Concise Synthesis of Isocoumarin-3-carboxylic Acid Esters

Abstract

A concise synthesis of isocoumarin-3-carboxylic acid ester derivatives has been developed by the Pd catalyzed one-pot fluorocarbonylation/lactonization/β-elimination cascade reaction starting from easily prepared hydroxyesters. ortho-Bromobenzaldehyde derivatives were converted to 2-chloro-1-hydroxy-2-arylpropionic acid esters in two steps via Darzens reaction. The resulting 1-hydroxypropionates were smoothly converted to isocoumarin-3-carboxylic acid esters in good yields by the newly developed cascade reaction in an efficient manner. The synthetic utility was demonstrated by the first total synthesis of penicipyran C. A new cascade reaction for synthesizing isocoumarin-3-carboxylic acid esters involving Pd-catalyzed fluorocarbonylation/lactonization/β-elimination was developed. The substrates for this cascade reaction were easily prepared from several ortho-bromobenzaldehydes. This cascade reaction gave several isocoumarin-3-carboxylic acid esters in good to excellent yield, and one of the resultant isocoumarin derivatives led to the first total synthesis of penicipyran C.