Catalytic Asymmetric Total Synthesis of Grisemycin, a Thioangucycline Polyketide

Angucycline natural products, the largest class of aromatic polyketides, have been extensively studied for decades yet members possessing sulfur atoms (i.e., thioangucyclines) remain rare. In 2016, Zhang and co-workers isolated the structurally unprecedented thioangucycline grisemycin, from the marine actinomycete Streptomyces griseus. Grisemycin features a distinctive angucycline topology and exotic methylsulfoxide functional group of unknown biosynthetic origins. Herein we report the first total synthesis of this fascinating polyketide in enantioenriched form. Our findings suggest that grisemycin's caged skeleton can assemble from a genetically encoded angucycline Michael acceptor in the presence of methanethiol and an oxidant without enzymatic assistance.