Chemoenzymatic synthesis of antiinflammatory drugs in enantiomerically pure form

Article abstract of DOI:10.1016/S0957-4166(00)00184-1

A novel chemoenzymatic route to chiral antiinflammatory drugs in enantiomerically pure form is described. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00184-1

Tetrahedron: Asymmetry 11 (2000) 2403±2407
Chemoenzymatic synthesis of anti-in¯ammatory drugs in
enantiomerically pure form
Amit Basak,* Ahindra Nag, Gautam Bhattacharya, Subrata Mandal and Sikha Nag
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 20 April 2000; accepted 10 May 2000
Abstract
A novel chemoenzymatic route to chiral anti-in¯ammatory drugs in enantiomerically pure form is
described. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The synthesis of drugs exhibiting chirality in one enantiomeric form is an area of high priority
in pharmaceutical research.1 There are several reasons for this new trend: in many cases2 one
enantiomer of a chiral drug has a therapeutically useful action while the other does not, one enantiomer
is toxic and the other is safe or one enantiomer is an agonist and the other is an antagonist. In
addition, the new regulation3 regarding the introduction of drugs in one chiral form (racemates are
allowed but in that case pharmacological and toxicological e€ects of individual enantiomers need
to be evaluated) has forced industries to look for other ways to prepare homochiral drugs.
One of our prime objectives was to develop protocols for the preparation of drugs in one
enantiomerically pure form. We have chosen the nonsteroidal anti-in¯ammatory agents, mainly
the 2-aryl propionic acid derivatives for which the (S)-enantiomer is the pharmacologically more
active isomer.4 For Naproxen, the (S)-isomer is 28 times more active in vivo than its (R)-counterpart.
2. Discussion
Our initial approach to access these drugs was the enzyme-catalyzed hydrolysis of the corre-
sponding racemic esters using the well known hydrolytic enzymes porcine pancreatic lipase (PPL)
and porcine liver esterase (PLE). However, the results were disappointingly similar to those
reported earlier.5 The enantiomeric excess of the hydrolyzed product in the case of Ibuprofen was
ꢀ30%. This prompted us to replace the carbomethoxy group with the carbinol acetate and then
* Corresponding author.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00184-1

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A. Basak et al. / Tetrahedron: Asymmetry 11 (2000) 2403±2407
study the hydrolysis using PLE and PPL. We were pleased to discover that PPL performed
favourably in the hydrolytic reaction of (þ)-acetates 3a,b, derived from (þ)-Ibuprofen and (þ)-
Naproxen, giving the corresponding (S)-alcohols in high enantiomeric excess (Scheme 1). We
have extended the hydrolysis to the carbinol acetate 3c derived from (þ)-Flurbiprofen for which
the gastrointestinal toxicity is greatly enhanced by the presence of the (R)-isomer.6 In all cases,
the ee's were very high (as judged from the speci®c rotation) (Table 1). The hydrolytic reactions
1
were carried out up to a conversion of 35±48% (determined by H NMR of the crude reaction
mixture after work up). The alcohols and the unconverted acetates were separated by column
chromatography over silica gel. Previously, Sih and Gu7 prepared the homochiral acetates by a
PPL-mediated transesteri®cation of the corresponding racemic alcohols using vinyl acetate. Our
method o€ers an alternate route to these chiral alcohols by exploiting the enantioselective
hydrolytic ability of PPL. The steric course of hydrolysis could be explained on the basis of the
Jones model8 as shown in Fig. 1.
Scheme 1.
Table 1
The absolute con®gurations of the alcohols were determined by comparison with the literature
values for the (S)-isomer.10 For Flurbiprofen, we could not get a literature value of the speci®c
rotation of the corresponding alcohol. However, simply by analogy with the sign of rotation of
the alcohols derived from Ibuprofen and Naproxen and also from the rotation of the oxidation
product, the absolute con®guration was assumed to be S.

A. Basak et al. / Tetrahedron: Asymmetry 11 (2000) 2403±2407
2405
Figure 1.
2.1. Oxidation of the chiral alcohols to the chiral drugs
The oxidations of the (S)-(+)-alcohols were carried out with pyridinium dichromate (PDC)11
using DMF as solvent. The yield of (S)-(+)-acid was ꢀ60%. The speci®c rotations of (S)-(+)-
Ibuprofen, (S)-(+)-Naproxen and (S)-(+)-Flurbiprofen all matched well with the literature values12
(Table 2). The same oxidation to (S)-(+)-Flurbiprofen had been carried out previously by Griesbach
et al.13 using Jones' conditions (CrO3, H2SO4). Although Jones' oxidation might be economically
more viable, one advantage of the PDC reaction is that the rest of the material in the oxidation,
the aldehyde, can again be reoxidized to the acid, thus improving the yield.
In conclusion, a chemoenzymatic route to the anti-in¯ammatory drugs in one chiral form has
been developed. The method is operationally simple and produces the pharmacologically active
form in high enantiomeric purity.
Table 2
3. Experimental
3.1. General procedure for the synthesis of 2-aryl substituted propanol derivatives
3.1.1. Preparation of alcohols 2a±c
The methyl ester 1a±c (5 mmol) was reduced with sodium borohydride (5 mmol) in methanol
(25 ml). The mixture was allowed to stir for 4 h after which the reaction volume was reduced to 5
ml. Water was added and the mixture was extracted with ethyl acetate. The combined organic
layers were dried over anhydrous sodium sulphate and then evaporated. The product was puri®ed
by silica gel chromatography using hexane:ethyl acetate=3:1.
Spectral data. Alcohol 2a: ꢀH 7.10 (4H, m, Ar-H), 3.65 (2H, d, J=6.8 Hz, CH2OH), 2.90 (1H,
m, CH-CH2OH), 2.45 (2H, m, J=7.1 Hz, Ar-CH2), 1.89 (1H, m, CH3CHCH3), 1.27 (3H, d,
J=6.7 Hz, CHCH3), 0.91 {6H, d, J=6.7 Hz, CH(CH3)2}. Alcohol 2b: ꢀH 7.69 (2H, dd, J=5.3,
8.4 Hz, Ar-H), 7.60 (1H, s, Ar-H), 7.33 (1H, dd, J=1.8, 8.5 Hz, Ar-H), 7.12 (2H, m, Ar-H), 3.89

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A. Basak et al. / Tetrahedron: Asymmetry 11 (2000) 2403±2407
(3H, s, OMe), 3.75 (2H, d, J=6.8 Hz, CH2OH), 3.07 (1H, m, CH-CH2OH), 1.33 (3H, d, J=7.0
Hz, CHCH3). Alcohol 2c: ꢀH 7.26±7.56 (6H, complex, Ar-H), 7.02±7.13 (2H, m, Ar-H), 3.75 (2H,
d, J=6.8 Hz, CH2OH), 2.99 (1H, m, CH-CH2OH), 1.31 (3H, d, J=6.9 Hz, CHCH3).
3.1.2. Preparation of acetate
The alcohol 2a±c (2 mmol) was then acetylated with acetic anhydride, triethylamine (2.2 mmol)
and a catalytic amount of DMAP (5 mg) using dichloromethane as solvent. The mixture was
allowed to stir for 1 h at room temperature, and then washed with water and extracted with
dichloromethane. The organic layer was dried over Na2SO4 and then evaporated to leave a white
solid from which the product was isolated by silica gel chromatography using hexane:ethyl ace-
tate=7:1.
Spectral data. Acetate 3a: ꢀH 7.23±7.20 (4H, m, Ar-H), 4.34, 4.27 (2H, ABX, JAB=10.8 Hz,
JAX=6.8 Hz, JBX=5.4 Hz, CH2OAc), 3.21 (1H, m, CHCH3), 2.61 (2H, d, J=7.0 Hz, CH2CH),
2.18 (3H, s, COCH3), 2.01 {1H, m, CH(CH3)2}, 1.46 (3H, d, J=7.0 Hz, CH3CH), 1.06 {6H, d,
J=7.0 Hz, (CH3)2CH}. Acetate 3b: ꢀH 7.62 (2H, d, J=8.5 Hz, Ar-H), 7.57 (1H, s, Ar-H), 7.31
(1H, dd, J=1.7, 8.5 Hz, Ar-H), 7.12 (2H, m, Ar-H), 4.25, 4.17 (2H, AB of ABX, JAX=7.0 Hz,
JBX=7.3 Hz, JAX =10.8 Hz, CH2OH), 3.90 (3H, s, OCH3), 3.21 (1H, m, CHCH3), 2.05 (3H, s,
OCOCH3), 1.33 (3H, d, J=7.1 Hz, CHCH3). Acetate 3c: ꢀH 7.35±7.57 (6H, complex, Ar-H),
7.00±7.11 (2H, m, Ar-H), 4.14 (2H, m, CH2OCOCH3), 3.14 (1H, m, CHCH3), 2.05 (3H, s,
OCOCH3), 1.33 (3H, d, J=7.1 Hz, CHCH3).
3.1.3. Enzymatic hydrolysis of acetyl derivatives 3a±c
The acetyl derivative was hydrolyzed with the help of the enzyme pig pancreatic lipase (PPL).
The reaction mixture contained the acetyl derivative (2 mmol), phosphate bu€er (pH 8.0, 50 ml),
acetone (10 ml) and the enzyme (100 mg). The pH was maintained at 8.0 by intermittent addition
of 1N NaOH. After 50% conversion (estimated by TLC), the mixture was extracted with ethyl
acetate, dried over Na2SO4 and solvent was evaporated. The residue, upon chromatography on
silica gel, furnished the product which was isolated from hexane:ethyl acetate (1:1).
Speci®c rotation (CHCl3, c 1): alcohol 4a: [ꢁ]D=^13; alcohol 4b: [ꢁ]D=^17; alcohol 4c:
[ꢁ]D=^14.4.
3.1.4. Oxidation of the alcohols 4a±c to acids 5a±c
The alcohol 4a±c was reacted with 3.5 equivalents of pyridinium dichromate (PDC) in the
presence of DMF (10 ml). After 72 h, the mixture was partitioned between ethyl acetate and
aqueous NaHCO3. The aqueous layer was adjusted to pH 2 and then re-extracted with EtOAc.
The organic layer was dried with Na2SO4, ®ltered and evaporated to leave the acid as a white
solid (yield ꢀ50%) having identical 1H NMR with the authentic racemic sample.
Speci®c rotation (CHCl3, c 1): (S)-(+)-Ibuprofen: [ꢁ]D=+56, lit.12 [ꢁ]D=+59; (S)-(+)-Naproxen:
[ꢁ]D=+62, lit.12 [ꢁ]D=+66; (S)-(+)-Flurbiprofen: [ꢁ]D=+39, lit.5 [ꢁ]D=+41.4.
Acknowledgements
We are grateful to the Department of Biotechnology, Government of India, for funding the
research.

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