Divergent synthesis of complex withanolides enabled by a scalable route and late-stage functionalization.

Withanolides are a group of naturally occurring C28 steroids based on an ergostane skeleton. They possess a high degree of polyoxygenation, and the abundance of O-functional groups has enabled various natural alterations to both the carbocyclic skeleton and the side chain. Consequently, these molecules possess intricate structural features that lead to their highly varied display of biological activities including anticancer, anti-inflammatory and immunomodulating properties. Despite being intriguing leads for further discovery research, synthetic access to the withanolides remains highly challenging-compounds for current biological research are mainly isolated from plants, often inefficiently. Here we report the divergent synthesis of eleven withanolides in 12 to 20 steps, enabled by a gram scale route and a series of late-stage functionalizations, most notably a bioinspired photooxygenation-allylic hydroperoxide rearrangement sequence. This approach sets stage for further biological research disconnected from a reliance on minute quantities of the parent natural products or their simple derivatives.