A Unified Strategy Targeting the Thiodiketopiperazine Mycotoxins Exserohilone, Gliotoxin, the Epicoccins, the Epicorazines, Rostratin A and Aranotin

Abstract

A unified synthetic strategy directed towards mycotoxins belonging to the thiodiketopiperazine family is reported. The building blocks for a number of natural products—including exserohilone, gliotoxin, the epicoccins, the epicorazines, rostratin A and aranotin—have been synthesised stereoselectively from a common precursor. This key intermediate was constructed through an efficient and highly diastereoselective [2+2] cycloaddition between a ketene and an enecarbamate derived from L-pyroglutamic acid. The annelation of the second ring was accomplished through ring-closing metathesis and enol ether–olefin ring-closing metathesis to provide both cis- and trans-annelated azabicyclic cyclohexenones, as well as an annelated seven-membered cyclic enol ether. A Pd-catalysed elimination of allyl acetate gave rise to the cyclohexadienol structure of gliotoxin. Dimerisation of one building block to afford the diketopiperazine core was demonstrated.