Synthesis of Novel Sultam Scaffolds: Method and Library Development

Abstract

The development of methods to produce diverse set of small molecules to be utilized as chemical probes in chemical biology is a continuing emerging area critical in the pursuit of broadening the understanding of biological pathways and search for new therapeutics and biological probes to improve human health. In particular, sultams as non-natural lactam surrogates have recently gained attention as a novel class of compounds with extensive chemical and biological profiles that will be further discussed in introduction to Chapter 1. The virtues of diversity-oriented synthesis (DOS) paired with “Click, Click, Cyclize” paradigm in designing methods and libraries for the production of novel and unique sultam compounds provide a facile and efficient pathway in achieving this goal. Despite these attributes, methodologies for the synthesis of sultams and their corresponding libraries are limited in literature relative to lactam surrogates. A more in detail analysis of this gap will be introduced in the introduction of each chapter. It is the purpose of this dissertation to develop novel methods and production of libraries based on scaffolds generated from these methods. Through these methods and libraries, we aim to produce various sultam compounds that present opportunities in accessing underexplored and underrepresented regions of chemical space with potentials for serving as chemical probes in search for unknown biological activities. An outline of the following chapters of this thesis is shown in Figure A.1. The goal of Chapter 1 is to introduce methods and library development previously reported from the Hanson group. The introduction reviews the libraries that utilize Click “3+2” Huisgen cycloaddition reaction and/or intermolecular nucleophilic aromatic substitution (SNAr) for peripheral diversification. Then efforts on production of two novel sultam libraries based on one-pot Click-aza-Michael of RCM-derived sultam scaffolds and one-pot Click-SNAr of “4+4” derived scaffolds. Chapter 2 introduces a review of recent advances in synthesis of molecules containing triazole motifs via one-pot multicomponent Click reactions (MCR). This review is categorized into three sections, including 2-, 3-component MCR, 4-, 5-, 6-component MCR, and development of novel catalysts for Cu-catalyzed azide–alkyne coupling (CuAAC) reactions. This review will be then followed by studies towards application of one-pot, sequential, multicomponent reaction strategy for the facilitated synthesis of “4+4” dibenzofused 8-membered sultam scaffolds and their analogs produced from 3-, 4-, 5-component reactions. Lastly, Chapter 3 discusses recent advances in the synthesis of various biologically active tetramic acids and their analogs. The review is divided into three sections: synthesis of tetramic acids via Dieckmann reaction, via methods other than Dieckmann condensation, and modification of existing tetramic acids for diversification and studies towards reactivity profile of tetramic acids. Subsequent section of this chapter includes our recent work on synthesis of sultam analogs of tetramic acids via intramolecular sulfa-Dieckmann cyclization. Further diversifications utilizing condensation with isocyanates to produce 3-carboxamide substituted sultam analogs of tetramic acids are reported.