Enantioselective organocatalytic [1,2]-rearrangements

Abstract

The research documented in this thesis focusses on the development of enantioselective organocatalytic [1,2]-rearrangement processes. Synthetic and mechanistic studies of the isothiourea-catalysed enantioselective [1,2]-rearrangement of allylic ammonium ylides is described. Preliminary studies towards the catalytic enantioselective [1,2]-Wittig rearrangement of allylic ethers have shown promise.

Chapter 1 introduces the fundamental concepts that underpin sigmatropic rearrangements, specifically the concurrence of [1,2]- and [2,3]-rearrangement of ammonium ylides. An overview of the literature is presented, highlighting mechanistic investigations and application to the synthesis of stereodefined products. The aims of this research project are set out and the challenges thereof contextualised.

Chapter 2 details the discovery and optimisation of the isothiourea-catalysed enantioselective [1,2]- rearrangement of allylic ammonium ylides. Using this protocol, a range of unnatural α-amino acid derivatives (21 examples) were synthesised in up to excellent yield (87%) and up to excellent enantiocontrol (93:7 er). Importantly, the developed protocol minimises the competitive thermallyallowed [2,3]-rearrangement.

Chapter 3 describes the design and execution of a range of mechanistic experiments for the isothioureacatalysed [1,2]-rearrangement. Crossover studies using ¹³C-isotopic labelling and quantitative 13CNMR ascertained a mostly intramolecular process (up to 32% intermolecular reaction). Radical trapping experiments showed improved enantioselectivity of rearrangement while simultaneously inhibiting intermolecular reaction. EPR experiments have revealed radical trapping is exclusive to the [1,2]- rearrangement and does not occur during [2,3]-rearrangement. Collaborative computational investigations have probed the origin of enantiocontrol, as well as the origin of [1,2]- to [2,3]- rearrangement selectivity, and provided a detailed analysis of the proposed catalytic cycle.

Chapter 4 introduces the topic of [1,2]-Wittig rearrangement and describes conceptual parallels with the [1,2]-rearrangement of ammonium ylides. Understanding gained in Chapters 2 and 3 has been applied towards the development of a Brønsted base-catalysed [1,2]-Wittig rearrangement of allylic ethers.

Chapter 5 evaluates the conclusions that can be drawn from the research documented in this thesis and provides guidance towards the future direction of this research.

Date of Award	1 Dec 2020
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Andrew Smith (Supervisor)