Abstract
Verruculogens are fumitremorgin alkaloids that contain an unusual eight-membered endoperoxide ring attached to a fused pentacyclic core. Due to their potent bioactivity and unusual structures, this family of compounds has attracted significant interest from the synthetic community. Using enzymatic C−H peroxidation and rhodium-catalyzed C−C bond activation, we were able install the eight-membered endoperoxide and the pentacyclic core of the natural product, 13-oxoverruculogen. Central to this route was the use of 13-epi-fumitremorgin B as the first substrate analog to be endoperoxidated by verruculogen synthase (FtmOx1). To further assess the native substrate promiscuity, we synthesized and subjected numerous substrate analogs to FtmOx1 for endoperoxidation. Additionally, using our established route, we synthesized isotope-labeled analogs of FtmOx1’s native substrate, fumitremorgin B, to probe the mechanism of endoperoxidation.