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

The Strychnos alkaloids have long been regarded as landmark targets for chemical synthesis due to their captivating architectures and notorious biological properties. The family has fascinated synthetic and medicinal chemists for almost 100 years, since the decades-long debate over the structure of the 'flagship' member strychnine, and its first total synthesis by Woodward. Featuring a dense array of carbo- and heterocyclic rings, and numerous stereochemical challenges, these molecules have inspired many synthetic strategies. In spite of this rich history, the design of approaches that can 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 and highly concise entry to the Strychnos natural products. We show how the rapid assembly of a tryptamine-tethered TDO enables the synthesis of family member akuammicine in just three steps from tryptamine, with minimal waste generation. We further demonstrate exceptional levels of stereocontrol in unprecedented asymmetric cycloadditions of chiral thiophene S,S-dioxides; these afford tricyclic indolines that are of interest for medicinal chemistry applications, and also enable highly concise, stereoselective and scalable syntheses of the Strychnos alkaloids by either intra- or intermolecular asymmetric cycloadditions. Our results highlight the potential of TDOs as important building blocks in asymmetric cycloaddition chemistry for the streamlined synthesis of polycyclic organic frameworks; in the case of the Strychnos alkaloids, this means that both natural products and analogues that have previously been inaccessible can now be prepared in a handful of transformations.