An efficient synthesis of (R)-3-hydroxytetradecanoic acid

Article abstract of DOI:10.1016/S0957-4166(98)00441-8

A short, efficient synthesis of (R)-3-hydroxytetradecanoic acid, a key component of bacterial endotoxins, using (R)-oxirane acetic acid ethyl ester as the source of chirality is described. The method is general and can be used in the preparation of other chiral 3-hydroxy acids.

Full text of DOI:10.1016/S0957-4166(98)00441-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4113–4115
An efficient synthesis of (R)-3-hydroxytetradecanoic acid
∗
Guangfei Huang and Rawle I. Hollingsworth
Department of Chemistry, Michigan State University, East Lansing, MI 48824-1322, USA
Received 19 October 1998; accepted 20 October 1998
Abstract
A short, efficient synthesis of (R)-3-hydroxytetradecanoic acid, a key component of bacterial endotoxins, using
R)-oxirane acetic acid ethyl ester as the source of chirality is described. The method is general and can be used in
(
the preparation of other chiral 3-hydroxy acids. © 1998 Elsevier Science Ltd. All rights reserved.
(R)-3-Hydroxytetradecanoic acid is the most common fatty acid constituent of the lipid A component
of bacterial lipopolysaccharides (LPS) (Fig. 1). The lipid A is responsible for most of the endotoxic
1,2
activities of LPS.
Although several methods have been reported for the formation of 3-hydroxy acids, current syntheses
3
4
5
for (R)-3-hydroxytetradecanoic acid either give products in low optical purity, in low yield or are limi-
6
ted to small scale preparations. 3-Hydroxytetradecanoic acid of very high optical purity is essential for
Figure 1. The structure of a typical bacterial lipid A
∗
Corresponding author. E-mail: rih@argus.cem.msu.edu
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00441-8

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G. Huang, R. I. Hollingsworth / Tetrahedron: Asymmetry 9 (1998) 4113–4115
the synthesis of lipid A because at least four such fatty acid residues are present. A synthesis employing a
fatty acid preparation that was 93% optically pure would yield a lipid A product that was only 75% pure
containing 16 isomers. Here we report an efficient synthesis for (R)-3-hydroxytetradecanoic acid in high
enantiomeric excess from (S)-3-hydroxy-γ-butyrolactone (1).7 It should be useful in the preparation
,8
of other chiral 3-hydroxy acids. As shown in the scheme, (S)-3-hydroxy-γ-butyrolactone was treated
9
with NaI–TMSCl–CH CN at room temperature to give the iodohydrin 2. This was converted to the
3
10
oxiraneacetic acid ester 3 by treatment with Ag O in CH CN at room temperature. Compound 3 was
2
3
selectively ring-opened with decyl magnesium bromide and CuI in anhydrous THF at −30°C to give
1
1
(
R)-3-hydroxytetradecanoic acid ethyl ester 4 in 97% yield [99.3% ee; NMR spectrum of (S)-(−)-α-
12
methoxy-α-(trifluoromethyl)phenylacetyl ester ]. Finally, the 3-hydroxy ester was saponified to give
R)-3-hydroxytetradecanoic acid 5.
(
Acknowledgements
We are grateful for the financial support of Synthon Corporation and the Michigan State University
Research Excellence Fund.
References
1
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1
1. To a suspension of CuI (3.81 g, 20.0 mmol) in 50 mL anhydrous THF (dry nitrogen) was added dropwise decylmagnesium
bromide (40 mL, 1.0 M in ether) at −30°C with stirring. After 30 min, the epoxide 3 (2.60 g, 20.0 mmol) in 10 mL
anhydrous THF was added dropwise and the reaction mixture was stirred for 1 h at −30°C. It was then allowed to reach

G. Huang, R. I. Hollingsworth / Tetrahedron: Asymmetry 9 (1998) 4113–4115
4115
room temperature and was stirred overnight. The reaction was quenched with saturated NH
separated. The aqueous layer was extracted three times with ether. The combined ether extracts were washed with saturated
NaCl solution, dried (Na SO ), concentrated and separated on a silica column. The yield was 97%. IR (CDCl ): 3027 (s),
928 (s), 2857 (s), 1213 (s), 1208 (s) cm ; H NMR (300 MHz, CDCl ): δ 4.15 (2H, q, J=7.2 Hz), 3.97 (1H, m), 2.48
1H, dd, J=16.5, 3.0 Hz), 2.37 (1H, dd, J=16.5, 9.0 Hz), 1.40 (2H, m), 1.23 (21H, br, s), 0.86 (3H, t, J=6.6 Hz);
4
Cl in water and the phases
2
4
3
−1 1
2
(
3
1
3
C
3
NMR (75 MHz, CDCl ): 173.15, 68.01, 60.65, 41.24, 36.47, 31.88, 29.60, 29.55, 29.50, 29.32, 25.45, 22.66, 14.14, 14.09;
+
HRMS Exact mass: calcd for C16
33 3
H O , [M+H] , 273.2430. Found 273.2438.
12. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.