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.
Type
Thesis, PhD Doctor of Philosophy
Collections
Description of related resources
Attaba , N , Taylor , J E , Slawin , A M Z & Smith , A D 2015 , ' Enantioselective NHC-catalyzed redox [4+2]-hetero-Diels-Alder reactions using α,β-unsaturated trichloromethyl ketones as amide equivalents ' , The Journal of Organic Chemistry , vol. 80 , no. 19 , pp. 9728–9739 . https://doi.org/10.1021/acs.joc.5b01820Related resources
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