α,β-Unsaturated acyl ammonium intermediates in enantioselective organocatalysis
Abstract
The research outlined in this thesis focuses on the study of the reactivity of α,β-unsaturated acyl
ammonium intermediates and their utility in the development of new enantioselective processes
exploiting isothiourea organocatalysts.
Chapter 2: A novel isothiourea-catalysed domino process has been developed demonstrating the
synthetic power of α,β-unsaturated acyl ammonium intermediates to generate a library of
complex heterocyclic compounds.
The use of these intermediates, generated in situ from trichlorophenol-activated ester and
HyperBTM, proved successful in the development of an asymmetric Michael-Michaellactonisation
reaction with 1,3-dicarbonyls. This method gives a quick and simple approach to a
wide range of highly functionalised lactones (20 examples) bearing three contiguous stereocentres
in moderate to good yields (46-79%). Excellent diastereo- and enantioselectivities (up to >95:5
dr, up to >99:1 er) were obtained due to the catalyst controlled nucleophilic addition. Resulting
indane derivatives represent potential biologically and pharmaceutically relevant molecules.
Chapter 3: The scope of the new domino reaction was extended employing benzazoles as an
alternative pro-nucleophile class. Utilising acyl benzothiazoles selective N-cyclisation was
observed through the operation of a domino Michael-lactamisation-Michael reaction, whilst the
use of acyl benzimidazoles gave an alternative domino reaction pathway and selective access to
quaternary stereocentres. The stereodivergence of these domino processes was studied by varying
the electronic properties of the benzothiazole nucleophiles. A broad scope of complex fused
polycycles (26 examples) was synthesised using this methodology with good to excellent yields
(up to 94%) and high levels of stereocontrol (up to >95:5 dr; up to 97:3 er).
Chapter 4: A new general concept for α-unsaturated acyl ammonium catalysis has been
developed which exploits 4-nitrophenoxide release from an α,β-unsaturated 4-nitrophenyl ester
substrate to facilitate catalyst turnover. This method was used for the enantioselective isothioureacatalysed
Michael addition of nitroalkanes to α,β-unsaturated 4-nitrophenyl esters (27 examples,
up to 79% yield, 99:1 er). The synthetic utility of this methodology was demonstrated through a
simple synthesis of highly enantioenriched pyrrolidinones. Mechanistic investigations including
kinetic analysis, catalyst labelling and crossover studies have delivered a fundamental
understanding of this process, with the application of a recently reported variable time
normalisation graphical analysis method used to allow the complex reaction kinetics to be probed. Chapter 5: Alternative catalyst turnover within α,β-unsaturated acyl ammonium catalysis was
further explored. A novel approach to highly enantioenriched y-nitro esters was developed, which
exploits the use of silyl nitronates to both undergo enantioselective Michael addition and facilitate
catalyst turnover, through a silyl migration/[3,3]-rearrangement pathway, unprecedented in
enantioselective catalysis. Application of silyl nitronates, as more active surrogates than their
parent nucleophiles nitroalkanes, allows their use as stoichiometric reagents with a wide range of
resulting y-nitro-substituted silyl esters (25 examples) obtained with good to excellent diastereoand
enantioselectivity (up to >95:5 dr, up to >99:1 er).
Type
Thesis, PhD Doctor of Philosophy
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