Chemoenzymatic Synthesis of <i>tert</i> ‐Butyl ((3 <i>R</i> , 6 <i>R</i> )‐6‐methyl‐piperidin‐3‐yl)carbamate: A Key Intermediate in Orexin Receptor Antagonist and IRAK4 Inhibitor

Abstract tert ‐Butyl ((3 R ,6 R )‐6‐methylpiperidin‐3‐yl)carbamate is a pivotal pharmaceutical intermediate and active pharmacophore in drug synthesis, encompassing applications in orexin receptor antagonist and IRAK4 inhibitor. To date, a simple and efficient synthetic route remains a challenging issue for chemists in constructing chiral centers. In this study, we present a practical process for the preparation of tert ‐butyl ((3 R ,6 R )‐6‐methylpiperidin‐3‐yl)carbamate, the key chiral intermediate via a chemoenzymatic strategy from commercially available ethyl N ‐Boc‐D‐pyroglutamate, which undergoes transamination‐spontaneous cyclization process by transaminase (ATA) biocatalyst. Our study outlines a shortened‐step streamlined procedure circumventing a significant amount of toxic chemicals and hazardous reaction conditions, and features cost‐effective and high optical purity with &gt;99.9% enantiomeric excess. The process features great prospect of industrialization application.