[Babcock_Hall]

We have been trying to follow literature models, including the order of addition, as closely as possible.  However we did communicate with a carbohydrate chemist yesterday who suggested adding TMSOTf before adding the alcohol as an option.  There are a great number of variables to explore.

[rolnor]

Sounds good.

[Babcock_Hall]

You can mix the protected methylglucopyranoside with TMSBr to get the bromo-sugar and then react this with the alcohol+1,1eqv. TEA in DCM.

This is starting to look more attractive, but I have not searched it via SciFinder yet.  One can buy tetra acetyl 1-bromoglycosides, and I found one supplier that is particularly inexpensive.

[rolnor]

That sounds great if you can buy the bromosugar. Its like putting on a MEM-group on a alcohol.
It can be a bit slow because you have bulk but it should be OK. I know people use additives such as silver perchlorate. I think TEA makes a triethylammonium species with MEM-chloride so its a catalyst. Silver triflate could be very effective also for speeding things up. Solvent acetonitrile I think.

[Babcock_Hall]

Rituparna Das and Balaram Mukhopadhyay "Chemical O-Glycosylations: An Overview," ChemistryOpen 2016, 5:401–433.  DOI:10.1002/open.201600043
This is a good review at moderate depth.

[rolnor]

I had 3,5-O-p-Toluylribofuranosyl chloride and dissolved this in MeOH+TEA, I got a very nice yield of the 1-O-Methyl ribofunanoside. The bromosugar is more reactive than chloro.

[Babcock_Hall]

We are trying to couple a donor (tetra-acetylglucose-trichloromethylimidate) to an alcohol acceptor.  The other functional groups on the alcohol are a sulfonyl group and a diethyl ester of a phosphonate.  We used BF₃-etherate as the acid promoter.  The purified product had H-1 NMR signals for both portions of the molecule, although the integrals for the glucose portion were a little lower than theoretical.  Unfortunately the yield was in the vicinity of 10%.  In my reading boron trifluoride and TMSOTf are the most commonly used Lewis acid promoters.  I might be inclined to look for an alternative Lewis acid, but realistically we are running out of time.

[rolnor]

Thats sad to hear, you need time to fix this. Or luck…
To make a new invention , like finding another, more suitable Lewis-acid, is a long-term project, not a quick-fix.
Try the glycosyl-bromide+the alcohol.

[Babcock_Hall]

Is there something in particular about the brominated derivative that you think makes it a good choice?

[rolnor]

Chloride is also fine.

[Babcock_Hall]

Why are either the chloride or bromide preferable to the trichloromethylimidate? 

[rolnor]

You dont need Lewis acid for the halides.

[Babcock_Hall]

We were advised to try a different disconnection altogether.  We are performing the glycosylation step using a penta-acetylated glycoside and a brominated alcohol.  We used boron trifluoride etherate as the promoter, following several published protocols (acetate is the leaving group).  The first synthesis went fairly well, but purifying the product away from unreacted starting material is difficult.

[Babcock_Hall]

Just a quick update.  We joined the phosphonate portion of the molecule to the glycoside portion of the molecule in the most recent reaction.  The next step will be oxidation.

[Babcock_Hall]

The oxidation and purification went successfully.