The Design and Synthesis of β-Keto Vinyl Sultams and Macrocyclic β-Keto Vinyl Sultams: Novel Analogs of Tetramic Acids

Abstract

Sulfur (S)-containing heterocyclic compounds possessing R1R2N–SO2R3 functionality have been recognized as important due to their innate physical properties that affect biological systems marking them as attractive targets for probing biological pathways. Specifically, sulfonamides and sultams represent two significant compound classes, which exhibit broad ranges of biological activities. Similarly, natural products possessing the tetramic acid core structural motif have emerged as a rich chemotype due to their potent and broad biological activities. Several bioactive tetramic acid-containing compounds have been reported with a variety of activities, including antibacterial, anticancer and anti-inflammatory activities, as well as unique biological profiles in different cell assays. Tetramic acid analogs are also known to modulate protein-protein interactions. In light of the biological significance of the tetramic acid subunit, and the notable physical properties of sulfur containing compounds, we have become interested in the generation of S-analogs of tetramic acids in order to screen for biological activity, and to serve as new probes in Chemical Biology studies with our collaborators. One such class is β-keto sultams, and their unsaturated analogs, both of which represent relatively unexplored chemical space. While there are several reports in the literature for the synthesis of tetramic acid-containing compounds, there are a relatively limited number of examples of the corresponding β-keto sultam analogs. Moreover, their unsaturated analogs are even more limited. It is the purpose of this thesis to start our investigations to explore the substitution of the β-keto sultam group for the iv β-keto lactam subunit in drug-like tetramic acid-containing molecules, which ultimately has the potential to modulate biological activity as well as ADME profiles of the resulting analogs compounds. This thesis will describe the design and synthesis of β-keto sultam analogs of tetramic acids and their corresponding unsaturated and macrocyclic derivatives as novel electrophilic probes that can be modulated electronically, sterically, and stereochemically