Collective asymmetric synthesis of the Strychnos alkaloids via thiophene S,S-dioxide cycloadditions

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 an important challenge. Here we show that thiophene S,S-dioxides (TDOs) offer a modular, rapid entry to Strychnos natural products via inverse electron demand Diels-Alder cascades. We demonstrate that exceptional levels of stereocontrol can be achieved in asymmetric TDO cycloadditions, affording tricyclic indolines of utility in medicinal chemistry research and enabling the stereoselective synthesis of eight Strychnos alkaloids by the shortest routes described so far, including a 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.