DFT-Based Stereochemical Rationales for the Bifunctional Brønsted Acid/Base-Catalyzed Diastereodivergent and Enantioselective aza-Henry Reactions of α-Nitro Esters

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A pair of chiral bis(amidine) [BAM] proton complexes provide reagent (catalyst)-controlled, highly diastereo- and enantioselective direct aza-Henry reactions leading to α-alkyl-substituted α,β-diamino esters. A C 2 -symmetric ligand provides high anti -selectivity, while a nonsymmetric congener exhibits syn -selectivity in this example of diastereodivergent, enantioselective catalysis. A detailed computational analysis is reported for the first time, one that supports distinct models for selectivity resulting from the more hindered binding cavity of the C 1 -symmetric ligand. Binding in this congested pocket accommodates four hydrogen bond contacts among ligands and substrates, ultimately favoring a pre- syn arrangement highlighted by pyridinium-azomethine activation and quinolinium-nitronate activation. The complementary transition states reveal a wide range of alternatives. Comparing the C 1 - and C 2 -symmetric catalysts highlights distinct electrophile binding orientations despite their common hydrogen bond donor–acceptor features. Among the factors driving unusual high syn -diastereoselection are favorable dispersion forces that leverage the anthracenyl substituent of the C 1 -symmetric ligand.