The development of radical methodologies for the syntehsis of thiolactones and carbon-sulfer bond formation

Abstract

This thesis entitled "The Development of Radical Methodologies for the Synthesis of Thiolactones and Carbon-Sulfur Bond Formation" is divided into 7 chapters in which Chapter 1, the introduction, presents an overview of the thiol-ene and thiol-yne reaction, in particular in an intramolecular context. It also provides a short review of the methods currently available for the synthesis of thiolactones, a fascinating class of compound with far-reaching applications from medicinal chemistry to materials science. Chapter 2 discusses our unsuccessful efforts at developing a thio-Dénès-modified Ueno-Stork cyclization for the synthesis of γ-thiolactones. However, this chapter does contain the first example of the direct radical cyclization of an α-bromo allylic thioester. In Chapter 3 the development of a methodology for the direct radical cyclization of thioacids onto alkenes and alkynes for the synthesis γ-thiolactones is reported. We introduce the acyl thiol-ene (ATE) and acyl thiol-yne (ATY) terminology and expand on the importance of distinguishing these reactions from their non-acyl analogues with support from computational studies of the ATE cyclization reaction. Divulged in Chapter 4 is a strategy for the synthesis of δ-thiolactones based on the ATE reaction of γ-alkenyl esters followed by Steglich thiolactonization. γ-Alkenyl esters may also be converted to γ-thiolactone, thus allowing for divergent approach to both compound classes. Chapter 5 exploits atmospheric oxygen as an initiator for the intermolecular thiol-ene reaction, proving capable of generating thiyl radicals from thioacids, alkanethiols and thiophenols to generate a plethora of robust thioester and thioether linkages. In this chapter we report our optimization of this reaction process and conduct a concise mechanistic study which validates our proposed radical mechanism. Furthermore, we also conduct a near exhaustive examination of the scope of this reaction in terms of functional group compatability. Chapter 6 gives overall conclusions on the results and methodological advancements obtained from the previous chapters. Finally, Chapter 7 comprises the experimental procedures for the synthesis of all the compounds described in the previous chapters, as well as the methods used for the different techniques employed.