A New Synthesis of Enantiopure Amine Fragment: An Important Intermediate to the Anti-HIV Drug Lenacapavir

• DOI: 10.1021/acs.joc.4c02380
• Publication Date: 2024-12-16T18:51:47Z
• Authors: Anand H. Shinde; Ramakrishna Sayini; Piyal Singh; Justina M. Burns; Saeed Ahmad; G. Michael Laidlaw; B. Frank Gupton; Douglas A. Klumpp; Limei Jin
• Keywords: Enantiopure drug; Kinetic resolution; Amide

Herein, we describe a new seven-step approach to prepare (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine ((S)-4) from the inexpensive 2-(3,5-difluorophenyl)acetic acid. The key steps in sequence include (1) Weinreb amide-based ketone synthesis provide an entry point core structure; (2) simple functional group transformations afford racemic amine 4-rac; and (3) dynamic kinetic resolution (DKR) access chiral (S)-4. This process delivered enantiopure (S)-4 overall isolated yield of approximately 15%. was demonstrated on decagram scale, requires no chromatographic purifications. Single-crystal X-ray crystallography measurements verified structure absolute configuration.