Total Synthesis of Spirotryprostatin A

Key words

spirotryprostatin A - Mizoroki–Heck reaction - diketopiperazines - spirocycles

Significance

Spirotryprostatin A, a spirocyclic diketopiperazine natural product that was isolated in 1996, was found to be an inhibitor of the mammalian cell cycle in G2/M phase and thus an interesting lead in drug discovery. A number of syntheses of spirotryprostatin A have been disclosed, and Fukuyama now describes a synthetic strategy that relies on a Heck reaction for the elegant installation of the quaternary stereocenter.

Comment

A silyl enol ether derived from diketopiperazine A underwent a Mukaiyama aldol reaction with aldehyde B to afford enone C, which was converted into aldehyde D in six steps. Addition of aryl Grignard E followed by oxidation of the resulting secondary alcohol furnished ketone F, which gave spirocycle G in the key Heck reaction. The anilide was then introduced through Beckmann rearrangement (G → H). H could be advanced into the target molecule in five additional steps.