Facile synthesis of (Z)-tetracos-5-enoic acid and racemic cis-4-(2-octadecylcyclopropane-1-yl)-butanoic acid

Article abstract of DOI:10.1016/S0009-3084(03)00092-6

(Z)-Tetracos-5-enoic acid and racemic cis-4-(2-octadecylcyclopropane-1-yl)- butanoic acid have been prepared from 1-eicosene by a new facile route. Periodic acid cleavage of the epoxide of 1-eicosene gave nonadecanal which was condensed with 4-carboxybutyltriphenylphosphonium bromide to give predominately (Z)-tetracos-5-enoic acid. Simmons-Smith type cyclopropanation of (Z)-tetracos-5-enoic acid gave a minor proportion of racemic cis-4-(2-octadecylcyclopropane-1-yl)-butanoic acid accompanied by major amounts of its methyl ester.

Full text of DOI:10.1016/S0009-3084(03)00092-6

Chemistry and Physics of Lipids 126 (2003) 49–53
Facile synthesis of (Z)-tetracos-5-enoic acid and racemic
cis-4-(2-octadecylcyclopropane-1-yl)-butanoic acid
a
a
b,∗
Geoffrey D. Coxon , James D. Douglas , David E. Minnikin
a
Department of Chemistry, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
b
School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Received 11 March 2003; received in revised form 17 June 2003; accepted 17 June 2003
Abstract
(
Z)-Tetracos-5-enoicacidandracemiccis-4-(2-octadecylcyclopropane-1-yl)-butanoicacidhavebeenpreparedfrom1-eicosene
by a new facile route. Periodic acid cleavage of the epoxide of 1-eicosene gave nonadecanal which was condensed with
-carboxybutyltriphenylphosphonium bromide to give predominately (Z)-tetracos-5-enoic acid. Simmons–Smith type cyclo-
4
propanation of (Z)-tetracos-5-enoic acid gave a minor proportion of racemic cis-4-(2-octadecylcyclopropane-1-yl)-butanoic acid
accompanied by major amounts of its methyl ester.
©
2003 Elsevier Ireland Ltd. All rights reserved.
Keywords: Fatty acids; Mycolic acids; Cyclopropane rings; Wittig reaction; Alkene stereochemistry
1
. Introduction
colic acid synthesis in extracts of M. smegmatis was
stimulated by 2 (Besra et al., 1993a; Wheeler et al.,
1993a) and strongly inhibited by the cyclopropene
ester 3 (Scheme 1) analogue of 2 (Besra et al., 1993b;
Wheeler et al., 1993b). Fatty acid desaturases are
known to be inhibited by cyclopropene fatty acids
(Johnson et al., 1967). For continuing studies on my-
colic acid biosynthesis it is desirable to have ready
access to a supply of 2, but the previous synthe-
sis (Besra et al., 1993a) is inconvenient. The key
step is an acetylenic coupling of 1-bromooctadecane
with 1-tetrahydropyranoloxyhex-5-yne (Besra et al.,
1993a). This chemistry is not routine; reasonable
yields (50–60%) are only obtained by acetylenic
coupling using n-butyl lithium in the highly toxic
solvent hexamethylphosphorus triamide (HMPA)
High molecular weight, C70–C90, 2-alkyl-3-hydroxy
mycolic acids (e.g. 1, Scheme 1) have been found
to be key structural components of the cell envelope
of pathogenic mycobacteria such as Mycobacterium
tuberculosis (Minnikin, 1982; Watanabe et al., 2001,
2
002). The biosynthetic pathways leading to mycolic
acids are the target for existing drugs, such as iso-
niazid (Takayama and Qureshi, 1984; Kremer et al.,
2
reveal new drug targets. A key initial step in mycolic
acid biosynthesis appears to be the ꢀ -desaturation
000), and detailed knowledge of these pathways may
5
of tetracosanoate to (Z)-tetracos-5-enoic acid (2)
(Scheme 1) (Takayama and Qureshi, 1984). My-
(
Besra et al., 1993a). The cyclopropene ana-
∗
Corresponding author. Tel.: +44-121-415-8126;
logue 3 (Besra et al., 1993b; Hartmann et al.,
1994) was selectively hydrogenated to give the
fax: +44-121-414-5925.
E-mail address: d.e.minnikin@bham.ac.uk (D.E. Minnikin).
0
009-3084/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/S0009-3084(03)00092-6

5
0
G.D. Coxon et al. / Chemistry and Physics of Lipids 126 (2003) 49–53
OH
CO Me
2
Me(CH2)17 cis
(CH )
cis
(CH2)11
2 14
(
CH ) Me
2 23
1
Me(CH2)17
(CH ) CO H Me(CH )
(CH ) CO Me
2 3 2
2 3
2
2 17
cis
3
2
Me(CH2)19 cis
(CH )
cis
(CH2)14OH
2 14
8
OAc
CO Me
2
Me(CH2)19 cis
(CH )
cis
(CH2)11
2 14
(
CH ) Me
2 23
9
Scheme 1. Fatty acid structures.
racemic cyclopropane analogue 4 (Scheme 2)
7 can be prepared from 2 by Simmons–Smith type
(Hartmann et al., 1994).
cyclopropanation.
This communication presents a much more con-
venient route to 2, involving a Wittig reaction
between the phosphonium salt 4-carboxybutyltriphe-
nylphosphonium bromide and nonadecanal. The latter
is easily obtained from readily available 1-eicosene
2. Results and discussion
1-Eicosene was quantitatively epoxidised with m-
(5) (Scheme 2). The racemic cyclopropane analogue
chloroperoxybenzoic acid and the resulting unpuri-
(
i) m-chloroperoxy-
benzoic acid
Me(CH )
O
Me(CH2)16
2 17
(
ii) H IO6 86%
5
6
5
-
+
Br Ph P (CH ) CO H
3
2 3
2
NaN(SiMe ) /THF
73%
3
2
Me(CH2)17 cis
(CH ) CO H
2 3 2
2
Et Zn, ClCH I
2
2
1,2-dichloroethane
21%
64%
Me(CH2)17 cis (CH ) CO Me Me(CH )
(CH ) CO H
2 3 2
2 3
2
2 17
cis
4
7
Scheme 2. Synthesis of unsaturated and cyclopropane fatty acids and esters.

G.D. Coxon et al. / Chemistry and Physics of Lipids 126 (2003) 49–53
51
fied 1-epoxyeicosane was cleaved with ortho-periodic
acid (Kusamran and Polgar, 1971) to give nonade-
canal 6, in 86% overall yield after chromatography
recorded using a Micromass Auto Spec M spectrom-
eter. Melting points (uncorrected) were carried out on
a Kofler hot stage apparatus. Thin layer chromatog-
raphy (TLC) used Fluka 70643 aluminium-backed
TLC cards. Flash column chromatography was per-
formed at medium pressure using Fluka 60738 silica
(Scheme 2). A Wittig reaction of 6 with the phos-
phonium salt 4-carboxybutyltriphenylphosphonium
bromide yielded 2 (73%). Treatment of a tetrahy-
drofuran suspension of the phosphonium salt with
sodium(bis)trimethylsilylamide (NaN[SiMe3]2), at
ambient temperature, generated the unstabilised yield.
Addition of the aldehyde 6, followed by stirring for
◦
gel 60 and petroleum ether (bp 40–60 C) (petrol) and
diethyl ether (5:2) as eluent. Starting materials and
chemical reagents were all purchased from Aldrich,
Fluka or Lancaster Synthesis.
4
h at ambient temperature, yielded predominantly
the Z isomer of 2 in a ratio of 30:1, as indicated by
the C NMR spectrum.
3.2. Nonadecanal (6)
1
3
The non-stereoselective cyclopropanation of 2 was
accomplished using a modified Simmons–Smith pro-
cedure (Nishimura et al., 1969). The addition of four
equivalents of chloroiodomethane and two equiv-
alents of diethylzinc to the alkene 2, dissolved in
m-Chloroperoxybenzoic acid (2.58 g, 14.98 mmol)
was added to a solution of 5 (3 g, 10.7 mmol) in
1,2-dichloroethane (50 ml) and the solution was stirred
at room temperature for 3 h. The reaction mixture was
washed with sat. aq. NaHCO3 (30 ml), followed by
water (30 ml) and the organic layer dried (MgSO4) and
evaporated to dryness. TLC analysis (petrol:diethyl
ether 99:1) showed complete conversion of the alkene
◦
dichloroethane at −30 C, was followed by stirring
◦
at 0 C for 4 h. After work-up, TLC analysis showed
two spots with indicating that the reaction had af-
forded both the free acid 7 (21%) (Scheme 2) and the
methyl ester 4 (64%); the remaining 15% of material
was lost in this reaction.
This facile synthetic route allows the production
of bulk quantities of the unsaturated acid 2 and the
racemic cis-cyclopropane acid 7 for studies on my-
colic acid biosynthesis (Wheeler et al., 1993a,b).
Synthetic routes to chiral analogues of 7 are now
available (Coxon et al., 1999). One of these ap-
proaches has been employed to produce an enantiomer
of a bis-cyclopropyl “meromycolyl” intermediate 8
(R 0.9) to its epoxide (R 0.2) so the residue was dis-
f
f
solved in dry diethyl ether (10 ml) and a suspension
of ortho-periodic acid (3.81 g, 16.8 mmol) in diethyl
ether (50 ml) was added. The reaction mixture was
stirred rapidly at room temperature for 1 h and then
poured into a 1:1 mixture of water and diethyl ether
(100 ml). The ethereal layer was washed with satu-
rated aqueous NaHCO3 (50 ml) followed by water
(3 × 50 ml) and dried (MgSO4). Removal of the di-
ethyl ether gave a residue which was purified by flash
chromatography to yield nonadecanal 6 (2.59 g, 86%)
◦
◦
(Scheme 1) (Al Dulayymi et al., 2000) and a deriva-
as a white solid; mp 61–63 C (lit. 60–62 C, Falorni
+
tive of a single enantiomer 9 (Scheme 1) of a natural
mycolic acid from M. tuberculosis (Al Dulayymi
et al., 2003). In pioneering studies (Gensler et al.,
et al., 1999), m/z 282.2928 (M ).
3.3. (Z)-Tetracos-5-enoic acid (2)
1
977), racemic bis-cyclopropyl meromycolates were
prepared.
Sodium bis(trimethylsilyl) amide (5.3 ml, 10.6
mmol) was added, under N2, to a stirring suspension
of 4-carboxybutyltriphenylphosphonium bromide
(1.75 g, 3.54 mmol) in anhydrous tetrahydrofuran
3
. Experimental
(
100 ml). The reaction mixture was stirred for 10 min
at room temperature before adding nonadecanal 6
1.0 g, 1 eq., 3.54 mmol). After stirring for a further
3
.1. General
(
1H and 13C NMR spectra were recorded on Bruker
AC 200 spectrometer in CDCl3. IR spectra were
taken on a Nicolet FT-IR PCIR instrument as liquid
films. Electron impact (EI) mass spectra (MS) were
2 h at ambient temperature, the reaction was quenched
with ammonium chloride solution (20 ml, 10% w/v)
and extracted with dichloromethane (40 ml). The or-
ganic layer was washed with water (2 × 50 ml), dried

5
2
G.D. Coxon et al. / Chemistry and Physics of Lipids 126 (2003) 49–53
(
MgSO4) and reduced in vacuo. The crude prod-
Al Dulayymi, J.R., Baird, M.S., Roberts, E., 2003. The synthesis
of single enantiomer of major ␣-mycolic acid of
a
a
uct was purified by flash chromatography to give 2
Mycobacterium tuberculosis. Chem. Commun. 228–229.
Besra, G.S., Minnikin, D.E., Wheeler, P.R., Ratledge, C., 1993a.
Synthesis of methyl (Z)-tetracos-5-enoate and both enantiomers
of ethyl (E)-6-methyltetracos-4-enoate; possible intermediates
in the biosynthesis of mycolic acids in mycobacteria. Chem.
Phys. Lipids 66, 23–34.
◦
(900 mg, 73%) as a white solid; mp 43–45 C (lit.
◦
+
4
2–44 C, Besra et al., 1993a), m/z 366.3512 (M ).
IR and NMR data were in accord with those published
previously for compound 2; the relative intensity
of the vinylic 13C signals for the E-isomer (128.1,
Besra, G.S., Minnikin, D.E., Simpson, M.J., Baird, M.S., Wheeler,
P.R.,
1
3
31.4) and the Z-isomer (128.6, 131.9) indicated a
0:1 preponderance in favor of the latter cyclopropane
Ratledge, C., 1993b. Inhibition of mycolic acid biosynthesis
in a cell-wall preparation from Mycobacterium smegmatis by
methyl 3-(2-octadecylcyclopropen-1-yl) butanoate, a structural
analogue of a key precursor. Chem. Phys. Lipids 66, 35–40.
Coxon, G.D., Knobl, S., Roberts, E., Baird, M.S., Al-Dulayymi,
J.R., Besra, G.S., Brennan, P.J., Minnikin, D.E., 1999. The
synthesis of both enantiomers of lactobacillic acid and mycolic
acid analogues. Tetrahedron Lett. 40, 6689–6692.
acid 2.
3
.4. Racemic cis-4-(2-octadecylcyclopropane-1-yl)-
butanoic acid (7) and racemic methyl cis-4-(2-
octadecylcyclopropane-1-yl)-butanoate (4)
Falorni, M., Giacomelli, G., Porcheddu, A., Taddei, M., 1999.
A simple method for the reduction of carboxylic acids to
aldehydes or alcohols, using H2 and Pd/C. J. Org. Chem. 64,
(
Z)-Tetracos-5-enoic acid (800 mg, 2.18 mmol) was
dissolved in 1,2-dichloroethane (40 ml), under N2, and
◦
cooled to −30 C. Diethyl zinc (3.90 ml, 4.36 mmol),
8962–8964.
followed by chloroiodomethane (1.56 g, 3.12 mmol),
Gensler, W.J., Marshall, J.P., Langone, J.J., Chen, J.C., 1977.
Synthesis of d,l-methyl meromycolate. J. Org. Chem. 42, 118–
125.
Hartmann, S., Minnikin, D.E., Römming, H.-J., Baird, M.S.,
Ratledge, C., Wheeler, P.R., 1994. Synthesis of methyl 3-(2-
octadecylcyclopropen-1-yl)propanoate and methyl 3-(2-octade-
cylcyclopropen-1-yl)pentanoate and cyclopropane fatty acids as
possible inhibitors of mycolic acid biosynthesis. Chem. Phys.
Lipids 71, 99–108.
were added and the mixture was stirred under N2 at
◦
0
C for 4 h. The reaction was quenched with aqueous
ammonium chloride (10% w/v), the organic phase
separated and the aqueous phase washed with chloro-
form (2 × 40 ml). The combined organic phases were
washed with water (2 × 30 ml), dried (MgSO4) and
reduced in vacuo. The residue was purified by flash
chromatography to provide two products; racemic cis
,6-methanotetracosanoic acid (7) (16 mg, 21%) (Rf
.55, mp 43–45 C, m/z 380.3636) and racemic cis
,6-methanomethyltetracosanoate (4) (52 mg, 64%)
Johnson, A.R., Pearson, J.A., Shenstone, F.S., Fogerty, A.C.,
1967. Inhibition of the desaturation of stearic to oleic acid by
5
0
5
cyclopropene fatty acids. Nature 214, 1244–1245.
Kremer, L., Baulard, A.R., Besra, G.S. 2000. Genetics of mycolic
acid biosynthesis. In: Hatfull, G.F., Jacobs, W.R (Eds.),
Molecular Genetics of Mycobacteria. ASM Press, Washington,
DC, pp. 173–191.
◦
◦
(
R 0.95, mp 44–48 C, m/z 394.6743). IR and NMR
f
data were in accord with those published previously
for compound 4 (Hartmann et al., 1994).
Kusamran, K., Polgar, N., 1971. Determination of the position of
ethylenic linkages in lipids. Lipids 6, 961–962.
Minnikin, D.E., 1982. Lipids: complex lipids, their chemistry,
biosynthesis and roles. In: Ratledge, C., Stanford, J.L. (Eds.),
The Biology of the Mycobacteria, vol. 1. Academic Press,
London, pp. 95–184.
Acknowledgements
Nishimura, J., Kawabata, N., Furukawa, J., 1969. A novel synthesis
of methylcyclopropanes. Tetrahedron 25, 2647–2656.
Takayama, K., Qureshi, N., 1984. Structure and synthesis of lipids.
In: Kubica, G.P., Wayne, L.G. (Eds.), The Mycobacteria: A
Source Book, Part A. Marcel Dekker, New York, pp. 315–344.
Watanabe, M., Aoyagi, Y., Ridell, M., Minnikin, D.E., 2001.
Separation and characterization of individual mycolic acids in
representative mycobacteria. Microbiology 147, 1825–1837.
Watanabe, M., Aoyagi, Y., Mitome, H., Fujita, T., Naoki, H., Ridell,
M., Minnikin, D.E., 2002. Location of functional groups in
mycobacterial meromycolate chains; the recognition of new
structural principles in mycolic acids. Microbiology 148, 1881–
1902.
DEM received support from the UK Medical Re-
search Council Cooperative (G9901077) and Project
(G9901075) grants.
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