Enzymatic resolution of substituted mandelic acids

Article abstract of DOI:10.1016/S0040-4039(03)01270-X

A series of substituted mandelic acids were prepared and subjected to enzymatic resolution utilizing Lipase PS 'Amano'.

Full text of DOI:10.1016/S0040-4039(03)01270-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5477–5481
Enzymatic resolution of substituted mandelic acids
Robert F. Campbell,a Kevin Fitzpatrick,a Tord Inghardt,b Olle Karlsson,b Kristina Nilsson,b
John E. Reillya,* and Larry Yeta
aAlbany Molecular Research, Inc., 21 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
bAstraZeneca R & D Mo¨lndal, S-431 83, Mo¨lndal, Sweden 43183
Received 1 May 2003; accepted 21 May 2003
Abstract—A series of substituted mandelic acids were prepared and subjected to enzymatic resolution utilizing Lipase PS ‘Amano’.
© 2003 Elsevier Science Ltd. All rights reserved.
The syntheses of the mandelic acids are outlined in
Schemes 1–3. Conversion of 3-mercaptobenzoic acid (7)
to 3-(methylthio)benzaldehyde (8) was accomplished in
a straightforward manner (Scheme 1). Subsequent
cyanohydrin formation and acidic hydrolysis provided
racemic 3-(methylthio)mandelic acid (1). 3-Nitroman-
delic acid (2) was prepared in a similar manner starting
from 3-nitrobenzaldehyde (9).
The kinetic resolution of racemic substrates by enzyme
catalysis, especially efficient processes for lipase-cata-
lyzed hydrolysis of esters and acylation of secondary
alcohols, has become a standard reaction in organic
synthesis.1 During the course of our studies, we
required the use of several enantiomerically pure substi-
tuted mandelic acids. Attempts to resolve several of
these mandelic acids with various chiral amines via
their diastereomeric salts were unsuccessful.2 We report
herein, the successful enzymatic resolution of racemic 3-
and 3,5-substituted mandelic acids 1–6 (Fig. 1) with
Lipase PS ‘Amano’.3–5
The preparations of mandelic acids 3, 4 and 6 began
with 3,5-dinitrobenzene (Scheme 2). Thus, reduction of
the carboxylic acid followed by selective reduction of
one of the nitro groups provided nitrobenzene 12.6
Generation of the diazonium salt followed by treatment
with a mixture of copper(I) chloride and copper(II)
chloride gave chlorobenzene 13. Aldehyde formation
followed by generation of the cyanohydrin and acidic
hydrolysis provided 3-chloro-5-nitromandelic acid (3).
Reductive amination of chlorobenzene 13 in a one-pot/
two-step procedure gave the dimethylamino analogue
14, which was converted to 3-chloro-5-dimethyl-
aminomandelic acid (4) using the standard procedures.
Figure 1.
Scheme 1.
* Corresponding author. E-mail: john.reilly@albmolecular.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01270-X

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R. F. Campbell et al. / Tetrahedron Letters 44 (2003) 5477–5481
Scheme 2.
Scheme 3.
Scheme 4.
By protecting mandelic acid 3 as the corresponding
acetonide derivative, it was possible to carry out the
nitro group reduction and subsequent derivatization to
the pyrrole.7 Deprotection under basic conditions pro-
vided 3-chloro-5-(pyrrole-1-yl)mandelic acid (6).
3-Dimethylamino-5-(trifluoromethyl)mandelic acid (5)
was prepared using similar methodology starting with
benzoic acid 16 (Scheme 3). In this case, it was shown
that the reductive amination of the preformed mandelic
acid could be carried out without any difficulties.

R. F. Campbell et al. / Tetrahedron Letters 44 (2003) 5477–5481
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Table 1. Enzymatic resolution of racemic mandelic acids with lipase PS ‘Amano’a

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R. F. Campbell et al. / Tetrahedron Letters 44 (2003) 5477–5481
Scheme 5.
Scheme 6.
has proven to be quite general on a multi-gram scale
with both electron withdrawing and electron donating
groups tolerated on the aromatic ring. This has allowed
synthetic efforts toward the substituted mandelic acids
to consider all means available followed by a straight-
forward enzymatic resolution to give the individual
enantiomers. The utility of these compounds in further
syntheses will be reported in due course.
The enzymatic resolution of the racemic mandelic acids
was then studied. Mandelic acids 1–6 were resolved
with Lipase PS ‘Amano’ (50% wt/wt) in the presence of
excess vinyl acetate in tert-butyl methyl ether at 55°C,
with the reaction progress monitored by HPLC, to
afford R-(−)-alcohols 1–6 and S-acetates 18–23
(Scheme 4). These resolutions proved to be quite gen-
eral for various substituents, giving reasonable yields
and selectivity in greater than 95% ee (Table 1).8 The
S-acetates 18–23 were hydrolyzed under basic condi-
tions (NaOH, methanol) in a separate manipulation to
provide S-(+)-alcohols 1–6 without any racemization
(as confirmed by chiral HPLC analyses).
Acknowledgements
We thank AstraZeneca for the opportunity to collabo-
rate on this project and subsequently publish this body
of work.
The stereochemical assignments of the products were
initially made based on the work described by Chadha
et al., where 2-hydroxy-4-phenylbutanoic acid and an
unsaturated isomer were resolved utilizing Lipase PS
‘Amano’ (Scheme 5).3
References
1. For reviews on the use of lipases in organic synthesis, see:
(a) Sih, C. J.; Wu, S. H. Topics Stereochem. 1989, 19, 63;
(b) Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl.
1989, 28, 695; (c) Boland, W.; Fro¨ssl, C.; Lorentz, M.
Synthesis 1991, 1049; (d) Faber, K.; Riva, S. Synthesis
1992, 895; (e) Theil, F. Chem. Rev. 1995, 95, 2203; (f)
Schmid, R. D.; Verger, R. Angew. Chem., Int. Ed. Engl.
1998, 37, 1608.
Later studies in our laboratory using commercial sup-
plies of each enantiomer of mandelic acid confirmed
that the (S)-enantiomer of mandelic acid was preferen-
tially acylated by Lipase PS ‘Amano’ as shown by
chiral HPLC analyses (Scheme 6).
A representative procedure for enzymatic resolution of
racemic mandelic acids follows: A mixture of ( )-1 (2.0
g, 10.1 mmol), Lipase PS ‘Amano’ (1.0 g), and vinyl
acetate (5.0 mL) in tert-butyl methyl ether (5.0 mL) was
heated at 55°C for 24 h. The reaction was filtered and
the filter cake was washed with ethyl acetate (100 mL).
The filtrate was concentrated in vacuo and chro-
matographed on silica gel, eluting with chloro-
form:methanol:concentrated ammonium hydroxide
(6:3:1) to afford R-(−)-1 (630 mg, 32%) as a yellow oil
and S-18 (850 mg, 35%) as a tan solid.8,9 HPLC
Analysis of R-(−)-1: 98.6% purity, 96.0% ee, Chiralcel
OD Column (95:5:0.5 hexanes/ethanol/TFA mobile
phase, 1.0 mL/min flow rate, UV detector at 228 nm).
2. (a) Zingg, S. P.; Arnett, E. M.; McPhail, A. T.; Bothner-
By, A. A.; Gilkerson, W. R. J. Am. Chem. Soc. 1988, 110,
1565; (b) Patil, A. O.; Pennington, W. T.; Paul, I. C.;
Curtin, D. Y.; Dykstra, C. E. J. Am. Chem. Soc. 1987,
109, 1529; (c) Colon, D. F.; Pickard, S. T.; Smith, H. E. J.
Org. Chem. 1991, 56, 2322.
3. For an example of the enzymatic resolution of an a-
hydroxy carboxylic acid using Lipase PS ‘Amano’, see:
Chadha, A.; Manohar, M. Tetrahedron: Asymmetry 1995,
6, 651.
4. Lipase PS ‘Amano’ (Pseudomonas cepacia; Lot No.
LPSAW09505) was purchased from Amano Pharmaceuti-
cal Co., Ltd, Nagoya, Japan.
5. For examples of the use of enzymes in the resolution of
mandelic acid and mandelate esters, see: (a) Strauss, U. T.;
Faber, K. Tetrahedron: Asymmetry 1999, 10, 4079; (b)
Zhang, W.; Wang, P. G. J. Org. Chem. 2000, 65, 4732; (c)
Queiroz, N.; da Grac¸a Nascimento, M. Tetrahedron Lett.
2002, 43, 5225.
In summary, chiral resolutions of substituted racemic
mandelic acids were achieved using Lipase PS ‘Amano’.
In this way, both the R-(−)- and S-(+)-alcohols were
obtained in optical purities of >95% ee. The reaction

R. F. Campbell et al. / Tetrahedron Letters 44 (2003) 5477–5481
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Nystro¨m, J.-E. World Patent WO 0042059, 2000.
6. Meindl, W. R.; von Angerer, E.; Scho¨nenberger, H.;
Ruckdeschel, G. J. Med. Chem. 1984, 27, 1111.
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8. For additional experimental details, including spectro-
scopic data, and additional examples, see: Inghardt, T.;
9. Depending on the chromatography eluents used and the
drying time, products may have been isolated as their
ammonium salts. When necessary, salts were neutralized in
a separatory funnel with aqueous acid or by passing
through a weakly acidic ion exchange resin.