Efficient and Divergent Total Synthesis of (−)-Epicoccin G and (−)-Rostratin A Enabled by Double C(sp³)–H Activation

Dithiodiketopiperazines are complex polycyclic natural products possessing a variety of interesting biological activities. Despite their interest, relatively few total syntheses have been completed. We herein report the enantio­selective, scalable, and divergent total synthesis of two symmetrical pentacyclic dithiodiketo­piperazines, (−)-epicoccin G and (−)-rostratin A. A common intermediate was synthesized on a multigram scale from inexpensive, commercially available starting materials using an enantio­selective organo­catalytic epoxidation and a double C­(sp3)–H activation as key steps, with the latter allowing the efficient simultaneous construction of the two five-membered rings. In addition to the cis,cis-fused target (−)-epiccocin G, the more challenging (−)-rostratin A, possessing two trans ring junctions, was obtained for the first time on a 500 mg scale through the optimization of each step and validation on multigram quantities. Both natural products were synthesized with high overall yields (13–20%). This study should facilitate access to this fascinating and yet understudied family of biologically active natural products.