Enantioselective isothiourea catalysis via C(1)-ammonium enolate intermediates : applications and mechanistic studies

  • Calum McLaughlin

Student thesis: Doctoral Thesis (PhD)


The absolute stereochemistry of organic compounds can have a profound influence on the conformation, properties, and function of molecules. Therefore, sustainable synthetic methods that enable the catalytic, stereoselective preparation of enantioenriched compounds is a central research goal in chemistry.

Catalytically generated C(1)-ammonium enolate intermediates, derived from chiral tertiary amine Lewis base catalysts such as isothioureas, have emerged as synthetically useful intermediates for the enantioselective synthesis of α-functionalised carbonyl compounds at the carboxylic acid oxidation level, motifs that are found in many biologically relevant molecules. Despite the widespread application of C(1)-ammonium enolates in the synthesis of chiral heterocycles, there is typically a requirement for relatively high catalyst loadings, stoichiometric additives and/or auxiliary base for effective reactivity in the formation of acyclic α-functionalised products. In addition, a fundamental mechanistic understanding of these processes, governed by intermolecular catalyst turnover via an aryloxide, remains elusive and compatible electrophiles are limited to alkene and carbonyl derivatives.

The research goals of this thesis targeted the development of novel methodologies in isothiourea catalysis via C(1)-ammonium enolates using aryloxide catalyst turnover in reaction with alternative electrophiles, specifically looking to address the previous limitations of sustainability and mechanistic understanding (Scheme I). Herein, we report the base-free enantioselective α-functionalisation of esters via a Michael addition reaction of aryl esters to vinyl bis-sulfones enabled by a multifunctional aryloxide (Chapter 2). Using ¹⁹F{¹H} NMR reaction monitoring, a thorough mechanistic investigation was carried out to interrogate this methodology, enabling a large amount of mechanistic information to be collected, including elucidation of the turnover limiting step (Chpater 3). We also report the regio-, diastereo- and enantioselective dearomatisation of pyridinium salts using isothiourea catalysis via C(1)-ammonium enolate intermediates for the synthesis of 1,4-dihydropyridine heterocyclic motifs (Chapter 4). An enantioselective nucleophilic aromatic substitution protocol was also targeted, however, attempts to render both inter- and intramolecular variations of this transformation enantioselective proved challenging (Chapter 5).
Date of Award30 Jun 2021
Original languageEnglish
Awarding Institution
  • University of St Andrews
SupervisorAndrew David Smith (Supervisor)

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