Hexacyclinol

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Hexacyclinol
Hexacyclinol-2D-skeletal.png
(1) The structure for hexacyclinol proposed by Rychnovsky and synthesized by Porco, Jr.
Hexacyclinol-from-xtal-2010-3D-balls-B.png
Names
IUPAC name
(2aS,3R,5aR,6aS,7R,8R,8aS,10R)-7-hydroxy-3-(1-methoxy-1-methylethyl)-10-(2-methylprop-1-en-1-yl)-1a,5a,6a,7,7a,7b,8,8a-octahydro-2H-8,2a-(epoxymethano)phenanthro[2,3-b:6,7-b']bisoxirene-2,5(3H)-dione
Identifiers
3D model (JSmol)
ChemSpider
MeSH C469535
Properties
C23H28O7
Molar mass 416.470 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Hexacyclinol is a natural metabolite of a fungus, Panus rudis. Significant controversy surrounded its proposed structure until its total synthesis by John Porco, Jr. in 2006.

Controversy over structure[edit]

(2) The structure of hexacyclinol proposed by Gräfe and purportedly synthesized by La Clair.

Natural products chemist Udo Gräfe collected a sample of P. rudis HKI 0254 from a dead log in Siberia from which hexacyclinol was isolated. His group's 2002 paper showed that the compound behaved as an antiproliferative drug against cancer cell lines and proposed a structure (2) for the compound.[1]

An initial total synthesis was published by James J. La Clair in 2006, purporting a synthesis of Gräfe's proposed structure based on 1H nuclear magnetic resonance (NMR) spectra.[2] Natural products chemist Scott D. Rychnovsky simulated the 13C nuclear magnetic resonance spectrum of the structure proposed by Gräfe and found that it did not correspond to the spectrum of the structure allegedly synthesized by La Clair. Rychnovsky proposed a different structure (1) based on panepophenanthrin, another molecule isolated from a different strain of P. rudis.[3] The scientific community then began criticizing La Clair's work, claiming that his work was sloppy or that he fabricated data.[4] La Clair's publication of his purported synthesis was retracted in 2012, citing a lack of validation of its claims.[5]

In 2006, a group led by John Porco, Jr. synthesized Rychnovsky's proposed structure. They showed that the 1H- and 13C-NMR spectra matched that of the compound isolated by Gräfe, confirming Rychnovsky's structure.[6] La Clair claimed that since the two structures were isomers, it is possible that they would have similar 1H-NMR spectra.[4] However, a later paper by Saielli and Bagno claims that there would be significant differences in the 1H- and 13C-NMR spectra of compounds (1) and (2).[7]

The controversy was covered extensively by a number of science blogs.[8]

In response to the controversy, Nobel Prize-winning synthetic chemist E.J. Corey remarked, "Occasionally, blatantly wrong science is published, and to the credit of synthetic chemistry, the corrections usually come quickly and cleanly."[4]

References[edit]

  1. ^ Brigitte Schlegel; Albert Härtl; Hans-Martin Dahse; Friedrich A. Gollmick; Udo Gräfe; Heinrich Dörfelt; Barbara Kappes (2002). "Hexacyclinol, a New Antiproliferative Metabolite of Panus rudis HKI 0254". The Journal of Antibiotics. 55 (9): 814–817. doi:10.7164/antibiotics.55.814. PMID 12458771.
  2. ^ La Clair, James J. (2006). "Total Syntheses of Hexacyclinol, 5-epi-Hexacyclinol, and Desoxohexacyclinol Unveil an Antimalarial Prodrug Motif". Angewandte Chemie International Edition. 45 (17): 2769–2773. doi:10.1002/anie.200504033. PMID 16470558. (Retracted)
  3. ^ Scott D. Rychnovsky (2006). "Predicting NMR Spectra by Computational Methods: Structure Revision of Hexacyclinol". Organic Letters. 8 (13): 2895–2898. doi:10.1021/ol0611346. PMID 16774284.
  4. ^ a b c Bethany Halford (28 July 2006). "Chemical & Engineering News: Latest News - Hexacyclinol Debate Heats Up". Chemical & Engineering News. Retrieved 2 December 2010.
  5. ^ James J. La Clair (2012). "Retraction: Total Syntheses of Hexacyclinol, 5-epi-Hexacyclinol, and Desoxohexacyclinol Unveil an Antimalarial Prodrug Motif". Angewandte Chemie International Edition. 51 (47): 11661. doi:10.1002/anie.201206869.
  6. ^ John A. Porco Jr.; Shun Su; Xiaoguang Lei; Sujata Bardhan; Scott D. Rychnovsky (2006). "Total Synthesis and Structure Assignment of (+)-Hexacyclinol". Angewandte Chemie International Edition. 45 (35): 5790–5792. doi:10.1002/anie.200602854. PMID 16871643.
  7. ^ Giacomo Saielli; Alessandro Bagno (2009). "Can Two Molecules Have the Same NMR Spectrum? Hexacyclinol Revisited". Organic Letters. 11 (6): 1409–1412. doi:10.1021/ol900164a. PMID 19215104.
  8. ^ Carmen Drahl and Bethany Halford (26 February 2009). "Hexacyclinol-The Data Debate / CENtral Science". Chemical & Engineering News blog. Retrieved 2 December 2010.