Mechanistic studies on the highly diastereoselective hydrogenation of chiral enamines to produce beta-amino esters and amides

ORGN 6

David M. Tellers, Norihiro Ikemoto, Nelo Rivera, Spencer D. Dreher, Jinchu Liu, Eugenia Njolito, Angie Huang, Yi Hsiao, J. Christopher McWilliams, J. Michael Williams, Yongkui Sun, Joseph D. Armstrong, David J. Mathre, and Edward J. J. Grabowski. Department of Process Research and the Catalysis and Reaction Discovery and Development Lab, Merck and Co., Inc, PO Box 2000, Rahway, NJ 07065-0900

Enantiopure beta-amino acids and their derivatives are precursors for a variety of important drugs. A useful method for preparing this class of compounds involves either diastereo- or enantioselective hydrogenation of the corresponding dehydro-beta-amino acid, ester or amide. While there are homogeneous catalysts capable of reducing dehydro-beta-amino acids with high enantioselectivity, these systems typically require separation of the Z- and E-enamine prior to hydrogenation thereby limiting overall utility of the method. The limited examples of auxiliary-based hydrogenation methods appearing in the literature proceed with moderate selectivity. We have developed a protocol for the preparation of chiral enamine esters and amides as the Z-isomer. Subsequent diastereoselective hydrogenation using heterogeneous noble metal catalysts produces the corresponding beta-amino esters and amides in excellent diastereoselectivity (eq 1). The high isomeric purity of the Z-enamine and a novel method for preparing the catalysts are essential in obtaining high selectivity. These aspects, along with key mechanistic features of the hydrogenation, will be described.

Asymmetric Reactions and Syntheses 8:00 AM-12:00 PM, Sunday, September 7, 2003 Sheraton New York -- Imperial Ballroom A, Oral Division of Organic Chemistry The 226th ACS National Meeting, New York, NY, September 7-11, 2003