| Tóm tắt: | <p>The work described herein details the development of new methodologies for the synthesis of 2,3-disubstituted pyrrolidines and piperidines <em>via</em> an <em>endo-trig</em> cyclisation. This was realised through two approaches: firstly, a Lewis acid catalysed cation triggered annulation strategy, and secondly an asymmetric Brønsted acid catalysed cation triggered annulation strategy.</p>
<p><strong>Chapter 1</strong> is a literature review, providing an overview of the current approaches and limitations associated with the synthesis azacycles, specifically focusing on methods which introduce maximum complexity around the ring in a single step. The lack of approaches which utilise an <em>endo-trig</em> cyclisation required an overview of potential solutions, with contemporary methods to generate carbocations discussed in detail, ultimately forming the basis of the research described in this thesis.</p>
<p><strong>Chapter 2</strong> details the development of a Lewis acid catalysed cation triggered annulation in HFIP which enabled the diastereoselective synthesis of a range of functionalised piperidine and pyrrolidine products. In this approach, a complementary protecting group strategy was developed, before utilising a range of alcohol and non-alcohol electrophiles which were able to act as alkylating agents following the generation of a carbocation.</p>
<p><strong>Chapter 3</strong> presents the extension of the work described in Chapter 2 to an enantioselective transformation. A series of approaches were tested, with chiral phosphoric acid catalysis shown to be the most successful. This method followed the same disconnection utilised previously, with an alcohol employed as an alkylating agent, this time in the absence of both the metal catalyst and HFIP as the solvent.</p>
<p><strong>Chapter 4</strong> documents studies towards the pharmaceutical molecule Atrasentan utilising the method developed in Chapter 2. An extensive optimisation of the substrate synthesis is discussed, along with multiple strategies to derivatise the pyrrolidine core towards Atrasentan.</p>
<p><strong>Chapter 5</strong> provides an overview of the major conclusions of this work and discusses potential future directions for this methodology.</p>
<p><strong>Chapter 6</strong> details the experimental procedures used and documents the spectroscopic data for all the compounds described in this work.</p>
<p><strong>Chapter 7</strong> lists the references cited within this work.</p>
|
|---|