Preparation of a key intermediate en route to the anti-HIV drug lenacapavir

A very efficient 4-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 oxidation of the resulting secondary alcohol to the desired ketone which relies solely on catalytic amounts of TEMPO together with NaClO as terminal oxidant, ultimately affording the targeted ketone in 67% overall yield and representing a po-tentially cost-effective route to this key intermediate.