Enantioselective Synthesis of Quaternary Oxindoles: Desymmetrizing Staudinger–Aza-Wittig Reaction Enabled by a Bespoke HypPhos Oxide Catalyst
Changmin Xie, Jacob Kim, Binh Khanh, Shixuan Cao, Rong Ye, Xinyi Wang, Peng Liu, Ohyun Kwon
Abstract
This paper describes a catalytic asymmetric Staudinger–aza-Wittig reaction of (o-azidoaryl)malonates, allowing access to chiral quaternary oxindoles through phosphine oxide catalysis. We designed a novel HypPhos oxide catalyst to enable the desymmetrizing Staudinger–aza-Wittig reaction through the PIII/PV═O redox cycle in the presence of a silane reductant and an IrI-based Lewis acid. The reaction occurs under mild conditions, with good functional group tolerance, a wide substrate scope, and excellent enantioselectivity. Density functional theory revealed that the enantioselectivity in the desymmetrizing reaction arose from the cooperative effects of the IrI species and the HypPhos catalyst. The utility of this methodology is demonstrated by the (formal) syntheses of seven alkaloid targets: (−)-gliocladin C, (−)-coerulescine, (−)-horsfiline, (+)-deoxyeseroline, (+)-esermethole, (+)-physostigmine, and (+)-physovenine.