 h,

cooled, then concentrated under reduced pressure. The

residue was dissolved in ether, washed with aqueous hydrogen

chloride (2 M), brine and dried (MgSO₄). Concentration under

reduced pressure and ﬂash chromatography of the residue [light

M^ϩϩ H, 311.2403. C₁₈H₃₅O₂Si requires M, 311.2406); ν_max

/

cm^Ϫ11733, 1629, 1473, 1257, 1066, 1017, 838 and 775; δ_H0.04

and 0.08 (each 3 H, s, SiCH₃), 0.86 (3 H, t, J 7.5, 9-H₃), 0.93

[9 H, s, SiC(CH₃)₃], 1.09 (3 H, d, J 7, 2-CH₃), 1.57 (2 H, m,

8-H₂), 1.74 (3 H, d, J 1.5, 6-CH₃), 2.10 (1 H, dd, J 13.5, 8, 3-H),

2.48 (1 H, m, 2-H), 2.59 (1 H, dd, J 13.5, 6, 3-HЈ), 3.94 (1 H, t, J 6,

7-H), 4.94 and 5.09 (each 1 H, s, 4-CH), 5.75 (1 H, s, 5-H)

and 9.67 (1 H, d, J 1.5, 1-H); δ_C10.0, 13.1, 13.4, 18.3, 25.8,

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

3551

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petroleum:ether (5:1)] gave the title compound 65 (0.89 g, 96%)

as a colourless oil, [α]_D²²30 (c 1.12, CHCl₃) (Found: M^ϩϩ H,

407.2981. C₂₄H₄₃O₃Si requires M, 407.2981); ν_max/cm^Ϫ13400,

1697, 1629, 1439, 1254, 1066, 1019, 837 and 776; δ_H0.04 and

0.08 (each 3 H, s, SiCH₃), 0.86 (3 H, t, J 7.5, 13-H₃), 0.96 [12 H,

m, SiC(CH₃)₃, 6-CH₃], 1.58 (5 H, m, 4-CH₃, 12-H₂), 1.73 (3 H,

d, J 1, 10-CH₃), 2.06 (2 H, m, 7-H₂), 2.52 (1 H, m, 6-H), 2.98

(2 H, s, 3-H₂), 3.94 (1 H, t, J 6.5, 11-H), 4.84 and 4.98 (each 1 H,

s, 8-CH), 5.04 (1 H, d, J 9, 5-H), 5.67 (1 H, d, J 1, 2-CH), 5.75

(1 H, s, 9-H) and 6.36 (1 H, s, 2-CHЈ); δ_CϪ4.9, Ϫ4.6, 10.1, 13.2,

16.1, 18.3, 20.6, 25.9, 29.2, 31.4, 40.7, 45.8, 80.0, 114.6, 126.1,

127.7, 130.0, 134.3, 138.4, 140.2, 144.1 and 172.4; m/z (C.I.) 407

(M^ϩϩ 1, 4%), 292 (34) and 275 (100).

cm³, 7 µmol) and -(ϩ)-diethyl tartrate (0.48 M in dichloro-

methane; 0.018 cm³, 8.7 µmol) were added to the alcohol

67 (58 mg, 0.148 mmol) and powdered 3 Å molecular sieves

in dichloromethane (0.3 cm³) at Ϫ20 ЊC. After stirring for

0.5 h, tert-butyl hydroperoxide (3 M in isooctane; 0.1 cm³, 0.3

mmol) was added and the reaction mixture stirred for 3.75 h

then warmed to 0 ЊC. Water (0.1 cm³) was added and, after

stirring for 0.5 h, the mixture was warmed to room temperature.

Aqueous sodium hydroxide (30%; saturated with sodium chlor-

ide) was added and the mixture stirred for 0.5 h before being

diluted with water and dichloromethane. The organic layer was

dried (MgSO₄) and concentrated under reduced pressure. Flash

chromatography of the residue [light petroleum:ether (6:1)]

gave the title compound 68 (37 mg, 61%) as a colourless oil, [α]_D²⁰

14 (c 1.4, CHCl₃) (Found: M^ϩ, 408.3058. C₂₄H₄₄O₃Si requires

M, 408.3060); ν_max/cm^Ϫ13444, 1627, 1463, 1255, 1066, 1017, 836

and 775; δ_H0.04 and 0.08 (each 3 H, s, SiCH₃), 0.86 (3 H, t,

J 7.5, 13-H₃), 0.93 [12 H, m, SiC(CH₃)₃, 6-CH₃], 1.56 (2 H, m,

12-H₂), 1.64 (3 H, d, J 1, 4-CH₃), 1.7 (1 H, br s, OH), 1.72 (3 H,

d, J 1, 10-CH₃), 2.05 (2 H, d, J 7, 7-H₂), 2.16 (1 H, d, J 14, 3-H),

2.51 (2 H, m, 3-HЈ, 6-H), 2.71 and 2.93 (each 1 H, d, J 5, 2-CH),

3.63 (1 H, dd, J 12, 8.5, 1-H), 3.75 (1 H, dd, J 12, 3, 1-HЈ), 3.93

(1 H, t, J 6.5, 11-H), 4.85 and 4.98 (each 1 H, s, 8-CH), 5.08

(1 H, d, J 9.5, 5-H) and 5.75 (1 H, s, 9-H); δ_C10.6, 13.7, 17.4,

18.7, 21.1, 26.3, 29.6, 31.7, 43.2, 46.3, 50.3, 59.2, 63.0, 80.4,

115.1, 126.3, 129.3, 135.6, 140.9 and 144.6; m/z (C.I.) 426

(M^ϩϩ 18, 2%), 409 (M^ϩϩ 1, 2), 294 (6), 277 (70) and 113

(100).

Methyl (4E,6S,9E,11R)-11-tert-butyldimethylsilyloxy-4,6,10-

trimethyl-2,8-dimethylenetrideca-4,9-dienoate 66

Ethereal diazomethane was added to the unsaturated acid 65

(434 mg, 1.07 mmol) in ether (10 cm³) at 0 ЊC until no further

gas was evolved and the reaction mixture remained a pale

yellow colour. A few drops of glacial acetic acid were added and

the reaction mixture was washed with saturated aqueous

sodium hydrogen carbonate, dried (MgSO₄) and concentrated

under reduced pressure. Flash chromatography of the residue

[light petroleum:ether (10:1)] gave the title compound 66 (381

mg, 85%) as a colourless oil, [α]_D¹⁷28 (c 0.96, CHCl₃) (Found:

M^ϩ, 420.3052. C₂₅H₄₄O₃Si requires M, 420.3060); ν_max/cm^Ϫ1

1727, 1630, 1440, 1255, 1142, 1067, 1019 and 838; δ_H0.04

and 0.08 (each 3 H, s, SiCH₃), 0.86 (3 H, t, J 7.5, 13-H₃),

0.93 [12 H, m, SiC(CH₃)₃, 6-CH₃], 1.56 (5 H, m, 12-H₂,

4-CH₃), 1.73 (3 H, d, J 1, 10-CH₃), 2.05 (2 H, m, 7-H₂), 2.51

(1 H, m, 6-H), 2.98 (2 H, s, 3-H₂), 3.77 (3 H, s, OCH₃), 3.93

(1 H, t, J 6.5, 11-H), 4.84 and 4.97 (each 1 H, s, 8-CH), 5.03

(1 H, d, J 9, 5-H), 5.54 (1 H, d, J 1.5, 2-CH), 5.75 (1 H, s, 9-H)

and 6.21 (1 H, d, J 1, 2-CHЈ); δ_CϪ5.0, Ϫ4.6, 10.1, 13.1, 16.1,

18.3, 20.6, 25.9, 29.2, 31.3, 41.2, 45.8, 51.8, 77.2, 80.0, 114.6,

125.4, 126.1, 127.2, 130.2, 134.4, 139.0, 140.2, 144.2 and

167.9; m/z (C.I.) 438 (M^ϩϩ 18, 11%), 421 (M^ϩϩ 1, 9) and

289 (100).

(2R,4E,6S,9E,11R)-11-tert-Butyldimethylsilyloxy-2,2-epoxy-

methano-4,6,10-trimethyl-8-methylenetrideca-4,9-dien-1-ol 69

Following the procedure outlined for the synthesis of the

epoxide 68, the alcohol 67 (100 mg, 0.255 mmol), -(Ϫ)-diethyl

tartrate (3.2 mg, 15 µmol), titanium() isopropoxide (3.6 mg,

12.8 µmol) and tert-butyl hydroperoxide (3 M in isooctane;

0.17 cm³, 0.51 mmol) gave, after ﬂash chromatography [light

petroleum:ether (5:1)] the title compound 69 (97 mg, 93%) as

a colourless oil, [α]_D²⁰50 (c 1, CHCl₃) (Found: M^ϩ, 408.3054.

C₂₄H₄₄O₃Si requires M, 408.3060); ν_max/cm^Ϫ13426, 1628,

1463, 1256, 1067, 836 and 775; δ_H0.04 and 0.08 (each 3 H, s,

SiCH₃), 0.86 (3 H, t, J 7.5, 13-H₃), 0.93 [12 H, m, SiC(CH₃)₃,

6-CH₃], 1.55 (3 H, m, 12-H₂, OH), 1.69 and 1.75 (each 3 H,

d, J 1, 4-CH₃, 10-CH₃), 2.03 (1 H, dd, J 9, 3, 7-H), 2.08 (1 H,

dd, J 9, 2.5, 7-HЈ), 2.21 and 2.44 (each 1 H, d, J 14, 3-H),

2.53 (1 H, m, 6-H), 2.70 and 2.93 (each 1 H, d, J 5, 2-CH),

3.65 (1 H, dd, J 12.5, 9, 1-H), 3.73 (1 H, dd, J 12.4, 4.5,

1-HЈ), 3.94 (1 H, t, J 6.5, 11-H), 4.87 and 4.98 (each 1 H, s,

8-CH), 5.07 (1 H, d, J 9, 5-H) and 5.75 (1 H, s, 9-H); δ_C10.6,

13.7, 17.4, 18.7, 21.0, 26.3, 29.6, 31.7, 43.1, 46.2, 50.3, 59.3,

62.9, 80.4, 115.1, 126.4, 129.3, 135.6, 140.8 and 144.6; m/z

(C.I.) 426 (M^ϩϩ 18, 3%), 409 (M^ϩϩ 1, 2), 277 (50) and 123

(100).

(4E,6S,9E,11R)-11-tert-Butyldimethylsilyloxy-4,6,10-

trimethyl-2,8-dimethylenetrideca-4,9-dien-1-ol 67

Diisobutylaluminium hydride (1 M in hexane; 5 cm³, 4.97

mmol) was added slowly to the ester 66 (0.949 g, 2.26 mmol) in

tetrahydrofuran (13.5 cm³) at Ϫ78 ЊC. The mixture was stirred

for 1 h then saturated aqueous ammonium chloride (2.5 cm³)

was added. After warming to 0 ЊC, Celite^was added and the

reaction mixture was allowed to warm to room temperature

and stirred for 0.5 h then ﬁltered, and the ﬁltrate concentrated

under reduced pressure. Flash chromatography of the residue

[light petroleum:ether (10:1)] gave the title compound 67 (0.796

g, 90%) as a colourless oil, [α]_D²²(c 0.75, CHCl₃) (Found:

M^ϩϩ H, 393.3195. C₂₄H₄₅O₂Si requires M, 393.3189); ν_max

/

cm^Ϫ13343, 1630, 1463, 1256, 1066, 1018, 898, 836 and 775;

δ_H0.03 and 0.08 (each 3 H, s, SiCH₃), 0.85 (3 H, t, J 7.5, 13-H₃),

0.94 [12 H, m, SiC(CH₃)₃, 6-CH₃], 1.45 (1 H, t, J 6.5, OH), 1.58

(5 H, m, 4-CH₃, 12-H₂), 1.72 (3 H, d, J 1, 10-CH₃), 2.06 (2 H, m,

7-H₂), 2.52 (1 H, m, 6-H), 2.89 (2 H, br s, 3-H₂), 3.94 (1 H, t,

J 6.5, 11-H), 4.06 (2 H, d, J 6.5, 1-H₂), 4.85 (1 H, s, 8-CH), 4.93

(1 H, s, 2-CH), 4.98 (1 H, s, 8-CHЈ), 5.06 (1 H, d, J 9.5, 5-H),

5.10 (1 H, s, 2-CHЈ) and 5.75 (1 H, s, 9-H); δ_CϪ5.0, Ϫ4.6, 10.6,

13.7, 16.2, 18.7, 21.1, 26.3, 29.6, 31.8, 44.7, 46.3, 65.9, 75.4,

80.5, 111.5, 114.9, 126.5, 131.4, 134.1, 140.7, 144.8 and 147.4;

m/z (C.I.) 410 (M^ϩϩ 18, 10%), 393 (M^ϩϩ 1, 35), 278 (58) and

261 (100).

(2R,4E)-2,2-Epoxymethano-4-methyl-6-phenylhept-4-en-1-ol 70

Following the procedure outlined for the synthesis of the

hydroxy epoxide 68, the allylic alcohol 61 (3.9 g, 18.1 mmol)

was treated with -(Ϫ)-diethyl tartrate (0.185 cm³, 1.08 mmol),

titanium() isopropoxide (0.269 cm³, 0.903 mmol) and tert-

butyl hydroperoxide (3 M in isooctane; 12.0 cm³, 36.1 mmol)

to give, after ﬂash chromatography [light petroleum:ether

(4:1–3:1–1:1)] the title compound 70 (2.6 g, 62%) as a colour-

less oil, a 1:1 mixture of epimers at C(6) (Found: M^ϩϩ NH₄,

250.1808. C₁₅H₂₄NO₂requires M, 250.1807); ν_max/cm^Ϫ13423,

3027, 1601, 1492, 1450 and 1045; δ_H1.34 (3 H, d, J 7, 7-H₃),

1.73 (3 H, d, J 1.5, 4-CH₃), 2.21 and 2.48 (each 1 H, d, J 14,

3-H), 2.67 and 2.91 (each 1 H, m, 2-CH), 3.66 (3 H, m, 1-H₂,

6-H), 5.43 (1 H, d, J 9.5, 5-H) and 7.26 (5 H, m, ArH); m/z

(C.I.) 250 (M^ϩϩ 18, 98%), 234 (46), 232 (M^ϩ, 40) and 220

(100).

(2S,4E,6S,9E,11R)-11-tert-Butyldimethylsilyloxy-2,2-epoxy-

methano-4,6,10-trimethyl-8-methylenetrideca-4,9-dien-1-ol 68

Titanium() isopropoxide (0.35 M in dichloromethane; 0.02

3552

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

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(2S,4E)-2,2-Epoxymethano-4-methyl-6-phenylhept-4-enyl

phenylcarbamate 71

M) and dried (MgSO₄). Concentration under reduced pressure

and ﬂash chromatography of the residue [light petroleum:ether

(5:1)] gave the title compound 74 (152 mg, 52%), a colourless

oil, as a 1:1 mixture of epimers at C(4Ј) (Found: M^ϩϩ NH₄,

424.2518. C₂₂H₃₈NO₅Si requires M, 424.2519); ν_max/cm^Ϫ11806,

1451, 1250, 1115, 1071, 861 and 837; δ_H0.03 [9 H, s, Si(CH₃)₃],

0.09 (2 H, m, SiCH₂), 1.34 (3 H, d, J 7, 5Ј-H₃), 1.80 (3 H, m,

2Ј-CH₃), 2.37 and 2.49 (each 1 H, d, J 14, 1Ј-H), 3.60 (5 H, m,

4Ј-H, 1Љ-CH₂, CH₂CH₂O), 4.14, 4.20, 4.37 and 4.39 (each 0.5 H,

d, J 8, 5-H), 4.60 and 4.63 (each 0.5 H, d, J 6, OHCHO), 4.69

(1 H, s, OCH₂O), 5.43 (1 H, d, J 9.5, 3Ј-H) and 7.24 (5 H, m,

ArH); m/z (C.I.) 424 (M^ϩϩ 18, 100%), 369 (14) and 320 (25).

Phenyl isocyanate (0.056 cm³, 0.474 mmol) was added to the

alcohol 70 (100 mg, 0.431 mmol) and triethylamine (0.066 cm³,

0.474 mmol) in dichloromethane (1.0 cm³) at 0 ЊC. The reaction

mixture was stirred for 1 h and then washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. Flash

chromatography of the residue [light petroleum:ether (5:1)]

gave the title compound 71 (110 mg, 73%) as a colourless oil,

ν_max/cm^Ϫ13329, 1737, 1714, 1540, 1498, 1445, 1217 and 1068;

δ_H1.33 (3 H, d, J 7, 7-H₃), 1.76 (3 H, d, J 1.5, 4-CH₃), 2.25, 2.31,

2.49 and 2.55 (each 0.5 H, d, J 14, 3-H₂), 2.71 and 2.82 (each

1 H, m, 2-CH), 3.71 (1 H, m, 6-H), 4.10, 4.13, 4.27 and 4.33

(each 0.5 H, d, J 12, 1-H), 5.46 (1 H, d, J 9, 5-H), 6.70 (1H, m,

NH) and 7.26 (10 H, m, ArH); m/z (C.I.) 369 (M^ϩϩ 18, 75%),

352 (M^ϩϩ 1, 100), 288 (61) and 250 (37).

(2S,4E)-4-Methyl-6-phenyl-2-[(2-trimethylsilylethoxy)methoxy-

methyl]hept-4-ene-1,2-diol 75

Lithium hydroxide monohydrate (78 mg, 1.85 mmol) was added

to the cyclic carbonate 74 (150 mg, 0.369 mmol) in dimethoxy-

ethane–water (5:1) and the mixture stirred for 3 h at room

temperature then diluted with water and extracted with ether.

The extract was dried (MgSO₄) and concentrated under

reduced pressure. Flash chromatography of the residue [light

petroleum:ether (1:1)] gave the title compound 75 (114 mg,

81%) as a colourless oil, ν_max/cm^Ϫ13424, 1452, 1249, 1110, 1057,

860 and 836; δ_H0.00 [9 H, s, SiC(CH₃)₃], 0.93 (2 H, m, SiCH₂),

1.27 (3 H, m, 7-H₃), 1.85 (3 H, d, J 1.5, 4-CH₃), 2.00 (1 H, m,

1-OH), 2.26 (2 H, m, 3-H₂), 2.76 and 2.77 (each 0.5 H, s, 2-OH),

3.54 (7 H, m, 1-H₂, 6-H, CH₂CH₂O, 1Ј-H₂), 4.39 and 4.44 (each

0.5 H, d, J 6.5, OHCHO), 4.47 (1 H, s, OCH₂O), 5.43 (1 H, d,

J 9, 5-H) and 7.12 (5 H, m, ArH); m/z (C.I.) 398 (M^ϩϩ 18, 15%)

and 280 (16).

Benzyl (2S,4E)-2,2-epoxymethano-4-methyl-6-phenylhept-4-

enyl carbonate 72

Benzyl chloroformate (0.195 cm³, 1.38 mmol) was added to the

epoxy alcohol 70 (160 mg, 0.69 mmol) and pyridine (0.122 cm³,

1.52 mmol) in tetrahydrofuran (2 cm³) at Ϫ20 ЊC. The mixture

was allowed to warm to room temperature and stirred for 16 h

then diluted with ether, washed with aqueous hydrogen chloride

(1.5 M), dried (MgSO₄) and concentrated under reduced pres-

sure. Flash chromatography of the residue [light petroleum:

ether (10:1)] gave the title compound 72 (228 mg, 90%) as a

colourless oil, (Found: M^ϩϩ NH₄, 384.2164. C₂₃H₃₀NO₄

requires M, 384.2175); ν_max/cm^Ϫ13029, 1752, 1601, 1494, 1261,

958 and 699; δ_H1.30 (3 H, m, 7-H₃), 1.72 (3 H, s, 4-CH₃), 2.25,

2.30, 2.44 and 2.49 (each 0.5 H, d, J 14, 3-H), 2.65 and 2.68

(each 0.5 H, d, J 5, 2-CH), 2.79 (1 H, m, 2-CHЈ), 3.69 (1 H, m,

6-H), 4.09, 4.10, 4.20 and 4.24 (each 0.5 H, d, J 11.5, 1-H), 5.16

(2 H, s, ArCH₂), 5.43 (1 H, d, J 9.5, 5-H) and 7.26 (10 H, m,

ArH); m/z (C.I.) 384 (M^ϩϩ 18, 100%) and 250 (16).

(2R,4E)-2-Hydroxy-4-methyl-6-phenyl-2-[(2-trimethylsilyl-

ethoxy)methoxymethyl]hept-4-enal 76

Dimethyl sulfoxide (0.056 cm³, 0.79 mmol) in dichloromethane

(0.125 cm³) was added to oxalyl chloride (0.035 cm³, 0.395

mmol) in dichloromethane (0.5 cm³) at Ϫ50 ЊC. The reaction

mixture was stirred for 2 min and the alcohol 75 (100 mg, 0.263

mmol) in dichloromethane (0.24 cm³) was added. The mixture

was stirred for 15 min, triethylamine (0.134 cm³, 1.64 mmol)

was added, and the mixture allowed to warm to room temper-

ature. After partitioning between water and dichloromethane,

the organic phase was washed with aqueous hydrogen chloride

(3 M) and brine, dried (MgSO₄) and concentrated under

reduced pressure. Flash column chromatography of the residue

[light petroleum:ether (3:1)] gave the title compound 76 (47 mg,

46%) as a colourless oil (Found: M^ϩϩ NH₄, 396.2580. C₂₁H₃₈-

NO₄Si requires M, 396.2570); ν_max/cm^Ϫ13454, 1736, 1451, 1250,

1111, 1058, 860 and 836; δ_H0.01 [9 H, s, Si(CH₃)₃], 0.93 (2 H, m,

SiCH₂), 1.23 (3 H, m, 7-H₃), 1.68 and 1.72 (each 1.5 H, d, J 1.5,

4-CH₃), 2.12 and 2.21 (each 1 H, d, J 14, 3-H), 3.51 (6 H, m,

2-OH, 6-H, 1Ј-H₂, CH₂CH₂O), 4.36 and 4.40 (each 0.5 H, d, J 7,

OHCHO), 4.42 (1 H, s, OCH₂O), 5.31 (1 H, m, 5-H), 7.18 (5 H,

m, ArH) and 9.48 and 9.53 (each 0.5 H, s, 1-H); m/z (C.I.) 396

(M^ϩϩ 18, 80%), 248 (64) and 90 (100).

(4R)-4-[(2E)-2-Methyl-4-phenylpent-2-enyl]-4-hydroxymethyl-

1,3-dioxolan-2-one 73

The phenyl carbamate 71 (60 mg, 0.171 mmol) was stirred in

aqueous perchloric acid (5%)–acetonitrile (1:3, 1 cm³) for 17 h

then the mixture was diluted with hexane and washed with

brine, dried (MgSO₄) and concentrated under reduced pressure.

Flash chromatography of the residue [light petroleum:ether

(1:1)] gave the title compound 73 (21 mg, 45%) as a colourless

oil, a 1:1 mixture of epimers at C(4Ј) (Found: M^ϩϩ NH₄,

294.1682. C₁₆H₂₄NO₄requires M, 294.1705); ν_max/cm^Ϫ13444,

1799, 1450, 1201 and 1070; δ_H1.36 (3 H, d, J 7.5, 5Ј-H₃), 1.80

(3 H, m, 2Ј-CH₃), 2.35 (3 H, m, 1Ј-H₂, OH), 3.50 (1 H, m, 1Љ-H),

3.72 (2 H, m, 1Љ-HЈ, 4Ј-H), 4.18, 4.23, 4.42 and 4.48 (each 0.5 H,

d, J 9, 5-H), 5.43 (1 H, d, J 9.5, 3Ј-H) and 7.24 (5 H, m, ArH);

m/z (E.I.) 276 (M^ϩ, 5%), 261 (4), 144 (81) and 105 (100).

Aluminium trichloride (1 M in nitrobenzene; 1.1 cm³, 1.15

mmol) was added to the benzyl carbonate 72 (350 mg, 0.956

mmol) in dichloromethane (3.5 cm³) at Ϫ20 ЊC and the mixture

allowed to warm slowly to room temperature for 2 h. Water was

added and the organic phase washed with aqueous hydrogen

chloride (3 M), dried (MgSO₄) and concentrated under reduced

pressure. Flash chromatography, as above gave the dioxolanone

73 (200 mg, 76%).

(2S,4E)-2,2-Epoxymethano-4-methyl-6-phenylhept-4-enal 77

The epoxy alcohol 70 (100 mg, 0.431 mmol), 4-methyl-

morpholine-N-oxide (87 mg, 0.645 mmol) and powdered 3 Å

molecular sieves were stirred in dichloromethane (5 cm³) for 10

min then tetrapropylammonium perruthenate (8 mg, 21.6

µmol) was added and the suspension stirred for 3.5 h. The

mixture was ﬁltered through a short column of silica and con-

centrated under reduced pressure to give the title compound 77

(62 mg, 63%) as a colourless oil (Found: M^ϩϩ NH₄, 248.1656.

C₁₅H₂₂NO₂requires M, 248.1650); ν_max/cm^Ϫ11728, 1601, 1494,

1451, 1026, 869, 760 and 701; δ_H1.32 (3 H, d, J 7, 7-H₃), 1.68

and 1.71 (each 1.5 H, d, J 1.5, 4-CH₃), 2.60 (2 H, m, 3-H₂), 2.97

(2 H, m, 2-CH₂), 3.68 (1 H, m, 6-H), 5.40 (1 H, m, 5-H), 7.23

(4R)-4-[(2E)-2-Methyl-4-phenylpent-2-enyl]-4-[(2-trimethyl-

silylethoxy)methoxymethyl]-1,3-dioxolan-2-one 74

(2-Trimethylsilylethoxy)methyl chloride (0.27 cm³, 1.45 mmol)

was added to the dioxolanone 73 (200 mg, 0.725 mmol) and

diisopropylethylamine (0.5 cm³, 2.89 mmol) in dichloro-

methane (0.5 cm³) at 0 ЊC. The mixture was allowed to warm to

room temperature and was stirred for 16 h, then diluted with

dichloromethane, washed with aqueous hydrogen chloride (3

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

3553

View Article Online

(5 H, m, ArH) and 8.95 (1 H, s, 1-H); δ_C18.1, 22.7, 23.0,

36.8, 36.9, 38.5, 38.6, 49.5, 61.1, 61.2, 126.4, 127.4, 128.7,

128.8, 128.9, 135.0, 135.1, 147.0, 147.1 and 199.2; m/z (C.I.)

248 (M^ϩϩ 18, 100%).

93%), a colourless oil, as a 1:1 mixture of epimers at C(3)

(Found: M^ϩϩ Na, 767.4857. C₄₆H₇₂NaO₄Si₂requires M,

767.4867); ν_max/cm^Ϫ13073, 1734, 1428, 1367, 1256, 1151, 1112,

1068 and 837; δ_H0.06 and 0.10 (each 3 H, s, SiCH₃), 0.92 [15 H,

m, OSiC(CH₃)₃, 15-H₃, 8-CH₃], 1.12 [9 H, s, OSiC(CH₃)₃], 1.34

[9 H, s, OC(CH₃)₃], 1.54 (5 H, m, 6-CH₃, 14-H₂), 1.73 and 1.74

(each 1.5 H, d, J 1, 12-CH₃), 2.04 (2 H, m, 9-H₂), 2.49 (3 H, m,

2-H₂, 8-H), 2.73 (2 H, s, 5-H₂), 3.95 (1 H, t, J 6.5, 13-H), 4.60

(1 H, m, 3-H), 4.78 (1 H, s, 10-CH), 4.82 and 4.85 (each 0.5 H, s,

4-CH), 4.97 (3 H, m, 7-H, 10-CHЈ, 4-CHЈ), 5.76 (1 H, s, 11-H),

7.42 (6 H, m, ArH) and 7.72 (4 H, m, ArH); δ_CϪ4.9, Ϫ4.6,

10.1, 13.2, 15.9, 18.3, 19.4, 20.5, 26.0, 27.0, 28.1, 29.2, 29.7,

31.3, 31.4, 41.2, 43.0, 45.76, 45.81, 74.1, 80.07, 80.16, 112.4,

114.6, 126.2, 127.4, 127.5, 129.59, 129.64, 130.7, 133.7, 134.1,

134.4, 134.5, 136.0, 140.1, 144.2, 147.3 and 169.8; m/z (ESP)

762 (M^ϩϩ 18, 81%), 654 (44), 598 (36) and 466 (53).

(4E,6S,9E,11R)-11-tert-Butyldimethylsilyloxy-4,6,10-trimethyl-

2,8-dimethylenetrideca-4,9-dienal 78

4-Methylmorpholine-N-oxide (130 mg, 0.963 mmol), the alco-

hol 67 (360 mg, 0.918 mmol) and powdered 3 Å molecular

sieves were stirred in dichloromethane (9 cm³) for 5 min then

tetrapropylammonium perruthenate (6.4 mg, 18.4 µmol) was

added. The suspension was stirred for 2 h, ﬁltered through a

short column of silica and concentrated under reduced pressure

to give the title compound 78 (289 mg, 81%) as a colourless oil,

[α]_D²³24.6 (c 1.27, CHCl₃) (Found: M^ϩϩ H, 391.3024. C₂₄H₄₃-

O₂Si requires M, 391.3032); ν_max/cm^Ϫ11698, 1463, 1361, 1256,

1066, 1017, 837 and 776; δ_H0.04 and 0.08 (each 3 H, s, SiCH₃),

0.86 (3 H, t, J 7.5, 13-H₃), 0.94 [12 H, m, SiC(CH₃)₃, 6-CH₃],

1.58 (5 H, m, 4-CH₃, 12-H₂), 1.73 (3 H, s, 10-CH₃), 2.06 (2 H,

m, 7-H₂), 2.53 (1 H, m, 6-H), 2.95 (2 H, br s, 3-H₂), 3.94 (1 H, t,

J 6.5, 11-H), 4.82 and 4.97 (each 1 H, s, 8-CH), 5.04 (1 H, d, J 9,

5-H), 5.75 (1 H, s, 9-H), 6.09 and 6.28 (each 1 H, s, 2-CH) and

9.65 (1 H, s, 1-H); δ_CϪ5.0, Ϫ4.6, 10.1, 13.2, 16.1, 18.2, 20.6,

25.9, 29.2, 31.3, 37.1, 45.8, 79.9, 114.6, 126.1, 129.7, 134.5,

134.6, 140.2, 144.2, 148.5 and 194.3; m/z (C.I.) 408 (M^ϩϩ 18,

3%), 391 (M^ϩϩ 1, 6), 276 (9) and 259 (100).

tert-Butyl (6E,8S,11E,13R)-13-tert-butyldimethylsilyloxy-

6,8,12-trimethyl-4,10-dimethylene-3-(2-trimethylsilylethoxy)-

methoxypentadeca-6,11-dienoate 81

(2-Trimethylsilylethoxy)methyl chloride (0.04 cm³, 0.225 mmol)

was added to diisopropylethylamine (0.078 cm³, 0.415 mmol)

and the alcohol 79 (57 mg, 0.113 mmol) in dichloromethane

(0.3 cm³). The mixture was stirred for 16 h, diluted with

ether, washed with aqueous hydrogen chloride (3 M), dried

(MgSO₄) and concentrated under reduced pressure. Flash

chromatography of the residue [light petroleum:ether (25:1)]

gave the title compound 81 (87 mg), a colourless oil, as a 1:1

mixture of epimers at C(3) (Found: M^ϩϩ NH₄, 654.4952.

C₃₆H₇₂NO₅Si₂requires M, 654.4949); ν_max/cm^Ϫ11736, 1368,

1250, 1029 and 836; δ_H0.04 (3 H, s, SiCH₃), 0.05 [9 H, s,

SiC(CH₃)₃], 0.08 (3 H, s, SiCH₃), 0.86 (3 H, t, J 7.5, 15-H₃), 0.97

[14 H, m, SiC(CH₃)₃, SiCH₂, 8-CH₃], 1.48 [9 H, s, OC(CH₃)₃],

1.55 (5 H, m, 6-CH₃, 14-H₂), 1.73 (3 H, s, 12-CH₃), 2.02 (1 H,

dd, J 13.5, 7.5, 9-H), 2.10 (1 H, m, 9-HЈ), 2.51 (3 H, m, 2-H₂,

8-H), 2.69 (2 H, s, 5-H₂), 3.55 (0.5 H, m, CH₂CHHO), 3.67

(1 H, m, CH₂CHHO), 3.77 (0.5 H, m, CH₂CHHO), 3.94 (1 H,

t, J 6.5, 13-H), 4.50 (1 H, dd, J 8.5, 5, 3-H), 4.65 (2 H, s,

OCH₂O), 4.85 (1 H, s, 10-CH), 4.97 (1 H, s, 4-CH), 4.99 (1 H, s,

10-CHЈ), 5.05 (1 H, d, J 9, 7-H), 5.16 (1 H, s, 4-CHЈ) and 5.76

(1 H, s, 11-H); m/z (C.I.) 654 (M^ϩϩ 18, 2%), 464 (4), 422 (6) and

391 (7).

tert-Butyl (6E,8S,11E,13R)-13-tert-butyldimethylsilyloxy-3-

hydroxy-6,8,12-trimethyl-4,10-dimethylenepentadeca-6,11-

dienoate 79

n-Butyllithium (1.6 M in hexane; 1.1 cm³, 0.18 mmol) was

added slowly to 1,1,1,3,3,3-hexamethyldisilazane (0.38 cm³,

0.181 mmol) at 0 ЊC and the mixture stirred for 0.5 h. The

solvent was removed under a stream of argon and tetrahydro-

furan (2.5 cm³) and tert-butyl acetate (0.244 cm³, 0.186 mmol)

were added. After 45 min, the aldehyde 78 (235 mg, 0.603

mmol) in tetrahydrofuran (2.5 cm³) was added and the stirring

continued for 1 h. Water was added and the mixture allowed to

warm to room temperature. The organic phase was washed with

aqueous hydrogen chloride (1 M), dried (MgSO₄) and concen-

trated under reduced pressure. Flash chromatography of the

residue [light petroleum:ether (10:1)] gave the title compound

79 (267 mg, 88%) as a colourless oil, a 1:1 mixture of epimers at

C(3); ν_max/cm^Ϫ13459, 1732, 1717, 1462, 1369, 1256, 1152, 1066,

836 and 775; δ_H0.04 and 0.08 (each 3 H, s, SiCH₃), 0.86 (3 H, t,

J 7.5, 15-H₃), 0.93 [12 H, m, SiC(CH₃)₃, 8-CH₃], 1.55 [14 H, m,

OC(CH₃)₃, 6-CH₃, 14-H₂], 1.74 (3 H, s, 12-CH₃), 2.08 (2 H, m,

9-H₂), 2.52 (3 H, m, 2-H₂, 8-H), 2.71 and 2.81 (each 1 H, d, J 15,

5-H), 3.13 and 3.16 (each 0.5 H, d, J 4.5, 3-OH), 3.94 (1 H, t,

J 6.5, 13-H), 4.43 (1 H, m, 3-H), 4.84 (1 H, s, 10-CH), 4.94 (1 H,

s, 4-CH), 4.97 (1 H, s, 10-CHЈ), 5.06 (1 H, d, J 9, 7-H), 5.18

(1 H, s, 4-CHЈ) and 5.75 (1 H, s, 11-H); δ_CϪ5.0, Ϫ4.6, 10.1,

13.2, 15.8, 18.3, 20.6, 25.9, 28.1, 29.2, 31.4, 41.2, 43.4, 43.5,

45.6, 45.9, 70.2, 70.3, 80.0, 81.3, 111.8, 114.6, 126.1, 130.8,

134.1, 134.2, 140.2, 140.2, 144.2, 147.6 and 172.1; m/z (ESP)

1035 (10%), 1030 (2), 524 (M^ϩϩ 18, 100), 319 (16), 153 (20).

(2E,6E,8S,11E,13R)-13-tert-Butyldimethylsilyloxy-6,8,12-

trimethyl-4,10-dimethylenepentadeca-2,6,11-trienoic acid 86

Triethylamine (0.066 cm³, 50 mmol) and trimethylsilyl triﬂuoro-

methanesulfonate (0.078 cm³, 0.426 mmol) were added to the

tert-butyl ester 80 (65 mg, 0.102 mmol) in ether (1.5 cm³) at

0 ЊC. After 6 h, the reaction was diluted with ether, washed

with brine, dried (MgSO₄) and concentrated under reduced

pressure. Flash chromatography of the residue [light petroleum:

ether (5:1–2:1)] gave the title compound 86 (40 mg, 68%) as a

colourless oil (Found: M^ϩ, 432.3064. C₂₆H₄₄O₃Si requires M,

432.3060); ν_max/cm^Ϫ13400–2300, 1693, 1627, 1284, 1253, 1066,

1020, 837 and 775; δ_H0.04 and 0.08 (each 3 H, s, SiCH₃), 0.87

(3 H, t, J 7, 15-H₃), 0.98 [12 H, m, SiC(CH₃)₃, 8-CH₃], 1.56 (5 H,

m, 6-CH₃, 14-H₂), 1.71 (3 H, s, 12-CH₃), 2.05 (2 H, m, 9-H₂),

2.53 (1 H, m, 8-H), 2.97 (2 H, s, 5-H₂), 3.94 (1 H, t, J 6.5, 13-H),

4.83 and 4.98 (each 1 H, d, J 1.0, 10-CH), 5.05 (1 H, d, J 9,

7-H), 5.43 and 5.55 (each 1 H, s, 4-CH), 5.75 (1 H, s, 11-H), 6.01

(1 H, d, J 15, 2-H) and 7.45 (1 H, d, J 15, 3-H); m/z (C.I.) 433

(M^ϩϩ 1, 2%), 403 (3) and 301 (100).

tert-Butyl (6E,8S,11E,13R)-13-tert-butyldimethylsilyloxy-3-

tert-butyldiphenylsilyloxy-6,8,12-trimethyl-4,10-dimethylene-

pentadeca-6,11-dienoate 80

tert-Butyldiphenylsilyl chloride (0.173 cm³, 0.664 mmol) and

imidazole (94 mg, 1.38 mmol) were added to the alcohols 79

(280 mg, 0.553 mmol) in N,N-dimethylformamide (0.5 cm³) at

0 ЊC. The mixture was allowed to warm to room temperature

and stirred for 16 h before being diluted with hexane and

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Flash chromatography of the residue [light

petroleum:ether (12:1)] gave the title compound 80 (381 mg,

tert-Butyl (6E,8S,11E,13R)-13-tert-butyldimethylsilyloxy-3-(4-

methoxyphenoxy)methoxy-6,8,12-trimethyl-4,10-dimethylene-

pentadeca-6,11-dienoate 82

The alcohol 79 (224 mg, 0.443 mmol), diisopropylethylamine

(0.153 cm³, 0.885 mmol) and (4-methoxyphenoxy)methyl chlor-

3554

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

View Article Online

ide (153 mg, 0.885 mmol) in dichloromethane (1.1 cm³) were

heated under reﬂux for 1.6 h. The reaction mixture was cooled,

diluted with dichloromethane, washed with aqueous hydrogen

chloride (1 M), brine and dried (MgSO₄). After concentration

under reduced pressure, ﬂash chromatography of the residue

[light petroleum:ether (25:1)] gave the title compound 82 (188

mg, 66%), a colourless oil, as a 1:1 mixture of epimers at C(3)

(Found: M^ϩϩ NH₄, 660.4654. C₃₈H₆₆NO₆Si requires M,

660.4659); ν_max/cm^Ϫ11733, 1509, 1214, 1005 and 835; δ_H0.05

and 0.08 (each 3 H, s, SiCH₃), 0.86 (3 H, t, J 7.5, 15-H₃), 0.93

[12 H, m, SiC(CH₃)₃, 8-CH₃], 1.40 [9 H, s, OC(CH₃)₃], 1.56

(5 H, m, 6-CH₃, 14-H₂), 1.74 (3 H, s, 12-CH₃), 2.02 (1 H, dd,

J 13.5, 7.5, 9-H), 2.10 (1 H, m, 9-HЈ), 2.53 (3 H, m, 2-H₂, 8-H),

2.68 (2 H, s, 5-H₂), 3.80 (3 H, s, OCH₃), 3.94 (1 H, t, J 6.5,

13-H), 4.64 (1 H, m, 3-H), 4.86 (1 H, s, 10-CH), 4.99 (2 H, s,

4-CH, 10-CHЈ), 5.04 (1 H, d, J 9.5, 7-H), 5.12 (1 H, d, J 7,

OCHHO), 5.17 (2 H, m, 4-CHЈ, OCHHO), 5.76 (1 H, s, 11-H)

and 6.84 and 7.01 (each 2 H, m, ArH); δ_CϪ5.0, Ϫ4.6, 10.1,

13.2, 15.8, 18.3, 20.5, 25.9, 28.0, 29.1, 31.4, 41.3, 41.7, 45.8,

55.7, 80.0, 80.6, 91.9, 114.5, 117.4, 126.1, 130.3, 134.7, 140.2,

144.2, 151.9, 154.5 and 169.9; m/z (C.I.) 660 (M^ϩϩ 18, 21%).

(6E,8S,11E,13R)-13-Ethyl-3-(4-methoxyphenoxy)methoxy-

6,8,12-trimethyl-4,10-dimethylenetrideca-6,11-dien-13-olide 85

2,6-Dichlorobenzoyl chloride (0.016 cm³, 0.111 mmol) was

added to triethylamine (0.017 cm³, 0.122 mmol) and the

hydroxy acid 84 (25 mg, 53 µmol) in tetrahydrofuran (0.5 cm³).

The mixture was stirred for 2 h, ﬁltered, diluted with toluene (25

cm³) and added slowly, over 2 h, to 4-(dimethylamino)pyridine

(65 mg, 0.53 mmol) in toluene (10.6 cm³) at 95 ЊC. When the

addition was complete, the mixture was stirred for 0.5 h, cooled

and concentrated under reduced pressure. The residue was dis-

solved in ether, washed with aqueous hydrogen chloride (1 M),

saturated aqueous sodium hydrogen carbonate, brine and dried

(MgSO₄). Concentration under reduced pressure and ﬂash

chromatography of the residue [light petroleum:ether (10:1)]

gave the title compound 85 (10.5 mg, 43%), as mixtures of epi-

mers at C(3) (Found: M^ϩϩ H, 455.2803. C₂₈H₃₉O₅requires M,

455.2797); ν_max/cm^Ϫ11734, 1647, 1622, 1508, 1442, 1243, 1214,

1079, 1015, 903 and 828; δ_H0.84 and 0.85 (1.2 H and 1.8 H, t,

J 7.5, 2Ј-H₃), 0.96 and 1.01 (1.2 H and 1.8 H, d, J 7, 8-CH₃),

1.40 (1.2 H, s, 6-CH₃), 1.63–1.76 (5.6 H, m, 6-CH₃, 12-CH₃,

1Ј-H₂), 1.81 (1.2 H, s, 12-CH₃), 2.03–2.30 (2 H, m, 9-H₂),

2.38 (0.4 H, m, 8-H), 2.53–2.92 (4.6 H, m, 2-H₂, 5-H₂, 8-H),

3.80 and 3.81 (1.8 H and 1.2 H, s, OCH₃), 4.63 (1 H, t, J 7,

13-H), 4.77 (1 H, m, 3-H), 4.84–5.32 (7 H, m, OCH₂O, 4-CH₂,

7-H, 10-CH₂), 5.86 and 5.88 (0.4 H and 0.6 H, s, 11-H) and

6.81–7.07 (4 H, m, ArH); δ_C8.6, 9.1, 14.7, 15.8, 16.0, 16.5, 20.3,

22.9, 25.2, 25.9, 33.1, 34.6, 39.9, 40.8, 42.0, 45.1, 45.2, 46.2,

55.7, 73.3, 76.8, 77.2, 78.1, 79.9, 91.57, 91.64, 113.8, 114.3,

114.4, 114.6, 115.1, 116.5, 117.1, 117.2, 126.4, 129.7, 130.5,

130.8, 133.2, 133.7, 134.1, 134.4, 143.0, 144.2, 145.1, 151.4,

151.5, 154.5, 154.6, 169.5 and 170.1; m/z (C.I.) 472 (M^ϩϩ 18,

18%), 455 (M^ϩϩ1, 10), 331 (63), 155 (45) and 124 (100).

(6E,8S,11E,13R)-13-tert-Butyldimethylsilyloxy-3-(4-methoxy-

phenoxy)methoxy-6,8,12-trimethyl-4,10-dimethylenepentadeca-

6,11-dienoic acid 83

Following the procedure outlined above for the synthesis

of the acid 86, the ester 82 (41 mg, 63.9 µmol) gave, after ﬂash

chromatography [light petroleum:ether (3:1–1:1)], the α,β-

unsaturated carboxylic acid 86 (8 mg, 30%) followed by the title

compound 83 (13 mg, 35%) as a colourless oil, a 1:1 mixture

of epimers at C(3) (Found: M^ϩϩ NH₄, 604.4032. C₃₄H₅₈NO₆Si

requires M, 604.4033); ν_max/cm^Ϫ13400–2300, 1714, 1509, 1216,

1006 and 835; δ_H0.05 and 0.09 (each 3 H, s, SiCH₃), 0.87 (3 H,

t, J 7.5, 15-H₃), 0.94 [12 H, m, SiC(CH₃)₃, 8-CH₃], 1.56 (5 H, m,

6-CH₃, 14-H₂), 1.74 (3 H, s, 12-CH₃), 2.03 (1 H, dd, J 13.5, 7.5,

9-H), 2.10 (1 H, m, 9-HЈ), 2.58 (3 H, m, 2-H₂, 8-H), 2.70 (2 H,

s, 5-H₂), 3.78 (3 H, s, OCH₃), 3.94 (1 H, t, J 6.5, 13-H), 4.66

(1 H, m, 3-H), 4.86 (1 H, s, 10-CH), 5.03 (3 H, m, 4-CH, 7-H,

10-CHЈ), 5.10 and 5.18 (each 1 H, d, J 7, OCHHO), 5.22 (1 H,

s, 4-CHЈ), 5.77 (1 H, s, 11-H) and 6.82 and 6.97 (each 2 H, d,

J 9, ArH); δ_CϪ5.0, Ϫ4.6, 10.1, 13.2, 15.8, 18.3, 20.5, 25.9, 29.1,

31.4, 39.9, 41.8, 45.7, 55.6, 80.0, 91.5, 114.4, 114.7, 117.2, 126.1,

130.1, 134.8, 140.2, 144.2, 151.5, 154.5 and 175.8; m/z (C.I.) 604

(M^ϩϩ 18, 2%), 455 (19), 331 (50) and 123 (100).

Acknowledgements

We thank the EPSRC for a studentship (to P. M. S.), Schering

Agrochemicals for support, and Dr P. Riordan of Schering for

helpful discussions.

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(6E,8S,11E,13R)-13-Hydroxy-3-(4-methoxyphenoxy)methoxy-

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84

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114.5, 115.1, 115.2, 117.2, 127.2, 130.2, 134.6, 139.3, 143.9,

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3556

J. Chem. Soc., Perkin Trans. 1, 1998, 3541–3556

Article Doi

Approaches to a synthesis of galbonolide B

DOI: 10.1039/a805856c

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