The Strychnos alkaloids have long been regarded as landmark targets for chemical synthesis due to their captivating architectures and notorious biological properties. However, the design of approaches that access multiple family members in an asymmetric, concise, and atom economical fashion remains a significant challenge. Here we show that thiophene S,S-dioxides (TDOs) offer a modular, rapid entry to the Strychnos natural products via inverse electron demand Diels-Alder cascades. Exceptional levels of stereocontrol are demonstrated in asymmetric TDO cycloadditions, which afforded tricyclic indolines of utility in medicinal chemistry research, and enabled stereoselective syntheses of eight Strychnos alkaloids by the shortest routes described to date, including the first synthesis of the iconic family member brucine. Using a machine-learning approach, computational studies provide insight into the source of stereoinduction, and reveal an intriguing and unexpected spontaneous cheletropic extrusion of SO2.
asymmetric synthesis
,computational chemistry
,synthetic chemistry methodology
,natural product synthesis
