Asymmetric Synthesis of (S)-3-Amino-4-methoxy-butan-1-ol by Way of Reductive Amination

A new synthesis of (S)-3-amino-4-methory-butan-1-ol is reported. The synthesis is based on the preparation of the primary, nonprotected enamine of the commercially available beta-keto ester methyl 4-methoicy-3-oxo-butanoate and asymmetric catalytic enamine hydrogenation using a Ru-MeOBIPHEP catalyst. Alternatively, the process is performed by asymmetric catalytic reductive amination of the beta-keto ester with ammonium acetate and hydrogen using a similar Ru catalyst. Both process versions provided initial ee values of 97-98% which were upgraded to >= 99% by product crystallization. Ester to alcohol conversion was best accomplished by LiBH4 reduction after transitory Boc protection of the amino group.