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Structure Revision of Hexacyclinol / Total Synthesis pt. I   

4 June 2006 14,592 views 13 Comments

Hexacyclinol.jpg

Total Synthesis: La Clair. ACIE, 2006, 45, 2769. DOI: 10.1002/anie.200504033

Stuctural Reassignment: Rychnovsky. Org. Lett., 2006, ASAP. DOI: 10.1021/ol0611346

After reading some very interesting discussion at Dylan’s Tenderblog, and receiving this request, I’ve decided to post on this intriguing issue. Some months back, La Clair at the Xenobe Research Institute (San Diego) published the first total synthesis of hexacyclinol. This synthesis was an impressive piece of work, including an interesting [2+2+2] step to put in the peroxide.

Hexacyclinol_3.jpg
Based on the isolation by Gräfe, using structure 1 as the target, this work now seems to be in dispute. Scott Rychnovsky has just published in a thorough Org. Lett. on the reassignment on hexacyclinol based upon calculated 13C chemical shift data using HF/3-21G geometries and mPW1PW91/6-31G(d,p) GIAO NMR predictions. His conclusions have resulted in the structure 2, shown above.

Hexacyclinol_1.jpg

Comparing the assignments, both structures do contain similar features, and share some functional groups. However, it is clear that there are massive discrepancies, especially in the construction of the main ring-systems and the controversial peroxide.
Hexacyclinol_2.jpg

Rychnovsky’s work gains extra credence, as his structure is moderately similar to three other natural products, namely elisapterosin B, maoecrystal V, and elisabethin A. Using the same calculation techniques, his predictions match the structures of these compounds remarkably well. Also, his biosynthesis pathway is reasonable, and contains species with similar spectra to the natural product.
Thus, one must examine the data used by LaClair, which begins to look questionable in the publication notes (quoting directly): “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 (1), however, this was done incorrectly at [~]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.

Intriguing stuff. So how closely to the data sets for the synthetic product and that obtained from nature match? “Samples of synthetic hexacyclinol … were identical in Rf, HPLC retention, physical properties, and spectral data to authentic samples … isolated in our laboratories.[2] The optical rotation of synthetic 1 … was comparable to that obtained in samples of isolated 1 … as well as that reported by Gräfe and co-workers … thereby confirming the absolute stereochemistry of hexacyclinol (1).” Interestingly, that reference, [2], points to unpublished work.

So, irrefutable proof of missasignment, and a possible retraction looming? No. Not until more evidence is gathered (e.g. a synthesis of 2 or an x-ray structure). But I’ll keep you posted.

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13 Comments

  • Tot. Syn. says:

    I’ve just noticed that Dylan’s got a post on it too!
    http://blog.tenderbutton.com/?p=137

  • marc says:

    a minor point, but you’ve drawn the [2+2+2] substrate with one too many C-C bonds (in the 1,3-diene)

  • Tot. Syn. says:

    Yep, got that now. Thanks for that. I spent most of my time just amazed at this turn of events!!

  • […] It has been interesting to see the bizarre controversies erupting over La Clair’s (dunno him) total synthesis of hexacyclinol versus Scott Rychnovsky’s computer simulated NMR spectra (Prehaps not ChemDraw NMR?)… you can read it in SO much more detail at Tenderblog and, for an even closer look at the synthesis, at Totally Synthetic. I ain’t goin there, besides I think this Xenobe Research Institute is just a Scientology cover to find a drug that will make Tom Cruise tall enough to ride Splash Mountain at Disneyland with his daughter fiancé. I mean… aside from Alexander Shulgin who the hell uses a P.O. box in a publication? […]

  • Jeremiah says:

    My plastic model kit doesn’t like La Chair’s structure… I don’t see a bimolecular [2+2+2] reaction occurring with this kind of strain.

  • Jeremiah says:

    heh… La Clair, not La Chair. mea culpa.

  • Tot. Syn says:

    Exactly – you can’t develop the overlap. And remember, the mechanism for a [2+2+2] with O2 goes with formation of the epoxide-oxide first… even more difficult!

  • Jeremiah says:

    Indeed, I declair shenanigans.

  • Jeremiah says:

    GAH… declare. :\

  • […] I mean, fine, there is something fishy about his research and the lack of experimental data and the queer [2+2+2] cyclization and the very sparce collection of NMRs (and the fact that he did a 37 step synthesis without acknowledging… balhbalbhalhb… Jesus, it’s just getting old. If you’re such a clever goddamn scientist, you go out and prove him wrong. Find some proof… not ‘my model kit doesn’t stretch that far’ (though, I’m a bit confused how it would work). […]

  • Mitch says:

    Great post, thanks for giving us your take on this. :)

    Mitch

  • […] Bad news bears (See VIP: Total Synthesis and Structure  Assignment of (+)-Hexacyclinol).  James La Clair’s precious and dubious synthesis of Hexacyclinol, the vaulted controversy detailed here, here, here and here (Update: here) appears to be reheating.  Scott D. Rychnovsky’s reassignment of the original structure of Hexacyclinol, which appeared after La Clair’s first ‘synthesis’ of the structure, made waves when it became somewhat obvious that either in La Clair’s solo authorship of his Angew paper he totally made up the already improbable synthesis (he had the help of the Bionic Bros)  or Rychnovsky was simply wrong.  While I gave James the benefit of the doubt, and this being based off a ‘new blip’ I still will not rescind that benefit, I’m growing much more concerned as Rychnovsky’s reputation is as good as one can get in terms of credibility.  […]

  • […] written loads about this in four posts (1, 2 – which contains my opinions, 3, 4), and frankly nothing has changed, other than the fact that […]