Studies towards the total synthesis of the amphidinolide C family of natural products

Osnowski, Andrew P. (2013) Studies towards the total synthesis of the amphidinolide C family of natural products. PhD thesis, University of Glasgow.

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Abstract

The amphidinolide compounds represent an extensive array of marine natural products, a number of which demonstrate potent anti-cancer bioactivity in vitro. Amphidinolide C represents an attractive synthetic target due to a combination of potent bioactivity and complex molecular architecture. This project deals with a modular and convergent total synthesis approach to amphidinolide C from which two synthetic fragments of similar size and complexity, termed ‘northern’ and ‘southern’, were synthesised in a stereoselective fashion. The stereochemical commonality between the branched chains of the 2,5-trans tetrahydrofuran systems found within both fragments, led to the conclusion that a keystone common intermediate could be applied to the synthesis of each. Previous efforts within the group have shown that 2,5-trans tetrahydrofuran-3-ones could be prepared through a diastereoselective rearrangement of a free or metal-bound oxonium ylide generated from a metal carbenoid. This thesis details the scalable preparation of the intermediate tetrahydrofuranone through tandem oxonium ylide and [2,3]-sigmatropic rearrangement. Subsequent discussions show the applicability of the intermediate to forming the C-(18)—C-(34) fragment of amphidinolide C and the C-(18)—C-(29) fragment of amphidinolide F, through the use of palladium cross-coupling methodology; alternative methods found to prepare the ‘northern’ fragment are also discussed. Additionally, the C-(1)—C-(8) fragment was prepared from the common intermediate system, the key steps in this synthesis involved introduction of the C-(4) methyl group through homogeneous catalytic hydrogenation and Luche reduction to afford the C-(7) alcohol.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Amphidinolide C, Amphidinolide F, natural product, total synthesis, metal carbenoid, oxonium ylide
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Funder's Name: UNSPECIFIED
Supervisor's Name: Clark, Professor J.S.
Date of Award: 2013
Depositing User: Mr Andrew Osnowski
Unique ID: glathesis:2013-4712
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 13 Nov 2013 10:52
Last Modified: 17 Jan 2014 14:09
URI: http://theses.gla.ac.uk/id/eprint/4712

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