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Trapping the Elusive Aza-Oxyallylic Cation Intermediate: Aza-[4+3] Cycloaddition Reactions and their Application Toward Target Directed Synthesis
AuthorBarnes, Korry L.
AdvisorJeffrey, Christopher S.
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The aza-oxyallylic cation is a reactive intermediate that undergoes a [4+3] cycloaddition reaction with dienes to form seven-membered nitrogen heterocycles. Although the existence of this intermediate had been proposed for over 50 years, only recently has experimental evidence been established to support its existence. The intermediate was generated by base-mediated dehydrohalogenation of α-haloamide precursors synthesized from the corresponding acid halide in dichloromethane, respectively. From the analogous azaoxyallylic cation intermediates generated in situ, a series of bicyclic lactam scaffolds were easily prepared from a [4+3]-cycloaddition reaction of the corresponding α-haloamide and either furan or cyclopentadiene as the diene moiety. With the exception of one case, all monoaryl and monoalkyl haloamides provided selectively the endo diastereoisomer (≥19:1). Computational and experimental evidence suggest that an N-alkoxy substituent provides necessary stabilization to the aza-oxyallylic cation intermediate. Balanol is a fungal metabolite first isolated from Verticillium balanoides and has been shown to be a potent protein kinase C (PKC) inhibitor. Starting from the α-chlorocycloadduct synthesized in Chapter 2, a concise synthesis of the hexahydroazepine-containing fragment was undertaken that was both scalable and stereoselective. Polyhydroxylated azepanes are a relatively new class of compounds with broad therapeutic potential in a variety of biological and pharmaceutical applications. A general synthesis of (±)-(4R, 5R, 6R)-4,5,6-trihydroxy-3,3- dimethylazepane is achieved in only five short synthetic steps starting from the corresponding cycloadduct, allowing for rapid access to the seven-membered iminosugar class of compounds. The reaction sequence is efficient, diastereoselective, scalable, and has the capability of incorporating a wide variety of functional groups at the ring three-postion. Polyhydroxylated piperidines are a functionally rich class of biologically active compounds that also have broad therapeutic potential. Previously described aza-[4+3] cycloadditions of putative aza-oxyallylic cations provide heterocyclic scaffolds that enabled a concise synthesis of polyhydroxylated piperidines. Chemoselective amide reduction and subsequent hemiaminal ether ring opening of four α-chlorocycloadducts by aluminum hydride provided in one pot four novel 3-chloroazepines. Aziridinium ion-mediated ring contraction and chloride displacement was triggered by silver acetate, followed by acetate hydrolysis under basic conditions to give the corresponding tetrahydropyridine diols. Alkene dihydroxylation catalyzed by osmium tetroxide installed the final hydroxyl groups, which yielded four novel polyhydroxylated N-alkoxypiperidine iminosugar analogs in good overall yield and high diastereoselectivity. Expanding on the originally reported methodology of dehyrohalogenation of αhaloamides as a means to generate aza-oxyallylic cation intermediates, efforts were undertaken to explore alternative methods to generate the afformentioned intermediates that could incorporate heteroatoms at the α-position. 2-methoxy-N-(phenylmethoxy)acetamide and 2- phthalyl-N-(phenylmethoxy)acetamide were synthesized to serve as model substrates and screened according to solvent, base, and oxidant in order to determine conditions that would allow for aza-oxyallylic cation formation. All compounds were fully characterized by NMR, IR, and high-resolution mass spectrometry. Additionally, six compounds that were of exceptionally high crystallinity were characterized by single crystal X-ray diffraction.