Theoretical Insights into the Substrate-Dependent Diastereodivergence in (3 + 2) Cycloaddition of α-Keto Ester Enolates with Nitrones

Abstract

Controlling catalytic asymmetric space has received increasing attention for the on-demand synthesis of chiral molecules of interest. However, the identification of the key parameters controlling the stereo-determining step in transition metal catalysis is challenging and involves the thorough characterization of the rate- and stereo-determining transition state(s). In this paper, we describe the computational analysis of the (3 + 2) cycloaddition of Ni(II)–enolate with cyclic (E)-nitrone to provide a comprehensive analysis of how the bond-forming processes are regulated in the two-electron manifold in the triplet state. Our molecular orbital analysis, in particular, reveals the occurrence of the singly occupied molecular orbital–highest occupied molecular orbital (SOMO–HOMO) level inversion in the Ni(II)–enolate. Further, distortion and interaction analysis are also used to explain the substrate-dependent diastereodivergence in this reaction by alternating the structure of the nitrone. Using a range of computational analyses, we show that the rate- and stereo-determining step in the (3 + 2) cycloaddition of (E)-nitrone is regulated integrally by (1) isomerism of the octahedral Ni(II) complex, (2) E/Z isomerism of the Ni(II)–enolate, and (3) steric repulsion between the reactants and ligand.