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Totally Synthetic by Paul H. Docherty, 27 July 2006

Total Synthesis of Hexacyclinol


J. A. Porco, S. Su, X. Lei, S. Bardhan, S. D. Rychnovsky, Angew. Chem. Int. Ed. 2006, 45, 5790-5792.

DOI: 10.1002/anie.200602854

So the structure has been confirmed. And using a nice total synthesis too. So do we know whether La Clair has lied? Not conclusively; someone would have to follow his synthesis exactly, and try to see where the discrepancies creep in [1]. However, it’s very difficult to see any element of honesty in his work, and what’s more annoying is why. Afterall, had he gone after the original target, completed the synthesis and then discovered that the spectral data didn’t match, it would hardly be the first example. This happens often enough, and he could simply have postulated his thoughts on the discrepancy, as the authors of this paper did with their total synthesis of pseudo-brevenal.

Rychnovsky, and others working in the field of NMR prediction using DFT methods (rather than ChemDraw) get a boost. Clearly, his method, given in the previous paper, had a lot of validity now. It’s clear from the Porco paper that they have a lot of experience in that area, so their proposed (and now confirmed) structure wasn’t pulled out of thin air (they had previously worked on the related structure, panepophenanthirin). But for those working on total syntheses where the targets configuration isn’t well defined - you have another tool.

So the dust has settled - and it looks like Rychnovsky was right. But lets disregard the controversy for now, and look at the total synthesis. John Porco’s approach to this reassigned structure bears relations to his work on the similar natural product, panepophenanthrin.

This work hinges on the fact that both targets are actually dimeric; however, in the case of Hexacyclinol, a further cyclisation has occured to deliver the product. Thus, they created the monomer in four steps from the literature, and noticed spontaneous cyclisation immediately, using TREAT-HF to perform the deprotection of the TES group. Et3N.3HF is btw a far safer fluorinating agent than the more common

So with the monomer in hand, they left it sitting around neat for 3 days, and achieved a 87% yield of dimer. The final cyclisation was promoted by K-10 clay, acting as a Lewis acid, delivering hexacyclinol in 99%. A nice total synthesis!