Atroposelective P^III/P^V=O Redox Catalysis for the Isoquinoline‐Forming Staudinger–aza‐Wittig Reaction

Abstract

Herein, we describe the feasibility of atroposelective PIII/PV=O redox organocatalysis by the Staudinger–aza‐Wittig reaction. The formation of the isoquinoline heterocycle thereby enables the synthesis of a broad range of valuable atropisomers under mild conditions with enantioselectivities of up to 98:2 e.r. Readily prepared azido cinnamate substrates convert in high yield with stereocontrol by a chiral phosphine catalyst, which is regenerated using a silane reductant under Brønsted acid co‐catalysis. The reaction provides access to diversified aryl isoquinolines, as well as benzoisoquinoline and naphthyridine atropisomers. The products are expeditiously transformed into N‐oxides, naphthol and triaryl phosphine variants of prevalent catalysts and ligands. With dinitrogen release and aromatization as ideal driving forces, it is anticipated that atroposelective redox organocatalysis provide access to a multitude of aromatic heterocycles with precise control over their configuration.

Chiral Bisphosphine-Catalyzed Asymmetric Staudinger/aza-Wittig Reaction: An Enantioselective Desymmetrizing Approach to Crinine-Type Amaryllidaceae Alkaloids

“…All energies mentioned are solvated Gibbs free energies. It should be noted that Kwon, , Fianchini, and Cossío have conducted excellent computational studies on the chiral monophosphine-catalyzed Staudinger/aza-Wittig reaction, however, the full profile of bisphosphine-catalyzed Staudinger/aza-Wittig reaction system seems to be more complicated. For example, a notable issue is the orientation problem of the second phosphorus atom.…”

“…More recently, another achievement was disclosed by Sparr and co-workers, in which the atroposelective Staudinger/aza-Wittig reaction was realized, with HypPhos used as the catalyst. 9 Our interest in AS/aWR was motivated by the specific goal to unravel its alluring but yet-to-be-proved potential for natural product synthesis. We envisioned that if this reaction could be extended to the general 2,2-disubstituted cyclohexane-1,3dione scaffolds, it would offer a powerful tool for the asymmetric synthesis of cis-3a-aryl-hydroindole-containing natural products.…”

“…However, only 1,3-diketones embodied in aromatic backbones (e.g., 1,3-indanediones) were explored in this work, thereby limiting its application in natural product synthesis. More recently, another achievement was disclosed by Sparr and co-workers, in which the atroposelective Staudinger/aza-Wittig reaction was realized, with HypPhos used as the catalyst …”