A History of the Hexacyclinol Hoo-Hah

On November 14, a chemistry journal retracted a six-year-old paper that had set chemists' tongues wagging as soon as it was published. The retracted report detailed a total synthesis of an intricate molecule called hexacyclinol. Look back at how the story unfolded.

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  1. Sept. 2002: A German team reports how they discovered the molecule hexacyclinol in a fungus. Hexacyclinol blocks cell growth—a property that tends to make researchers think that they could be looking at the potential inspiration for a drug for cancer or other diseases. The team assigns a structure for the molecule based on a battery of spectroscopic data.
  2. Feb. 9, 2006: James J. La Clair of San Diego's Xenobe Research Institute publishes his 37-step synthesis of hexacyclinol in Angewandte Chemie.
  3. Mar. 29, 2006: La Clair presents his work on hexacyclinol at the ACS national meeting in Atlanta. (Thanks to the blog Retraction Watch for making us aware of this presentation).
  4. Jun. 1, 2006: Scott Rychnovsky of the University of California, Irvine, publishes a computational study that calls into question the original structure assigned to hexacyclinol in 2002—the structure La Clair reported he synthesized. Rychnovsky suggests a rather different-looking alternative structure.
  5. Jun. 3, 2006: Stanford graduate student Dylan Stiles calls attention to La Clair's work and the Rychnovsky results at his blog, Tenderbutton. (The Tenderbutton blog is now archived but can be accessed with username: tender ; password:button ).

    In February of this year, a total synthesis was published by James La Clair, a massive 37-step synthesis that made my head hurt when I went through it.

    This is where things start to get a little fishy. Notice footnote 22 of the main text:

    "The 1H NMR spectra for this Communication were determined by contract services. The spectra provided in the Supporting Information were collected by N. Voss (Berlin, Germany). The operator added the peak for CDCl3 to the spectrum of synthetic hexacyclinol, however, this was done incorrectly at d=7.5 ppm and against the request of the author. Additionally, one spectrum was duplicated and a copy of the spectra for natural 5-epi-hexacyclinol was not provided."

    Huh? The operator added a solvent peak? Why would anybody do that? Modifying data is a cardinal sin in science.—Dylan Stiles, Tenderbutton

  6. June 2006: A cadre of chemistry bloggers weighs in on the controversy.
  7. La Clair is the only author [of the hexacyclinol total synthesis], which is highly unusual for such a large effort.—Derek Lowe, In the Pipeline
  8. July 27, 2006: John Porco's research group at Boston University reports that they've synthesized hexacyclinol—the revised structure proposed by Rychnovsky, that is. Rychnovsky is a coauthor on the work.
  9. July and August 2006: News outlets begin posting stories about the controversy. La Clair takes a thrashing in the blogosphere, C&EN's Bethany Halford reports.
  10. The structure of ...the antiproliferative compound hexacyclinol—has become a controversial topic among organic chemists in recent months
    Despite the brouhaha, La Clair praises Porco's and Rychnovsky's reports and says the work is helping to elucidate the chemistry of these metabolites.—
    Bethany Halford, C&EN
  11. This is turning into the biggest stink-bomb in organic synthesis in many years.—Derek Lowe, In The Pipeline
  12. Nature reporter Emma Maris's story about the hexacyclinol controversy runs with the catchy title "The Proof is in the Product". The headline is emblazoned on a t-shirt sold by the University of California, Irvine's chapter of Iota Sigma Pi, the national honor society of women in chemistry. (UCI is Rychnovsky's home institution.) *Have you got a photo of the t-shirt?* Share it with [email protected]