Synthesis of polyunsaturated constituents of phenolic lipids

Chemistry and Physics of Lipids

85 (1997) 157–174

Synthesis of polyunsaturated constituents of phenolic lipids¹

John H.P. Tyman*, N. Visani

Department of Chemistry, Brunel Uni6ersity, Uxbridge, Middlesex, UB8 3PH, UK

Received 22 October 1996; revised 10 December 1996; accepted 11 December 1996

Abstract

The diene, (ZZ)-[(8,11)-pentadecadienyl]salicylic acid, (or 2-hydroxy-6-[(ZZ)-pentadeca-8,11-dienyl]benzoic acid),

has been synthesised by two routes. In the ﬁrst, the key intermediate methyl or ethyl 2-hydroxy-6-(7-bromohep-

tyl)benzoate has been converted to methyl or ethyl 2-hydroxy-6-(10-hydroxydec-8-ynyl)benzoate and thence by

reaction of the corresponding bromide with 1-pentynylmagnesium bromide to methyl or ethyl 2-hydroxy-6-(pen-

tadeca-8,11-diynyl)benzoate. Selective reduction afforded methyl or ethyl 2-hydroxy-6-[(ZZ)-pentadeca-8,11-di-

enyl]benzoate. An attempt to employ the Grignard reagent from methyl 2-methoxy-6-(non-8-ynyl)benzoate and

reaction with 1-bromohex-2-yne was ineffective because of a side reaction of the former with ethylmagnesium

bromide to give a ketone. In the third approach ethyl 2-methoxy-6-methylbenzoate was alkylated with 1-iodote-

tradeca-7,10-diyne and the product selectively reduced as before to the O-methyl ether ethyl ester. A variety of C₁₄

intermediates has been prepared for the derivation of the 8(E),11(E), 8(E),11(Z) and 8(Z),11(E) stereoisomers by the

alkylation procedure. A similar methodology of alkylation can be adopted for obtaining corresponding trienes in

Science Ireland Ltd.

Keywords: Phenolic lipid; Anacardic acid; Dienes; Trienes; Synthesis; Alkynes

component of the nut-shell is anacardic acid (1;

m=15, n=0,2,4,6), a salicylic acid bearing a C₁₅

1. Introduction

alkyl, alkenyl, alkadienyl or alkatrienyl group in

Phenolic lipids are widely distributed in many

the 6-position (Tyman, 1979, 1991, 1996). Some

botanical and biological species most notably in

other examples are the C₁₃and C₁₅compounds (1;

the Anacardiaceae, for example Anacardium occi-

m=13,15, n=0,2) in the pistachio nut, Pistacia

dentale, the cashew tree, in which the principal

6era (Yalpani and Tyman, 1983) and C₁₇members

(1; m=17, n=6) in the African plum Spondias

mombin (Coates et al., 1994; Arogba, 1987). Nut-

* Corresponding author. Tel.: 01895 274000.

¹Long Chain Phenols, Part 34. Part 33, ref. 30.

PII S0009-3084(96)02654-0

158

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

meg, the liverwort, Schistochila appendiculata (As-

akawa et al., 1987), and brown algae (Kazlauskas

et al., 1980) are some other sources of saturated

and unsaturated anacardic acids, although the

unsaturated members are generally more proliﬁc

in a wide range of species including certain gerani-

ums (Walters et al., 1989), mushrooms (Gianetti

et al., 1978), and the Ginkgo biloba tree (Tyman,

1996; Itokawa et al., 1987).

Anacardium occidentale also contains 5-alkenyl-

resorcinols, the cardols (2, n=0,2,4,6) and 3-

alkenylphenols, the cardanols (3, n=0,2,4,6) and

similar structures with C₁₁and C₁₃homologues

are abundant in numerous species notably the

Grevillea (Tyman, 1996) and with higher homo-

logues in rye, Cereale secale (Kozubek and Ty-

man, 1995). Structures isomeric with the cardols

are the 3-alkenylcatechols, the urushiols (4; m=

15,17, n=0,2,4,6) of the Rhus genus such as Rhus

6ernicifera which contains not only the C₁₅,

8Z,11Z,14-triene (4, n=6) but the isomeric

The isolation of mixed anacardic acids ex-

tracted (Tyman et al., 1989) from, for example,

the cashew by ammoniated TLC (Tyman and

Morris, 1967) or by a column chromatographic

method (Nagabhushana and Ravindranath, 1995)

is laborious and their subsequent separation into

mono-, di- and triene constituents by argentation

chromatography (Jacobs and Tyman, 1971) is ex-

pensive and time-consuming although preparative

HPLC separations represent an advance in

methodology (Tyman, 1991). Synthesis from read-

ily available intermediates is nevertheless of inter-

est particularly of the diene and triene

constituents to obtain larger quantities and to aid

stereochemical structure/property studies.

Saturated anacardic acids (1; m=15, n=0)

were ﬁrst synthesised by the thermolysis of basic

copper salts of 2-alkylbenzoic acids (Durrani and

Tyman, 1979a) and in improved yields by alkyl-

lithium addition to the aryne from 2-ﬂuoro or

3-ﬂuoromethoxybenzene (Durrani and Tyman,

1979b), a method which was applied to the syn-

thesis of (15:1)-anacardic acid, ginkgolic acid (Ty-

man, 1976). More recently saturated and

monounsaturated anacardic acids have been pre-

pared (Visani, 1988; Tyman and Visani, 1996) by

the C-alkylation of the readily available methyl or

ethyl 6-methyl-2-methoxybenzoates. The recently

described synthesis of (15:2)-anacardic acid, anac-

ardic acid diene (Zehnter and Gerlach, 1995), by

the Diels-Alder addition of 1-methoxycyclohexa-

1,3-diene (obtained from Birch reduction of

methoxybenzene, followed by conjugation) with

homologous propiolic esters, an extension of

work in which methyl propiolate was employed

(Kanakam et al., 1989) and with subsequent steps

by strategies employed in our own work for the

synthesis of (15:2)-cardol (Baylis et al., 1981) and

(15:2)-cardanol (Caplin and Tyman, 1982), has

prompted us to publish our results. This was

completed some years ago (Visani, 1988) and

referred to in a review but with no practical

details (Tyman and Visani, 1986).

8Z,11E,13E

and

8Z,11Z,13Z

compounds

(Miyakoshi et al., 1991). The thitsiols of Burmese

lac, and other South Eastern Asian lacs, from

Melanorrhea usitata are isomeric 4-alkenylcate-

chols (5; m=15,17, n=0,2,4,6) (Sargent and

Wanachareontrajkul, 1989).

Many of these species are pest-resistant and

indeed the properties particularly of anacardic

acids in this respect are legendary (Tyman, 1979).

In more recent work a wide variety of other

properties have been revealed. Thus they have

been found to be inhibitory towards methicillin-

resistant Staphylococcus aureus (MSA) (Muroi

and Kubo, 1996), to a number of enzymes such as

prostaglandin synthase (Grazzini et al., 1991),

glycerol-3-phosphate dehydrogenase (Irie et al.,

1996), and i-lactamase (Coates et al., 1994). Fur-

thermore they have proved useful molluscicides

(Sullivan et al., 1982), thus of incidental interest

for the control of schistosomiasis (Kubo et al.,

1986), to have antitumour properties (Kubo et al.,

1993a), and further applications for their long-es-

tablished antimicrobial activity (Kubo et al.,

1993b). Many potential technical uses (Tyman,

1996) have been discovered and the more unsatu-

rated members such as the diene and triene ap-

pear to have greater interest in structure/property

studies (Sullivan et al., 1982).

1.1. Synthesis of dienes

Synthetic work towards the dienes (and trienes)

of cardanol, cardol, urushiol and thitsiol primar-

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

159

ily by acetylenic and Wittig reaction routes (Ty-

man, 1996) has been more extensive than with the

anacardic acids where alkylation and acetylenic

methods have been generally adopted. The ulti-

mate objective in our work was to synthesise the

four stereoisomers in the diene series, namely the

8(Z),11(Z), the 8(E),11(E), the 8(Z),11(E), and

the 8(E),11(Z) compounds, commencing with the

natural 8(Z),11(Z) isomer and to extend the work

to the syntheses of stereoisomeric trienes.

In the acetylenic approach (Scheme 1), an ArC₁

synthon (6), ethyl 2-methoxy-6-methylbenzoate

was reacted with 6-chlorohexanol (HO-protected

with ethyl vinyl ether) to afford an ArC₇interme-

diate (7; R=Me) (ethyl 6-(7-hydroxyheptyl)-2-

methoxybenzoate). From the derived bromide (8;

R=Me), with lithioprop-2-ynol (HO-protected as

the t-butyldimethylsilyl ether) an ArC₁₀hydroxy

intermediate, ethyl 6-(10-hydroxy-8-decynyl)-2-

methoxybenzoate (9; R=Me) was obtained and

thence the ArC₁₀bromide (10; R=Me) which

with a C₅synthon (1-pentyne), afforded the ArC₁₅

diyne (11; R=Me), ethyl 2-methoxy-6-(pen-

tadeca-8,11-diynyl)benzoate. Catalytic reduction

in ethanol containing quinoline with Pd-BaSO₄/

hydrogen gave the corresponding diene, ethyl

(Z,Z)-2-methoxy-6-(pentadeca-8,11-dienyl)benzo-

ate (12; R=Me) and hydrolysis/demethylation

with lithium t-butyl thiolate afforded (1; m=15,

n=4).

Scheme 2. Attempted synthesis of 8Z,11Z-diene by the route

ArC₁ArC₇ArC₉ArC₁₅

.

4-TsCl, pyr.; DMSO, LiBr, (iii) BuLi, THF,

HCꢀCCH₂OSiBu^tMe₂, HMPA; H₃O⁺, (iv)

PBr₃, pyr., Et₂O, (v) HCꢀCC₃H₇, EtMgBr,

THF; CuI, heat, 50°C, (vi) Pd-BaSO₄/H₂, quino-

line, EtOH, (vii) LiSBu^t, DMF.

In a variation of this method (shown in Scheme

1), (7) was demethylated and converted to the

bromide with boron tribromide to give ethyl 6-(7-

bromoheptyl)-2-hydroxybenzoate (8; R=OH).

Reaction of this with lithioprop-2-ynol (HO-pro-

tected as before) afforded ethyl 6-(10-hydroxy-8-

decynyl)-2-hydroxybenzoate (9; R=OH). The

bromide (10; R=Br) formed with ethereal phos-

phorus tribromide containing pyridine, reacted

with excess 1-pentynylmagnesium bromide in

THF containing copper(I) iodide to give (11; R=

OH),

ethyl

2-hydroxy-6-(pentadeca-8,11-

diynyl)benzoate. This was catalytically reduced to

the diene (12; R=OH) as for the methyl ether

and the product hydrolysed to afford (1; m=15,

n=4).

1.1.1. Reagents

1.1.2. Reagents

(i) LiNⁱPr₂, THF, HMPA; Cl(CH₂)₆-

OCH(Me)OEt, −70°C to 65°C, heat; H₃O⁺, (ii)

(ii) (8, R=OH), BBr₃, CH₂Cl₂, −70°C to

20°C, (iii) Excess, LiCꢀCCH₂OCH(Me)OEt,

THF, HMPA, (iv) PBr₃, pyr., Et₂O, (v) Excess,

BrMgCꢀCC₃H₇, CuI, THF, (vi) Pd-BaSO₄/H₂,

quinoline, (vii) EtOH, KOH; H₃O⁺.

In the second acetylenic approach (Scheme 2), a

related ArC₇intermediate (13), methyl 2-

methoxy-6-(7-tosylheptyl)benzoate was converted

with the lithium acetylide-diaminoethane complex

to a terminal alkyne, ArC₉(14), methyl 2-

methoxy-6-(8-nonynyl)benzoate, but attempts to

react this with the C₆synthon, 1-bromo-2-hexyne,

to form (15) did not succeed due to a side-reac-

tion of the methoxycarbonyl group, resulting in a

ketone (16).

Scheme 1. Synthesis of 8Z,11Z-diene by the route, ArC₁

ArC₇ArC₁₀ArC₁₅

.

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J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

1.1.3. Reagents

(i) LiN^IPr₂, THF, HMPA, Cl(CH₂)₆-

OCH(Me)OEt, −70°C to 65°C, heat; H₃O⁺, (ii)

4-TsCl, pyr., heat, (iii) LiCꢀCH–H₂N-

(CH₂)₂NH₂, DMSO, 10°C, (iv) THF, EtMgBr;

CuCl, BrCH₂CꢀCC₃H₇.

In the alkylation strategy in our work, ethyl

6-methyl-2-methoxybenzoate (6) was alkylated

with a diunsaturated C₁₄component, 1-iodotetra-

7,11-diyne (18), to afford the ArC₁₅diyne (11;

R=Me) from which the ArC₁₅diene (12; R=

Me) was obtained by catalytic reduction. The

required product (1; m=15, n=4) was derived by

hydrolysis and demethylation (Scheme 3).

1.1.4. Reagents

(i) LiNPrⁱ₂, THF, HMPA; I(CH₂)₆Cꢀ

CCH₂CꢀCC₃H₇, −70°C to 25°C, (ii) Pd-

BaSO₄/H₂, EtOH, quinoline, (iii) LiSBu^t, DMF.

The alkylation of (6) is applicable to other

intermediates for the synthesis of anacardic acids

having the ﬁrst double bond at other positions, at

for example the 4-position. Thus, the reaction of

(6) with HO-protected 3-chloropropanol led to

ethyl 6-(4-hydroxybutyl)-2-methoxybenzoate.

The required C₁₄diyne reactant, 1-iodote-

tradeca-7,10-diyne (19), employed for Scheme 3

was synthesised by an acetylenic route (Scheme

4(a)). 6-Chloro or 6-bromohexan-1-ol protected

as the 1-ethoxyethyl ether was reacted with

lithium acetylide to form 8-(1-ethoxyethoxy)oct-1-

yne (17). Its magnesiobromo derivative was re-

acted with 1-bromohex-2-yne in THF containing

cuprous chloride and removal of the protective

group afforded 1-hydroxytetradeca-7,10-diyne

(18). Alternatively in a study of the relative effec-

tiveness of protective groups, deprotected (17) was

converted to the t-butyldimethylsilyl ether which

was then reacted with 1-bromohex-2-yne as be-

Scheme 4. Synthesis of stereoisomeric diene C₁₄alkylation

reactants.

fore, followed by removal of the protective group.

Reaction of the trimethylsilyl (TMS) ether of (18)

with sodium iodide in acetonitrile gave 1-iodote-

tradeca-7,10-diyne (19). Catalytic reduction of the

diyne (18) with palladium-barium sulphate in the

presence of quinoline resulted in 1-(Z,Z)-1-hy-

droxytetradeca-7,10-diene (20). These approaches

are depicted in Scheme 4, which also shows the

preparation by the routes (b), (c) and (d), from

(17) of the three stereoisomeric tetradecadienols.

In (b), the magnesiobromo derivative of (17) was

reacted with (E)-1-bromohex-2-ene to afford the

7-yne-(E)10-ene (21) which upon catalytic hydro-

genation with Pd-BaSO₄gave 7(Z),10(E)-1-hy-

droxytetradeca-7,10-diene (22). By route (c),

reduction of (21) with sodium in ammonia af-

forded after deprotection, (E,E)-1-hydroxyte-

tradeca-7,10-diene (23). From route (d), (17) by

reaction with (Z)-1-bromohex-2-ene in THF con-

taining copper(I) chloride and deprotection, the

7(E),10(Z)-1-hydroxytetradeca-7,10-diene

(24)

was obtained.

1.1.5. Reagents

(a) (i) CH₂ꢀCHOEt, 4-TSA, (ii) LiCꢀCH,

NH₃, THF, HMPA, (iii) MeOH, HCl, (iv)

Bu^tMe₂Cl, DMF, imidazole; EtMgBr, THF;

CuCl, BrCH₂CꢀCC₃H₇; (v) Bu₄NF, THF, (vi)

Scheme 3. Synthesis of 8Z,11Z-diene by route ArC₁ArC₁₅

.

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

161

ses involved the selective catalytic reduction of an

internal triple bond in the presence of a terminal

double bond, in the compound hept-6-ene-4-yn-1-

ol, a procedure which was found impractical in

our work carried out with catalysts available 10

years earlier.

Me₃SiCl, pyr.; MeCN, NaI; (vii) Pd-BaSO₄, H₂,

EtOAc, quinoline, (in step (ii), 6-halogenohexan-

1-ol was alternatively treated with LiCꢀCH–

H₂NCH₂CH₂NH₂, THF, DMSO; MeOH, HCl.),

(viii) EtMgBr, THF, CuCl, BrCH₂CꢀCC₃H₇;

MeOH, HCl. (b) (i) EtMgBr, THF; CuCl, THF,

(E)–BrCH₂CHꢀCHC₃H₇, (ii) Pd-BaSO₄, H₂,

EtOAc, quinoline; MeOH, HCl. (c) (i) Na/NH₃,

THF, HMPA; MeOH, HCl. (d) (17) (i) EtMgBr,

THF; CuCl, THF, (Z)–BrCH₂CHꢀCHC₃H₇; Na/

NH₃, THF, HMPA; MeOH, HCl.

Since the use of the acetylenic bromide (10)

with a C₅reactant appeared unpromising, experi-

ments towards the triene (Visani, 1988) were di-

rected to the alkylation route by reaction of a

triunsaturated C₁₄iodide, from 1-hydroxytetra-

13-ene-7,10-diyne, with the carbanion of ethyl

2-methoxy-6-methylbenzoate. 1-Ethoxyethyl 7-oc-

tynyl ether (17) was converted to the magnesio-

bromo derivative with ethyl magnesium bromide

and reacted in THF containing copper(I) chloride

with 1-bromohex-5-ene-2-yne to give the 7,10-

diyn-13-ene (26). Removal of the protective group

with 1% methanolic hydrochloric acid afforded

the diynenol (27) which was converted to the

iodide (28) by conversion to the trimethylsilyl

ether in pyridine solution and reaction of the

TMS ether with sodium iodide in acetonitrile

solution. The carbanion of ethyl 2-methoxy-6-

methylbenzoate reacted with the iodide to give

ethyl 2-methoxy-6-pentadeca-8,11-diyn-14-enyl)-

benzoate (29) which was puriﬁed by ﬂash chro-

matography. Reduction with dibromoborane-

dimethyl sulphide complex resulted in the

8(Z),11(Z),14-triene (30) as shown in Scheme 5.

1.2. Synthesis of trienes

Compared with the diene series the synthesis of

trienes by acetylenic routes has met with greater

difﬁculties. Thus in the cardanol series attempts

to react the 3-methoxy analogue of the ArC₁₀

bromide (10), namely 3-(10-bromo-8-decynyl)-

methoxybenzene, with the mono Grignard reagent

of either penta-1,4-diyne (Brandsma and Verkui-

jsse, 1981) or pent-1-yne-4-ene (Brandsma, 1971)

followed by selective reduction of the triyne or

diynene were unsuccessful. Model experiments on

the selective catalytic hydrogenation of nona-4-

yn-1-ene to produce nona-1,4-diene proved im-

practical.

By contrast greater success has been obtained

in the urushiols (4), the thitsiols (5) and with the

compound,

5-methoxy-3-[(ZZ)-pentadeca-8,11,

14-trienyl]-1,2,4-trihydroxybenzene (25) by way of

Wittig reaction methodology.

1.2.1. Reagents

(i) 4-TSA, CH₂ꢀCHOEt, (ii) EtMgBr, THF;

CuCl, BrCH₂CꢀCCH₂CHꢀCH₂, (iii) MeOH,

HCl, (iv) Me₃SiCl, pyridine; MeCN, NaI, (v)

LNiPrⁱ₂, THF, HMPA, MeC₆H₃(OMe)CO₂Et, (vi)

(i-C₅H₁₁)BH, THF.

The experimental work (Sato, 1973) in which

the synthesis of the dimethyl ether of 3-[(ZZZ)-

pentadeca-8,11,13-trienyl]-catechol was reported

has not been revealed but recently (Miyakoshi et

al., 1991) full details of Wittig routes have been

described by another group for the 8(Z),11(Z),14

and 8(Z),11(E),13(E) triene isomers of (4; m=15,

n=6). Progress has also been made (Sargent and

Wangchareontrakul, 1989) with the synthesis of

thitsiols (5; m=15, n=4,6). A Wittig route (Sar-

gent and Wangchareontrakul, 1989) which in the-

ory could lead to the 8(Z),11(Z),14-triene in the

cardol series (2; n=6) was bypassed to give the

trihydroxymethoxy compound (25). These synthe-

2. Experimental procedures

2.1. Extraction of material

Natural cashew nut-shell liquid was extracted

from raw nuts (Anacardium occidentale) as de-

scribed (Tyman, 1973).

162

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

University of Swansea. Elemental analyses were

2.2. Chromatography

carried out by Butterworth Laboratories.

TLC was performed on silica gel GF254,

column chromatography on silica gel (60–120

mesh) (BDH), ﬂash chromatography with

Kieselgel 60 (40–63 mv) (Merck), dry ﬂash chro-

matography with Kieselgel 60H and with 60GF

(Merck) and with alumina (aluminiumoxid 60GF,

neutral type E (Merck)). Argentation TLC was

performed on HPTLC plates containing silica gel

60 incorporating 10% silver nitrate (Tyman and

Morris, 1967; Jacobs and Tyman, 1971).

2.4. Preparation of general intermediates

All reactions were effected in anhydrous condi-

tions under nitrogen.

C₅and C₆alkenyl and alkynyl bromides were

prepared by three methods, (1) by reaction of the

alkenol or alkynol in diethyl ether containing

pyridine, with phosphorus tribromide at −30°C,

(2) by reaction of the trimethylsilyl ether in ace-

tonitrile with lithium bromide (Moshidis, 1986)

and (3) from the 4-toluenesulphonate by reaction

in DMSO with lithium bromide (Kabalka et al.,

1986; Brandsma and Verkuijsse, 1981). By

method (1), 1-bromohex-5-ene, (E)-1-bromohex-

2-ene, 1-bromohex-2-yne, 1-bromohex-2-yne-5-

ene, and other bromides were obtained as given in

Section 2.7. By method (2), 1-bromo-9-decene and

2.3. Spectroscopy

Infrared spectra were recorded on a Perkin

Elmer 5100 instrument, liquids as neat ﬁlms or as

1

carbon tetrachloride solutions. H-NMR spectra

were obtained on a Varian CFT-20 (80 MHz)

instrument. Mass spectra were determined on a

modiﬁed AEI MS 902 instrument and accurate

mass measurements by the SERC centre at the

methyl

6-(7-bromoheptyl)-2-methoxybenzoate

were derived. Method (3) was employed for ethyl

6-(7-bromoheptyl)-2-methoxybenzoate and 1-bro-

mooct-7-yne.

Alkyl iodides were obtained from the

trimethylsilyl (TMS) derivative with sodium io-

dide in acetonitrile containing TMS chloride

(Morita et al., 1979). 1-Iodooct-7-yne, 1-iodote-

tradeca-7-ene and 1-iodooctadeca-9-ene and other

iodides as indicated in Section 2.7 were prepared

by this method.

C₆Alkynols and alkenols envisaged as neces-

sary for the ArC₉+C₆route to the C₁₅diene were

adapted from standard routes. Thus (E)-hex-2-en-

1-ol was obtained from the dilithio derivative of

prop-2-yn-1-ol and 1-bromopropane followed by

Li/ammonia reduction. Hex-2-yn-1-ol was also

isolated and catalytically hydrogenated in ethanol

containing quinoline and Pd-BaSO₄to (Z)-hex-2-

en-1-ol. Hex-2-yn-1-ol was also derived from

dilithio salt of prop-2-yn-1-ol by reaction with

iodopropane and as described (Brandsma and

Verkuijsse, 1981) by reaction of lithio 1-pentyne

with paraformaldehyde in 81% yield.

Diunsaturated C₆components were also pre-

pared. Hex-5-en-2-yn-1-ol was synthesised from

the magnesiobromo derivative of prop-2-ynyl 1-

ethoxyethyl ether by reaction with 1-chloroprop-

Scheme 5. Synthesis of 8Z,11Z,14-triene.

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

163

2-ene in THF containing copper(I) chloride. Fol-

lowing removal of the ethoxyethyl group by acidic

methanolysis, the product was obtained in 35%

yield (required for C₆H₈O, m/z, 96.0575; found,

96.0576).

Hexa-2,5-diyn-1-ol (Brandsma, 1971) was pre-

pared from the foregoing prop-2-ynyl 1-

ethoxyethyl ether by reaction with 1-bromo-

prop-2-yne by reaction in THF containing cop-

per(I) chloride.

Methyl and ethyl 2-methoxy-6-methyl ben-

zoates were prepared as indicated (Hauser and

Pogany, 1980) but with minor modiﬁcations.

The alkylation of these compounds to satu-

rated, monoalkenyl and alkynyl compounds has

been described (Visani, 1988; Tyman and Visani,

1996) by conversion of the respective alkyl 2-

methoxy-6-methylbenzoate in THF at −70°C to

the carbanion with lithium diisopropylamide, ad-

dition of HMPA and then of the alkyl, alkenyl or

alkynyl halide.

Ethyl 2-hydroxy-6-methylbenzoate (1.00 g, 5.56

mmol) in dry THF (10 cm³) was converted to the

benzyl ether by treatment with sodium hydride

(0.29 g, 6.16 mmol) and after the addition of

tetrabutylammonium iodide (20 mg) benzyl chlo-

ride was introduced (0.70 g, 5.56 mmol). The

reaction mixture was stirred at ambient tempera-

ture for 24 h and then, after TLC monitoring,

addition of further catalyst and reﬂuxing for 24 h,

worked up to give (1.64 g) ethyl 2-benzyloxy-6-

methylbenzoate which was substantially pure by

TLC and was characterised chromatographically

and spectroscopically.

Methyl 2-hydroxy-6-methylbenzoate (1.00 g,

6.02 mmol) was converted to the methoxymethyl

ether (Corey and Venkateswalu, 1972; van Heer-

den et al., 1978), by stirring in dichloromethane

(10 cm³) containing the phase transfer catalyst

Adogen 464 (0.02 mmol), and sodium hydroxide

(0.36 g, 9.03 mmol) in water (3.5 cm³) at ambient

temperature for 20 min. Iodomethyl methyl ether

(Yung et al., 1978) (3.12 g, 24.09 mmol) was then

added and following reaction for 30 min, the

mixture was worked up by dilution with water

and dichloromethane extraction to give a red-

coloured liquid (1.63 g) which was puriﬁed by dry

ﬂash chromatography to afford methyl 2-

methoxymethyl-6-methylbenzoate (1.15 g) in 91%

yield. It was characterised by its ¹H- NMR and its

mass spectrum.

2.5. Protecti6e groups

A wide variety of protective groups were exam-

ined both for the aromatic component and the

respective side-chain material.

2.5.1. The aromatic component

Ethyl 2-hydroxy-6-methylbenzoate (3.0 g, 16.7

mmol) was converted to the TMS ether with

hexamethyldisilazane (4.02 g, 25.0 mmol) and a

catalytic quantity (2 drops) of TMS chloride by

reﬂuxing for 9 h. Concentration and distillation of

the residue afforded ethyl 6-methyl-2-trimethyl-

siloxybenzoate (3.50 g) in 83% yield, b.p. 104°C/

2.5.2. The side-chain component

The triphenylmethyl, the t-butyldimethyl and

the 1-ethoxyethyl groups were examined.

1-Hydroxyoct-7-yne (1.00 g, 7.94 mmol) was

converted to the trityl ether (Chaudhary and Her-

nandez, 1979) with trityl chloride (2.43 g, 8.73

mmol), 4-dimethylaminopyridine (0.05 g, 0.39

mmol) and triethylamine (2 cm³) in DMF (25

cm³) by stirring overnight at ambient temperature.

After work-up by dichloromethane extraction and

recovery and puriﬁcation by dry ﬂash chromatog-

raphy, 1-triphenylmethoxy-oct-7-yne was derived

as a yellow liquid (1.61 g) in 55% yield.

1

0.9 mm and characterised from its H-NMR and

mass spectra.

Ethyl 2-hydroxy-6-methylbenzoate (1.0 g, 6.67

mmol) was converted to the t-butyldimethylsilyl

ether (Corey and Venkateswalu, 1972) in DMF (6

cm³) containing imidazole (0.94 g, 13.9 mmol)

and reacted with dimethyl-t-butylsilyl chloride

(1.0 g, 6.67 mmol) in DMF (2 cm³) at 35°C

during 48 h to give ethyl 2-dimethyl-t-butylsiloxy-

6-methylbenzoate (1.55 g) after aqueous sodium

bicarbonate work-up and ethereal extraction. It

1-Dimethyl-t-butylsiloxyoct-7-yne was prepared

(Corey and Venkateswalu, 1972) in 99% yield

from 1-hydroxyoct-7-yne (2.0 g, 15.87 mmol) with

t-butyldimethylsilyl chloride (2.87 g, 19.04 mmol)

1

was characterised by TLC, and its H-NMR and

mass spectra.

164

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

the mixture maintained under reﬂux for 2–3 h.

The reaction mixture was quenched by the grad-

ual addition of saturated ammonium chloride and

stirred at ambient temperature to evaporate the

ammonia. Ethereal extraction, washing and evap-

oration afforded the crude product which was

puriﬁed by chromatography.

The combined alkynylation/reduction proce-

dure (Patterson, 1985) was also used. To 100%

ammonia containing ferric nitrate, lithium in

small pieces was added, the blue colour being

allowed to disappear between each addition. The

alkyne in THF was then introduced and the mix-

ture allowed to reﬂux for 1 h after which the

halide was added over 20 min and the mixture

allowed to reﬂux for 2 h. Lithium wire was then

introduced until a persistent blue colour remained

for 30 min. The reaction mixture was quenched

with saturated ammonium chloride and the am-

monia allowed to evaporate. The crude product

was extracted with ether and puriﬁed after con-

centration by distillation or chromatography.

and imidazole (2.70 g, 39.7 mmol) in DMF (4

cm³) by reaction at 35°C during 12 h. Aqueous

work-up, ethereal extraction followed by dry ﬂash

chromatography gave the pure derivative as a

clear liquid (3.78 g).

1-Ethoxyethyl ethers were prepared as de-

scribed (Tyman, 1979; Harwood, 1985). In the

general method used the alcohol (1 M) was added

dropwise to ethyl vinyl ether (2.8 M) cooled to

0°C and containing 4-toluenesulphonic acid (50

mg) while the temperature was maintained be-

tween 0–10°C. After 3 h the mixture was allowed

to warm to below 20°C, then cooled prior to the

addition of saturated potassium carbonate solu-

tion. After work-up by ethereal extraction, drying

and concentration, an almost theoretical yield of

the 1-ethoxyethyl ether of the respective alcohol

was obtained. In this way 3-chloropropyl 1-

ethoxyethyl ether, 7-chlorheptyl 1-ethoxyethyl

ether, prop-2-ynyl 1-ethoxyethyl ether and 1-

ethoxyethyl oct-7-ynyl ether were prepared.

2.6. General conditions for reduction of

carbon-carbon triple bonds

2.6.3. Hydroboration

Diisoamylborane was prepared (Dupont et al.,

1954) by adding an equal volume of a 1 M

solution of borane-THF complex to a 2 M solu-

tion of 2-methylbut-2-ene in THF kept at −5–

0°C. The mixture was stirred at 0–5°C for 2 h,

then transferred via a canula to the reaction ﬂask

containing the alkyne to be reduced.

Dicyclohexylborane was similarly prepared

from cyclohexene (2 mols) and borane-THF com-

plex in THF at −5–0°C. The resultant precipi-

tate was stirred at the same temperature for 1 h.

The alkyne in THF was added at 0°C and the

reaction monitored by TLC.

2.6.1. Catalytic hydrogenation

To a suspension of 5% Pd-BaSO₄(50% w/w) in

ethyl acetate, a solution of quinoline (1 drop/g

catalyst) in ethyl acetate was added and the mix-

ture shaken with hydrogen in a glass vessel for 20

min. The alkyne in ethyl acetate was added

through a septum and the mixture shaken at

ambient temperature until the theoretical uptake

of hydrogen had been achieved. The mixture was

ﬁltered through celite and the combined ﬁltrate

and washings, washed with dilute hydrochloric

acid, dried and evaporated to give the crude

product which was puriﬁed chromatographically.

In this way, (Z)-hex-2-en-1-ol and (Z)-1-bromo-

hex-2-ene and other compounds were derived as

described in the experimental.

The dibromoborane-dimethylsulphide complex

(1 M) in dichloromethane was also used by addi-

tion to the alkynyl compound in 1,2-

dichloroethane at 10–15°C during 1–2 h. The

product was puriﬁed by chromatography.

2.6.2. Alkali metal-ammonia reduction

2.7. Synthesis of dienes and trienes

To 100% ammonia small pieces of sodium (3

mol) were added. The alkyne in THF containing

10% HMPA was introduced to the solution and

All reactions were carried out in dry conditions

under nitrogen.

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

165

2.7.1. Ethyl 6-(7-hydroxyheptyl)-2-

methoxybenzoate (7)

2.7.3. Ethyl 6-(7-bromoheptyl)-2-hydroxybenzoate

(8; R=OH)

n-Butylithium (38.9 mmol) was added to a solu-

tion of diisopropylamine (38.9 mmol) in dry THF

(120 cm³) under nitrogen and the mixture stirred

at ambient temperature for 15 min. Ethyl 2-

methoxy-6-methylbenzoate (5.0 g, 27.8 mmol) in

dry THF (60 cm³) was added to the mixture at

−70°C and after 5–10 min HMPA (10 cm³) was

introduced into the orange-red solution followed

by 1-ethoxyethyl 6-chloroethyl ether (8.69 g, 41.7

mmol). After the reaction mixture had been

stirred at −70°C for 7 h it was heated at 90°C for

16 h, cooled and then worked up by pouring into

dilute aqueous sulphuric acid which removed the

protective group. Puriﬁcation of the crude

product isolated by ethereal extraction and con-

centration, by distillation, b.p. 165°C/0.125

mmHg, afforded the pure product as a pale or-

ange oil (4.45 g) in 60% yield; w_max3600–3300

(OH), 1725 (CꢀO), 1600, 1580, 1465, 1265 (C–O)

cm⁻¹; l (CDCl₃) 7.3–6.5 (m, 3H, ArH), 4.3 (q, 7

Hz, 2H, OCH₂CH₃), 3.7 (s, 3H, OMe), 3.55 (t, 7

Hz, 2H, CH₂OH), 2.5 (t, 8 Hz, 2H, ArCH₂), 1.65

(s, 1H, D₂O exch., CH₂OH), 1.6–1.1 (m, 10H,

(CH₂)₅). In a similar way the corresponding

methyl ester was derived (required for C₁₆H₂₄O₄,

C, 68.53, H, 8.63; found, C, 68.90, H, 8.86%).

Ethyl 6-(7-hydroxyheptyl)-2-methoxybenzoate

(4.0 g, 13.6 mmol) in dichloromethane (50 cm³)

and boron tribromide (19.0 g) in dichloromethane

(30 cm³) were separately cooled to −75°C and

then slowly mixed at that temperature. After 5

days at that temperature during which the mix-

ture was monitored by TLC, it was poured into

diethyl ether (300 cm³), and water (400 cm³) con-

taining hydrobromic acid (10 cm³). The recovered

organic material was puriﬁed by column chro-

matography to give the product as the major

fraction (2.58 g) in 53% yield as a yellow liquid;

w_max3060, 1720 (CꢀO, ester), 1670, (CꢀO, H-

bonded), 1600, 1575, 1450 cm⁻¹; l (CDCl₃) 12.0

(s, 1H, D₂O exch., HOAr), 7.3–6.5 (m, 3H, HAr),

4.35 (q, 2H, 7 Hz, OCH₂CH₃), 3.35 (t, 2H, 6 Hz,

CH₂Br), 3.1–2.7 (m, 2H, CH₂Ar), 2.2–1.2 (m,

13H, (CH₂)₅+OCH₂CH₃); m/e, 344 (M⁺, 5%),

298, 296, (M⁺−OEt, 16%).

Some 2-hydroxy-6-(7-bromoheptyl)benzoic acid

(0.5 g) was also formed.

2.7.4. Methyl and ethyl

6-(7-bromoheptyl)-2-methoxybenzoate (8;

R=Me)

Two methods were used for this compound.

The ﬁrst from the methyl ester and the second

from the 4-tosyl derivative of the ethyl ester.

2.7.2. Methyl

6-(4-hydroxybutyl)-2-methoxybenzoate

(1) Methyl

6-(7-hydroxyheptyl)-2-methoxyben-

Methyl 2-methoxy-6-methylbenzoate (5.0 g,

27.78 mmol) was converted to the carbanion as in

the preceding example and reacted with 1-

ethoxyethyl 3-chloropropyl ether (6.95 g, 33.33

mmol) in THF containing HMPA and diglyme as

cosolvents ﬁrst at −70°C during 5–6 h and then

at ambient temperature. Work-up as before gave

a dark orange liquid (12.21 g) which was puriﬁed

by ﬂash chromatography with ethyl acetate/light

petroleum to give, after substantial recovery of

the starting material, the product as an orange

liquid (1.13 g) in 23% yield; w_max3600–3300 (OH),

zoate (0.5 g, 1.79 mmol), chlorotrimethylsi-

lane (0.49 g, 4.47 mmol) and lithium bromide

(0.31 g, 3.57 mmol) were reacted in dry ace-

tonitrile (4 cm³) by reﬂuxing for 48 h to give

a crude product which after isolation was

puriﬁed by preparative TLC (30% ethyl ac-

etate/light petroleum) to afford a pale yellow

liquid (0.23 g) in 37% yield; w_max3060, 3000,

1730 (CꢀO), 1600, 1580, 1470, 1265 cm⁻¹; l

(CDCl₃) 7.0–6.3 (m, 3H, HAr), 3.6 (s, 3H,

CO₂CH₃), 3.5 (s, 3H, OCH₃), 2.95 (t, 6 Hz,

2H, CH₂Br), 2.35 (t, 5 Hz, CH₂Ar), 1.5–1.1

(m, 10H, (CH₂)₅); m/e, 344, 342 (M⁺, 2%).

Found, 342.0821; C₁₆H₂₃O⁷₃⁹Br requires

342.0831.

1730 (CꢀO), 1600, 1580, 1470, 1270 (C–O) cm⁻¹

;

l (CDCl₃) 7.2–6.8 (m, 3H, ArH), 3.8–3.4 (m, 5H,

CO₂Me+CH₂OH), 3.2 (s, 3H, OMe), 2.5 (m, H,

ArCH₂), 2.05 (s, 1H, D₂O exch., OH), 1.8–1.3 (m,

4H, 2CH₂).

(2) Ethyl 2-methoxy-6-(7-tosyloxyheptyl)benzoate

was prepared from the alcohol (7) in pyridine

166

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

cm⁻¹; l (CDCl₃) 10.2 (s, 1H, D₂O exch. HOAr),

solution with 4-toluenesulphonyl chloride.

The tosyl ester (0.62 g, 1.43 mmol) in DMSO

(5 cm³) was treated with lithium bromide

(0.19 g, 2.14 mmol) and the mixture heated at

70°C for 1.5 h. Following dilution in ice-cold

water and ethereal extraction the product,

ethyl 2-methoxy-6-(7-bromoheptyl) benzoate,

(0.49 g) formed in 99% yield was found to be

substantially pure.

7.3–6.7 (m, 3H, HAr), 4.6 (q, 2H, OCH₂CH₃), 4.4

(t, 2H, CH₂OH), 3.3–2.9 (m, 2H, CH₂CꢀC),

2.5–2.1 (m, 3H, (1H D₂O exch.), CH₂Ar+

CH₂OH), 2.0–1.9 (m, 13H, (CH₂)₅+CH₃); m/e

273 (M⁺−OEt, 6%). Found: C, 72.5; H, 8.7.

C₂₄H₂₈O₄requires C, 72.2; H, 8.5%.

2.7.7. Ethyl 6-(10-hydroxy-8-decynyl)-2-

methoxybenzoate (9, R=Me)

The preceding method was superior to the use

of lithamide to generate the acetylide ion from the

1-ethoxyethyl 2-propynyl ether which gave a 41%

yield of the product. Variations such as employing

the 4-toluenesulphonyl ester of prop-2-ynol and

its t-butylsilyldimethyl ether were not useful alter-

natives. The latter experiment, with t-

butyldimethylsiloxy 2-propynyl ether (1.98 g, 10.9

mmol) and ethyl 6-(7-bromoheptyl)-2-methoxy-

benzoate (1.30 g, 3.64 mmol) gave ethyl 6-(10-t-

butyldimethylsiloxy-8-decynyl)-2-methoxybenzo-

ate (0.48 g). The alcohol protective group was

removed by stirring the compound with tetrabuty-

lammonium ﬂuoride (3 moles) in THF (50 cm³) to

give ethyl 6-(10-hydroxy-8-decynyl)-2-methoxy-

benzoate.

The acetylenic alcohol was accompanied by

0.51 g of the propynyl ether, ethyl 2-methoxy-6-

(7-prop-2-ynoxyheptyl)benzoate; w_max3300, 2930,

2860, 2100 (CꢀC), 1725 (CꢀO), 1600, 1580, 1470

cm⁻¹; l (CDCl₃) 7.3–6.6 (m, 3H, HAr), 4.4 (q, 8

Hz, 2H, OCH₂CH₃), 4.1 (d, 5 Hz, 2H, OCH₂Cꢀ

C), 3.8 (s, 3H, OCH₃), 3.5 (t, 3H, 2H,

(CH₂)₅CH₂O), 2.4 (t, 1H, CꢀCH), 1.6–1.3 (m,

10H, (CH₂)₅), 1.0 (t, 3H, CH₂CH₃); m/e 332

(M⁺). Found 332.1987. C₂₀H₂₈O₄requires

332.1981.

2.7.5. Methyl 6-(7-iodoheptyl)-2-methoxybenzoate

Methyl 6-(7-hydroxyheptyl)-2-methoxybenzoate

(0.5 g, 1.78 mmol) was converted to the TMS

ether with chlorotrimethylsilane (0.23 g, 2.14

mmol) in the presence of pyridine (0.34 g, 4.28

mmol). After removal of excess pyridine, reaction

of the crude TMS ether with sodium iodide (0.40

g, 2.67 mmol) in reﬂuxing acetonitrile (15 cm³)

containing chloromethylsilane (0.29 g, 2.67 mmol)

during 1 h gave after work-up and puriﬁcation the

iodide as a pale yellow liquid (0.50 g) in 72%

yield; w_max3080, 3010, 1735 (CꢀO, ester), 1600,

1580, 1475, 1275 (C–O) cm⁻¹; l (CDCl₃) 7.0–6.3

(m, 3H, HAr), 3.6 (s, 3H, CO₂CH₃), 3.5 (s, 3H,

OCH₃), 2.95 (t, 6 Hz, 2H, CH₂I), 2.35 (t, 5 Hz,

2H, CH₂Ar), 1.5–1.1 (m, 10H, (CH₂)₅). m/e, 390,

(M⁺, 19%).

2.7.6. Ethyl 6-(10-hydroxy-8-decynyl)-2-

hydroxybenzoate (9; R=H)

1-Ethoxyethyl 2-propynyl ether (prepared from

prop-2-ynol and ethyl vinyl ether) (0.56 g, 4.37

mmol) under nitrogen in THF (10 cm³) at 0°C

was slowly treated with n-butyl-lithium (3.45 ml,

1.27 M). After the mixture had been stirred for 1

h at 5–10°C, ethyl 6-(7-bromoheptyl)-2-hydroxy-

benzoate (0.5 g, 1.46 mmol) in THF (10 cm³) was

introduced followed by HMPA (2 cm³). The mix-

ture was stirred for 19 h and was monitored by

TLC. When reaction was complete the mixture

was poured into iced water containing dilute sul-

phuric acid. Ethereal extraction afforded the

crude product which was puriﬁed by preparative

TLC to give a viscous orange oil (0.26 g), in 56%

yield; w_max3600–3200 (OH), 2240, 2210 (CꢀC),

1720, 1650, (phenolic OH), 1600, 1580, 1450

2.7.8. Methyl 6-(10-bromo-8-decynyl)-2-

methoxybenzoate (methyl ester corresponding

to 10)

Methyl

6-(10-hydroxy-8-decynyl)-2-methoxy

benzoate (0.3 g, 0.94 mmol), and phosphorus

tribromide (0.085 g, 0.31 mmol) were reacted in

diethyl ether containing pyridine in catalytic

amount to give after column chromatography

(20% diethyl ether in light petroleum) the product

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

167

as a yellow liquid (0.28 g) in 78% yield; w_max3070,

2240 (CꢀC), 1730, (CꢀO), 1665, 1605, 1580, 1470

cm⁻¹; l (CDCl₃) 7.5–6.6 (m, 3H, HAr), 3.8–3.9

(m, 4H, OCH₂CH₃+CH₂Br), 3.6 (s, 3H, OCH₃),

3.1–2.7 (m, 2H, CH₂Ar), 2.5–2.0 (m, 2H,

CH₂CꢀC), 1.8–1.1 (m, 10H, (CH₂)₅), 0.9 (t, 6

Hz, 3H, OCH₂CH₃); m/e, found 380.0996.

C₁₉H₂₅O⁷₃⁹Br requires 380.0988.

(5.97 g) in 72% yield. Acidic methanolysis gave

1-hydroxy-7-octyne.

This alcohol (2.0 g, 15.9 mmol) with t-

butyldimethylsilyl chloride (2.87 g, 19.0 mmol) in

DMF (4 cm³) containing imidazole (2.70 g, 29.7

mmol) was reacted at 35°C for 12 h. Work-up by

dilution with diethyl ether, water washing and

puriﬁcation by dry ﬂash chromatography afforded

the product as a clear liquid (3.78g) in 99% yield.

The ethyl ester (10, R=Me) was prepared sim-

ilarly.

2.7.9.3. 1-Hydroxytetradeca-7,10-diyne (18)

2.7.9.3.1. Method 1. 1-t-Butyldimethylsiloxy-7-

octyne (3.50 g, 14.6 mmol) was treated with ethyl-

magnesium bromide (2.91 g, 21.9 mmol) in THF

at 40°C. To the magnesiobromo derivative cop-

per(I) chloride (100 mg) and 1-bromo-2-hexyne

(2.81 g, 17.5 mmol) were added and the reaction

mixture heated for 2 h at 50–55°C. After cooling

and work-up with aqueous ammonium chloride,

ethereal extraction and puriﬁcation of the recov-

ered crude product by dry ﬂash chromatography

1-t-butyldimethylsiloxytetradeca-8,11-diyne was

obtained as a pale yellow liquid (3.80 g) in 81%

yield; m/e, found 320.2539. C₂₀H₃₆OSi, requires

320.2535. 1-Hydroxytetradeca-8,11-diyne was ob-

tained as a pale yellow liquid (0.27 g) in 52% yield

from the silyl ether (0.8 g, 2.50 mmol) with tetra-

butylammonium ﬂuoride (1.96 g, 7.50 mmol) in

THF (20 cm³) by reaction over 12 h, aqueous

dilution, ethereal extraction, and recovery of the

crude product which was puriﬁed by dry ﬂash

chromatography (20% ethyl acetate and light

petroleum); w_max3300–3100 (O–H), 2980, 2240

(CꢀC) cm⁻¹; l (CDCl₃) 3.6–3.4 (m, 5H,

CH₂OH+CꢀCCH₂CꢀC, 1H D₂O exch.), 2.3–

2.0 (m, 4H, 2, CH₂CꢀC), 1.9–1.2 (m, 2,

CH₂CꢀC+(CH₂)₄+CH₂CH₃); m/e, found

206.1681. C₁₄H₂₂O requires 206.1671.

2.7.9. Ethyl 2-methoxy-6-

(pentadeca-8,11-diynyl)benzoate (11; R=Me)

This compound was prepared by two methods.

In Method A, ethyl 2-methoxy-6-methylbenzoate

was alkylated with 1-iodotetradeca-7,10-diyne and

in Method B, the preceding ArC₁₀bromide was

alkylated with 1-pentynyl bromide.

2.7.9.1. Method A, 1-iodotetradeca-7,10-diyne

(19). 6-Chlorohexan-1-ol or the bromo compound

was converted to the 1-ethoxyethyl derivative by

reaction with ethyl vinyl ether as described and

thence to 1-ethoxyethyl 7-octynyl ether with

lithium acetylide or the lithium acetylide-di-

aminoethane complex. After removal of the pro-

tective group, 1-hydroxy-7-octyne was converted

to the t-butyldimethyl derivative. This C₈material

was then converted to the magnesiobromo deriva-

tive with ethylmagnesium bromide which was re-

acted with 1-bromo-2-hexyne to give the

t-butyldimethyl silyl ether of 1-hydroxy-7,10-te-

tradecadiyne in 81% yield. After removal of the

protective group with ammonium ﬂuoride, 1-

iodotetradeca-7,10-diyne was obtained from the

trimethylsilyl derivative in pyridine by treatment

with sodium iodide.

2.7.9.3.2. Method 2. 1-(1-Ethoxy)ethoxy-7-oc-

tyne (3.0 g, 16.5 mmol) in dry THF (30 cm³) was

reacted with ethylmagnesium bromide (12.4 cm³

from a pre-prepared solution containing (0.23 g/

cm³)), during 1 h at 50–60°C under nitrogen.

After the addition of copper(I) chloride (0.5 g),

the mixture was cooled to 30°C, treated with

1-bromohex-2-yne (2.92 g, 18.1 mmol) and then

reacted for 1 h at 60°C. Work-up with saturated

2.7.9.2. 1-t-Butyldimethylsiloxy-7-octyne. 1-(1-

Ethoxy)ethoxy-6-bromohexane (10.0 g, 39.5

mmol) and lithium acetylide-diaminoethane com-

plex (4.0 g, 43.5 mol) were reacted in DMSO (22

cm³) under nitrogen at 8–10°C during 2 h after

which the mixture was poured into ice water.

Extraction with light petroleum and recovery af-

forded the crude product which was puriﬁed by

dry ﬂash chromatography to give a pale yellow oil

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J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

ammonium chloride solution, ethereal extraction

and puriﬁcation of the crude product by dry ﬂash

chromatography afforded a pale yellow liquid

(3.29 g) in 72% yield consisting of the ethoxyethyl

derivative of 1-hydroxy-7,10-diyne; w_max3300,

2100 (CꢀC), 1450, 1440 cm⁻¹; l (CDCl₃) 4.5 (q,

5 Hz, 1H, OCHO), 3.7–3.1 (m, 4H, 2, OCH₂),

2.3–1.8 (m, 6H, 3, CꢀCCH₂), 1.8–1.0 (m, 11H,

(CH₂)₄+CH₂CH₃); m/e, 183 (M⁺−CH₃, 16%).

Removal of the protective group by acidic

methanolysis gave 1-hydroxy-7,10-diyne (18); m/e,

found 206.1681. C₁₄H₂₂O requires 206.1671.

1-Hydroxytetradeca-7,10-diyne (0.25 g, 1.21

mmol), chlorotrimethylsilane (0.16 g, 1.46 mmol)

and pyridine (0.23 g, 2.90 mmol) afforded the

TMS ether which by stirring with chlorotrimethyl-

silane (0.2 g, 2.05 mmol) and sodium iodide (0.51

g, 2.05 mmol) in dry acetonitrile (15 cm³), work-

up and puriﬁcation by dry ﬂash chromatography

gave the iodo compound, 1-iodotetradeca-8,11-

diyne (19), as an orange liquid (0.65 g).

Ethyl 2-methoxy-6-methylbenzoate (0.28 g,

1.44 mmol) was converted in THF solution un-

der nitrogen to the carbanion with lithium diiso-

propylamide (from n-butyl-lithium and diiso-

propylamine both in 2.02 mmol). Following the

addition of HMPA, the mixture was cooled to

−70°C and 1-iodotetradeca-7,10-diyne (0.55 g,

1.74 mmol) then added. After reaction over 10 h

the crude product was isolated by ethereal extrac-

tion. Puriﬁcation by dry ﬂash chromatography

with diethyl ether and light petroleum afforded a

pale yellow liquid (0.48 g) comprising ethyl 2-

methoxy-6-(pentadeca-8,11-diynyl)benzoate (11,

R=Me), in 78% yield; w_max3310, 3100, 2960,

2860, 1750 cm⁻¹(CꢀO); l (CDCl₃) 7.2–6.6 (m,

3H, HAr), 4.36 (q, 7 Hz, 2H, OCH₂CH₃), 3.8 (s,

3H, OCH₃), 3.5 (t, 2H, CꢀCCH₂CꢀC), 2.5 (t,

2H, CH₂Ar), 2.3–1.3 (m, 19H, 2CH₂CꢀC,

(CH₂)₅, CH₂CH₃).

(10 cm³). After 10 min ethyl 6-(10-bromo-8-de-

cynyl)-2-methoxy-benzoate (0.31 g, 0.785 mmol)

in THF (10 cm³) was added, the reaction mixture

was kept at 50°C for 3 h and following continued

reaction at ambient temperature overnight,

worked up by dilution with ammonium chloride

solution. Ethereal extraction gave the crude

product which was puriﬁed by dry ﬂash chro-

matography to afford a viscous yellow liquid,

ethyl

2-methoxy-6-(pentadeca-8,11-diynyl)-ben-

zoate; w_max3070, 2940, 2870, 2120 (CꢀC), 1700

(CꢀO), 1600, 1470 cm⁻¹; l (CDCl₃), 7.3–6.7 (m,

3H, ArH), 3.8 (q, 2H, 6 Hz, OCH₂CH₃), 3.7 (s,

3H, OMe), 2.7 (q, 2H, 2 Hz, CꢀCCH₂CꢀC),

2.5 (t, 2H, ArCH₂), 2.4 (t, 4H, 2×CH₂CꢀC),

2.1 (m, 12H, (CH₂)₅+CH₂CH₂CH₃), 1.7 (t, 7 Hz,

3H, OCH₂CH₃), 1.3 (t, 3H, 8 Hz, CH₂CH₃).

2.7.10. Methyl 2-methoxy-6-(8-nonynyl)benzoate

(14)

For this preparation methyl 2-methoxy-6-(7-to-

sylheptyl)benzoate was ﬁrst obtained from methyl

6-(7-hydroxyheptyl)-2-methoxybenzoate (9.81 g,

18.9 mmol), 4-toluenesulphonyl chloride (8.25 g,

43.3 mmol), and pyridine (4.56 g, 57.7 mmol) at

0°C with monitoring of the reaction mixture by

TLC. After 5 h, work-up with water (10 cm³), and

extraction with diethyl ether (90 cm³), the crude

product (14.3 g) obtained was puriﬁed by ﬂash

chromatography (ethyl acetate and light

petroleum). A yellow liquid (5.37 g) was obtained

in 43% yield together with a by-product which

appeared spectroscopically to be ethyl 4-toluene-

sulphonate (5.2 g).

The preparation of the nonynyl compound

from the foregoing tosyl derivative with lithium

acetylide in THF/HMPA was not successful

whereas with the lithium acetylide-diaminoethane

complex, reaction proceeded well.

Lithium acetylide-diaminoethane complex (0.22

g, 2.42 mmol) under nitrogen in DMSO (1.5 cm³)

was treated at 10°C with methyl 2-methoxy-6-(7-

tosylheptyl)benzoate (1.05 g, 2.30 mmol) in dry

THF (10 cm³) and after stirring for 3 h, the

reaction mixture was diluted with water and ex-

tracted with light petroleum to give the crude

product which was puriﬁed by dry ﬂash chro-

matography to give a pale yellow liquid (0.49 g) in

2.7.9.4. Method B ( for ethyl 2-methoxy-6-(pen-

tadeca-8,11-diynyl)benzoate (11, R=Me). To 1-

pentyne (1.00 g, 14.7 mmol) in THF (7 cm³),

ethylmagnesium bromide (2.54 g, 1.1 mmol) was

added and after complete reaction at 40°C during

30 min, half of the solution was treated under

nitrogen with copper(I) iodide (100 mg) and THF

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

169

74% yield; w_max3300 (CꢀCH), 2130 (CꢀC),

1735 (CꢀO), 1270 cm⁻¹(C–O); l (CDCl₃) 6.9–

6.2 (m, 3H, HAr), 3.5 (s, 3H, CO₂CH₃), 3.4 (s,

3H, OCH₃), 2.2 (t, 7 Hz, 2H, CH₂Ar), 2.1–1.7 (m,

2H, CH₂CꢀC), 1.6 (t, 2 Hz, 1H, CꢀCH), 1.5–

0.8 (m, 10H, (CH₂)₅). m/e, 289 (M⁺+1), 5%,

288, (M⁺, 23%). Found, 288.1718. C₁₈H₂₄O₄re-

quires 288.1725. Found, C, 75.20; H, 8.60. Re-

quired, C, 75.0; H, 8.4%. Similar results were

obtained in the alkylation procedure of lithium

acetylide-diaminoethane complex with methyl or

ethyl 2-methoxy-6-(7-bromoheptyl)benzoate pre-

pared from the 7-tosyl derivative by reaction in

DMSO with lithium bromide.

6-(pentadeca-8,11-dienyl)benzoate; C₂₅H₃₈O₃re-

quires m/z, M⁺386. Found, (M⁺, 386).

This was identical by argentation chromatogra-

phy (Tyman, 1977) and spectroscopically with the

O-methyl ether methyl ester of anacardic acid

diene obtained from the acid by methylation with

dimethyl sulphate in acetone or xylene containing

potassium carbonate.

Demethylation of ethyl 6-methoxy-2-pentade-

cylbenzoate with lithium t-butylthiolate has been

described (Visani, 1988; Tyman and Visani, 1996)

and the hydrolysis of methyl ginkgolate effected

with methanolic potassium hydroxide.

In the hydrolysis no change of the double bond

positions appears to take place. For example in

the hydrolysis of ethyl 6-(11-dodecenyl)-2-

methoxybenzoate the corresponding acid was

formed.

2.7.11. 2-Methoxy-6-(pentadeca-8,11-diynyl)-

phenyl ethyl ketone (16)

Methyl 2-methoxy-6-(8-nonynyl)benzoate (0.60

g, 2.08 mmol) in THF (15 cm³) was treated with

ethylmagnesium bromide (0.36 g, 2.70 mmol) and

the mixture heated at 40°C during 1 h. After

cooling to 25°C, copper(I) chloride (100 mg) was

added followed by 1-bromo-2-hexyne (0.37 g, 2.29

mmol) in THF (10 cm³). The reaction mixture

was heated at 60°C for 2 h and after cooling was

then worked up by pouring into saturated ammo-

nium chloride solution and ethereal extraction to

give a crude product (1.05 g) which upon dry ﬂash

chromatography afforded a yellow liquid (0.63 g).

The spectral data on this material indicated it to

be ketonic due to reaction of EtMgBr at both the

ester and acetylenic groups.

Ethyl

6-(11-dodecenyl)-2-methoxybenzoate

(0.86 g, 2.48 mmol) in ethanol (3 cm³) was added

to ethanol (5 cm³) containing sodium hydroxide

(0.20 g, 4.97 mmol) dissolved in water (3 cm³) at

60°C and the mixture reﬂuxed for 48 h and mon-

itored by TLC. Upon work-up by acidiﬁcation

and ethereal extraction followed by ﬂash chro-

matography, 6-(11-dodecenyl)-2-methoxybenzoic

acid was obtained as a viscous oil (0.31 g, 39%);

w_max3600–3300, 3080, 3010, 1700 (CꢀO, acid),

1600, 1580, 1470, 1290, 1270 cm⁻¹; l (CDCl₃)

10.6 (s, 1H, COOH, D₂O exch.), 7.4–6.6 (m, 3H,

HAr), 5.6–4.8 (m, 3H, CHꢀCH₂), 3.9 (s, 3H,

OMe), 2.7 (t, 7 Hz, 2H, CH₂Ar), 2.2–1.2 (m, 18H,

(CH₂)₉); m/z, 319 (M⁺+1, 13%), 318 (M⁺, 5%).

Found, C, 75.3; H, 8.60. C₂₀H₃₀O₃requires C,

75.40; H, 9.40.

This was conﬁrmed by treatment of methyl

2-methoxy-6-(8-nonynyl)benzoate with ethylmag-

nesium bromide at 30–40°C whereby a ketonic

product 2-methoxy-6-(8-nonynyl)phenyl ethyl ke-

tone was derived; w_max3300, 3360, 2920, 2850,

2.7.13. Preparation of stereoisomeric

1-hydroxytetradeca-7,10-dienes

2120, 1700 (CꢀO, ester), 1600, 1580, 1465 cm⁻¹

;

m/e, 286 (M⁺, 18%). Found, 286.1931. C₁₉H₂₆O₂

requires 286.1932.

2.7.13.1. (7E,10E)-1-Hydroxytetradeca-7,10-diene

(23). 1-(1-Ethoxy)-ethoxy-7-octyne (3.0 g, 16.5

mmol) was lithiated with lithamide (prepared

from lithium (0.22 g, 32.97 mmol) and liquid

ammonia (220 cm³)). (E)-1-Bromohex-2-ene (3.49

g, 21.43 mmol) was added and the mixture then

reﬂuxed for 2 h to give (21). After reductive

treatment by the addition of lithium wire (0.2 g),

2.7.12. (Z,Z) Ethyl 2-methoxy-6-(pentadeca-8,

11-dienyl)benzoate (12, R=Me)

Total catalytic reduction of the 8,11-diyne gave

ethyl 2-methoxy-6-pentadecylbenzoate; m/z (M⁺,

390, (25%)). Partial reduction in ethyl acetate

containing quinoline gave (Z,Z) ethyl 2-methoxy-

170

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

the mixture after 1 h was quenched with saturated

ammonium chloride solution, the excess ammonia

evaporated, and the extracted product puriﬁed by

dry ﬂash chromatography to give, after removal

of the protective group by acidic methanolysis,

and puriﬁcation, (E,E)-1-hydroxytetradeca-7,10-

diene, (1.48 g, 48%).

(30 cm³) containing sodium iodide (1.80 g, 12

mmol) and chlorotrimethylsilane (1.3 g, 12.0

mmol). The pure product was obtained by dry

ﬂash chromatography as a yellow liquid (1.29 g,

50% yield).

This diene compound was also prepared by

reduction of 1-iodo-10(E)-tetradecen-7-yne with

diisoamylborane.

2.7.13.2. (10E)-1-Hydroxytetradeca-10-ene-7-yne

(21). 1-(1-Ethoxy)-ethoxy-7-octyne (3.0 g, 16.5

mmol) was treated with ethylmagnesium bromide

(2.85 g, 21.42 mmol) at ambient temperature then

at 40°C and copper(I) chloride (100 mg) added,

followed by (E)-1-bromohex-2-ene (2.95 g, 18.1

mmol). The reaction mixture was heated at 50–

60°C for 2 h, cooled and then poured into satu-

rated ammonium chloride solution. After

work-up by ethereal extraction and removal of

the protective group by acidic methanolysis the

product was obtained containing some 1-hydroxy-

7-octyne.

1-Iodo-10(E)-tetradecen-7-yne (3.25 g, 10.22

mmol) was treated with freshly-prepared di-

isoamylborane (1.59 g, 10.32 mmol) in dry THF

at 0°C. The reaction mixture was quenched with

glacial acetic acid and then neutralised with

sodium hydroxide solution. Prep TLC showed

two bands the lower of which was the required

product (0.53 g); w_max3100, 2980, 1650, 1470

cm⁻¹; l (CDCl₃) 5.8–5.0 (m, 4H, 2×CHꢀCH),

3.2

(t,

6

Hz,

2H,

OCH₂),

2.3–2.0

(CHꢀCHCH₂CHꢀCH+OH, D₂O exch.), 1.9–1.2

(m, 14H, (CH₂)₅+2CH₂), 0.8 (t, 6 Hz, CH₃).

The trimethylsilyl ether of 1-hydroxytetradeca-

7(Z),10(E)-diene was converted with sodium io-

dide in acetonitrile to the corresponding iodide.

Found: m/z, M⁺, 320.1008. C₁₄H₂₅OI requires

320.1003.

2.7.13.3. (7Z,10E)-1-Hydroxytetradeca-7,10-diene

(22). Reduction of 1-hydroxytetradeca-10(E)-ene-

7-yne with diisoamylborane at 0°C gave 1-hy-

droxy-tetradeca-7(Z),10(E)-diene.

2.7.13.7.

Methyl

2-methoxy-6-[pentadeca-

2.7.13.4. (7Z,10Z)-1-Hydroxytetradeca-7,10-diene

(20). 1-Hydroxytetradeca-7,10-diyne upon cata-

lytic hydrogenation in ethyl acetate containing

Pd-BaSO₄and quinoline afforded (Z,Z)-1-hy-

droxytetradeca-7,10-diene.

8(Z),11(E)-dienyl]benzoate. Methyl 2-methoxy-6-

methylbenzoate was converted to the anion with

lithium diisopropylamide and reacted in THF

containing

HMPA

with

1-iodotetradeca-

7(Z),10(E)-diene to afford the product after chro-

matographic puriﬁcation in 21% yield.

Similar alkylations were carried out with 1-

iodotetradeca-7(E),10(E)-diene and with the

7(Z),10(E) isomer.

2.7.13.5. (7E,10Z)-1-Hydroxytetradeca-7,10-diene

(24). (Z)-Hex-2-en-1-ol was similarly prepared

from hex-2-yn-1-ol and converted to the bromide.

Reaction with 1-(1-ethoxy)-ethoxy-7-octynylmag-

nesium bromide in the presence of copper(I) chlo-

ride afforded after removal of the protective

group, the compound 1-hydroxytetradeca-7-yne-

10(Z)-ene, lithium reduction of which in situ gave

1-hydroxytetradeca-7(E),10(Z)-diene.

2.7.14. Experiments in the synthesis of the triene,

ethyl (ZZ) 2-methoxy-6-(pentadeca-8,11,14-

trienyl)benzoate (30)

1-(1-Ethoxy)ethoxyoct-7-yne (17) (3.0 g, 16.5

mmol) was treated with ethyl magnesium bromide

(2.89 g, 21.4 mmol) in THF at 40°C followed by

copper(I) bromide (100 mg) and then 1-bromo-

hex-5-ene-2-yne (2.88 g, 18.1 mmol). The reaction

mixture was heated at 50–60°C during 2 h, cooled

and poured into saturated ammonium chloride

2.7.13.6. 1-Iodotetradeca-7(E),10(E)-diene. 1-Hy-

droxytetradeca-7(E),10(E)-diene (1.68 g, 8.00

mmol), chlorotrimethylsilane (1.04 g, 9.60 mmol),

with pyridine (1.52 g, 9.20 mmol) formed the

TMS ether which was then reﬂuxed in acetonitrile

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

171

3. Results and discussion

solution. After ethereal extraction and recovery

the crude yellow product was puriﬁed by dry

ﬂash chromatography to give 1-ethoxyethyl-13-

tetradec-13-ene-7,10-dienyl ether (26) as a pale

yellow liquid in 79% yield; w_max3070, 2980,

2910, 2860, 2200 (CꢀC) cm⁻¹; l (CDCl₃) 5.3–

4.8 (m, 3H, CHꢀCH₂), 4.7 (q, 1H, 7 Hz, OCH₂),

3.7–3.1 (m, 4H, 2OCH₂) 3.0 (t, 2 Hz, Cꢀ

CCH₂CꢀC), 2.8–2.7 (m, 2H, CꢀCCH₂

CHꢀCH₂), 2.1–2.0 (m, 14H, 2CH₃+(CH₂)₄); m/

e, 216 (M⁺−CH₃+OEt).

1-Hydroxytetradec-13-ene-7,10-diyne (27) was

derived by treatment with methanolic hydrochlo-

ric acid.

Upon reaction of this alcohol with dibromob-

orane-dimethyl sulphide complex, and conver-

sion to the iodide, partial reduction occurred of

one unsaturated bond, probably resulting in a

dieneyne. Found: m/z, M⁺, 316.0680. C₁₄H₂₁I

requires 316.0689.

In the present synthetic work in the anacardic

series for 8,11-dienes and 8,11,14-trienes

acetylenic routes were adopted primarily because

an ArC₇intermediate can readily be obtained

from an ArC₁starting material (methyl 2-

methoxy-6-methylbenzoate) by the use of the

readily available HO-protected 6-chlorohexan-1-

ol. In Wittig reactions the use of an ArC₈is

required involving preparations with the less

available 7-halogenoheptan-1-ols. Although steric

control of the stereochemistry of the Wittig reac-

tion is now possible the availability of selective

catalytic and chemical reduction together with

advances in boration methodology (Brown and

Campbell, 1981) have greatly enhanced the utility

of acetylenic syntheses.

The choice of protective group for the aromatic

and for the side-chain components was studied in

our approach. The benzyl, methoxymethyl and

trimethysilyl groups were found to be less beneﬁ-

cial than the methyl group in alkyl-2-methoxy-6-

methylbenzoates particularly in the alkylation of

the carbanion. For the side-chain component the

ethoxyethyl group (readily introduced by reaction

of the hydroxy compound with ethyl vinyl ether)

was superior to the trityl and t-butyldimethylsilyl

groups, a feature conﬁrmed from earlier work

with the phenolic lipids of the cardanol (Caplin

and Tyman, 1982) and cardol (Baylis et al., 1981)

series.

Demethylation of polyunsaturated phenolic

lipids is subject to side reactions and this problem

is increased where hydrolysis is a concomitant

reaction. Wherever possible phenolic intermedi-

ates were employed as in Scheme 1 to avoid

demethylation as the terminal step. For the

hydrolysis of the model compound ethyl 6-(dodec-

11-enyl)-2-methoxybenzoate, potassium t-butox-

ide under mild ambient conditions (Gassman and

Schenk, 1977) was less effective than warm

sodium hydroxide. Finally it was found that

with the model compound ethyl 2-methoxy-6-

pentadecylbenzoate, lithium t-butyl thiolate

(Bartlett and Johnson, 1970; Wolfe et al.,

1975) effected simultaneous demethylation and

hydrolysis. Unsaturated compounds also re-

Treatment of the 7,10-diyn-13-en-1-ol (0.40 g,

1.92 mmol), with chlorotrimethylsilane (0.25 g,

2.3 mmol), and pyridine (0.37 g, 4.6 mmol) af-

forded the TMS ether which with sodium iodide

(0.43 g, 2.88 mmol) in acetonitrile (10 cm³) con-

taining chlorotrimethylsilane (0.31 g, 2.88 mmol)

and work-up by ﬂash chromatography gave an

orange liquid (0.20 g), 1-iodotetradeca-13-ene-

7,10-diyne (28) in 33% yield; w_max3295, 3050,

2920, 2850, 2110 (CꢀC), 1730, 1640 cm⁻¹

;

6.0–5.3 (m, 3H, CHꢀCH₂), 3.4 (t, 7 Hz, 2H,

CꢀCCH₂CꢀC), 3.2 (t, 7 Hz, 2H, CH₂I), 3.0

(t, 3 Hz, 2H, CH₂CꢀC), 2.8–1.8 (m, 8H,

(CH₂)₄).

Alkylation of the carbanion of ethyl 2-

methoxy-6-methylbenzoate with the preceding io-

dide was effected in THF containing HMPA

and the product ethyl 2-methoxy-6-(pentadeca-

8,11-diynyl-14-enyl)-benzoate (29) puriﬁed by

ﬂash chromatography. Reduction with dibro-

moborane-dimethyl sulphide complex afforded

the triene, (Z,Z)-ethyl 2-methoxy-6-(pentadeca-

8,11,14-trienyl)benzoate (30). Argentation chro-

matographic comparison with the methylation

product of (15:3)-anacardic acid indicated the re-

quired product had been formed.

172

J.H.P. Tyman, N. Visani / Chemistry and Physics of Lipids 85 (1997) 157–174

triene-1-ol would give access to the fourth

stereoisomer, the 8(E),11(E),14-triene.

Greatly expanded boration methodology has

enabled selective reduction of alkyne bonds in the

presence of alkenes possible by the use of

modiﬁed boranes (Brown and Campbell, 1980)

although in our experience chromatographic and

spectroscopic monitoring of reaction progress is

essential in their usage.

Scheme 6. Synthesis of stereoisomeric triene C₁₄alkylation

reactants.

Their selectivity is probably superior to cata-

lytic and chemical reductions where both double

and triple bonds are present. Although selective

catalytic reduction of the triple bond in

CH₂ꢀCHCH₂CꢀCCH₂CH₂OH has been appar-

ently achieved (Miyakoshi et al., 1991; Sargent

and Wanachareontrajkul, 1989) our own model

experiments were much less selective indicating

that a terminal vinyl group is more susceptible

than an internal alkyne. Other experiments (Ty-

man, 1991; Tyman and Visani, 1996) have indi-

cated that a terminal alkyne protected by the

trimethylsilyl group enables an internal alkyne to

be preferentially reduced as found by others

(Schmidt and Arens, 1967).

An attempt to adapt a route to 5,6-dehy-

droarachidonic acid (Corey and Kang, 1982),

based upon the employment of an allenic interme-

diate with the organotin reactant 1,1-di-n-butyl-1-

stannacyclohexadiene, for the synthesis of the

triene (30) was partially successful but will be

described elsewhere.

sponded with retention of unsaturation. The alter-

native reagents for demethylation, namely

trimethylsilyl iodide (Yung and Lyster, 1977) and

trimethylsilyl chloride-sodium iodide (Olah et al.,

1979) resulted also in some side reaction of the

unsaturation.

The strategy of Scheme 1 for the diene, involv-

ing the reaction of the ArC₁₀bromide with pen-

tynyl magnesium bromide was successful whereas

that of Scheme 2 failed through side reaction of

ethyl magnesium bromide with the ester group of

the ArC₉as well as the alkyne group, resulting in

non-selectivity and formation of the ketone (16).

This difﬁculty might be overcome by the use of an

alternative to the ethyl as protecting group for the

ester, although this was not examined at the time.

However another aspect of this proposed route

was that it required a C₆component which was

necessary in the C₁₄alkylation methodology of

Scheme 3, because in this strategy the synthesis of

isomeric C₁₄reactants involved the use of the two

isomeric (Z) and (E) monounsaturated C₆com-

pounds as depicted in Scheme 4. The bromides of

the two diunsaturated C₆alcohols, hexa-2,5-diyn-

1-ol and hexa-5-ene-2-yn-1-ol and those of (E,E)-

hexa-2,5-dien-1-ol and (E)-hexa-2,5-diene-1-ol

were to be used for the preparation of isomeric

C₁₄reactants required for the stereoisomeric

triene series by reaction with (17) as shown in

Scheme 6.

Acknowledgements

We thank the Dow Chemical Co., Smith Kline

and French Ltd. and the Society of Chemical

Industry for ﬁnancial support.

In the ﬁrst place, the use of (17) had led to the

diynol (26) which was employed as shown in

Scheme 5 for the synthesis of (30) and only partial

progress was made towards the preparations of

analogues, (31) required for the 8(E),11(Z)-14-

triene, and (32) for the 8(Z),11(E),14-triene. Re-

duction of (26) to (E,E)-tetradeca-7,10,13-

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.

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Synthesis of polyunsaturated constituents of phenolic lipids

DOI: 10.1016/S0009-3084(96)02654-0

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