Melissa Pighetti, MChem
Yale University
Catalytic Enantioselective Aziridination of Z-Disubstituted Alkenes by Aspartyl Beta-Turn-Based Dirhodium(II) Metallopeptides
As highly versatile synthetic intermediates, enantiopure aziridines have consistently motivated synthetic efforts toward their preparation. Over the past three decades, metal-catalyzed nitrene transfer to alkenes has become the leading approach to this synthetic challenge. Despite notable advances, limitations in the scope of metal-catalyzed asymmetric aziridinations remain. In particular, a stereospecific, directing-group-free method to synthesize cis-aziridines from open-chain Z-disubstituted alkenes has, so far, remained elusive. Here, a catalyst-directed, enantioselective aziridination method is disclosed, tailored to open-chain Z-disubstituted alkenes and catalyzed by a dirhodium(II) metallopeptide. The transformation provides cis-aziridines in up to 86% yield and 88% ee. We also explore a data science model that uncovers patterns in molecular features that reflect enantioselectivity across two nitrene transfer reactions catalyzed by dirhodium(II) metallopeptides: the aziridination described here and a related benzylic amination reaction. This model is trained on molecular descriptors of both catalysts and substrates and used to interpret the differences between the two reactions. By linking a new synthetic methodology to cross-reaction, data science-driven modeling, this study offers both an efficient route to valuable aziridine scaffolds and a framework for analyzing enantioinduction across mechanistically diverse transformations.
As highly versatile synthetic intermediates, enantiopure aziridines have consistently motivated synthetic efforts toward their preparation. Over the past three decades, metal-catalyzed nitrene transfer to alkenes has become the leading approach to this synthetic challenge. Despite notable advances, limitations in the scope of metal-catalyzed asymmetric aziridinations remain. In particular, a stereospecific, directing-group-free method to synthesize cis-aziridines from open-chain Z-disubstituted alkenes has, so far, remained elusive. Here, a catalyst-directed, enantioselective aziridination method is disclosed, tailored to open-chain Z-disubstituted alkenes and catalyzed by a dirhodium(II) metallopeptide. The transformation provides cis-aziridines in up to 86% yield and 88% ee. We also explore a data science model that uncovers patterns in molecular features that reflect enantioselectivity across two nitrene transfer reactions catalyzed by dirhodium(II) metallopeptides: the aziridination described here and a related benzylic amination reaction. This model is trained on molecular descriptors of both catalysts and substrates and used to interpret the differences between the two reactions. By linking a new synthetic methodology to cross-reaction, data science-driven modeling, this study offers both an efficient route to valuable aziridine scaffolds and a framework for analyzing enantioinduction across mechanistically diverse transformations.
