A modular approach to stereoselective homoaldol reaction via photoredox/Cr/Co triple catalysis

Summary

Stereoselective homoaldol reactions offer an efficient route to valuable γ-hydroxy carbonyl compounds, which widely occur in natural products and bioactive molecules. However, achieving catalytic asymmetric homoaldol additions remains a significant challenge due to homoenolate's amphoteric nature. Herein, we present a modular approach for stereoselective homoaldol reactions utilizing photoredox/Cr/Co triple catalysis, granting precise control over quadruple selectivity. Our method employs easily accessible acyloxy- and amide-substituted 1,3-dienes as homoenolate precursors, operating through a radical-polar crossover mechanism under mild conditions. This obviates the need for strong bases and stoichiometric chiral reagents, characteristic of classical approaches. The robustness and practicality of this method were demonstrated through late-stage modifications and the formal synthesis of bioactive compounds and natural products. Our preliminary mechanistic investigations encompassing radical trapping, control experiments, UV-vis spectroscopy, Stern-Volmer quenching, and deuterium-labeling provide valuable insights into the reaction pathway.