The Development of a,b Unsaturated Sultam Probes for use in Chemical Biology

Abstract

The field of chemical biology has become a powerful driving force among the continuing effort to elucidate medicinally relevant biological hot spots. These so called hot spots consist of reactive nucleophiles and electrophiles found along bio-pathways. Many nucleophilic amino acid residues, such as cysteine and serine, are known to react with a-b unsaturated electrophiles like Michael acceptors. In recent years systematic assays to uncover hot spot reactivity, including Activity Based Protein Profiling (ABPP), have risen to the forefront of chemical biology. However, these assays are dependent upon chemical probe molecules designed to interact with a given type of biological entity. Therefore, a persistent need exists for novel chemical probes with easily modifiable chemical, stereochemical, and electronic properties. Ideally these chemical properties are synthetically built into the probe in a rapid and combinatorial manner to yield a unique and easily modified probe molecule. This dissertation presents the design and synthesis of sultam chemical probes with a focus on a-b unsaturated systems. Chapter 1 contains a short review on a-b unsaturated Michael acceptors and biological reactivity, as well as the pharmaceutical history of enolic a-b unsaturated tetramic acids when combined with sultam molecules. Chapter 2 outlines the synthesis of six membered-triazole-fused sultams containing a-b unsaturated Michael acceptors. These chemical probes were generated via intermolecular click chemistry and ring closer by a novel C-vinylation reaction to form the sultam itself. Chapter 3 highlights the a-functionalization of tetramic acid inspired sultam probes or ‘sultamic acids,’ to generate endo-enol and exo-enamine-a-b unsaturated sultam probes. These probes will be given to collaborators for use in chemical biology assays.