Catalyst-controlled site-selective methylene C–H lactonization of dicarboxylic acids

Abstract

Catalyst-controlled site-selective activation of β- and γ-methylene carbon-hydrogen (C–H) bonds of free carboxylic acids is a long-standing challenge. Here we show that, with a pair of palladium catalysts assembled with quinoline-pyridone ligands of different chelate ring sizes, it is possible to perform highly site-selective monolactonization reactions with a wide range of dicarboxylic acids, generating structurally diverse and synthetically useful γ- and δ-lactones via site-selective β- or γ-methylene C–H activation. The remaining carboxyl group serves as a versatile linchpin for further synthetic applications, as demonstrated by the total synthesis of two natural products, myrotheciumone A and pedicellosine, from abundant dicarboxylic acids.