Computational predictions on the stereoselectivity of N-heterocyclic carbene catalyzed β-lactam synthesis

Recent theoretical studies on N-heterocyclic carbenes catalyzed Staudinger reactions revealed that the stereoselectivities are determined by an elementary reaction step, that is, the reaction of an imine with N-heterocyclic carbene-ketene zwitterionic intermediate (INTN-k). To better understand the stereoselectivities of some of the experimentally reported reaction systems, the corresponding transition states were studied further by using an ONIOM approach. A combination of B3LYP/6-31G(d) and PM3 levels of theory was used for transition state optimization, and M06-2X/6-31+G(d,p) level for single point calculations. The calculations were found to provide predictions that were in qualitative agreement with the sense and magnitude of experimental stereoselectivities. By analyzing the electronic structures of the transition states, the origin of divergent stereoselectivities in different N-heterocyclic carbenes catalyzed system can be attributed to the cooperation of the electrostatic and steric effects involved in the reaction of imines with N-heterocyclic carbene-ketene intermediates. These results may provide useful information for selecting the N-heterocyclic carbene catalysts in the synthesis of beta-lactams. (C) 2011 Elsevier Ltd. All rights reserved.