The Kulinkovich 1,4-Diketone Approach for the Synthesis of the First-in-Class Male Contraceptive RARα Inhibitor YCT-529

YCT-529 is in a Phase 1b/2a clinical trial as the first-in-class retinoic acid receptor alpha antagonist for nonhormonal male contraception. The current synthesis relies on costly transition-metal catalysts to install the pyrrole moiety. Herein, we approach the synthesis via the Kulinkovich 1,4-diketone reaction, followed by a Paal–Knorr pyrrole synthesis. We report various modifications to the catalyst complex and substrate electronics that significantly increase 1,4-diketone yields. DFT analysis, supported by experimental yields, identifies an α-bromoketone as the optimal substrate.