Synthesis of (−)-Cotylenol, a 14-3-3 Molecular Glue Component

Small molecules that modulate the 14-3-3 protein-protein interaction (PPI) network represent valuable therapeutics and tool compounds. However, access has been lost to 14-3-3 PPI molecular glues of the cotylenin class, leading to investigations into the practical chemical syntheses of congeners and analogues. Here we report a concise synthesis of (-)-cotylenol via a 10-step asymmetric entry into a diversifiable 5-8-5 core. This route features a mild Liebeskind-Srogl fragment coupling that tolerates unprecedented steric hindrance to produce a highly congested ketone, and a tandem Claisen-ene cascade that establishes the 8-membered ring. Late-stage control of stereochemistry and functionality leads to (-)-cotylenol and sets the stage for focused library synthesis.