Tandem allylic amination and [2,3]-rearrangement for the synthesis of enantioenriched α-amino acid derivatives

Abstract

This thesis details the development of tandem allylic amination and [2,3]-rearrangement methodologies for the synthesis of enantioenriched α-amino ester derivatives. Chapter 1 aims to introduce [2,3]-sigmatropic rearrangements and give an overview of the relevant literature precedents in terms of catalytic stereoselective [2,3]-rearrangements of allylic ammonium ylides. The different types of tandem catalytic processes and some key examples are then discussed. Finally, the aims of this thesis are presented. Chapter 2 details the development of a tandem palladium and isothiourea relay catalysis for the enantioselective [2,3]-rearrangement of allylic ammonium ylides. In this one-pot methodology, the intermediate ammonium salt is generated in situ via a palladium catalysed allylic amination. The subsequent enantioselective [2,3]-rearrangement is promoted by a chiral isothiourea catalyst to generate syn-α-amino ester derivatives in moderate to high yield (32-91%) and excellent stereocontrol (up to >95:5 dr and >99:1 er). The synthetic utility of the products is then demonstrated with a range of derivatisation reactions. Moreover, mechanistic experiments give insight into the mechanism of this palladium/isothiourea relay catalysis. Chapter 3 focuses on the synthesis of enantioenriched pyrrolidines via a tandem palladium-catalysed allylic amination/[2,3]-rearrangement methodology. Starting from enantiopure proline-derivatives, pyrrolidines were obtained in good to excellent yield (61-94%) and diastereoselectivity (up to 91:9 dr) with moderate enantioenrichment (up to 80:20 er). This process relies on transfer of chirality from the starting material to the product. Chapter 4 summarises the work described in this thesis and discusses potential future work within the area.