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

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.