On the mechanism and stereochemistry of chiral lithium-carbenoid-promoted cyclopropanation reactions

Abstract

An investigation into the mechanism and stereochemistry of chiral lithium-carbenoid-promoted cyclopropanation reactions by using density functional theory (DFT) methods is reported. Previous work suggested that this type of cyclopropanation reaction may proceed by competition between a methylene-transfer mechanism and a carbometalation mechanism. In this paper, it is demonstrated that the intramolecular cyclopropanation reactions promoted by chiral carbenoids 1 and 2 proceed by the methylene-transfer mechanism. The carbometalation mechanism was found to have a much higher reaction barrier and does not appear to compete with the methylenetransfer mechanism. The Lewis base group does not enhance the carbometalation pathway enough to compete with the methylene-transfer pathway. The present computational results are consistent with experimental observations for these cyclopropanation reactions. The factors governing the stereochemistry of the intramolecular cyclopropanation reaction by the methylene-transfer mechanism were examined to help elucidate the origin of the stereoselectivity observed in experiments. Both the directing group and the configuration at the C 1 centre were found to play a key role in the stereochemistry. Carbenoid 1 has a chiral C 1 centre of R configuration. The Lewis base group directs the cyclization of carbenoid 1 to form a single product. In contrast, the Lewis base group cannot direct the cyclization of carbenoid 2 to furnish a stereoselective product due to the S configuration of the chiral C 1 centre in carbenoid 2. This relationship of the stereochemistry to the chiral character of the carbenoid has implications for the design of new efficient carbenoid reagents for stereoselective cyclopropanation. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.