Catalytic enantioselective acyl transfer for the synthesis of atropisomers

Abstract

This thesis details the development of enantioselective, isothiourea-catalysed, acyl-transfer methodology for the synthesis of atropisomers.

Chapter 1 aims to introduce organocatalysis in the context of the current state-of-the art in Lewis base catalysis and its application in enantioselective acyl transfer. Following this, the importance of axial chirality and the current art in the synthesis of biaryl and non-biaryl atropisomers is introduced. The potential for isothiourea catalysis to provide a new platform in this area is then outlined.

Chapter 2 outlines development of methodology for the acylative desymmetrisation of biaryl phenols. After optimisation of the desymmetrisation of a model system, computational and experimental techniques were used to probe the selectivity and mechanism of the process. The methodology was then extended to a scope of 14 biaryl substrates, providing highly enantioenriched products (up to 98:2 er, 54% isolated yield). Discussion of the mechanism of their formation, and the enantioselectivity of the process is also provided.

Chapter 3 outlines attempts to extend the methodology developed in chapter 2 to the synthesis of molecules with a C–N stereogenic axis. The synthesis of several target biaryl heterocycle substrates was attempted and tentative attempts to adapt current acyl transfer methodology to these species is described. Additionally, the synthesis of atropisomeric anilides via N-acylation of secondary anilines is detailed.

Chapter 4 contains a summary of the work that has been carried out for this thesis and the potential extensions to future work within the field of Lewis base organocatalysis.

Chapter 5 provides the experimental details for the synthesis of the compounds which are contained in this thesis, as well as the associated analytical data for their characterisation.