B.R.S.M. Pain is temporary, publications are eternal



Three Rings in One Step: A Quick Approach to IKD-8344

Zou and Wu, Angew. Chemie. Int. Ed., Early View, 2012


It's feels like ages since my last total synthesis post, but I couldn't resist writing something about this unusual looking macrodiolide with its rather unmemorable name and ridiculous number of THF rings. Aesthetic reasons aside, with subnanomolar activity against leukaemia in mice, as well as some antiparasitic effects, this Steptomyces-derived natural product appears to be a more worthy target than many. Wu and single co-author Zou reported a modern yet slightly oldschool synthesis in Angewandte a couple of weeks back and it's been high up my 'to blog' list ever since. The route used is a delightful blend of old and new marrying modern asymmetric aldol chemistry with every first year undergrad's favourite way to make ethers - the trusty SN2 Williamson ether synthesis. This disconnection, leading back to a substrate containing two β-mesyloxyketones (with α-stereogenic centres!), would definitely have worried me, but the methodology, which the group has developed over a number of years, works very well. The synthesis is simplified somewhat by the fact that the natural product is dimeric, as macrodiolides tend to be, and the group are really able to showcase their methodology here, forming all three THF rings in the monomer unit in a single step.

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Cyanolide A Aglycon

Total Synthesis of the Cyanolide A Aglycon

Scott D. Rychnovsky et al., J. Am. Chem. Soc., 2011, Article ASAP; [PDF] [SI] [GROUP]

DOI: 10.1021/ja204228q

Update: the excellent See-Arr-Oh has guest blogged this at Tot. Syn.

Here's a hot target - this is the fifth synthesis of cyanolide A (fourth this year) since its fairly recent isolation in 2010 (see end of post for links). And it's not surprising given its potent activity against... snails. On a serious note, the reason for all the interest is the need for more effective molluscicides to eliminate the snails which act as hosts to the parasite responsible for schistosomiasis, which is common in the developing world, and sounds quite unpleasant. The double Sakuri reaction used here by Rychnovsky and coworkers here is a cool and original disconnection for this important molecule. Also, no protecting groups*!

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