Expanding the Promiscuity of a Copper-Dependent Oxidase for Enantioselective Cross-Coupling of Indoles

Herein, we disclose the highly enantioselective oxidative cross-coupling of 3-hydroxyindole esters with various nucleophilic partners as catalyzed by copper efflux oxidase. The biocatalytic transformation delivers functionalized 2,2-disubstituted indolin-3-ones with excellent optical purity (90-99 % ee), which exhibited anticancer activity against MCF-7 cell lines, as shown by preliminary biological evaluation. Mechanistic studies and molecular docking results suggest the formation of a phenoxyl radical and enantiocontrol facilitated by a suited enzyme chiral pocket. This study is significant with regard to expanding the catalytic repertoire of natural multicopper oxidases as well as enlarging the synthetic toolbox for sustainable asymmetric oxidative coupling.

Automated summary

In this study, the highly enantioselective oxidative cross-coupling of 3-hydroxyindole esters with various nucleophilic partners using copper efflux oxidase as catalyst was reported. The biocatalytic transformation produced functionalized 2,2-disubstituted indolin-3-ones with excellent optical purity (90-99% ee) that showed anticancer activity against MCF-7 cell lines, as indicated by preliminary biological evaluation. Mechanistic studies and molecular docking results revealed the formation of a phenoxyl radical and enantiocontrol facilitated by a suitable enzyme chiral pocket. This study is significant in expanding the catalytic repertoire of natural multicopper oxidases and enlarging the synthetic toolbox for sustainable asymmetric oxidative coupling.