Copper-Catalyzed Enantioselective Vinylogous Hydroxylation with Nitrosobenzene

Catalytic asymmetric vinylogous hydroxylation remains a largely uncharted transformation. This limitation mainly arises from two inherent obstacles: selectivity issues (regio- and enantioselectivities) and the oxidative reactivity of common oxygen donors, both of which severely compromise overall catalytic efficiency. Against this backdrop, we herein disclose a novel synthetic route enabled by copper catalysis. The procedure proceeds through an enantioselective vinylogous nitroso aldol addition, followed by copper-mediated cleavage of the N-O bond. This unified protocol provides a general, efficient approach to enantioenriched γ-hydroxy-α,β-(E)-unsaturated carbonyl scaffolds, tolerating a wide range of alkyl substrates decorated with diverse functional substituents. Mechanistically, a critical reaction intermediate was isolated and fully characterized via HRMS, 1H NMR, and 13C NMR spectroscopy. These unambiguous spectroscopic data firmly corroborate a stepwise reaction manifold, including initial C-O bond formation and subsequent N-O bond fragmentation. The synthetic practicability of our method is underscored by its implementation in the asymmetric formal syntheses of four bioactive natural products, including (+)-α-conhydrine, botcinin E, botcinin F, and (-)-kunstleramide. Finally, four downstream derivatizations of the target products further demonstrate the broad synthetic versatility of this copper-catalyzed vinylogous hydroxylation strategy.