2680
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).