Studies towards the total synthesis ofthe amphidinolide C family of naturalproducts

QD Chemistry

Osnowski, Andrew P. ; Clark, J.S.

University:University of Glasgow

Department:School of Chemistry

关键词: Amphidinolide C, Amphidinolide F, natural product, total synthesis, metal carbenoid, oxonium ylide;   

Others  :  http://theses.gla.ac.uk/4712/1/2013OsnowskiPhD.pdf

来源: University of Glasgow

【 摘 要 】

The amphidinolide compounds represent an extensive array of marine natural products, a number of which demonstrate potent anti-cancer bioactivity in vitro. Amphidinolide Crepresents an attractive synthetic target due to a combination of potent bioactivity andcomplex 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-transtetrahydrofuran-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. Subsequentdiscussions 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.