Development of methods for the synthesis of natural product-like macrocycles

This thesis describes a modular diversity-oriented synthesis approach, which exploited a ‘build→couple→couple→pair’ reaction sequence, to generate a library of natural product-like macrocycles. The use of a fluorous−tagged building block allowed the expedient purification of the substrates between the ‘couple→couple’ stages of the sequence. Building blocks were iteratively linked onto the fluorous tagged building block to give linear substrates bearing two terminal alkenes. These substrates were subjected to ring-closing metathesis to yield diverse macrocyclic scaffolds. Subsequent, deprotection and diversification steps yielded natural product-like macrocycles. Using this approach, over 13 macrocyclic scaffolds were prepared which, in turn, after diversification, yielded over 55 diverse macrocycles, each with unique scaffolds. In addition this project also saw the synthesis of the corresponding linear compounds.

Chapter 1 discusses the importance of macrocycles in nature, how this class of molecules have been poorly explored and methods that have been used to explore chemical space. Chapter 2 describes the synthesis of the building blocks and the proposed method to prepare the library of diverse macrocycles. Chapter 3 explores the reactivity of the building blocks and developments required to improve the efficiency of the library synthesis. Chapter 4 describes the final library synthesis from building blocks to final compounds. This work aims to prepare compounds with potential bioactivity; however, the biological evaluation of the compounds is beyond the remit of the study.