Although the amine transaminase from Vibrio fluvialis has often been applied as a catalyst for the biocatalytic preparation of various chiral primary amines, it is not suitable for the transamination of a-hydroxy ketones and aryl-alkyl ketones bearing an alkyl substituent larger than a methyl group. We addressed this problem through a systematic mutagenesis study of active site residues to expand its substrate scope towards two bulky ketones. We identified two mutants (F85L/ V153A and Y150F/V153A) showing 30-fold increased activity in the conversion of (S)-phenylbutylamine and (R)-phenylglycinol, respectively. Notably, they facilitated asymmetric synthesis of these amines with excellent enantiomeric purities of 98 % ee.
Theb iocatalytic synthesis of chiral amines has become av aluable addition to the chemists toolbox. However, the efficient asymmetric synthesis of functionalised amines bearing more than one stereocentre,s uch as 1,3-aminoa lcohols, remains challenging. By employing ak eto reductase (KRED) and two enantiocomplementary amine transaminases (ATA), we developed ab iocatalytic route towards all four diastereomers of 4-amino-1-phenylpentane-2-ol as ar epresentative molecule bearing the 1,3amino alcohol functionality.S tarting from ar acemic hydroxy ketone,akinetic resolution using an (S)-selective KRED provided optically active hydroxy ketone( 86% ee)a nd the corresponding diketone.Furthert ransamination of the hydroxy ketone was performed by either an (R)-or an (S)-selective ATA, yieldingt he (2R,4R)-and (2R,4S)-1,3-amino alcohol diastereomers. Ther emaining two diastereomers were accessible in twos ubsequent asymmetric steps: the diketonew as reducedr egio-ande nantioselectively by the same KRED, which yielded the (S)-configuredh ydroxy ketone.E ventually, the subsequent transamination of the crude product with (R)-and (S)-selective ATAs yielded the remaining (2S,4R)and (2S,4S)-diastereomers,respectively.
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