Graduate Thesis Or Dissertation


Total Synthesis of Goniomitine : Development of Aminal and α-Amino Radicals in the Synthesis of Nitrogen-Rich Natural Products Public Deposited

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  • Aminal radical intermediates were generated by the method of radical translocation and reacted in C-C bond forming reactions with electronically deficient alkenes (Schiedler et al. Org. Lett. 2012, 14, 6092). Aminal radical intermediates can participate in inter- and intra-molecular reactions using both Bu3SnH and (TMS)₃SiH as hydride donors. Carbon–carbon bonds were formed selectively at the aminal carbon in the presence of α-amino alkyl groups within the molecule. Bicyclic aminals also participated in C-C bond formation affording products in high diastereoselectivity. The application of aminal radical intermediates toward the synthesis of the nitrogen- rich alkaloid goniomitine was investigated. The first generation route involved the development of an acyclic aminal bearing the nitrogen of a 2,3-disubstituted indole and the N-(2-iodobenzyl)formamide nitrogen atom. In the reaction of N- (hydroxymethyl)-N-(2-iodobenzyl)formamide and the indole substrate, none of the desired acyclic aminal was observed. A second generation route utilized an α-aminoalkyl radical intermediate (generated by radical translocation) to construct the indole framework of goniomitine. The synthesis commenced with a copper-catalyzed Ullmann reaction of an aryl iodide and ethyl-substituted lactam providing the corresponding N-aryl coupling product in 96% yield. Subsequent zinc-catalyzed alkylation with acrylonitrile gave the product in 76% yield, thus installing the quaternary stereocenter of the natural product. Bromination followed by elimination provided the vinyl bromide precursor for the α- amino radical reaction. Upon treatment with tributyltin hydride and AIBN in refluxing benzene, the substrate underwent homolytic C-Br cleavage, radical translocation and subsequent 5-exo-trig cyclization to provide the desired indoline product as a 3:1 diastereomeric mixture in 83% yield. The indoline was subjected to LiAlH₄ to reduce the methyl ester as well as the nitrile to the corresponding primary amine. Upon heating, the amine underwent intramolecular condensation with the lactam, providing the aminal framework of goniomitine. A final oxidation with MnO₂ afforded the natural product in a total of six linear steps and 27% overall yield.
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