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

Abstract

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.

Chiral Vicinal Diamines Derived from Mefloquine

“…From the perspective of potential catalytic applications, enantiomerically pure 11-aminomefloquine 4 and 12 offer two activation sites: the primary and secondary amine. 15 The NH 2 group was devised to form a covalent bond and thus to activate carbonyl derivatives by lowering LUMO energy in the expected intermediate iminium or iminium ion. 16 The ancillary secondary amine unit provides a basic center to activate a nucleophile ( Figure 3 ).…”

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

“…Bispidine-based chiral amines developed by our group show good ability in promoting asymmetric reactions through enamine catalysis. 18 We envisaged such organocatalysts might have the potential to achieve the diastereodivergent goal since they possess unique core and multiple hydrogen-bonding donors and acceptors.…”

Mechanistic Study of the N-Quaternized Pyridoxal-Catalyzed Biomimetic Asymmetric Mannich Reaction: Insights into the Origins of Enantioselectivity and Diastereoselectivity

“…The Mannich reaction, which has been extensively studied in the past 100 years, − remains an enormously valuable method for C–C bond construction. Carbonyl catalysis is a prevailing activation mode in organocatalysis, − which involves the reaction of the carbonyl compound with amine leading to an imine intermediate, followed by the deprotonation process to generate the α-amino carbanion complex.…”