Selective synthesis of unnatural α-, β- and γ-amino esters

Reductive amination of keto esters 1 with alpha-methylbenzylamine (alpha-MBA) in the presence of hydrogen and Raney-Ni allows direct access to diastereomeric amino esters 2 in good to high de (72-94%). For the alpha-keto ester 1d and the beta-keto esters 1a, 1b and 1c the reaction is optimally performed in the presence of AcOH, while the (gamma-keto ester 1h requires Ti(OiPr)(4). The reductive amination product of 1d is an advanced homophenylalanine building block for Angiotensin Converting Enzyme (ACE) inhibitor drugs. The reductive amination product of 1h is converted in two additional steps to a protected chiral 2-methylpyrrolidine 4h, which is an advanced amine intermediate for pharmaceutical drugs, e.g. ABT-239. The strategy presented here obviates the need for preforming enamine or imine intermediates for amino ester synthesis. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007).