Nucleophilic heterocyclic carbene catalysis : generation of azolium enolates for novel enantioselective inter- and intramolecular formal [4+2] cycloadditions

Abstract

N-Heterocyclic carbene (NHC)-catalysed processes that utilise azolium enolates intermediates have been used for a broad range of transformations such as enantioselective cycloaddition, protonation, halogenation, Mannich reactions and desymmetrisation processes. One efficient way to quickly build molecular complexity is through cycloadditions such as formal [4+2] cycloadditions. In this context, ketenes, aldehydes, esters, enals and α-halo aldehydes have been used in numerous reactions for the construction of 6-membered rings. Nevertheless, the current limitations include lack of stability from the precursors and unwanted side-reactions. To broaden the synthetic utility of azolium enolates, alternative precursors are necessary This has been addressed in this thesis in novel inter- and intramolecular formal [4+2] cycloadditions using α-aroyloxyaldehydes and enone-acids as bench-stable azolium enolate precursors. An intermolecular NHC-catalysed [4+2]-hetero-Diels-Alder process using α-aroyloxyaldehydes as azolium enolate precursors and trichloromethyl ketone Michael acceptors was first explored. This methodology led to the formation of syndihydropyranones in up to 95% yield, >95:5 dr and >99:1 er. A sequential [4+2] cycloaddition/nucleophilic ring-opening with amines or alcohols led to the selective synthesis of either highly functionalised diamides or γ-ester amide derivatives in up to 90% with excellent diastereo- and enantioselectivity. This highlighted the ability of trichloromethyl ketones to act as amide surrogates. An investigation of using carboxylic acids bearing a pendant enone, referred as enone-acid, led to the first NHC-catalysed formal [4+2] cycloaddition protocol. A range of dihydrobenzofurans were accessed in moderate to high yield, and high to excellent diastereoand enantioselectivity. This novel methodology could be extended to the synthesis of syndihydropyranone and syn-dihydrochromenone derivatives in moderate to high yield and excellent diastereo- and enantioselectivity.