NHC-catalysed enantioselective intramolecular formal [4+2] cycloadditions using carboxylic acids as azolium enolate precursors

Abstract

An NHC-catalysed intramolecular formal [4 + 2] cycloaddition protocol using carboxylic acid starting materials containing a tethered enone is reported. Optimisation studies using a model substrate showed that the use of the Yamaguchi reagent (2,4,6-trichlorobenzoyl chloride) for in situ preparation of a mixed anhydride was necessary for effective catalysis, leading to highest product yield and stereoselectivity. Using this protocol, a range of dihydrobenzofurans were accessed in moderate to high yield, and with high to excellent diastereo- and enantioselectivity (up to > 95:5 dr and > 99:1 er). This methodology was extended to the synthesis of syn-dihydrochromenone and syn-dihydropyranone derivatives in moderate to high yield and with excellent diastereo- and enantioselectivity.