Methods for Sultam Library Synthesis: One-pot, Sequential Protocols
University of Kansas
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The focus of this dissertation is to utilize vinyl sulfonamides in a series of reaction protocols towards the synthesis of sultam molecules by exploiting several salient features inherent to sulfonamides, including (i) electrophilicity of the β-carbon for Michael addition, (ii) low pKa suitable for alkylation, (iii) exploitation of the double bond for Heck, Diels-Alder and metathesis reactions. Overall, vinyl sulfonamides undergo several selective transformations to allow access to diverse sultams, which can be further utilized in library synthesis. Chapter one outlines the biological activity of sulfonamides and sultams and ends with a mini-review on the use of vinyl sulfonamides for sultam synthesis. Chapter two begins with a brief review of the bioactivity of acyl sulfonamides and acyl sultams, and then details a one-pot, sequential protocol employing complementary ambiphile (an entity having a nucleophilic and an electrophilic center) pairing (CAP) of vinyl sulfonamides with a variety of unprotected amino acids via aza-Michael addition followed by intramolecular EDC coupling (amidation). Utilizing this methodology diverse, sp3-rich mono- and bicyclic acyl sultams were synthesized in a highly scalable manner. In addition, stereochemically-rich building blocks were constructed and a method was developed to provide quick access to all possible isomers. This method was also further extended to include one-pot, sequential 3-, 4-, and 5-multicomponent protocols. Chapter 3 describes a stereo-controlled diversification of (8R,9aS)-8-hydroxy-2-(prop-2-yn-1-yl)hexahydro-pyrrolo[2,1-d][1,2,5]thiadiazepin-1(2H)-one 3,3-dioxide 3.1.1, utilizing a one-pot, click-OACC esterification protocol and a one-pot, sequential Mitsunobu alkylation pathway. The core (8R,9aS)-8-hydroxy-2-(prop-2-yn-1-yl)hexahydropyrrolo[2,1-d][1,2,5]thia-diazepin-1(2H)-one 3,3-dioxide, was synthesized rapidly on a multi-gram scale by a one-pot, sequential sulfonylation, Michael and EDC/amide coupling protocol. A compound library comprised of 135/158-members was generated utilizing these protocols. Chapter 3 also describes an efficient one-pot, sequential or 4-component protocol to access a library of stereochemically-rich acyl sultams containing varied elements of skeletal and peripheral diversity. The 3-component protocol consisted of sulfonylation of amines with 2-chloroethane sulfonyl chloride, aza-Michael with amino acids and amide coupling, and was extended to a similar 4-component procedure involving the aforementioned reactions followed by the fourth reaction, including: (i) a [3+2] Huisgen cycloaddition when propargyl amine was utilized in the sulfonylation step and (ii) carbamoylation when L-trans-hydroxyproline was employed in the aza-Michael reaction. The construction of two libraries of triazole-containing isothiazolidine 1,1-dioxides utilizing click/OACC esterification protocol is also reported in chapter 3. A core dihydroisothiazole 1,1-dioxide scaffold was prepared rapidly on multi-gram scale via ring-closing metathesis (RCM), followed by propargylation. In this method, an aza-Michael reaction employing three amino alcohols was used to generate three daughter scaffolds. This was followed by a one-pot, click/esterification protocol utilizing an oligomeric coupling reagent (OACC) to generate a 41-member library of triazole-containing isothiazole 1,1-dioxides. Chapter 4 describes the utilization of facilitated, chromatography-free intermolecular Monomer-on-Monomer Mitsunobu protocols on hydroxy-pyrrolo thiadiazepin-dioxide scaffolds. The MoM Mitsunobu reaction was employed by norbornenyl-tagged benzyl ethyl azodicarboxylate (Nb-BEAD) and Nb-tagged triphenylphosphine (Nb-TPP) whereby purification/sequestration of excess and spent reagents was rapidly achieved using ring-opening metathesis (ROM) polymerization. Facile purification was carried-out utilizing surface-initiated polymerization by three sequestration methods: (i) from free metathesis catalyst (G-II) (ii) Nb-tagged silica (Nb-Si) (iii) Nb-tagged Cobalt-graphite (Nb-Co/C) magnetic nanoparticles. Another purification protocol is reported which utilizes a ROMP derived process for the diversification of tricyclic sultams (epoxybenzo[d]isothiazole 1,1-dioxides). This chromatography-free method permits easy isolation of reductive-Heck products and retrieval of excess starting material utilizing a sequestration protocol involving metathesis catalysts and a catalyst-armed Si-surface.
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