Insights on the Origin of Regiodivergence in the Parallel Kinetic Resolution of <i>rac</i>-Aziridines Using a Chiral Lanthanum–Yttrium Bimetallic Catalyst

Abstract

Parallel kinetic resolution of racemic mixtures is an important method used in asymmetric synthesis of chiral compounds. In a recent example, a <i>rac</i>-<i>cis</i>-2,3-substituted chiral <i>N</i>-benzoyl aziridine was reacted with dimethyl malonate, in the presence of a La–Y heterobimetallic chiral BINAM Schiff base (L) catalyst, to form enantiomerically pure (ee > 98%) γ-amino acid derivatives through a ring-opening reaction in near-quantitative yields from both the enantiomers (∼48%). High regio- and enantioselectivities even with a <i>rac</i>-aziridine, having C2 and C3 substituents as similar as ethyl and <i>n</i>-propyl. Through a comprehensive computational investigation, we delineate the origin of regio-divergent and enantioselective formation of γ-amino ester derivatives. The Gibbs free energy of the transition state for the ring-opening at the propyl substituted C2 carbon leading to 3-benzamidoheptan-4-yl malonate is found to be 7.2 kcal/mol lower than that at the ethyl substituted C3 carbon in the case of (2<i>R</i>,3<i>S</i>)-aziridine. A reversal of the regio-chemical preference for its enantiomeric (2<i>S</i>,3<i>R</i>)-aziridine is noted where the ring-opening occurs at the ethyl substituted C3 carbon. The La–Y catalyst is found to initially “recognize” both the enantiomers of the <i>rac</i>-aziridine rather indiscriminately. The activation barriers for the most-preferred ring-opening for each enantiomer are found to be closely similar, suggesting that both enantiomers would react. The high regio-selectivity in the addition of lanthanum-bound malonate to the aziridine anchored onto the yttrium center is due to a unique geometric disposition of the aziridine in the stereocontrolling ring-opening transition state. The lowest-energy ring-opening transition state for each enantiomer of aziridine exhibited very similar geometries, while notable geometric distortions is identified in the malonate addition to less-preferred site of the same enantiomer