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Towards the Synthesis of Amphidinolides C, F and U

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Title: Towards the Synthesis of Amphidinolides C, F and U
Authors: Pyrkotis, Constantina
Item Type: Thesis or dissertation
Abstract: The amphidinolides are a family of structurally-related cytotoxic natural products which have shown powerful antitumour activity against murine lymphoma (LI210), human epidermoid carcinoma (KB) and human colon tumor cells (HCT116). They occur naturally in only minute amounts, in specific strains of the microscopic marine dinoflagellate amphidinium sp. Total synthesis therefore becomes an important potential source of these natural products. Chapter One presents the amphidinolide family and specifically the isolation, structural features, biosynthesis and elucidation of the absolute configuration of amphidinolides C, F and U, then goes on to review the syntheses of specific fragments of amphidinolides C and F. Finally, we discuss our retrosynthetic approach towards amphidinolide C. Chapter Two begins with our approach to the synthesis of the (C18-C25) THF-fragment, including a successful 9- step route which utilizes an asymmetric dihydroxylation-iodoetherification strategy. We continue with the installation of the simple side chain of amphidinolide F via a Wittig reaction and the synthesis of the (C18-C29) dithiane in three steps. We then go on to present our approaches towards the synthesis of the (C18-C34) fragment of amphidinolides C and U. Firstly, we investigated a Stille-NHK coupling approach towards the installation of the side chain of amphidinolides C and U which was unsuccessful. Secondly, we examined a Stille coupling approach for the synthesis of the (C27-C34) fragment by using Carreira's enantioselective formation of propargylic alcohols and Negishi carboalumination. Although we installed the C29 stereocentre with excellent enantioselectivity, application of the carboalumination reaction failed. Thirdly, we examined a Stille coupling for the synthesis of the (C27-C34) fragment by using cuprate chemistry and asymmetric CBS-reduction. This approach showed success in the synthesis of the complex side chain, but epimerization at the C29 stereocentre was observed at the final step. The fourth approach attempted was a three step synthetic transformation of the simple side chain of amphidinolides C and U which involved a diene-allylic hydroxylation, oxidation and NHK coupling. This route was finally chosen for the installation of the side chain. We then discuss our approach towards the (C10-C17) fragment of amphidinolides C and F which involves a dithiane alkylation approach. We show the syntheses of the (C15-C17)-dithiane in 5 steps starting from the (5)-Roche ester and the (Cl l-C14)-epoxide in 7 steps starting from D-malic acid or from the but-2-yne-l,4-diol and we then go on to talk about the dithiane coupling. Chapter Three reviews the findings presented in Chapter Two and describes the route towards the total synthesis of the three natural products. Chapter Four gives full experimental details, spectroscopic and physical data for all new compounds prepared.
Content Version: Open Access
Issue Date: Apr-2008
Date Awarded: Apr-2008
URI: http://hdl.handle.net/10044/1/72770
DOI: 10.25560/72770
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Armstrong, Alan
Sponsor/Funder: A. G. Leventis Foundation
Department: Department of Chemistry
Publisher: Imperial College London
Referenced By: 10.1016/j.tetlet.2009.02.093
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Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Chemistry PhD theses