Preparation of enantiomerically enriched aromatic β-amino acids via enzymatic resolution

Article abstract of DOI:10.1016/S0040-4039(00)00222-7

A range of enantiomerically enriched aromatic β-amino acids with high e.e. have been prepared via enzymatic resolution of ethyl ester derivatives. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00222-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2679–2681
Preparation of enantiomerically enriched aromatic β-amino acids
via enzymatic resolution
Susan J. Faulconbridge,a Karen E. Holt,b Luis Garcia Sevillano,b Christopher J. Lock,a,∗
Peter D. Tiffin,a,† Neil Tremayne a and Stephen Winter b
aCelltech Chiroscience Ltd, Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
bChirotech Technology Ltd, Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
Received 16 December 1999; accepted 3 February 2000
Abstract
A range of enantiomerically enriched aromatic β-amino acids with high e.e. have been prepared via enzymatic
resolution of ethyl ester derivatives. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amino acids and derivatives; asymmetric synthesis; enzymes and enzyme reactions; resolution.
The preparation of enantiomerically pure β-amino acids for incorporation into medicinal chemistry
programmes is an area of intense activity.1 Given the facile synthesis of racemic compounds of type
12 from the corresponding aromatic aldehyde we sought to develop an efficient biocatalytic resolution
process based on a simple ester derivative 2 (Scheme 1).3 Indeed, such an approach formed the
basis of the first resolution of β-phenylalanine wherein the N-acetyl ethyl ester was resolved with α-
chymotrypsin.4 The slow rate (25% hydrolysis after 90 h), however, renders this process impractical.
Scheme 1.
In this letter we disclose the first simple resolution of aromatic β-amino esters, wherein the nitrogen
atom is not protected.5 Racemic amino acids 1 were readily converted into their ethyl ester hydrochloride
salts by standard Fisher esterification. After basification to pH 12, the ester 2 was subjected to the
action of a range of commercially available enzymes from which lipase Amano PS emerged as the most
promising.
∗
†
Corresponding author.
Present address: Chemical Synthesis Department, Roche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Herts,
AL7 3AY, UK.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00222-7
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The influence of pH was found to have a pronounced effect on selectivity; with pH 8 being preferred.
Thus, for example, racemic β-phenylalanine ethyl ester gave 73% e.e. amino acid at pH 7 and 99% e.e.
amino acid at pH 8 at the same conversion. The stereochemical outcome of the reaction was determined
by correlation of the [α]D of the isolated β-phenylalanine with that reported in the literature.6 Thus, the
(S)-ester is preferentially hydrolysed.
This scaleable procedure is volume efficient (200 g/l) and allows access to both enantiomers of the
amino acid in high e.e. and yield.7
We believe that the facile hydrolysis of the recovered starting material is an advantageous feature of
the processes. The scope of the reaction was examined with respect to the tolerance of substituents in the
aromatic ring and the results, at 50% conversion are summarised in Table 1.
Table 1
In conclusion we have demonstrated the first simple bioresolution of aromatic β-amino esters using
a commercially available lipase without the need for a nitrogen protecting group. From Table 1 it is
apparent that the reaction is broadly applicable and allows easy access to both isomers.
Acknowledgements
We thank Steven Lloyd, Catherine Rippé and Sean Savage for analytical assistance. One of us (L.G.S.)
would like to thank the M.E.C. of Spain for funding.
References
1. For a general overview, see: Enantioselective Synthesis of β-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1996.
2. Rodionow, W. M.; Postovskaja, E. A. J. Am. Chem. Soc. 1929, 51, 841. Rodionow, W. M. J. Am. Chem. Soc., 1929, 51, 847.
3. For a review, see: Soloshonok, V. A. pp. 443–464 in Ref. 1. and Ng, J. S.; Topgi, R. S. Current Opinion in Drug Discovery
and Development 1998, 1, 314.
4. Cohen, S. G.; Weinstein, S. Y. J. Am. Chem. Soc. 1964, 86, 725.
5. The need for a N-protecting group has been inferred: Kobayashi, S.; Iimori, T.; Izawa, T.; Ohno, M. J. Am. Chem. Soc. 1981,
103, 2405.
6. Soloshonok, V. A.; Fokina, N. A.; Rybakova, A. V.; Shishkina, I. P.; Galushko, S. V.; Sorochinsky, A. E.; Kukhar, V. P.;
Savchenko, M. V.; Svedas, V. K. Tetrahedron: Asymmetry 1995, 6, 1601.
7. Typical procedure: Amano PS 18 g was added to a suspension of 3-amino-3-phenylpropionic acid ethyl ester 358 g (1.85
mol) in 50 mM KH2PO4 adjusted to pH 8.2 and the mixture stirred for 15 h. The resulting white precipitate was filtered
and washed with acetone to yield (S)-3-amino-3-phenylpropionic acid 136 g (44% yield, 99% ee). The aqueous filtrate was
basified to pH 9.5 and extracted with ethyl acetate. Evaporation gave (R)-3-amino-3-phenylpropionic acid ethyl ester which
was saponified with sodium hydroxide to yield (R)-3-amino-3-phenylpropionic acid 109 g (36%, 98% ee).

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