Work

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

Year: 2025

Type: article

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.

Source: Angewandte Chemie International Edition

DOI: 10.1002/anie.202503056

Authors: Marlene Arnold, Jasmin Hammes, Mike Ong, Christian Mück‐Lichtenfeld, Johannes M. Wahl

Institutions: Johannes Gutenberg University Mainz, University of Münster

Language: English

Topic: Cyclopropane Reaction Mechanisms

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: hybrid

Estimated APC paid: $5,510

Funder: European Research Council