B.R.S.M. Yield isn't everything


Solve your deprotection problems… with TNT

A busy week in the lab trying to finish this damn natural product. More things at the weekend.

Update 30/07/11: Forgot to give a reference for the Hoffmann paper, which is Angew. Chem. Int. Ed., 1993, 32, 101-103. It's not a bad piece of work, and was for a time the shortest route, despite being entirely linear.

Johann Mulzer, one of my favourite chemists, wrote a review back in 1991 titled 'Erythromycin Synthesis—A Never-ending Story?'. It's well worth a read as these natural products have inspired an awesome body of work, and were an important benchmark in stereoselective natural product synthesis for many decades. Woodward, Stork, Corey, Danishefsky, Evans, Paterson, Reinhard Hoffmann, Mulzer, Carreira and most recently White have all worked on them, which is some recommendation.[1]

Anyway, I was reading Hoffmann's synthesis of (9S)-dihydroerythronolide A today when I encountered a most unusual set of conditions for deprotection. To set the problem in context, the (unstable) triply protected compound below had been obtained, and only three steps remained to the glorious completion of the target; selective cleavage of the cyclopentylidene acetal, macrolactonisation (assisted by the conformation limiting p-methoxybenzylidene acetals) and a final deprotection. The problem was that the cyclopentylidene acetal couldn't be removed without cleaving the other protecting groups, despite encouraging results obtained earlier in model studies. Not wanting to start again, a method to slow down hydrolysis of the p-methoxybenzylidene acetals was needed.

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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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