Collective Asymmetric Synthesis of Thiosilvatins

Thiosilvatins are a family of biologically active sulfenylated diketopiperazine natural products. The first members were reported over 40 years ago, but total synthesis of a thiosilvatin has remained elusive. Here, we describe the first, collective, synthesis of the parent epidithiodiketopiperazine (−)‐dithiosilvatin and ten related thiosilvatins. Several of the targets are structurally revised. A catalytic asymmetric sulfenylation of triketopiperazines efficiently controls absolute configuration at the thioaminal units. Further synthetic highlights include a diastereoconvergent installation of the requisite cis‐orientation of the sulfur atoms and a tandem epidisulfide formation/O‐prenylation under mild Mitsunobu conditions. The described methods for late‐stage diversification of sensitive bis(methylthio)diketopiperazines offer a blueprint for systematically exploring this interesting 3D‐pharmacophore in stereochemically pure form. The first synthesis of the epidithiodiketopiperazine (−)‐dithiosilvatin is reported along with a collective approach to ten related thiosilvatins. The described methods offer a practical blueprint for exploring the dithiotiketopiperazine pharmacophore with absolute and relative stereocontrol.