γ-Cyclodextrin-Imidazolium Salt-Based Bioinspired Nanoreactor: Enantioselective Rhodium-Catalyzed Arylation of Unprotected Isatin with Arylboronic Acids.

Abstract

The optically active 3-aryl-3-hydroxy-2-oxindole skeleton is a promising pharmacophore in drug design and has led to the development of metal-catalyzed asymmetric reactions using designed chiral ligands for synthesizing 3-aryl-3-hydroxy-2-oxindoles from isatins (2,3-oxindoles), 3-aryl-2-oxindoles, and α-ketoamides. Although the arylation of isatins is vital for convergent synthesis, most studies have used N-protected isatins, requiring the removal of protecting groups to obtain the desired bioactive products. Despite limited success in the direct high-enantioselective arylation of unprotected isatins (NH isatins), such arylation holds significant potential for improving atomic and synthetic efficiencies. In aqueous media, cyclodextrins (CDs) with hydrophobic and chiral cavities can selectively include organic compounds, making them potential nanoreactors for asymmetric reactions. In this study, imidazolium salts bearing a  γ-CD were applied as N-heterocyclic carbene (NHC) ligands for the Rh-catalyzed asymmetric arylation of NH isatins in environmentally benign aqueous ethanol. The arylation was successfully achieved in high yield and enantioselectivity using our γ-CD-NHC-Rh catalyst. This suggests that the arylation proceeds in the γ-CD cavity (host) through the self-inclusion of NHC─Rh complex intermediates (guests). These bio-inspired transition metal catalysts based on host-guest linkage systems are expected to contribute significantly to the development of efficient organic synthesis reactions with high enantioselectivity.