α-Keto hydrazones in asymmetric aminocatalysis: reactivity through β-amino aza-dienamine intermediates

Abstract

α-Keto hydrazones behave as suitable precursors of nucleophilic β-amino aza-dienamine intermediates. Using a multifunctional tert-Leucine derived amino-thiourea as the catalyst, this reactivity was exploited to perform asymmetric 1,4-addition to nitroalkenes, affording densely functionalized products with excellent yields and enantioselectivities. Ensuing efficient and selective transformations provide valuable derivatives such as γ-nitrobutyric acids and functionalized pyrrolidines. Aggregation studies support the key role of the tert-Leucine fragment in the catalyst and the benzoic acid as co-catalyst, promoting disaggregation of thiourea dimers to generate (thiourea–NH₃⁺)(PhCOO⁻) ion pairs as catalytically relevant species. The formation of a highly ordered supramolecular ion pair complex [(heterochiral) Ia–NH₃⁺/PhCOO⁻]₂ accounts for the strong non-linear effect observed. A DFT study of the catalytic cycle revealed the formation of the intermediate enamine as the rate-limiting step. A suitable stereochemical model was proposed, further supported by a quantitative analysis of the non-covalent interactions (NCI analysis).