[mvcoote]

I have an O-acetyl protected sugar which is acyl linked to the carboxylic acid end of a fatty acid.  Deprotection has thus far been impossible without destroying the linkage.  Strong acid or base will also destroy the linkage and cannot be used.  Thus far, the enzymatic approach using Lipase Amano AS has failed and DIPEA has not worked either.  I've run out of ideas and any deprotection strategies / suggestions are appreciated.  TIA,

[Dan]

To be brutally honest, Ac was a poor choice of protecting group.

How complicated would it be to redesign the route? I have a feeling that would be more efficient that trying to do a selective deacylation.

Give a structure if you can - at least the identity of the sugar, linkage position and whether or not the fatty acid has unsaturation would be helpful.

[mvcoote]

Hi Dan,

Attached is a pic of the molecule....I considered a benzyl protected sugar but ruled it out due to the unsaturation on the backbone which would be destroyed by hydrogenolysis.  Redesigning the route is not a problem as long as it produces reasonable yields (looking for about 20mg total product at the least) and isn't cost prohibitive. Here is the structure:



Thanks,

[Dan]

Can you define all stereocentres? Is the configuration galacto?

If you are at liberty to give this info publicly, and also your current route, that would probably help. Can you just silyl protect instead of acetyl protection? You have a delicate looking glycoside there - both acid and base sensitive - so a fluoride deprotection might be the best option.

[mvcoote]

I guess it didn't translate to great from SMILES but it is a glucuronate.  The linkage is just simple Koenigs-Knorr reaction (brominated sugar at C1) activated by silver triflate in DCM so nothing too unusual there.  So you're suggesting silyl protected sugar and TBAF for deprotection?  That would probably work as long as the TMS isn't reactive with the Lewis activator (AgTOF).

[Dan]

With something more robust than TMS (TES/TIPS/TBS) I don't think the KK will be an issue. It may affect the anomeric distribution of the glycoside though - I'm not an expert in glycosylation, but as far as I remember a KK should give mostly beta on this system even without acetyl assistance at C2 - it just might not be as selective.

Do you need to cleave the uronic ester as well? That might be a tough one to work around.

[mvcoote]

I had the same thought:  if I don't have as much neighboring group participation from C2 on the sugar I may be more likely to get a mix of anomers where as now it is exclusively beta product (which is what I want).  That would be acceptable as long as I can adequately separate them.   Actually the methyl ester on the glucuronate has been pretty easy to remove with porcine liver esterase.   This has been a real challenging molecule to construct; as you noted it is a delicate creature. 

[Dan]

What about Lev (levulinoyl) protection? You'd still get the C2 assistance and the deprotection might be mild enough (hydrazine <RT) to take them off selectively...

[mvcoote]

Hadn't heard of that group before but it looks promising and available commercially; also hydrazine pka/pkb looks like it would be mild enough....something to consider