Graduate Thesis Or Dissertation
 

Enantioselective Total Syntheses of Quinolizidine Lycopodium Alkaloid Cermizine D and Cytotoxic Marine Macrolide Mandelalide A

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  • The enantioselective total synthesis of quinolizidine-containing natural product cermizine D and formal syntheses of senepodine G and cermizine C has been achieved. These natural products are members of the lycopodium alkaloids, which have attracted significant attention due to their exciting biological activities and the diverse structural scaffolds. Key steps in the synthetic sequence include the use of an organocatalyzed aza- Michael addition to access a common intermediate aldehyde, matched Evans alkylation using the underexplored iodomethyl thioether to establish the C₁₅ stereocenter and a sulfone aldehyde coupling to link the two major subunits. An unexpected outcome during the key coupling experiment led to a serendipitous, intramolecular cylization of sulfone and the formal syntheses of senepodine G and cermizine C. Additionally, an unexpected and rare example of a matched/mismatched relationship using 4-benzyl-3-acyloxazolidin- 2-one (Evans' auxiliary) was observed. Finally, the exploration in to the stereoslectivity for a conjugate addition reaction on a series of α, β-unsaturated sulfones was explored which led to the discovery of a highly stereoselective process that could be used to access piperidine-containing alkaloids. A 25-step enantioselective total synthesis of cytotoxic macrolide mandelalide A has been achieved. This macrolide has attracted considerable synthetic attention due to its complex molecular architecture and compelling cytotoxic activity in early cancer cell screening. The first generation approach exploited a silver-catalyzed cyclization (AgCC) reaction to construct the C₁₇-C₂₀ cis-substituted THF ring; however, the subsequent deoxygenation at C₁₉ could not be accomplished. The successful synthetic route utilized a diastereoselective Sharpless asymmetric dihydroxylation of cis-enyne to construct the C₂₀-C₂₁ anti-diol followed by AgCC cyclization of the C₂₀, C₂₁ dibenzoate to construct the C₁₇-C₂₀ THF ring system. Additional key steps include the Petasis olefination of the C₁₈ ketone followed by hydrogenation to access the C₁₈ methyl stereocenter, Wittig reaction to couple the northern and southern fragments and a Yamaguchi macrolactonization to access mandelalide A. Macrolactonization of the C₂₃-C₂₄ diol seco-acid furnished the 25- membered ring expanded C₂₄-macrolactone as the major product.
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  • 2017-08-23 to 2018-02-27

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file details VeerasamyNagarathanam2015.pdf 2017-08-23 Pubblico Scaricare