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Synthetic Efforts Toward Hypoestoxide, Platensimycin, And Guttiferone G

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Hypoestoxide is a novel diterpenoid isolated from a tropical shrub, hypoestes rosea. It has been shown to exhibit promising anti - cancer, malarial, and inflammatory activity. In particular, the in vivo anti-angiogenic activity that inhibits vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) make it especially interesting. Along with this biological profile, the challenging macrocyclic structure of hypoestoxide makes it a target of great interest to the synthetic community. The synthesis of this molecule's complex macrocyclic core was accomplished by using relay ring closing metathesis, and post-cyclization modifications were controlled by the shape of the molecule. Platensimycin is a recently isolated natural product produced by Streptomyces platensis. It was discovered in a novel antibiotic assay by screening a large number of South African soil samples. Platensimycin has been shown to have a unique mechanism of action by inhibiting Fab F, an enzyme responsible for bacterial fatty acid synthesis. In addition to the exciting biological activity, platensimycin has an intriguing molecular structure consisting of a hydrophobic and structurally compact core, and a hydrophilic aromatic head group. The synthesis of this molecule relied on a novel vinyl oxirane ring expansion to access the oxa-bicyclic moiety and an alkylative dearomatization to complete the carbocyclic core. Guttiferone G belongs to the family of [3.3.1] bicyclic polyprenylated phloroglucinol derived natural products, which have been isolated from various plant species found primarily in the tropical or subtropical regions. Their biological profiles have been shown to rival any known natural product class in terms of diversity and activity. It is this vast biological activity and structural similarity that make the development of a general approach to this family of particular interest. The common bicyclic core of these compounds was accessed by using an intramolecular bis-radical cyclization into a dienone that was itself made by oxidative dearomatization.

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2010-10-20

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Government Document

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dissertation or thesis

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