The origin of the stereoselective alkylation of 3-substituted-2-oxopiperazines: A computational investigation

Abstract

2-Oxopiperazines and their derivatives are important pharmacophores found in numerous bioactive products. The potency of these compounds depends on the nature and/or position of their substituent(s) as well as on their chirality. Hence, it is important to develop, control and optimize synthetic routes leading to enantiomerically pure substituted 2-oxopiperazines. In this work we report on the origin of this stereoselectivity, upon alkylation of 2-oxopiperazines at position C3, studied by means of quantum chemistry calculations. Indeed, this alkylation with methyl chloride is predicted to afford mainly the exo product with a 98:2 ratio. To this purpose, we model the reaction path leading to both enantiomers by scrutinizing the structures and energetics of the pre-reaction complexes, the transition states and the post-reaction complexes. The computational results are in good agreement with the experimental observations, and provide valuable insights into the origins of this specificity. From the conformational analysis of the piperazine ring and of intramolecular interaction patterns, we show that the enantiofacial discrimination is achieved by a subtle balance between sterical hindrance and control of the conformation of the piperazine ring.