B.R.S.M. Help! I'm trapped in a molecule factory!


Woodward Wednesdays 2: Erythromycin A

Update 01/10/11 - It seems that I never actually gave the references for the original papers. The synthesis was actually published in three back-to-back JACS papers - the first is J. Am. Chem. Soc., 1981, 103, 3210, and you can read on from there. I also found the relevant synarchive page to be helpful when writing this.

I hadn't planned to cover this synthesis, Woodward's last, so early in this series, but as a review on the use of thiopyrans as templates in polypropionate syntheses was recently published in Chem. Commun. it seems timely to mention it now.[1] Woodward once said in a talk at CIBA in India that

"Much of the art of directed synthesis involves the design of ways to place constraints on molecular motion, with the aim of bringing about desired changes and suppressing others"

A popular way of doing this, as has been said before, is through the use of cyclic templates, a tactic used extensively by chemists of the Woodward and Corey eras. The ease with which desulfurisation can be accomplished using Raney Nickel makes thianes and thiopyans uniquely suitable as temporary rings which can be cleaved mildly and selectively later on.[2] This property made them the cornerstone of Woodward's approach to erythromycin A where they were used to set 8 of the 10 stereocentres found on the macrocyclic ring.[3]

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(+/-)-Chloranthalactone A

Total Synthesis of (±)-Chloranthalactone A

Bo Liu et al., Org. Lett., 2011, ASAP; [PDF][SI][GROUP]

DOI: 10.1021/ol202190b

Despite being just 12 steps, Liu's synthesis of chloranthalactone A published last week is full of interesting chemistry including some pretty uncommon transformations. The compound itself shows some antifungal activity, and is also structurally very similar to the monomer unit of a number of related dimeric natural products which the Liu group are apparently interested in targeting. The compound also contains a trans-5/6 ring junction with an angular methyl group, which is not at all common in nature, given that such systems much prefer to be cis given half the chance.[1] This dangerously facile epimerisation meant that the group had to be very careful not to put any carbonyl groups near the ring junction at any point during the route, and lead to some creative chemistry.

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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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