Development of a Biocatalytic Process to Prepare (S)-N-Boc-3-hydroxypiperidine

(S)-N-Boc-3-hydroxypiperidine (S-NBHP) is a useful synthon for the synthesis of pharmaceutical intermediates including ibrutinib, the API of the newly approved drug Imbruvica, for the treatment of lymphoma. To our knowledge, there are no published biotransformation methods scalable to prepare S-NBHP. We report here the development of an efficient process catalyzed by recombinant ketoreductase (KRED) to reduce N-Boc-piperidin-3-one to obtain optically pure S-NBHP. The process has been optimized and demonstrated to have commercial potential with 100 g/L of substrate concentration, product of >99% ee with under 5% of enzyme loading (w/w).