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Title: Studies towards the total synthesis of FR182877
Author: Goldberg, Frederick Woolf
Awarding Body: University of London
Current Institution: Imperial College London
Date of Award: 2004
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FRl82877 is a novel hexacyclic natural product isolated from a soil sample, and is a promising anti-cancer lead. The structural highlight of FRl82877 is a tricyclic motif that includes a highly strained bridgehead olefin and a vinylogous carbonate. Chapter one presents the isolation, biosynthesis and biological action of FRl 82877, then goes on to review the two total syntheses and three model studies that have been reported in the literature. Chapter two presents the model studies that we have undertaken to synthesise the strained tricycle. Specifically, we discuss our approach to the bicyclic tetrahydropyranopyranone unit, including a successful route which utilised an aldol reaction between a dihydropyran and a range of carbonyl compounds. We then go on to discuss our approaches to the tricyclic motif. Firstly, we investigated an intramolecular aldol reaction, although no degree of desired reaction was observed. Intramolecular radical cyclisation reactions have also been investigated, although only reduced uncyclised products were obtained. Two different ring-closing metathesis approaches are also presented, and have been supported by computational investigations to predict which cyclisations are likely to succeed. The first approach attempted to form a bridgehead olefin compound directly, but although some degree of cyclisation was observed this route was not pursued. An alternative ring-closing metathesis approach where the bridgehead carbons were saturated was successful, and showed an interesting dependence on stereochemistry that was supported by the computational investigations. However, our efforts to dehydrogenate the ring-closed products to give the bridgehead olefin failed as the resulting bridgehead olefin was found to be prone to ring-opening and epoxidation reactions. Chapter three reviews the findings presented in chapter two and discusses avenues for future research. Chapter 4 gives full experimental details and spectroscopic and physical data for all new compounds prepared.
Supervisor: Armstrong, Alan ; Sandham, David Sponsor: Novartis ; EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available