Concise Total Syntheses of Leuconoxine-Type Alkaloids Enabled by Palladium/Norbornene-Catalyzed Pyrrole Difunctionalization

Abstract

Concise total syntheses of five leuconoxine-type alkaloids, i.e., chloromelodinine, leuconodine A, leuconodine F, melodinine E, and leuconoxine, are achieved through a pyrrole-centered strategy. The approach features a newly developed palladium/norbornene-catalyzed pyrrole double C─H functionalization reaction to generate the core skeleton and a divergent oxidative dearomatization to complete the end game. In addition, no protecting group was employed, and the strategic use of a chloro substituent offers a number of advantages in these syntheses, which could have implications beyond this work. The discovery of an unusual chloro 1,2-migration reaction enabled the first total synthesis of chloromelodinine E. This work represents the shortest syntheses of these natural products to date with 10–11 total steps.