There's an interesting scandal brewing in synthetic organic chemistry - well, actually, more than one, but I haven't covered the Sames matter at all. This is a new one. Back in February, Angewandte Chemie, one of the most prestigious outlets for organic synthesis we have, published online a paper by James J. La Clair on the total synthesis of a nasty molecule called hexacyclinol, originally isolated from a Siberian fungus.

The paper is remarkable in several ways, and not just because I'd never heard of La Clair. The synthesis is over 30 steps long, which is unfortunately not as uncommon as it should be. (I'm afraid that my bias against total synthesis is showing). But La Clair is the only author, which is highly unusual for such a large effort. And it must have been a large one, since the paper makes reference to starting on a molar scale and finished with over three grams of the penultimate intermediate. Experienced organic chemists will wonder if two or three decimal points have been misplaced there, but that's what it says.

Here's a paragraph for my fellow synthetic geeks - everyone else can skip ahead. When you read it closely, this synthesis has some pretty odd steps in it. One oxidation (aldehyde to acid in the presence of a dithiane) is accomplished through the slow addition of silver oxide in paraffin wax, of all things. If that's a reagent combination that's ever appeared in the literature, I've missed it. Silver oxide, sure - but not delivered by a cheese grater. There's a Mitsunobu inversion, via thiophenol, which occurs on a brutally hindered tertiary alcohol, which is certainly not something I'd expect to happen, or count on midway through a thirty-odd step route. A bit later, La Clair has a mesylation that's accomplished by adding methanesulfonyl chloride/triethylamine once an hour for five hours, which is sort of believable, as the kind of thing that you're driven to by frantic experimentation, but still a bit odd-sounding.

As mentioned, La Clair is the sole author, with an address given at the Xenobe Research Institute. The usual reaction to that statement is "The what?", as I've found empirically by wandering down my hallway at work. (Or, as Stiles puts it, "not to be confused with the Scientology outpost in low orbit around Mars") Xenobe's site is a bit odd, giving off the distinctive feel of a one-man operation. I particularly like what happens when you click the "Support" button and are informed that the Institute is not accepting donations at this time. Before Xenobe, La Clair was at Bionic Bros. GmbH, in Berlin, which sounds unavoidably like a firm from a William Gibson novel. This is where much of the synthesis was done, according to a footnote in which he acknowledges, glancingly, "the assistance of five technicians". (In his defense, that's very much the German style of chemistry, for better or worse).

Now we get to the brow-furrowing part. In the preprint section of the ACS journal Organic Letters, Scott Rychnovsky of Cal-Irvine unveils a computational technique for predicting the carbon-13 NMR spectra of complex structures. His test case is. . .hexacyclinol, La Clair's baby. But according to Rychnovsky, the published structure for the natural product has to be wrong. His method seems to work quite well on similar polycyclic terpenoid nightmare structures, but feeding the accepted hexacyclinol structure into it yields a terrible correlation.

So what's the correct structure? Rychnovsky points out that a related species of fungus has been shown to produce another natural product, panepophenanthrin. If that reacted with some methanol and a bit of acid, which might easily happen during the isolation procedure, it would produce a compound with the same molecular weight as hexacyclinol. . .and that structure, run through the NMR predictor, gives a fit that's right in line with the other known cases he used. Rychnovsky's quite sure that his proposed structure is the real structure of hexacyclinol.

But if it is, how on earth did La Clair get the data he has? His paper includes a proton NMR of the natural product and one of his synthetic material for comparison. They're identical. But if Rychnovsky's right, La Clair synthesized the wrong structure entirely. The spectra shouldn't match at all - that's one of the remaining reasons for total synthesis, to make the compound and see if the spectral data really fit. Now, Rychnovsky's argument hinges on the carbon spectrum, but that should be easy to obtain, given the monstrously huge scale that La Clair seems to have been working on. And given the discrepency between the two proposed structures, I can't see how the proton NMRs can possibly line up by chance.

The strangest part of La Clair's paper is its final footnote, added in proof. Here's how it starts; make of this what you will: "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." That doesn't make a whole lot of sense. The NMR operator "added the peak" for solvent to a spectrum? Why? And he put the peak in at 7.5 ppm (the wrong place, for non-chemists)? With what, Photoshop? No, this is very strange indeed.

One of these guys is wrong. And reading Rychnovsky's paper, it's clear that he's not in much doubt about who it is: "Recently, a provocative synthesis of hexacyclinol was reported (footnote to La Clair's paper), and interest in the paper triggered my reexamination of the original structural assignment." By the standards of organic chemistry, that's a gloved slap in the face in the public square. Someone at Angewandte Chemie should probably be feeling the sting, too.

Thanks to Dylan Stiles for calling this business to my attention - his post's comments, which are much more potentially libelous than things tend to get around here, are well worth a read for those interested. Update: La Clair has made an appearance in Dylan's comments, rather to everyone's surprise, I'd say. Still no word on a C-13 spectrum, though.