Intramolecular difunctionalization of alkynes involving cascade radical 1,4-heteroaryl migrations and formal total synthesis of a β-imidazolyl-γ-lactam alkaloid: isoanantine

Abstract

Several versions of the intramolecular difunctionalization of alkynes involving a variety of 1,4-heteroaryl migrations were explored to produce a series of β-heteroaryl-γ-lactams. Five nitrogen-containing heteroaromatics were used to investigate group migration reactions: 1-methylimidazole, pyridine, pyrimidine, quinoline, and N-methylpyrrole. These cascade radical reactions were used to produce the key molecules with two linked heterocycles through a single bond. One of the heterocycles is an unsaturated-γ-lactam and the other is a nitrogen-containing heteroaromatic that positions at the β-carbon of this lactam. Eight key molecules were constructed through this novel transformation in low-to-satisfactory yields (11~72%). A structure-reactivity relationship is also provided herein. This report is the first to describe an intramolecular difunctionalization of alkynes involving the migration of various nitrogen-containing heteroaryl groups. Novel skeletons such as these are usually found in natural products or in potential drug candidates, and it is noteworthy that the conversion of an unsaturated-β-imidazolyl-γ-lactam to a natural product, isoanantine, was also achieved through formal total synthesis