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Total synthesis of abyssomicin c, atrop-abyssomicin c, and abyssomicin d: Implications for natural origins of atrop-abyssomicin c

Academic Article
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Overview

related to degree

  • Harrison, Scott Timothy, Ph.D. in Chemistry, Scripps Research 2001 - 2006

authors

  • Nicolaou, K.C.
  • Harrison, Scott Timothy

publication date

  • January 2007

journal

  • Journal of the American Chemical Society  Journal

abstract

  • In this article, the total syntheses of the antibiotic abyssomicin C (1) and its biologically inactive sibling abyssomicin D (3) are described. A number of unforseen roadblocks in our synthetic plan encouraged innovation, which culminated in the discovery of a new Lewis acid-templated Diels-Alder reaction. En route to abyssomicin C, we prepared and characterized its stable conformational isomer atrop-abyssomicin C (57), which in the presence of a strong acid underwent an unusual interconversion with the targeted natural product. Close inspection of the X-ray crystallographic structures of these compounds led to hypotheses on the mechanism of their interconversion. Attempted reduction of both atropisomers revealed that atrop-abyssomicin C afforded abyssomicin D much more readily, suggesting that this previously unknown atropisomer may be synthesized by the host organism and serves as a direct precursor of abyssomicin D. Finally, to gain insight into the mechanism of antiobiotic activity, several synthetic intermediates and designed analogues were evaluated for biological activity.

subject areas

  • Anti-Bacterial Agents
  • Bicyclo Compounds, Heterocyclic
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Conformation
  • Staphylococcus aureus
  • Stereoisomerism
  • Structure-Activity Relationship
  • Time Factors
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Identity

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja067083p

PubMed ID

  • 17212423
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Additional Document Info

start page

  • 429

end page

  • 440

volume

  • 129

issue

  • 2

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