Highly selective asymmetric synthesis of 2-hydroxy fatty acid methyl esters through chiral oxazolidinone carboximides

Article abstract of DOI:10.1007/s11746-001-0244-9

Highly selective asymmetric synthesis of 2-hydroxy fatty acid methyl esters has been accomplished through chiral imide enolates. Five chiral oleic acid imides were prepared by reaction of oleic acid with pivaloyl chloride followed by reaction with five different lithiated chiral oxazolidinones including (R)-(+)-4-benzyl-2-, (S)-(-)-4-benzyl-2-, (4R, 5S)-(+)-4-methyl-5-phenyl-2-, (4S, SR)-(-)-4-methyl-5-phenyl-2-, and (R)-(+)-4-isopropyl-2-oxazolidinones in 88-92% yields. The chiral imides were reacted with NaN(Me₃Si)₂ at -78°C to give enolates, which subsequently reacted with 2-(phenylsulfonyl)-3-phenyloxaziridine to give hydroxylated products in 78-83% yields. Methanolysis of the hydroxylated products with magnesium methoxide gave methyl 2-hydroxyoleate. Enantiomeric excesses (ee) of the products were determined to be very high (98-99% ee) by ¹H nuclear magnetic resonance study after esterification of the hydroxy group with (S)-(+)-O-acetylmandelic acid. Enantioselective hydroxylation of other fatty acids including elaidic, petroselinic, vaccenic, and linoleic was evaluated under the similar conditions using (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary to give 98% ee values for all cases.

Full text of DOI:10.1007/s11746-001-0244-9

Highly Selective Asymmetric Synthesis
of 2-Hydroxy Fatty Acid Methyl Esters
Through Chiral Oxazolidinone Carboximides
Hong-Sik Hwang and Sevim Z. Erhan*
USDA, ARS, NCAUR, Peoria, Illinois 61604
methods. Among the enzymatic methods recently reported
ABSTRACT: Highly selective asymmetric synthesis of 2-hy-
droxy fatty acid methyl esters has been accomplished through
chiral imide enolates. Five chiral oleic acid imides were pre-
pared by reaction of oleic acid with pivaloyl chloride followed
by reaction with five different lithiated chiral oxazolidinones
including (R)-(+)-4-benzyl-2-, (S)-(−)-4-benzyl-2-, (4R,5S)-(+)-4-
methyl-5-phenyl-2-, (4S,5R)-(−)-4-methyl-5-phenyl-2-, and (R)-
(+)-4-isopropyl-2-oxazolidinones in 88–92% yields. The chiral
imides were reacted with NaN(Me3Si)2 at −78°C to give eno-
lates, which subsequently reacted with 2-(phenylsulfonyl)-3-
phenyloxaziridine to give hydroxylated products in 78–83%
yields. Methanolysis of the hydroxylated products with magne-
sium methoxide gave methyl 2-hydroxyoleate. Enantiomeric ex-
cesses (ee) of the products were determined to be very high
(98–99% ee) by 1H nuclear magnetic resonance study after es-
terification of the hydroxy group with (S)-(+)-O-acetylmandelic
acid. Enantioselective hydroxylation of other fatty acids includ-
ing elaidic, petroselinic, vaccenic, and linoleic was evaluated
under the similar conditions using (4R,5S)-(+)-4-methyl-5-
phenyl-2-oxazolidinone as a chiral auxiliary to give 98% ee val-
ues for all cases.
are the enantioselective α-hydroxylation of carboxylic acids,
including some fatty acids, with an α-oxidative enzyme sys-
tem from peas (Pisum sativum) (7,8). The method is effective
for some substrates but not for substrates containing a double
bond such as oleic acid.
Several chemical methods for asymmetric α-hydroxyla-
tion of carboxylic acids by use of MoO5/pyridine/hexa-
methylphosphorus triamide (MoOPH) with a camphor-based
chiral auxiliary (10) and 2-sulfonyloxaziridines with chiral
amides (11) or imides (12) have been reported. Among them
the method developed by Evans et al. (12) with oxazolidi-
nones as chiral auxiliaries and 2-(phenylsulfonyl)-3-phenyl-
oxaziridine as an oxidant has been most widely applied in
syntheses. In the method when a chiral oxazolidinone carbox-
imide of a carboxylic acid is deprotonated at the α-position
and the resulting enolate reacts with electrophilic oxygen, the
chiral oxazolidinone group controls the direction of the attack
from the less hindered face (Scheme 1). Although oxazolidi-
nones with different structural features were used, the di-
astereomeric excesses (de) reported generally ranged from 80
to 90% for R1 = Et, Ph, and CH2Ph. When bulkier R1 groups
such as t-C4H9 and i-C3H7 were used, the de were higher
(98% de).
Paper no. J9612 in JAOCS 78, 205–211 (February 2001).
KEY WORDS: Asymmetric, chiral imide, enantioselective,
fatty acid, hydroxylation, oleic acid, oxazolidinone.
Development of facile synthetic methods for the prepara-
tion of enantiomerically pure 2-hydroxy fatty acids would be
critical for their utilization in industrial applications, espe-
cially in physiological applications. Herein, we report the
successful chiral auxiliary-induced asymmetric synthesis of
Hydroxy fatty acids are of great interest because of their use-
fulness as lubricants, surfactants, plasticizers, and components
in detergents, coatings, and paints (1). The value of a hydroxy
fatty acid is often much enhanced when it exhibits a variety of
biological activities such as hormone secretion, ion transport,
cell proliferation, and other inflammatory responses (2). The
biological activity of a hydroxy fatty acid depends on the num-
ber, position, and stereochemistry of the hydroxy groups. 2-
Hydroxy fatty acids occur naturally in sphingolipids, as com-
ponents of wool wax and skin lipids, and in a few unusual seed
oils (3) and show antimicrobial activities (4).
Since chiral 2-hydroxy carboxylic acids are important
building blocks for the synthesis of optically active materials,
efforts have been made for enantioselective preparation of 2-
hydroxy acids using enzymatic (5–8) and chemical (9–12)
*To whom correspondence should be addressed at USDA, ARS, NCAUR,
1815 N. University St., Peoria, IL 61604.
E-mail: erhansz@mail.ncaur.usda.gov
SCHEME 1
Copyright © 2001 by AOCS Press
205
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H.-S. HWANG AND S.Z. ERHAN
2-hydroxy fatty acid methyl esters containing double bonds benchtop GC–MS system, operated with electron ionization
by use of the method of Evans et al. (12).
(EI) and equipped with a J&W Scientific (Folsom, CA) HP-
5MS column (30 m × 0.25 mm i.d.). Derivatizations for
GC–MS were carried out by silylating at ambient tempera-
ture with a Supelco (Bellefonte, PA) Sylon BTZ mixture that
EXPERIMENTAL PROCEDURES
Materials. All fatty acids (99% pure) were purchased from contained trimethylchlorosilane, N,O-bis(trimethylsilyl)acet-
Nu-Chek-Prep, Inc. (Elysian, MN), and all solvents were ob- amide and N-trimethylsilylimidazole. Preparative thin-layer
tained from Fisher Scientific Co. (Fairlawn, NJ) and used chromatography (TLC) was carried out on silica gel 60F254
without further purification except tetrahydrofuran (THF), (2-mm thick).
which was freshly distilled from sodium metal and benzophe-
Synthesis. As shown in Scheme 2, fatty acids 1a–1i under-
none ketyl before use. Unless otherwise specified, all other went reactions to give methyl esters of 2-hydroxy fatty acids
chemicals were purchased from Aldrich Chemical Co. (Mil- 4a–4i, which were transformed to chiral esters 5a–5i for
waukee, WI), and used without further purification.
NMR study. The following are the procedures for each reac-
tion. 1H NMR, 13C NMR, and IR spectra of all products are
Analysis. 1H nuclear magnetic resonance (NMR) and 13
C
NMR were performed with a Bruker (Rheinstetten, Germany) summarized in Table 1.
ARX 400 spectrometer. Fourier transform-infrared (IR) spec-
Synthesis of oxazolidinone carboximides. To a stirred so-
tra were obtained with a PerkinElmer (Bucks, England) lution of fatty acid (3.53 mmol) and 0.59 mL (4.23 mmol) of
Spectrum RX FT-IR System as film on NaCl plates. Gas chro- triethylamine in THF (30 mL) was added 0.46 mL (3.72
matography–mass spectrometry (GC–MS) analysis was con- mmol) of pivaloyl chloride at –78°C, and the mixture was
ducted on a Hewlett-Packard (Palo Alto, CA) 5890/5970 stirred for 10 min at −78°C and 30 min at 0°C. The resulting
SCHEME 2
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ASYMMETRIC SYNTHESIS OF 2-HYDROXY FATTY ACIDS
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H.-S. HWANG AND S.Z. ERHAN
JAOCS, Vol. 78, no. 2 (2001)

ASYMMETRIC SYNTHESIS OF 2-HYDROXY FATTY ACIDS
209
white slurry was cooled to −78°C and then a solution of lithi-
ated oxazolidinone [obtained by adding 1.41 mL (3.53 mmol)
of 2.5 M n-BuLi in hexane to a solution of 0.63 g (3.55 mmol)
of oxazolidinone in 20 mL of THF at −78°C and stirred for
15 min] was added. The mixture was stirred for 15 min at
−78°C and then warmed to room temperature (45 min). The
reaction was quenched with 10 mL of 1 N aqueous NaHSO4
solution. After adding water (30 mL), the mixture was ex-
tracted with dichloromethane (30 mL), washed with 5% aque-
ous NaHCO3 and with saturated aqueous NaCl solution, and
then dried over MgSO4. Column chromatography on alumina
with EtOAc/hexane (1:10) afforded a pure product as a color-
less oil in 87–92% yields.
Hydroxylation of 2a–2i. To a stirred solution of 2.26 mmol
of the chiral carboximide in THF (20 mL) at −78°C was
added 2.50 mL (2.50 mmol) of 1.0 M NaN(trimethylsilyl)2 in
THF during a period of 15 min, and the mixture was stirred
for 20 min at −78°C. To this solution was added a precooled
(−78°C) solution of 0.89 g (3.40 mmol) of 2-(phenylsul-
fonyl)-3-phenyloxaziridine (13) in THF (20 mL). The solu-
tion was stirred for 2 min at −78°C and then quenched by
rapid addition of 10-camphorsulfonic acid (2.60 g, 11.2
mmol) in THF (20 mL). The mixture was stirred at room tem-
perature for 30 min and diluted with dichloromethane (20
mL). The mixture was washed with water, 5% aqueous
NaHCO3, and saturated aqueous NaCl solution and then dried
over MgSO4. Column chromatography on alumina with
hexane/CH2Cl2/EtOAc (10:2:1) and then with 10% MeOH in
CH2Cl2 gave a crude product. The second chromatography
on silica gel with hexane/EtOAc (6:1) gave a pure product as
a colorless oil in 68–83% yields.
Methanolysis of 3a–3i. To a solution of 0.11 mmol of a 2-
hydroxy fatty acid carboximide in methanol/dichloromethane
(1:1, 6 mL) was added 0.33 mL of 8% magnesium methoxide
in methanol at 0°C. The mixture was stirred at 0°C for 30
min, and dichloromethane (30 mL) was added. The mixture
was washed with 0.5 N HCl (30 mL), 5% aqueous NaHCO3,
and saturated aqueous NaCl solution, dried over MgSO4, and
evaporated. The residue was passed through a short silica gel
column with hexane/EtOAc (6:1) as eluent to give the methyl
ester of 2-hydroxy fatty acid as a colorless oil in 90–97%
yields. EI–MS spectra of the silylated derivatives of products
are summarized here.
4a, 4b, 4c, 4d, and 4e: m/z 384 (M+, 18%), 369 (M+ − CH3,
100%), 325 (M+ − COOCH3, 91%). 4f: m/z 384 (M+, 22%),
369 (M+ − CH3, 100%), 325 (M+ − COOCH3, 68%). 4g: m/z
384 (M+, 21%), 369 (M+ − CH3, 100%), 325 (M+ − COOCH3,
77%). 4h: m/z 384 (M+, 17%), 369 (M+ − CH3, 80%), 325
(M+ − COOCH3, 100%). 4i: m/z 382 (M+, 26%), 367 (M+ −
CH3, 100%), 323 (M+ − COOCH3, 68%).
Esterification of 4a–4i with (S)-(+)-O-acetylmandelic
acid. The methyl ester of hydroxy fatty acid (0.10 mmol) was
dissolved in dichloromethane (3 mL, dried over MgSO4), and
(S)-(+)-O-acetylmandelic acid (30 mg, 0.15 mmol), 4-(di-
methylamino)pyridine (DMAP, 3.4 mg, 0.03 mmol), and di-
cyclohexylcarbodiimide (DCC, 31 mg, 0.15 mmol) were sub-
JAOCS, Vol. 78, no. 2 (2001)

210
H.-S. HWANG AND S.Z. ERHAN
phenyloxaziridine to give hydroxylated products 3a–3e in
68–83% yields.
Determination of de for 3a–3e was initially attempted
using GC–MS, but the molecule was decomposed at the ele-
vated temperature needed to perform the analysis. Therefore,
products 3a–3e were transformed to methyl 2-hydroxyoleate
(4a–4e) by the reaction with magnesium methoxide in
methanol. A literature method (14) was used to determine the
enantiomeric excess (ee) of methyl 2-hydroxyoleate (4a–4e)
using 1H NMR. Esterification reaction of 4a–4e with (S)-(+)-
O-acetylmandelic acid, DMAP, and DCC gave the chiral es-
ters 5a–5e in 88–99% yields. Pure 5a and 5b were isolated by
preparative TLC, and the proton NMR (400 MHz) spectra are
shown in Figure 1. The 1H NMR spectra of diastereomers 5a
and 5b have different chemical shifts, especially, for the four
peaks that appear in the regions of 5.9–6.1, 4.9–5.1, 3.5–3.8,
and 2.1–2.2 ppm. Among them, the methyl ester singlets
which appeared at 3.71 ppm for 5a (R-configuration at C2)
and 3.54 ppm for 5b (S-configuration at C2) were used to de-
termine the enantioselectivities due to their large chemical
shift differences. The absolute configuration of the products
was confirmed by comparison to 1H NMR spectra of the au-
thentic reference compounds, methyl (R)-(+)-lactate and (S)-
(−)-lactate. The chiral ester obtained by esterification of
methyl (R)-(+)-lactate with (S)-(+)-O-acetylmandelic acid
gave peaks at 6.01 (singlet), 5.09 (double doublets), 3.70 (sin-
glet), and 2.16 (singlet) while the chiral ester of methyl (S)-
(−)-lactate gave peaks at 5.97 (singlet), 5.16 (double dou-
blets), 3.55 (singlet), and 2.18 (singlet).
FIG. 1. Chemical shift differences in 1H nuclear magnetic resonance
spectra of diastereomers, (a) 5a and (b) 5b.
sequently added at 0°C. The mixture was stirred at 0°C for 30
min and at room temperature for 30 min. Hexane (10 mL) was
added, and the insoluble solid was removed by filtration.
Preparative TLC on silica gel with hexane/EtOAc (4:1) gave
an enantiomerically pure product as a colorless oil in 95–98%
yields.
RESULTS AND DISCUSSION
To determine the ee of methyl 2-hydroxyoleate (4a–4e),
the relative amounts of diastereomers in the chiral esters
5a–5e were calculated using the proton NMR before isolation
of one diastereomer. As shown in Table 2 (Entries 1–5), the
% ee of 4a–4e were very high (98–99%), presumably because
of the relatively bulky, long alkyl chain of the oleic acid with
no noticeable difference between the chiral auxiliaries. Dur-
ing the entire reaction sequence, no isomerization of the cis-
alkene was detected by NMR or TLC.
To examine the utility of this asymmetric hydroxylation
method to other fatty acids, elaidic (9E-), petroselinic (6Z-),
vaccenic (11E-), and linoleic (9Z-, 12Z-) acids were reacted
under similar conditions with (4R,5S)-(+)-4-methyl-5-phenyl-
For the initial stage of this study, 2-(phenylsulfonyl)-3-phenyl-
oxaziridine as an oxidant, oleic acid as a substrate, and five
different commercially available chiral auxiliaries including
(R)-(+)-4-benzyl-2-, (S)-(−)-4-benzyl-2-, (4R,5S)-(+)-4-
methyl-5-phenyl-2-, (4S,5R)-(−)-4-methyl-5-phenyl-2-, and
(R)-(+)-4-isopropyl-2-oxazolidinones were chosen. As shown
in Scheme 2, oleic acid carboximides 2a–2e were prepared
by reaction of the oleic acid with triethylamine and pivaloyl
chloride in THF followed by reaction with a lithiated oxazo-
lidinone in 88–92% yields. Asymmetric hydroxylation of the
carboximides 2a–2e was carried out by reaction with
NaN(Me3Si)2 at −78°C to give their corresponding enolates
and then reaction of the enolates with 2-(phenylsulfonyl)-3-
TABLE 2
Reaction Yields and Enantiomeric Excesses (ee) Values
Configuration at C2
of 3, 4, and 5
ee (%)
of 4
Entry
Yields (%)
1
2
3
4
5
6
7
8
9
2a (90), 3a (83), 4a (93), 5a (99)
2b (90), 3b (78), 4b (90), 5b (98)
2c (88), 3c (81), 4c (93), 5c (98)
2d (92), 3d (82), 4d (90), 5d (98)
2e (91), 3e (68), 4e (93), 5e (99)
2f (88), 3f (77), 4f (97), 5f (95)
2g (87), 3g (74), 4g (95), 5g (98)
2h (92), 3h (72), 4h (95), 5h (97)
2i (90), 3i (70), 4i (96), 5i (98)
R
S
R
S
R
R
R
R
R
99
98
99
98
98
98
98
98
98
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ASYMMETRIC SYNTHESIS OF 2-HYDROXY FATTY ACIDS
211
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6. Wong, C.-H., and J.R. Matos, Enantioselective Oxidation of 1,2-
2-oxazolidinone as a chiral auxiliary to give 5f–5i in high
yields (Scheme 1). As shown in Table 2 (Entries 6–9), their
ee of 4f–4i are 98% with no observable double-bond isomer-
ization for all cases.
Diols to -α-Hydroxy Acids Using Coimmobilized Alcohol and
L
Aldehyde Dehydrogenases as Catalysts, Ibid. 50:1992–1994
(1985).
The position of the hydroxy group in the products was con-
firmed by 13C NMR and mass spectra. The chemical shifts of
the C-2 (70.5 or 70.4 ppm) in the methyl esters of 2-hydroxy
fatty acids 4a–4i are consistent with the values in the litera-
ture (15). Further confirmation was obtained by silylating the
methyl esters of 2-hydroxy fatty acids 4a–4i with a silylating
reagent (Supelco Sylon BTZ mixture) followed by GC–MS
analyses. The EI mass spectra of the silylated products obey
a fragmentation pattern of 2-hydroxy fatty acids in the litera-
ture (16). The typical peaks for silylated 2-hydroxy fatty acids
by loss of CH3 (m/z = 369 for 4a–4h, m/z = 367 for 4i) and
loss of COOCH3 (m/z = 325 for 4a–4h, m/z = 323 for 4i) were
obtained in the EI mass spectra.
7. Adam, W., W. Boland, J. Hartmann-Schreier, H.-U. Humpf, M.
Lazarus, A. Saffert, C.R. Saha-Moller, and P. Schreier, α-Hy-
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(1985).
This research provides a convenient route to enantiomeri-
cally pure 2-hydroxy fatty acid methyl esters and could be
similarly applied to prepare other functionalized fatty acid es-
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ters.
12. Evans, D.A., M.M. Morrissey, and R.L. Dorow, Asymmetric
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ACKNOWLEDGMENTS
We thank Dr. Gerhard Knothe for sincere comments and Dr. David
Weisleder for the nuclear magnetic resonance spectra.
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[Received May 8, 2000; accepted October 10, 2000]
JAOCS, Vol. 78, no. 2 (2001)