Stereogenesis in Organic Addition Reactions: Cram’s Steric Control vs Charge-Transfer Control. A Natural Bond Orbital Analysis

In a rudimentary setting of asymmetric induction in the syntheses of acyclic systems, the competing addition reactions may occur at different rates on account of a stereogenic center placed in the immediate vicinity of the addition site. Coming from one side of the mirror, we would usually like one of the competing reactions to be much faster than the other and so the question what features of transition state impede or facilitate bond formation in such settings is a matter of great interest. To address this issue, we have proposed in the past that two effects determine relative stability of the alternative transition states in π-facial selection: Cram’s steric strain, and charge transfer into intrinsically electron deficient incipient bond. Here we model the donor-acceptor interactions of the incipient bond by introducing in common diastereoselection probes a low-lying, vacant NBO orbital that defines two stereogenic parameters, charge-transfer differentials and electron-affinity differentials. To test the model, we examine its explanatory and predictive power vis-à-vis effects of EWG/EDG substitution on the stereochemistry of (i) alkylation and metal hydride reduction of ketones, (ii) oxygenation of alkane C-H bonds, (iii) oxidations and 1,3dipolar cycloadditions of olefins, and (iv) cycloadditions of dienes. Depending on the extent of electronic perturbation of the probe, variation in the available log[Z]/[E] data is a linear function of charge-transfer differentials, a cubic function of electron-affinity differentials, or a function of system’s electron affinity. Thus, the two transition state effects, charge-transfer stabilization and steric-strain destabilization, are indeed necessary and sufficient to account for πfacial selection results in all examined reactions, including nucleophilic addition to C=O. Accordingly, an interplay of vicinal electron donation and steric strain is expected to underlie 1,2-asymmetric induction in related processes.