Concise synthesis of ximenynic acid

Article abstract of DOI:10.1080/00397911.2011.585443

An improved synthesis of ximenynic acid (1) starting from castor oil has been developed with the direct chlorination of ricinstearolic acid as the key step. By this modification, the synthetic route was more concise and economic. The separation of geometr

Full text of DOI:10.1080/00397911.2011.585443

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Concise Synthesis of Ximenynic Acid
Lutai Wang a , Jiabin Li b & Xiaowen Xue a
a Department of Medicinal Chemistry , China Pharmaceutical
University , Nanjing , China
b Department of Inorganic Chemistry , China Pharmaceutical
University , Nanjing , China
Accepted author version posted online: 12 Jan 2012.Published
online: 02 Aug 2012.
To cite this article: Lutai Wang , Jiabin Li & Xiaowen Xue (2012) Concise Synthesis of Ximenynic Acid,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:23, 3540-3543, DOI: 10.1080/00397911.2011.585443
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Synthetic Communications1, 42: 3540–3543, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.585443
CONCISE SYNTHESIS OF XIMENYNIC ACID
Lutai Wang,1 Jiabin Li,2 and Xiaowen Xue1
1Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing, China
2Department of Inorganic Chemistry, China Pharmaceutical University,
Nanjing, China
GRAPHICAL ABSTRACT
Abstract An improved synthesis of ximenynic acid (1) starting from castor oil has been
developed with the direct chlorination of ricinstearolic acid as the key step. By this modifi-
cation, the synthetic route was more concise and economic. The separation of geometric
somers was achieved by repeated urea fractionation.
Supplemental materials are available for this article. Go the publisher’s online edition of
Synthetic Communications to view the free supplemental file.
Keywords Chlorination; synthesis; ximenynic acid
INTRODUCTION
Ximenynic acid [(11E)-octadecen-9-ynoic acid, 1, Fig. 1], also known as santal-
bic acid, is a C18 conjugated enyne fatty acid isolated from the sandalwood oil from
the shrub Santalum spicatum.[1] Similar to other natural conjugated enyne fatty
acids, a variety of biological activities have been reported for ximenynic acid. Xime-
nynic acid has been extensively used in formulations to improve hair vitality by
stimulating the microvasculokinetic activity of the scalp.[2] It has also been reported
to possess anti-inflammatory and anticarcinogenic activities.[3]
The total synthesis of ximenynic acid was reported by Crombie and Jacklin
from n-heptaldehyde and propargyl bromide with seven steps early in 1950s.[4]
Recently, Jie and coworkers developed a nice approach to prepare ximenynic acid
from methyl ricinoleate.[5] Methyl ricinoleate was first converted into ricinstearolic
acid by bromination and dehydrobromination. Ricinstearolic acid was then esterified
with BF3=methanol, followed by the sulfonylation of the 12-hydroxy group with
Received February 6, 2011.
Address correspondence to Xiaowen Xue, Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009, China. E-mail: xwenxue@cpu.edu.cn
3540

CONCISE SYNTHESIS OF XIMENYNIC ACID
3541
Figure 1. Structure of ximenynic acid (1).
methanesulfonyl chloride and elimination to afford a mixture of ximenynic acid and
its 11Z-isomer. Pure ximenynic acid was separated by urea fractionation with a total
yield of 20%.
Here we report an improved synthesis of ximenynic acid from castor oil with
the following advantages. First, our synthesis exploits castor oil as the starting
material, which is more inexpensive and accessible. Second, the chlorination of
12-hydroxy was directly performed for ricinstearolic acid instead of methyl ricin-
stearolate, which avoids the protection of carboxylic group and later deprotection,
thus providing a more concise and economic synthetic route.
Scheme 1 delineates the improved synthesis of ximenynic acid developed in our
laboratories. Castor oil (2) was brominated first, followed by the elimination of
hydrobromide, to provide ricinstearolic acid (3) with a modified literature method.[4,6]
Ricinstearolic acid (3) was then chlorinated with SOCl2, followed by the elimination
of hydrochloride under aqueous KOH to yield a mixture of ximenynic acid (1) and its
(Z)-isomer (4). What should be mentioned here is that the elimination provided the
double bond only in the 11-position, and no 12-double bond product was isolated,
as proposed by Liu.[7] The separation of ximenynic acid isomers was then achieved
by repeated urea fractionation and geometrically pure ximenynic acid was yielded,
with a comparable overall yield with literature[5] (16% from castor oil for our method
compared to 20% from pure methyl ricinoleate for Jie’s approach). The melting point
1
and H NMR spectrum of 1 were in good agreement with those described in the
literature.[5]
In summary, we have successfully developed a concise synthetic route to
prepare ximenynic acid from easily available castor oil with a comparable yield.
The key steps involved the chlorination for 12-hydroxy of ricinstearolic acid and
the subsequent elimination of hydrochloride for 12-chlorooctadec-9-ynoic acid. A
mixture of (11E and Z)-octadecen-9-yonic acids (E=Z ¼ 0.82) was thus obtained
Scheme 1. Reagents and conditions: (a) Br2= EtOH= ꢀ5 ꢁC; (b) KOH=H2O=80 ꢁC=10 h; (c) SOCl2= 60 ꢁC=
3 h; (d) KOH=EtOH= 80 ꢁC=24 h; and (e) urea=CH3OH.

3542
L. WANG, J. LI, AND X. XUE
and the pure E-enyonic acid (i.e., ximenynic acid), was then separated by repeated
urea fractionation. The route is convenient and economical.
EXPERIMENTAL
Reagents were purchased from commercial sources and used without further
purification unless otherwise indicated. Melting points were determined with an
1
XT-4 melting-point apparatus and are uncorrected. H and 13C NMR spectra were
recorded on Bruker AV-300 (300 MHz) or AV-500 (500 MHz) instruments with
CDCl3 as the solvents, and mass spectra were performed on a Waters Q-TOF Micro.
12-Hydroxyoctadec-9-ynoic Acid (3)
Bromine (11.6 g, 67.5 mmol) was added dropwise to a solution of castor oil (2,
20 g, 67 mmol, containing ꢂ17 g of ricinoleic acid) in ethyl alcohol (12 mL) at ꢀ5 ꢁC
with stirring. When addition was complete, the product was refluxed with potassium
hydroxide (24 g) in water (16 g) for 10 h. The mixture was poured into water (120 mL),
acidified with sulfuric acid (5 M, 60 mL), extracted with diethyl ether (3 ꢃ 100 mL),
and dried over anhydrous sodium sulfate. Removal of ether gave ricinstearolic acid
(20 g). Recrystallization of the crude from petroleum ether gave 12-hydroxyoctadec-
1
9-ynoic acid 3 (12.9 g, 65% yield). Mp 51–53 ꢁC [lit.[4] 52 ꢁC]; H NMR (300 MHz,
CDCl3): d 0.88 (t, 3H, J ¼ 6.6 Hz), 1.29–1.52 (m, 18H), 1.60–1.67 (m, 2H), 2.17 (t,
2H, J ¼ 6.9 Hz), 2.22–2.44 (m, 4H), 3.65–3.73 (m, 1H); 13C NMR (1D þ DEPT,
125 MHz, CDCl3): d 14.0 (CH3), 18.7 (CH2), 22.6 (CH2), 24.6 (CH2), 25.6 (CH2),
27.7 (CH2), 28.6 (CH2), 28.7 (CH2), 28.8 (CH2), 28.9 (CH2), 29.2 (CH2), 31.8
(CH2), 33.9 (CH2), 36.2 (CH2), 70.3 (CH), 76.2 (C), 83.1(C), 179.2 (C); MS (ESI,
negative ion mode): m=z ¼ 295.1 [M ꢀ H]ꢀ; HRMS (ESI, negative ion mode) calcd.
for C18H31O3, m=z: 295.2273 [M-H]ꢀ; found, m=z: 295.2278.
(11E/Z)-Octadecen-9-ynoic Acid (1 and 4)
Thionyl chloride (10 g, 84 mmol) was added to a mixture of ricinstearolic acid
(3) (5.0 g, 16.9 mmol) and pyridine (0.5 mL) with stirring at rt. The mixture was
heated at 60 ꢁC for 3 h, and excess thionyl chloride was removed under reduced
pressure. Water (30 mL) was added to the residue and the mixture was extracted with
diethyl ether (3 ꢃ 30 mL), and the organic extract was washed with water (3 ꢃ 30 mL)
and then dried over anhydrous sodium sulfate. Removal of ether gave the crude
(6.8 g). It was used for next step without further purification.
The crude was refluxed with potassium hydroxide (6.8 g) and water (6.8 mL) in
ethyl alcohol (136 mL) for 24 h, acidified with sulfuric acid (5 M), extracted with
diethyl ether (3 ꢃ 100 mL), and dried over anhydrous sodium sulfate. After the
solvent was evaporated, the residue was purified by column chromatography with
petroleum ether and ethyl acetate (75:25, vol=vol) as eluent to yield a mixture of
(Z)- and (E)-enynoic acids (2.65 g, 57% yield) with 45% (E)-isomer. The ratio of E
1
to Z isomers (1 and 4) was determined by the signals of 12-H at their H NMR
spectrum.

CONCISE SYNTHESIS OF XIMENYNIC ACID
3543
(11E)-Octadecen-9-ynoic Acid (1)
The mixture of the crude acids (0.61 g), urea (2.61 g), and methanol (8 mL) was
warmed to dissolve the urea crystals. The solution was then kept at 5 ꢁC for 4 h. The
solution was filtered to recover the solid urea adduct. The collected urea adduct was
dissolved in diethyl ether (3ꢃ 10 mL) and then dried over anhydrous sodium sulfate.
The solvent was evaporated, and the residue was refractionated to yield pure ximenynic
1
acid 1 (0.25 g, 41% yield). Mp 38–39ꢁC [lit.[5] 39 ꢁC]; H NMR (300MHz, CDCl3): d
0.88 (t, 3H, J ¼ 6.9 Hz), 1.25–1.34 (m, 14H), 1.46–1.54 (m, 2H), 1.59–1.66 (m, 2H),
2.03–2.14 (m, 2H), 2.27 (t, 2H, J ¼ 6.9 Hz), 2.35 (t, 2H, J ¼ 7.5 Hz), 5.45 (d, 1H,
J ¼ 15.9 Hz), 6.04 (dt, 1H, J ¼ 15.6, 7.2 Hz); 13C NMR (1D þDEPT, 125 MHz,
CDCl3): d 14.0 (CH3), 19.3 (CH2), 22.6 (CH2), 24.6 (CH2), 28.6 (CH2), 28.74 (CH2),
28.77 (CH2), 28.8 (CH2), 28.9 (CH2), 29.7 (CH2), 31.7 (CH2), 32.9 (CH2), 34.0
(CH2), 79.3 (C), 88.5 (C), 109.8 (CH), 143.4 (CH), 180.1 (C); MS (ESI, negative ion
mode): m=z ¼ 277.3 [M ꢀ H]ꢀ; HRMS (ESI, negative ion mode) calcd. for
C18H29O2, m=z: 277.2168 [M ꢀ H]ꢀ; found, m=z: 277.2170.
ACKNOWLEDGMENT
This work was supported by funding from the China Pharmaceutical
University (211080).
REFERENCES
1. Hatt, H. H.; Schoenfeld, R. Some seed fats of the santalaceae family. J. Sci. Food. Agric.
1956, 7, 130–133.
2. Liu, Y. D.; Longmore, R. B. A biotransformation product of ximenynic acid and its
significance. Proceed. Nutrition Soc. Australia 1996, 20, 203.
3. Desai, V. B.; Shankaranarayana, K. H. Utilization of sandal seed oil. Res. Ind. 1990, 35,
232–233.
4. Crombie, L.; Jacklin, A. G. Total synthesis of ricinoleic acid. J. Chem. Soc. 1955,
1740–1748.
5. Jie, M. S. F. L. K.; Pasha, M. K.; Ahmad, F. Ultrasound-assisted synthesis of santalbic
acid and a study of triacylglycerol species in Santalum album (Linn.) seed oil. Lipids
1996, 31, 1083–1089.
6. Gunstone, F. D.; Schuler, H. R. Fatty acids, part 45: Epoxyoctadecenoates, dihydroxyoc-
tadecenoates, and diepoxyocanoates: Preparation, chromatographic properties, and
reaction with boron trifluoride etherate. Chem. Phys. Lipids 1975, 15, 174–188.
7. Liu, Y. D.; Longmore, R. B.; Fox, J. E. D. Separation and identification of ximenynic acid
isomers in the seed oil of Santalum spicatum R.Br. as their 4,4-dimethyioxazoline
derivatives. J. Am. Oil Chem. So. 1996, 73, 1729–1731.