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Totally Synthetic by Paul H. Docherty, 13 January 2009

Total Synthesis of Helicterin B, Helisorin & Helisterculin A


S. A. Snyder, F. Kontes, J. Am. Chem. Soc. 2009, 131, 1745-1752.

DOI: 10.1021/ja806865u

Helicterin B and the related compounds are dimeric (and tetrameric) natural products, that can be built using retro-Diels-Alder/Diels-Alder cascades. Porco’s total synthesis of the chamaecypanone C and Synder’s synthesis of helicterin B, united through the key use of a retro-Diels-Alder/Diels-Alder cascade, both cite an apparently inspirational paper by Bedekar back in 1992.

So what’s new with this very large molecule, other than its size (1510 g mol-1)? Not much, to be fair - Snyder mentions ‘mild inhibitory activity against the avian myeloblastosis virus’, but when the authors describe the activity as mild, you can be fairly sure it’s almost inactive. So we must clearly focus on the construction of the natural compounds.

Synder starts with the synthesis of the slightly simpler helisorin. The synthesis starts with a dimerisation of derivative of rosmarinic acid, which was produced in five steps, and then selective protection with para-trifluromethylbenzyl groups. This exotic protecting group was used after some experimentation, with Snyder trying to find exactly the right group to remove on the final step. Due to the functionality of the target, this meant removal without recourse to acid, base or oxidative deprotections - limiting their choices. So they found this ‘OTfBn ether’, which is removable using moderately powerful Lewis acids, but stable to milder.

The rosmarinic acid derivative was then oxidatively dimerised using a hypervalent iodine reagent (PIDA). This intermediate was then heated with a dienophile (also produced from rosmarinic acid), inducing the retro-Diels-Alder/Diels-Alder cascade and generating the core of Helisorin. However, one further carbon-carbon bond was still to be formed, and their protecting group selection becomes clear - using a mild Lewis Acid (LA) caused the proximal protected catechol to cyclise onto the bicyclooctane, whilst a stronger LA removed the protection groups to complete this target. The question is, why the stronger LA was not used for both steps: well, apparently that doesn’t work so well, and causes rupture of the dimethyl ketal instead.

With that success, the group were ready to move on to bigger targets, but they had a problem with the subtly different stereochemistry of the bicyclic cores of the helicterins. Converting the penultimate intermediate in the helisorin synthesis was the key, but required reduction of the ketone from the less favourable approach. Using hydride based routes was ineffective, but they were able to use the undesired product by performing an ‘equilibrative ketol shift’. The product of this reaction, a second ketone, was more receptive to reduction, presumably by coordination of the reducing agent (Me4NBH(OAc)3) from the desired face. A little lucky, but well done.

A few steps further, and they had the bicyclooctane sterochemisty just right. A weaker LA caused dimerisation of this intermediate, completing the bulk of the natural product. However, the final deprotection of the p-CF3-benzyl ethers was less successful as before, as a methyl group was also lost in reaction. This meant that they hadn’t completed helicterin A, but were lucky to find that they had isolated helicterin B instead!

Using the same common intermediate enabled an easy completion of helisterculin A! This is great work, and it’s always pleasing to read about it in a proper full paper.