P3: Preparation of (S)-1-cyclopropyl-2-methoxyethanamine by chemoenzymatic routes

(S)-1-Cyclopropyl-2-methoxyethanamine is a key chiral amine for the syntheses of  several drug candidates. Resolution of the racemic amine by lipase-catalyzed acylation provided the S-amine in 35% yield with 91% ee. Transaminase from Vibrio fluvalis gave a 38% yield of S-amine with 53% ee. With limited success of the resolution approaches, an efficient chemoenzymatic route was developed for the preparation of (S)-1-cyclopropyl-2-methoxyethanamine with no detectable R-enantiomer.  Cyclopropylglyoxylic acid was converted to (S)-cyclopropylglycine by reductive amination using leucine dehydrogenase from Thermoactinomyces intermedius with NADH cofactor recycling by formate dehydrogenase from Pichia pastoris. Both enzymes were cloned and expressed in recombinant E. coli. (S)-cyclopropylglycine obtained from enzymatic reductive amination was isolated as the N-Boc derivative and converted to the desired amine by reduction, methylation and Boc-deprotection.