Synthesis of Siccanin by Computational Subtarget Selection.

The species-selective SDH inhibitor siccanin presents unique opportunities for therapeutic development but suffers from poor physicochemical properties and challenging chemical problems. Here we report an approach to its synthesis that quickly intercepts its unusually hindered cis-syn-cis drimane core, i.e., its local chemical space. Computation helps rationalize and predict the reactivity, especially conformational preferences, configurational outcomes, and the reactivity of a key O-centered radical.