Synthesis of an unnatural anacardic acid analogue

Article abstract of DOI:10.1081/SCC-120002710

The unnatural E isomer of anacardic acid 7 has been synthesized employing the following key steps: Swern oxidation of a diastereoisomeric mixture of β-hydroxyphosphine oxides 13a/b to the corresponding ketone 14 followed by stereo-specific reduction to th

Full text of DOI:10.1081/SCC-120002710

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
SYNTHESIS OF AN UNNATURAL ANACARDIC ACID
ANALOGUE
Ivan R. Green & Felismino E. Tocoli
To cite this article: Ivan R. Green & Felismino E. Tocoli (2002) SYNTHESIS OF AN UNNATURAL
ANACARDIC ACID ANALOGUE, Synthetic Communications, 32:6, 947-957, DOI: 10.1081/
SCC-120002710
To link to this article: http://dx.doi.org/10.1081/SCC-120002710
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Date: 31 March 2017, At: 05:12

SYNTHETIC COMMUNICATIONS, 32(6), 947–957 (2002)
SYNTHESIS OF AN UNNATURAL
ANACARDIC ACID ANALOGUE
*
Ivan R. Green and Felismino E. Tocoli
Department of Chemistry, University of the Western
Cape, Private Bag X17, Bellville, 7530,
Republic of South Africa
ABSTRACT
The unnatural E isomer of anacardic acid 7 has been synthe-
sized employing the following key steps: Swern oxidation of
a diastereoisomeric mixture of b-hydroxyphosphine oxides
13a/b to the corresponding ketone 14 followed by stereo-
specific reduction to the pure threo isomer 13b which upon
treatment with sodium hydride underwent trans elimination
to afford the E ester 15.
Naturally occurring anacardic acids 1–4 are derivatives of 6-penta-
decenyl salicylic acid in which the C-15 side chain is either saturated viz.
1, has a Z double bond at C-8 viz., 2, has a Z, Z diene at C-8 and C-11 viz.,
3, or has a triene arrangement viz., 4.1
The spectrum of biological activity of the anacardic acids 1–4 ranges
from antibacterial2 to antitumor3 to a strong molluscicidal activity being
associated with the degree of unsaturation of the C-15 side chain.4 It has
been demonstrated that the role the length of the side chain plays in biological
*Corresponding author
947
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

948
GREEN AND TOCOLI
activity is very important with the saturated C-12 analogue 5 being more
active against Pseudonomous acnes than the most active anacardic acid 4.5
To our knowledge the only unsaturated anacardic acids synthesized
are 2 and 6 both having the Z geometry in the olefin bond.6,7 Thus one may
assume that for the C-15 series of anacardic acids, the Z geometry of the
double bond is necessary for biological activity. However, in order to
validate this assumption it would be necessary to synthesize at least one
alternative geometric isomer for comparative evaluations. This paper
describes the synthesis of the E analogue 7 of the natural Z anacardic
acid 2.
At the outset it was realized that the synthetic protocol had to ensure
that the E isomer was to be formed without any contamination from the Z
isomer to avoid any ambiguities in the biological evaluations. Modifications
to the Wittig olefin synthesis have favoured E olefins with stabilized ylides
and Z olefins with non-stabilized ylides but are not exclusively so.8 We
decided to focus on the modified Horner-Wittig protocol that was reported
to provide almost exclusively the E olefin.9,10
In an attempt to verify the methodology chosen, we embarked on the
synthesis of E 7-hexadecene 11. Thus, condensation between heptyl bromide
and triphenylphosphine in boiling acetonitrile followed by heating of the
product with aqueous sodium hydroxide,11 afforded the phosphine oxide 8
in 94% yield. Treatment of the phosphine oxide 8 with 1 equivalent of
n-butyllithium followed by quenching with nonal afforded the alcohols 9a
and 9b in 70% yield as a mixture of erythro 9a and threo 9b isomers in the
ratio of 4 : 1 based upon the signal intensities of the carbinol C-8 in the
13C-n.m.r. spectrum at 70.04 and 72.70 ppm respectively.7 Since conversion
of this mixture into an olefin would result in the incorrect Z geometry from
the erytho isomer 9a, the ratio of 9a : 9b was altered as shown in Scheme 1.
Swern oxidation12 of the diastereoisomeric mixture of alcohols 9a/9b
afforded the ketone 10 in 76% yield. This was followed by stereoselective
reduction with sodium borohydride reported to favour threo selectivity13 to
afford the alcohols 9a/9b in 80% yield and in this instance the ratio
of erythro 9a to threo 9b diastereoisomer was reversed and found by

UNNATURAL ANACARDIC ACID ANALOGUE
949
Scheme 1.
13C-n.m.r. spectroscopy to be 1 : 5 as evidenced by the relative intensities of
the C-8 signals at 70.04 and 72.7 ppm.7 Finally, treatment of this mixture of
9a/9b with 2 equivalents of sodium hydride in dimethyl formamide at 50ꢀC14
afforded the hexadecene 11 in 76% yield. The ratio of E : Z isomers was 5 : 1
as demonstrated by the relative peak heights for C-6 and C-9 for the E
isomer at 32.6 ppm compared to the signal at 27.2 ppm for the Z isomer
in the 13C-n.m.r. spectrum.7 Although, in our hands, this protocol did not
provide the E isomer exclusively, we decided to employ it for our synthesis
of the E anacardic acid 7.
Treatment of phosphine oxide 8 with 1 equivalent of n-butyllithium at
0ꢀC followed by quenching with aldehyde 126 afforded the b-hydroxy phos-
phine oxides 13a and 13b in 76% yield. This diastereoisomeric mixture was
oxidized by Swern methodology as before to yield the ketone 14 in 83%
yield. In the infrared spectrum of 14, two carbonyl stretching frequencies
were observed viz., 1728 cmꢁ1 for the ester and 1713 cmꢁ1 for the ketone
group while a strong band at 1190 cmꢁ1 was assigned to the P¼O group.
1
Diagnostic peaks in the H-n.m.r. spectrum are a two proton triplet at
2.40 ppm (J ¼ 7.0 Hz) for 70-H, and a doublet of doublet of doublets at

950
GREEN AND TOCOLI
3.56 ppm with coupling of 12.8 Hz between 90-H and 100-Ha, further coup-
ling of 11.6 Hz between 90-H and 100-Hb and finally coupling of 3.0 Hz
between 90-H and P which is assigned to 90-H.
Reduction of ketone 14 with sodium borohydride in boiling ethyl
alcohol as described earlier afforded exclusively the pure threo isomer
13b10 in 80% yield. A strong absorption band at 3358 cmꢁ1 in the infrared
spectrum confirmed the presence of the hydroxy group while absorptions at
1726 and 1164 cmꢁ1 are assigned to the ester and P¼O groups respectively.
Unfortunately the 80- and 90-H’s appeared as an overlapping multiplet
at 2.25 ppm which precluded an ambiguous assignment. However the
13C-n.m.r. spectrum demonstrated clearly that only the threo isomer 13b
was formed since there was only a signal at 72.6 ppm and none in the
region of 70 ppm.7
Treatment of the threo b-hydroxyphenylphosphine oxide 13b with 2
equivalents of sodium hydride in dimethylformamide at 50ꢀC produced
a single isomer (by GC) in 65% of the E-olefin 15. Assigment of the E
geometry is based on the following: there is a strong out-of-plane vibration
at 966 cmꢁ1 in the infrared spectrum15 while in the 13C-n.m.r. spectrum there
was only a signal at 32.6 ppm for 70- and 100-C and no peak at ꢂ 27 ppm.7
Again, there was a lack of clarity in the 1H-n.m.r spectrum due to the 80- and
90-H’s appearing as an overlapping multiplet at 5.37 ppm. Hydrolysis of
ester 15 was achieved by treatment with aqueous sodium hydroxide (20%)
in boiling dimethylsulphoxide to afford the corresponding acid 16 in 86%
yield. As expected the 13C-n.m.r. spectrum showed the 70- and 100-C’s as a
signal at 32.6 ppm. Finally, treatment of acid 16 with sodium ethane thiolate
in dimethyl formamide under reflux16 dimethylated the molecule to produce
the E-anacardic acid 7 in 73% yield (see Scheme 2).
Thus the first synthesis of the unnatural anacardic acid 7 has been
achieved in six steps and an overall yield of 21% starting from the known
aldehyde 12. Currently evaluations are being undertaken on a comparative
basis with the known anacardic acid 2 to establish the role of the geometry
of the 80-90 double bond in the C-15 side chain.
EXPERIMENTAL
1H and 13C NMR spectra were measured on a Varian Gemini-
200 MHz spectrometer at ambient temperature in deuterochloroform
using the residual chloroform as an internal reference. IR spectra were
recorded on a Perkin-Elmer FT-IR 1000 PC spectrometer as either thin
films or for Nujol mulls. Mass spectra were recorded on a VG Micromass
16F mass spectrometer at 70 eV or on a Finigan MAT GCQ. Elemental

UNNATURAL ANACARDIC ACID ANALOGUE
951
Scheme 2.
analyses were performed on a Heraeus CHN-RAPID analyzer, or on a NA
1500, CARLO ERBA instrument. Melting points are quoted uncorrected
and were recorded on a Fischer–John apparatus.
All reactions were monitored by thin layer chromatography (t.l.c.)
carried out on silica gel GF254 (0.25 mm) plates. Column chromatography
refers to dry-packed columns using Merck Kieselgel 60(70–230 mesh).
Solvents for chromatography were distilled before use. Tetrahydro-
furan (THF) was dried immediately before use. Methylene chloride was
distilled from P2O5. Triethylamine and DMF were stored over 3A molecular
sieves. The phrase ‘‘residue obtained upon work-up’’ refers to the residue
when the organic layer was separated, dried (MgSO4), and the solvent
evaporated under reduced pressure.
Heptyldiphenylphosphine Oxide 8
Heptylbromide (0.57 ml, 3.7 mmol) and triphenylphosphine (0.92 g,
3.7 mmol) in acetonitrile (6 ml) were heated under gentle reflux for 72 h.

952
GREEN AND TOCOLI
The residue obtained after removal of the solvent under vacuum was treated
with water (20 ml) and a 45% (w/v) aqueous sodium hydroxide solution
(20 ml) followed by heating under reflux for 30 min. The cooled solution
was extracted with dichloromethane to afford the phosphine oxide 8
(0.90 g; 94%) as a white solid, m.p. 58–59ꢀC (from hexane). nmax 1180
and 1118 cmꢁ1; dH 0.84 (3H, t, J ¼ 6.8 Hz, 7-H), 1.20–1.40 (8H, m, 3-, 4-,
5- and 6-H), 1.60 (2H, m, 2-H), 2.24 (2H, m, 1-H), and 7.41–7.70 (10H, m,
Ph2P). (Found: C, 75.7; H, 8.4%; Mþ 300. Calc. for C19H25PO: C, 75.9; H,
8.4%; Mþ 300).
7-Diphenylphosphinoylhexadecan-8-ol 9a and 9b
To a stirred solution of phosphine oxide 8 (2.0 g; 6.65 mmol) in tetra-
hydrofuran (THF) (10 ml) at 0ꢀC was added n-butyllithium (6.0 ml of a
1.43 M solution) and stirring was continued for 30 min. The red solution
was then cooled to ꢁ78ꢀC and nonyl aldehyde (0.93 g; 6.65 mmol) in THF
(5 ml) was added dropwise. The pale yellow solution was allowed to warm to
25ꢀC over 2 h and then quenched with water (50 ml). The THF was removed
under reduced pressure and brine (20 ml) was added and the aqueous
solution exhaustively extracted with methylene dichloride. The residue
obtained upon work-up was chromatographed using ethyl acetate–hexane
(1 : 4) initially and later hexane–ethylacetate–acetic acid (7 : 3 : 1) as eluent to
afford a mixture of erythro 9a and threo 9b alcohols (2.0 g; 70%) as white
crystals, m.p. 80–81ꢀC (from hexane). nmax 3338 and 1158 cmꢁ1; dH 0.78 and
0.86 (each 3H, t, J ¼ 6.8 Hz, 16- and 1-H), 1.04–1.85 (25H, m, 2- to 6-H and
9- to 15-H and 8-OH), 4.00 (1H, m, 7-H), 4.20 (1H, m, 8-H), and 7.45–7.83
(10H, M, Ph2P). dC due to the numerous overlapping peaks, only two vital
signals are quoted here viz. 70.04 and 72.70 in the ratio of 4 : 1. (Found:
C, 76.1; H, 10.4%; Mþ 442. Calc. for C28H43PO: C, 75.9; H, 9.8%; Mþ 442).
7-Diphenylphosphinohexadecan-8-one 10
To a solution of oxalyl chloride (1.8 ml; 20.9 mmol) in dichloro-
methane (50 ml) at ꢁ50ꢀC was added dropwise dimethylsulphoxide (3.5 ml;
45.5 mmol) under nitrogen. Stirring was continued for 10 min at this tem-
perature and then the alcohol mixture of 9a/9b (8.4 g; 19 mmol) in dichlor-
omethane (25 ml) was added dropwise over 5 min. After stirring and
additional 20 min at this temperature, triethylamine (9.5 ml; 68 mmol) was
added over 5 min and the resultant mixture allowed to warm to 25ꢀC over
1 h. Water (100 ml) was added and the aqueous mixture was extracted with

UNNATURAL ANACARDIC ACID ANALOGUE
953
dichloromethane. The residue obtained upon work-up was chromato-
graphed using ethyl acetate–hexane (2 : 3) as eluent to afford ketone 10
(6.35 g; 76%) as white crystals, m.p. 67–68ꢀC (from hexane). nmax 1705
and 1180 cmꢁ1; dH 0.80 and 0.85 (each 3H, t, J ¼ 6.8 Hz, 1- and 16-H),
0.95–1.40 (22H, m, 2- to 6-H and 10- to 15-H), 2.42 (2H, m, 9-H), 3.54
(1H, dt, J ¼ 11.5 and 3.0 Hz, 7-H), and 7.44–7.83 (10H, m, Ph2P). dC 13.9,
14.0, 22.4, 22.6, 23.0, 28.6, 28.8 (ꢃ2), 29.0, 29.3, 31.3, 31.7, 43.8, 56.5, 57.7,
128.6, 128.7, 128.8, 128.9, 130.3, 131.2, 131.4, 131.5, 132.1, 132.2 (ꢃ2), 132.4,
and 207.8. (Found: C, 76.1; H, 9.1% Mþ 440. Calc. for C28H41PO2: C, 76.3;
9.3% M 440).
7-Diphenylphosphinoylhexadecan-8-ol 9a and 9b
To ketone 10 (470 mg; 1.07 mmol) in ethyl alcohol (20 ml) was added
sodium borohydride (60 mg; 1.51 mmol) and the resulting mixture was
stirred and heated under reflux for 3 h. Saturated ammonium chloride
(15 ml) was added to the cooled solution and the ethyl alcohol was removed
under reduced pressure. Brine (15 ml) was added to the residue followed by
extraction with dichloromethane. The residue obtained upon work-up was
chromatographed using hexane–ethyl acetate–acetic acid (7 : 3 : 1) as eluent
to afford a mixture of erythro 9a and threo 9b alcohols (370 mg; 80%), as
white crystals m.p. 115–116ꢀC (from hexane). nmax 3326 and 1164 cmꢁ1; dH
0.80 and 0.83 (each 3H, t, J ¼ 6.8 Hz, 16- and 1-H), 1.10–1.65 (24H, m, 2- to
6-H and 9- to 15-H), 1.42 (1H, brs, 8-OH, D2O exchangeable), 3.90 (1H, m,
7-H), 4.21 (1H, t, J ¼ 7.2 Hz, 8-H), and 7.46–7.90 (10H, m, Ph2P). dC 14.0,
14.1, 22.2, 26.6, 28.7, 29.1, 29.2, 29.3, 29.4, 31.2, 31.4, 31.8, 36.8, 42.2, 70.0,
72.7, 128.5, 127.7 (ꢃ2), 128.9, 129.0, 130.6, 130.8, 131.0, 131.1, 131.3 and
131.7 (ꢃ2). (Found: C, 76.0; H, 10.3%; Mþ 442. Calc. for C28H43PO: C,
75.9; H, 9.8%; M 442).
E 7-Hexadecene 11
Sodium hydride (91 mg; 55% dispersion in oil, 2.0 mmol) was added in
one portion to a stirred solution of the alcohol 9a/9b (vide supra) (460 mg,
1.04 mmol) in dimethyl formamide (25 ml) at 25ꢀC. The clear solution was
heated to 50ꢀC for 30 min after which time a white precipitate formed.
Water (30 ml) was added to the cooled mixture followed by brine (20 ml)
and the resulting clear solution was extracted with ether and the residue
obtained upon work up was chromatographed using ethyl acetate–hexane
(1 : 9) as eluent to yield hexadecane 11 (117 mg; 76%) as a colourless oil

954
GREEN AND TOCOLI
comprising an E : Z ratio of 5 : 1 nmax 965 and 723 cmꢁ1; dH 0.87 (6H, t,
J ¼ 6.8 Hz, 7- and 16-H), 1.26 (20H, 2- to 5- and 10- to 15-H), 1.95 (4H, m,
6- and 9-H), and 5.38 (2H, m, 7- and 8-H). dC 14.1 (ꢃ2), 22.6, 22.7, 27.2,
28.8, 29.2, 29.3, 29.5, 29.6, 29.7, 31.8, 31.9, 32.6 (ꢃ2) and 130.5 (ꢃ2).
(Found: C, 85.7; H, 14.4%; Mþ 224. Calc. for C16H32: C, 85.7, H, 14.2%,
M 224).
Ethyl 6-(80-Hydroxy-90-diphenylphosphinopentadecyl)-2-
methoxybenzoate 13a/13b
Applying the same synthetic protocol described for the synthesis of
alcohols 9a/9b but using aldehyde 126 afforded a thick oil which was flash
chromatographed using hexane–ethyl acetate–acetic acid (7 : 3 : 1) as eluent
to yield a diastereoisomeric mixture of alcohols 13a/13b in 76% yield as
white crystals, m.p. 95–112ꢀC. nmax 3327, 1727 and 1165 cmꢁ1
.
Ethyl 6-(80-Oxo-90-diphenylphosphinoylpentadecyl)-2-
methoxybenzoate 14
Applying the same Swern synthetic protocol as before, oxidation of
the mixture of alcohols 13a/13b afforded after chromatography using
hexane–ethyl acetate–acetic acid as eluent, the ketone 14 in 83% yield as
thick yellow oil. nmax 1728, 1713 and 1190 cmꢁ1; dH 0.81 (3H, t, J ¼ 7.0 Hz,
150-H), 1.10–1.58 (20H, m, 20- to 60- and 100- to 140-H), 1.36 (3H, t,
J ¼ 7.2 Hz, OCH2CH3), 2.40 (2H, t, J ¼ 7.0 Hz, 70-H), 2.51 (2H, t, J ¼
7.4 Hz, 10-H), 3.56 (1H, ddd, J ¼ 12.8, 11.6 and 3.0 Hz, 90-H), 3.80 (3H, s,
OCH3), 4.38 (2H, q, J ¼ 7.2 Hz, OCH2CH3), 6.76 (1H, d, J ¼ 8.2 Hz, 3-H),
6.81 (1H, d, J ¼ 8.2 Hz, 5-H), 7.25 (1H, t, J ¼ 8.2 Hz, 4-H), and 7.45–7.80
(10H, m, Ph2P); dC 13.9, 14.3, 22.4 (ꢃ2), 23.0, 26.7, 28.6, 28.7 (ꢃ2), 28.8,
29.2, 29.3, 31.1, 31.3, 33.3, 43.8, 55.8, 56.5, 57.6, 61.1, 108.5, 121.5, 123.8,
128.6, 128.7, 128.8, 128.9, 130.2, 131.2, 131.4 (ꢃ2), 131.5, 132.2, 141.2,
156.3, 168.6 and 207.8. (Found: C, 73.4; H, 8.2%; Mþ 604. Calc. for
C37H49PO5: C, 73.4; H, 8.2%; M 604).
Threo Ethyl 6-(80-Hydroxy-90-diphenylphosphinoylpentadecyl)-2-
methoxybenzoate 13b
Ketone 14 was reduced by sodium borohydride as described earlier to
afford, after chromatography using hexane–ethyl acetate–acetic acid (7 : 3 : 1)

UNNATURAL ANACARDIC ACID ANALOGUE
955
as eluent, pure threo alcohol 13b in 80% yield, as white crystals, m.p.
130–131ꢀC (from ethyl acetate–hexane). nmax 3358, 1726 and 1164 cmꢁ1
;
dH 0.80 (3H, t, J ¼ 7.0 Hz, 150-H), 1.09–1.60 (23 H, m, 20- to 70-H, and
100- to 140-H, and 80-OH), 1.36 (3H, t, J ¼ 7.2 Hz, OCH2CH3), 2.10–2.40
(2H, m, 80- and 90-H), 2.45 (2H, t, J ¼ 8.0 Hz, 10-H), 3.80 (3H, s, OCH3), 4.37
(2H, q, J ¼ 7.2 Hz, OCH2CH3), 6.77 (1H, d, J ¼ 8.2 Hz, 3-H), 6.80 (1H, d,
J ¼ 8.2 Hz, 5-H), 7.25 (1H, t, J ¼ 8.2 Hz, 4-H), and 7.45–7.90 (10H, m,
Ph2P); dC 14.0, 14.3, 22.4 (ꢃ2), 26.2, 26.6, 28.5, 29.1, 29.3 (ꢃ2), 29.4,
31.2, 31.4, 33.4, 36.7, 42.0, 55.9, 61.1, 72.6, 108.5, 121.6, 123.2, 128.5,
128.7 (ꢃ3), 128.9, 130.0 (ꢃ2), 130.6, 130.8, 131.1, 131.3, 131.8, 141.3,
156.3, and 168.6. (Found: C, 73.1; H, 8.4%; Mþ 606. Calc. for
C37H51PO5: C, 73.2; H, 8.4%; M 606).
E Ethyl 2-Methoxy-6-(80-pentadecenyl)benzoate 15
Treatment of the threo alcohol 13b with 2 equivalents of sodium
hydride as described earlier afforded, after chromatography using ethyl
acetate–hexane (1 : 9) as eluent, the E olefin 15 in 65% yield as a clear oil
and a single isomer as shown by GC-MS. nmax 1731, 966 and 745 cmꢁ1; dH
0.87 (3H, t, J ¼ 7.0 Hz, 150-H), 1.27 (18H, m, 20- to 60-H and 110- to 140-H),
1.37 (3H, t, J ¼ 7.2 Hz, OCH2CH3), 1.95 (4H, m, 70- and 100-H), 2.54 (2H, t,
J 7.8 Hz, 10-H), 3.81 (3H, s, OCH3), 4.38 (2H, q, J ¼ 7.2 Hz, OCH2CH3),
5.37 (2H, m, 80- and 90-H), 6.75 (1H, d, J ¼ 8.4 Hz, 3-H), 6.80 (1H, d,
J ¼ 8.4 Hz, 5-H), and 7.25 (1H, t, J ¼ 8.4 Hz, 4-H); dC 14.1, 14.3, 22.6,
28.8, 29.0, 29.3, 29.5, 29.6 (ꢃ2), 31.2, 31.7, 32.6 (ꢃ2), 33.4, 55.9, 61.1,
108.5, 121.6, 123.9, 130.2, 130.4, 130.5, 141.3, 156.3 and 168.6. (Found: C,
77.3; H, 10.3%; Mþ 388. Calc. for C25H40O3: C, 77.2; H, 10.3%; M 388).
E 2-Methoxy-6-(80-pentadecenyl)benzoic Acid 16
A solution of the ester 15 (388 mg; 1 mmol) in dimethylsulphoxide
(2.3 mol) was treated with aqueous sodium hydroxide (2.3 ml of a 5 M
solution, 11.5 mmol) and heated at 110ꢀC for 12 h under reflux. The
cooled solution was acidified with 1 M HCl, diluted to 30 ml with water
and extracted with ethyl acetate. The residue obtained upon work-up
afforded the E-benzoic acid 16 (310 mg; 86%) as white crystals, m.p.
45–46ꢀC (from hexane). nmax 3258, 1715 and 966 cmꢁ1; dH 0.87 (3H, t,
J ¼ 6.4 Hz, 150-H), 1.28 (16H, m, 30- to 60-H and 110- to 140-H), 1.60 (2H,
m, 20-H), 1.95 (4H, m, 70- and 100-H), 2.73 (2H, t, J ¼ 7.6 Hz, 10-H), 3.80
(3H, s, OCH3), 5.36 (2H, m, 80- and 90-H), 6.81 (1H, d, J ¼ 8.4 Hz, 3-H), 6.87

956
GREEN AND TOCOLI
(1H, d, J ¼ 8.4 Hz, 5-H), and 7.31 (1H, t, J ¼ 8.4 Hz, 4-H); dC 14.1, 22.6,
28.8, 29.1, 29.3, 29.5, 29.6 (ꢃ2), 31.3, 32.6 (ꢃ2), 33.9, 56.2, 108.7, 121.4,
122.6, 130.4, 130.5, 131.2, 143.4, 156.8 and 170.8. (Found: C, 76.6; H,
10.2%; Mþ 360. Calc. for C23H36O3: C, 76.6; H, 10.2%; M 360).
E 6-(80-Pentadecenyl)salicyclic Acid 7
To a stirred suspension of sodium hydride (18 mg; 55% dispersion in
oil; 0.44 mmol) in dimethyl formamide (2 ml) at 0ꢀC was added dropwise
ethanethiol (0.03 ml; 0.42 mmol) under nitrogen. The mixture was stirred at
25ꢀC for 30 min and then a solution of acid 16 (50 mg; 0.133 mmol) in
dimethyl formamide (3 ml) was added and the resulting solution was
heated under reflux for 3 h. The solvent was removed under reduced press-
ure and the residue was acidified with 3 M HCl and extracted with ethyl
acetate. The residue obtained upon work up was chromatographed using
ethyl acetate–hexane (1 : 9) as eluent to afford the E-salicyclic acid 7 (35 mg;
73%) as white crystals, m.p. 68–69ꢀC (from ethyl acetate–hexane). nmax
3572–2540, 1661 and 966 cmꢁ1; dH 0.87 (3H, t, J ¼ 6.6 Hz, 150-H), 1.28
(16H, m, 30- to 60-H and 110- to 140-H), 1.60 (2H, m, 20-H), 1.94 (4H, m,
70- and 100-H), 2.80–2.96 (2H, m, 10-H), 5.37 (2H, m, 80- and 90-H), 6.77 (1H,
d, J ¼ 8.2 Hz, 3-H), 6.86 (1H, d, J ¼ 8.2 Hz, 5-H) and 7.35 (1H, t, J ¼ 8.2 Hz,
4-H). dC 14.1, 22.6, 28.2, 29.1, 29.3, 29.5, 29.6, 29.8, 31.3, 31.7, 32.6 (ꢃ2),
33.8, 97.5, 115.8, 122.4, 130.4 (ꢃ2), 135.2, 140.6, 163.8 and 174.2. (Found:
C, 76.6; H, 9.6%; Mþ 346.2513. Calc. for C22H34O3: C, 76.3; H, 9.8%; M
346.2508).
ACKNOWLEDGMENTS
The authors wish to thank the Councils of the University of the
Western Cape and the National Research Foundation for financial support
and to the Centre for Development Cooperative Services, The Netherlands
for a bursary (FET).
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Received in the USA April 5, 2001