Asymmetric synthesis of spiro[benzofuran-pyrrolidine]-indolinedione via bifunctional urea catalyzed [3 + 2]-annulation

Org Biomol Chem. 2024 Dec 10. doi: 10.1039/d4ob01614a. Online ahead of print.

Abstract

In this study, we unveil a highly enantioselective [3 + 2] annulation protocol, adept at merging N-2,2,2-trifluoroethylisatin ketimines with 3-alkylidene benzofuranones under quinine-derived urea catalysis. This strategy furnishes complex spiro[benzofuran-pyrrolidine]indolinedione architectures, featuring strategically positioned trifluoromethyl groups of considerable pharmacological significance. The method distinguishes itself by employing minimal catalyst loadings while ensuring energy efficiency and accommodating a broad spectrum of substrates, resulting in excellent yields and exceptional stereocontrol (38 examples, up to 98% yield, up to >20 : 1 dr, and up to 99 : 1 er). Mechanistic investigations, underpinned by SC-XRD and NMR NOE analyses, elucidate the stereochemical pathways driving selectivity, while a comprehensive evaluation of electronic and steric substituent effects further refines the reaction's scope.