Exploration of Oxidative Ritter-Type Reaction of α-Arylketones and Its Application for the Collective Total Syntheses of Erythrina Alkaloids

Although the classical Ritter reaction has been widely applied to prepare sterically hindered amides since 1948, it has intrinsic problems, such as harsh reaction conditions, the multistep preparation of synthetic precursors, and the use of solvent quantities of nitrile. In particular, only a few examples of the total synthesis of natural products using the Ritter reaction as a key step have been reported to date. In this article, we report the development of an oxidative Ritter-type reaction of alpha-arylketones to efficiently construct a sterically hindered N-acyl aza-quaternary carbon moiety. The current transformation features the use of 10 equiv of nitriles, a broad substrate scope (with 81 examples), a short reaction time, and mild reaction conditions. Notably, both the use of a limited amount of nitriles and producing carbocation intermediates via the C-H bond oxidation strategy address two intractable problems of the classical Ritter reaction. Furthermore, based on an unprecedented synthetic strategy using this oxidative Ritter reaction to construct a C-5 aza-quaternary carbon center, the collective total syntheses of erythrina alkaloids, including erysotramidine, 11-alpha-methoxyerysotramidine, 11-beta-hydroxyerysotramidine, erytharbine, the proposed 11-beta-methoxyerysotramidine and 10,11-dioxoerysotramidine, and the unnatural 11-alpha-hydroxyerysotramidine, have been completed using a common precursor through a one-step chemical transformation. [GRAPHICS] .

Automated summary

In this article, we report the development of an oxidative Ritter-type reaction for the efficient synthesis of sterically hindered N-acyl aza-quaternary carbon structures. The reaction demonstrates a broad substrate scope, short reaction time, and mild reaction conditions, addressing the issues of the classical Ritter reaction. Through this new reaction strategy, the total synthesis of erythrina alkaloids has been successfully achieved.