Selective 1,4-syn-Addition to Cyclic 1,3-Dienes via Hybrid Palladium Catalysis

1,4-cis-Disubstituted cyclic compounds play a pivotal role in pharmaceutical development, offering enhanced potency and bioavailability. However, their stereoselective and modular synthesis remains a long-standing challenge. Here, we report an innovative strategy for accessing these structures via mild conditions employing cyclic 1,3-dienes/alkyl(aryl)halides and amines. This procedure exhibits a wide substrate scope that tolerates various functional groups. The utility of this method is demonstrated in the efficient synthesis of a TRPV6 inhibitor, CFTR modulator, and other bioactive molecules. Combined experimental and computational studies suggest that the hybrid palladium-catalyzed radical-polar crossover mechanism is crucial for achieving exceptional 1,4-syn-addition selectivity (dr > 20:1).

Via hybrid palladium catalysis, we pioneered a redox neutral 1,4-syn-addition to 1,3-cyclic dienes for constructing diverse cyclic compounds, unlocking quick access to bioactive molecules.