Towards the total synthesis of azinomycin B
Finerty, Matthew James (2008) Towards the total synthesis of azinomycin B. PhD thesis, University of Warwick.Full text not available from this repository.
Official URL: http://webcat.warwick.ac.uk/record=b2339014~S15
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|
|Official Date:||September 2008|
|Institution:||University of Warwick|
|Theses Department:||Department of Chemistry|
|Sponsors:||University of Warwick|
|Extent:||204 leaves : ill., charts|
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