Nitrogen Insertion via Asymmetric Condensation and Chirality Transfer: A Stereodivergent Entry to Cyanocyclopropanes

Abstract The condensation of prochiral cyclobutanones and diphenylphosphinyl hydroxylamine is achieved under Brønsted acid catalysis. Interestingly, the competing aza‐Baeyer–Villiger reaction is completely suppressed and the axially chiral oxime esters can be isolated in excellent yield and selectivity (up to 96% yield, up to 97:3 er). Computational analysis highlights the crucial role of the Brønsted acid in facilitating a successful condensation. Building on the inherent reactivity of the corresponding oxime esters, a one‐pot protocol toward cyanocyclopropanes was discovered, which establishes two consecutive stereocenters. This unusual ring contraction is triggered by strong base and permits an axial‐to‐point chirality transfer with good enantiospecificity (up to 98% es). Fine‐tuning the reaction parameters enables stereodivergent access to both diastereomers of the cyanocyclopropanes, and the utility of this method is demonstrated through the formal synthesis of the drug tasimelteon.