Preparation of a Key Intermediate En Route to the Anti-HIV Drug Lenacapavir

Abstract

A very efficient four-step synthesis of the main fragment of Gilead’s anti-HIV drug lenacapavir is described. The route showcases a 1,2-addition to an intermediate aldehyde using an organozinc halide derived from a commercially available difluorobenzyl Grignard reagent. This sets the stage for the oxidation of the resulting secondary alcohol to the desired ketone, which relies solely on catalytic amounts of TEMPO together with NaClO as the terminal oxidant, affording the targeted ketone in 67% overall yield.

A new synthesis of the amine fragment: an important intermediate to the anti-HIV drug lenacapavir

“…8 Recently, Lipshutz and coworkers disclosed an efficient route to the ketone intermediate 7 (Scheme 1c). 11 The sequence involves the reaction of aldehyde 2 with the organozinc reagent to provide the alcohol intermediate (6). These synthetic methods, while successful, all invoke the use of one or more expensive raw material or reagent.…”