Building C(sp ³)-rich complexity by combining cycloaddition and C–C cross-coupling reactions

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres¹, cycloaddition reactions have featured in numerous total syntheses² and are a key component in the education of chemistry students³. Similarly, carbon–carbon (C–C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability⁴. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp² manner⁵. Despite the ability of cycloadditions to introduce multiple carbon sp³ centres in a single step, they are less used⁶. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.