Trapping the Elusive Aza-Oxyallylic Cation Intermediate: Aza-[4+3] Cycloaddition Reactions and their Application Toward Target Directed Synthesis
AuthorBarnes, Korry Lee
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. Althoughthe existence of this intermediate had been proposed for over 50 years, only recently hasexperimental evidence been established to support its existence. The intermediate wasgenerated by base-mediated dehydrohalogenation of α-haloamide precursors synthesized fromthe corresponding acid halide in dichloromethane, respectively. From the analogous azaoxyallyliccation intermediates generated in situ, a series of bicyclic lactam scaffolds wereeasily prepared from a [4+3]-cycloaddition reaction of the corresponding α-haloamide andeither furan or cyclopentadiene as the diene moiety. With the exception of one case, allmonoaryl and monoalkyl haloamides provided selectively the endo diastereoisomer (≥19:1).Computational and experimental evidence suggest that an N-alkoxy substituent providesnecessary stabilization to the aza-oxyallylic cation intermediate.Balanol is a fungal metabolite first isolated from Verticillium balanoides and has beenshown to be a potent protein kinase C (PKC) inhibitor. Starting from the α-chlorocycloadductsynthesized in Chapter 2, a concise synthesis of the hexahydroazepine-containing fragment wasundertaken that was both scalable and stereoselective. Polyhydroxylated azepanes are arelatively new class of compounds with broad therapeutic potential in a variety of biologicaland 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 correspondingcycloadduct, allowing for rapid access to the seven-membered iminosugar class of compounds.The reaction sequence is efficient, diastereoselective, scalable, and has the capability ofincorporating a wide variety of functional groups at the ring three-postion.Polyhydroxylated piperidines are a functionally rich class of biologically activecompounds that also have broad therapeutic potential. Previously described aza-[4+3]iicycloadditions of putative aza-oxyallylic cations provide heterocyclic scaffolds that enabled aconcise synthesis of polyhydroxylated piperidines. Chemoselective amide reduction andsubsequent hemiaminal ether ring opening of four α-chlorocycloadducts by aluminum hydrideprovided in one pot four novel 3-chloroazepines. Aziridinium ion-mediated ring contractionand chloride displacement was triggered by silver acetate, followed by acetate hydrolysis underbasic conditions to give the corresponding tetrahydropyridine diols. Alkene dihydroxylationcatalyzed by osmium tetroxide installed the final hydroxyl groups, which yielded four novelpolyhydroxylated N-alkoxypiperidine iminosugar analogs in good overall yield and highdiastereoselectivity.Expanding on the originally reported methodology of dehyrohalogenation of α-haloamides as a means to generate aza-oxyallylic cation intermediates, efforts were undertakento explore alternative methods to generate the afformentioned intermediates that couldincorporate heteroatoms at the α-position. 2-methoxy-N-(phenylmethoxy)acetamide and 2-phthalyl-N-(phenylmethoxy)acetamide were synthesized to serve as model substrates andscreened according to solvent, base, and oxidant in order to determine conditions that wouldallow for aza-oxyallylic cation formation.All compounds were fully characterized by NMR, IR, and high-resolution massspectrometry. Additionally, six compounds that were of exceptionally high crystallinity werecharacterized by single crystal X-ray diffraction.