Finerty, Matthew James (2008) Towards the total synthesis of azinomycin B. PhD thesis, University of Warwick.

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Abstract

Chapter One provides a review of the literature relating to the isolation, structure elucidation, biological activity, and mode of action of the azinomycins. It also provides an overview of the synthesis and biological activity of simplified synthetic analogues. Chemical strategies towards the natural products are presented, as are proposals for the biosynthetic construction of these complex metabolites. Chapter Two describes our synthetic efforts towards simplified analogue 90 of azinomycin B, containing an amide substituent at N5, using the N16–C17 amide bond disconnection. These studies involved the synthesis of α-azido-β-hydroxy ester 125 in eight steps and 5% overall yield from L-methyl serinate. Further progression of 125 to fully elaborate the right-hand domain could not be achieved. Chapter Three explores a new approach to the azinomycins, based around the formation of the C7−N16 enamide bond using copper mediated cross-coupling methodology. Amides related to the left-hand domain of the azinomycins, 140 and 142, were demonstrated to undergo copper-mediated cross-couplings with phenyl iodide in yields of 19% and 64% respectively, demonstrating the potential of this approach. Methods for the synthesis of suitable coupling partners were explored. The most efficient route utilised the Eschenmoser sulphide contraction to elaborate Rpyroglutamic acid to bromoalkylidenepyrrolidine 184 in 7 steps and 16% overall yield. Initial studies into the amidation of 184 suggest that protection of the pyrrolidine nitrogen will be required to facilitate cross-linking. Chapter Four details the synthesis and biological evaluation of a range of new bisepoxides based on the azinomycin “left-hand” domain, which possess rigid linkers. The most potent of these analogues was identified as bisepoxide 203 (GI50 = 0.33 μM). All the new analogues displayed reduced potency compared to those based around aliphatic linkers, suggesting that they cannot readily adopt viable conformations for ISC formation. Chapter Five contains detailed experimental procedures for the new compounds described within this thesis.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Antibiotics, Antineoplastic agents
Date:	September 2008
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Shipman, Mike
Sponsors:	University of Warwick
Extent:	204 leaves : ill., charts
Language:	eng
URI:	http://wrap.warwick.ac.uk/id/eprint/3712

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