| Highly enantioselective addition reactions between silyl ketene acetals and N-tert-butoxycarbonyl (N-Boc) aldimines were achieved utilizing thiourea catalyst 75. Extraordinary scope was observed in this methodology with regard to the imine substrate, with aryl and heteroaromatic derivatives generally affording nearly quantitative yield of the corresponding β-amino ester product in up to 98% ee. Reactions have been carried out on scales as high as 10 mmol with no detrimental effect on yield or enantioselectivity. The resulting N-Boc-protected, β-amino acid derivatives are readily deprotected under mildly acidic conditions, and are well suited for direct use in organic synthesis.; A mechanistic study of the catalytic asymmetric Mannich reaction was undertaken—exploring the kinetic rate law, catalyst structural and conformational elements crucial to enantioselectivity, as well as likely modes of substrate binding. Rate experiments were found to obey Michaelis-Menten kinetics, with first order dependence on catalyst 75 and silyl ketene acetal, and saturation kinetics with respect to the imine. This result implies the reversible formation of an imine-catalyst complex, established as a hydrogen-bonding interaction to the thiourea moiety of the catalyst. A ground state structure of the catalyst in solution was experimentally determined utilizing ROESY-2D NMR experiments. This structure is supported with additional computational and crystallographic evidence.; Catalyst structure/enantioselectivity correlation studies performed on imine addition reactions with our organic catalyst system have led to the discovery that the same chiral urea catalyst serves to activate related imine substrates via fundamentally different stereoinduction mechanisms, and to the identification of an extraordinarily simple and effective new catalyst for the asymmetric Mannich reaction. Our next-generation catalysts, derived from a single α-amino acid, have been shown to impart high asymmetric induction in the activation of N-Boc aldimines. |
