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

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.