Synthesis of ((3R,6R)-6-Methylpiperidin-3-yl)methanol via Biocatalytic Transamination and Crystallization-Induced Dynamic Resolution

An asymmetric synthesis of orexin receptor antagonist MK-6096 piperidine core, ((3R,6R)-6-methylpiperidin-3-yl)methanol (3), is described. The target is synthesized in four steps and 40% overall yield from methyl vinyl ketone and diethyl malonate. The key operation is a practical crystallization-induced dynamic resolution for the conversion of a trans/cis mixture of lactam acid 17 into the desired trans-lactam acid salt in >95% de and 91% yield. The substrate lactam acid mixture was prepared via a solvent-free Michael reaction and a practical biocatalytic transamination process.