Copper-Catalyzed Enantioselective Vinylogous Hydroxylation with Nitrosobenzene

Abstract

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.