Synthesis of N,4-diaryl substituted β-lactams via Kinugasa cycloaddition/rearrangement reaction

The methodology of construction of N,4-diaryl substituted beta-lactam framework, based on the Kinugasa cycloaddition/rearrangement sequence is presented. The series of protected chiral propargyl alcohols was treated with diaryl nitrones to afford mainly the cis-I adduct, providing direct access to the highly-functionalized azetitidin-2-one derivatives with a well-defined stereochemistry. Under the optimized reaction conditions, the unprotected chiral propargylic alcohols were also found to be suitable precursors of beta-lactams. The absolute configuration of adducts was determined by CD or HPLC-CD technique, which was shown to be reliable method of determination of the configuration at C-4 of 4-aryl-substituted azetidin-2-ones. Epimerization of the cis adduct to the respective trans isomer could be easily done by the oxidation of hydroxyl group next to the four-membered beta-lactam ring to the ketone, followed by a base-mediated epimerization of the malonyl fragment. (C) 2011 Elsevier Ltd. All rights reserved.