Novel isothiourea catalysts and reactivity

Abstract

This thesis documents the development of both novel isothiourea catalyst structures and new synthetic methodologies including the combination of isothiourea organocatalysis with novel activation modes and heterocyclic reaction partners.

Chapter 1 introduces the history and concepts of asymmetric organocatalysis with an emphasis on the development of isothioureas as small molecule organocatalysts. A focus is placed on both isothiourea catalysed kinetic resolutions and α,β-unsaturated acyl ammonium intermediates with reference to the key reactivity modes and current state-of-the-art reactivity to place the work presented in this thesis in context.

Chapter 2 describes the development of the isothiourea catalysed acylative kinetic resolution of pyrazolone-derived tertiary alcohols. Under the conditions developed, a diverse range of substituted pyrazolone tertiary alcohols could be successfully resolved with exceptional selectivity observed in most examples, including several that incorporate pharmaceutical compounds.

Chapter 3 describes the history and development of visible light photoredox catalysis and its applications to organic synthesis. The generation of nucleophilic α-amino radicals using photoredox catalysis is discussed and particular emphasis placed on the synthesis of γ-lactams using α-amino radicals. The development of the enantioselective synthesis of γ-lactams via dual isothiourea/photoredox catalysis is detailed. The protocol was then extended to a range of pivaloyl anhydrides and α-silyl amines. The development of α-amino acids as radical precursors in this reaction is then discussed including applying the methodology to synthesise a wide range of γ-lactams and extending the reaction to flow conditions.

Chapter 4 describes the development of two novel catalysts designed to circumvent the observed oxidative degradation of isothioureas by the excited state of many photocatalysts. The first strategy developed was the incorporation of the electron withdrawing CF2 group into the core of the isothiourea. Whilst this had the desired effect of decreasing isothiourea degradation by photocatalysts, the CF2 group reduced the nucleophilicity of the catalyst to the extent that reactivity in several previously reported isothiourea reactions was not observed. The second strategy developed was the rigidification of the isothiourea to minimise degradation pathways from the postulated radical cation intermediate. This catalyst showed greatly increased survivability whilst maintaining high reactivity and nucleophilicity. Gram-scale routes were developed to access both catalysts in both racemic and enantiopure form.