Water enables diastereodivergency in bispidine-based chiral amine-catalyzed asymmetric Mannich reaction of cyclic N-sulfonyl ketimines with ketones.

Tuning diastereoselectivity is a great challenge in asymmetric catalysis for the inherent stereochemical bias of the substrates. Here, we report a diastereodivergent asymmetric Mannich reaction of cyclic N-sulfonyl ketimines with ketones catalyzed by a bispidine-based chiral amine catalyst, in which additional water switches the diastereoselectivity efficiently. Both chiral anti- and syn-benzosultams with potential anti-HIV-1 activity are obtained in excellent yields and good to excellent ee values. Control experiments and density functional theory (DFT) calculations were applied to study the diastereodivergent mechanism, which reveal that the diastereodivergent catalysis should be state-determined, and the water reverses the energies of states to realize the diastereodivergency. The findings are quite new and might inspire more diastereodivergent asymmetric synthesis.

A Bispidine-Based Chiral Amine Catalyst for Asymmetric Mannich Reaction of Ketones with Isatin Ketimines.

A unique chiral amine organocatalyst with a bispidine structure was found to be efficient for the diastereo- and enantioselective Mannich reaction of isatin ketimines with ketones. A series of 3-substituted 3-amino-2-oxindoles bearing vicinal tertiary and quaternary chiral stereogenic centers were obtained in excellent yields with excellent dr and ee values. The gram-scale synthesis and transformation of the product showed the practicability of this methodology. In addition, a possible transition state model was proposed to explain the origin of the stereoselectivity.

Enantioselective Synthesis of Hydrothiazole Derivatives via an Isocyanide-Based Multicomponent Reaction.

Catalytic asymmetric synthesis of hydrothiazole derivatives was developed via a well-organized formal [2 + 1 + 2] cycloaddition reaction triggered by asymmetric addition of isocyanide to alkylidene malonate. Various chiral hydrothiazole derivatives were readily provided in good yield with high enantioselectivity (up to 98% yield, 98.5:1.5 er) utilizing a chiral Mg(OTf)2/N,N'-dioxide complex as the catalyst under mild conditions. Based on the experimental studies and the structure of the catalyst, a possible catalytic cycle was proposed to elucidate the reaction process and activation mode.