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.

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
• 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: https://theses.gla.ac.uk/id/eprint/4712