Combining Enantioselective Rh-Catalyzed Conjugate Addition and Ir-Catalyzed Allylic Alkylation in Stereodivergent, Multicomponent Coupling Reactions to Form Three Stereocenters

Stereodivergent dual catalysis has emerged as a powerful tool to selectively prepare all four stereoisomers in molecules containing two chiral centers from common starting materials. Most processes involve the use of two substrates, and it remains challenging to use dual catalyst approaches to generate molecules having three newly formed stereocenters with high diastereo- and enantioselectivity. Here we report a multicomponent, stereodivergent method for the synthesis of targets containing three contiguous stereocenters by the combination of enantioselective Rh-catalyzed conjugate addition and Ir-catalyzed allylic alkylation methodologies. Both cyclic and acyclic alpha,beta-unsaturated ketones undergo beta-arylation using aryl boron reagents to form an enolate nucleophile that can be subsequently allylated at the alpha-position. The reactions proceed often with >95 % ee and with >90 : 10 dr. Epimerization at the alpha-carbonyl center enables the preparation of any of the eight possible stereoisomers from common starting materials, as demonstrated for cyclohexanone products.

Automated summary

Stereodivergent dual catalysis is a powerful tool for selectively preparing four stereoisomers from molecules with two chiral centers. However, generating molecules with three newly formed stereocenters using dual catalyst approaches remains challenging.