B.R.S.M. To strive, to seek, to find and not to give a yield

28Jul/114

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.

I, for one, wouldn't have a clue how to do this, but Hoffmann had the ingenious idea of simply chucking in 10 equivalents of TNT. As in trinitrotoluene, the explosive. Wow. I know picric acid is an explosive that's also used around the lab, but I've never seen TNT in a reaction before. Where would you even get it? Do Aldrich sell it? Anyway, this very electron poor aromatic compound forms a charge transfer complex with the electron rich PMP rings, making them positively charged. This disfavours protonation of the oxygen atoms in these acetals, slowing their hydrolysis relative to the cyclopropylidene. And it works pretty well, as the yields show!

1. The review was in Angew. Chem. Int. Ed., 1991, 30, 1452-1454. In keeping with a recent Synthetic Remarks post, you might enjoy this informative  and free presentation on the erythronolides and erythromycins from a Baran group meeting a few years back. It's really very good.

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  1. This is completely awesome. I agree, it’s not something you often see, esp. in total synthesis. For the record, all the major suppliers seem to stock it, but you have to call or write them for pricing (no online ordering, obviously). If you’ve never filled out the legion of paperwork to procure iodine or hydrazine, I don’t recommend it….must be a similar situation here.

  2. You can buy 2,4-DNT (very cheap from Aldrich) and do the last nitration with KNO3 and oleum.

  3. W

  4. I had synthesized couple of grams of TNT (also completely deuterated) some years ago. It is stable and somehow safe to handle. I got nice almost colourless crystals. But deprotection chemistry with TNT is something very cool, although I doubt anyone will do this again.


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