Enantioselective Synthesis of Pharmaceutically Relevant Bulky Arylbutylamines Using Engineered Transaminases

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