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An Enantioselective Synthesis of ( S )-(+)-3-Aminomethyl-5-methylhexanoic Acid via Asymmetric Hydrogenation

2003; American Chemical Society; Volume: 68; Issue: 14 Linguagem: Inglês

10.1021/jo034397b

1520-6904

Mark J. Burk, Pieter D. de Koning, Todd M. Grote, Marvin S. Hoekstra, Garrett Hoge, Rex A. Jennings, William S. Kissel, Tung Le, Ian C. Lennon, Thomas A. Mulhern, James A. Ramsden, Robert A. Wade,

Chemical Reaction Mechanisms

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.