Enantioselective Synthesis of Pharmaceutically Relevant Bulky Arylbutylamines Using Engineered Transaminases

Abstract

ATAs engineered for having an enlarged small binding pocket were applied for the synthesis of enantiomerically pure (R)-benzo[1,3]dioxol-5-yl-butylamine, a chiral component of human leukocyte elastase inhibitor DMP 777 (L-694,458). Kinetic resolution of the racemic amine was performed by using the L59A variant of the (S)-selective ATA from Chromobacterium violaceum (Cv-ATA), providing the residual (R)-enantiomer in excellent yield and >99% ee. At moderate enzyme loading and absence of co-solvent, high volumetric productivity of 0.22 mol L−1 h−1 (42.5 g L−1 h−1) was achieved. Complementarily, the (S)-enantiomer was generated via kinetic resolution using the (R)-selective ATA-117-Rd11 from Arthrobacter sp. with acetone as the amino acceptor. In an alternative approach, we employed ATA-117-Rd11 for the asymmetric amination of the prochiral ketone precursor, which at 86% conversion gave the (R)-benzo[1,3]dioxol-5-yl-butylamine with excellent >99% ee. We further evaluated the utility of Cv-ATA L59A for the asymmetric synthesis of pharmaceutically relevant (S)-1-phenylbutan-1-amine, a chiral component of the deubiquitinase inhibitor degrasyn (WP1130). The enzyme showed good tolerance to high concentrations of isopropylamine, producing (S)-1-phenylbutan-1-amine in enantiomerically pure form (>99% ee). (Figure presented.).