Modular Approaches to Skeletally Diverse and Stereochemically-rich 7- to 11-membered Ring Sultams
Loh, Joanna K.
University of Kansas
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The overarching goal of this dissertation is the development of efficient methods for the generation of medium- and large-sized heterocycles, specifically 7- to 11-membered sultams, for facilitating probe and drug discovery. Chapter One summarizes the structural components that are prevalent in current marketed pharmaceutical agents, highlighting underrepresented rings, rings systems and frameworks, which have the potential to introduce chemical novelty into the existing limited list of chemical ring systems that describe the majority of the drugs. Chapter Two introduces the concept of pairing of a reaction triad, namely sulfonylation, SNAr addition and Mitsunobu alkylation, in varying order via the use of central o-fluorobenzene sulfonyl chloride building blocks that afford rapid access to both bridged- and fused-tricyclic, 7- to 10-membered benzofused sultams. This simple approach obviates the need for the construction of elaborate multi-functional scaffolds and merely requires use of o-fluorobenzene sulfonyl chlorides, amines and alcohols as building blocks. Simple changes in the reaction pair sequence (e.g., sulfonylation–SNAr vs sulfonylation–SNAr–Mitsunobu vs sulfonylation–Mitsunobu– SNAr), or changes in the building blocks (1,2-amino alcohol vs 1,3-amino alcohol), allows access to skeletal and stereochemical diversity. Chapter Three presents the concept of complementary pairing of activated sulfonyl aziridines (simple 6-atom bis-electrophilic synthon) via "chemo- and regioselective" aziridine ring-opening with an amino component of an amino alcohol (bis-nucleophiles). Subsequent intramolecular SNAr cyclization with the alcohol component of the amino alcohol affords unprecedented, functionally rich mediumsized benzofused sultams in overall, chemoselective “6+4” and “6+5” heterocyclization pathways. Moreover, the use of primary amines for the sulfonyl aziridine ring-opening step, whereby the resulting secondary amines cyclize via a subsequent intramolecular SNAr reaction, enables the generation of 7-membered benzofused sultams via an overall “6+1” atom cyclization sequence Chapter Four describes efforts aimed at the use of one-pot, sequential 3- or 4- component sulfonylation–aza-Michael–amide cyclization protocols to generate a library of skeletally and stereochemically diverse 7/4, 7/5 and 7/6-fused bicyclic acyl sultams. In this library effort, sulfonylation of different amines with 2-chloroethane sulfonyl chloride, followed by Michael reaction with a variety of amino acids, and subsequent amide cyclization provides access to the titled bicyclic sultams, which are currently being screened for biological activity as well as unique chemical properties.
- Chemistry Dissertations and Theses 
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