[Babcock_Hall]

Barrett AGM et al., J. Org. Chem. 2000, 65, 6508-6514
https://pubs.acs.org/doi/full/10.1021/jo000690p
We have previously used this method on the same or similar glycosides 2 or 3 times with success.  The reaction is carried out in DCM with about 7.6 moles of TBDMSOTf and about 11.5 moles of lutidine per mole of glycoside.  The glycoside has four hydroxyl groups that all must be protected, and an aromatic aldehyde group is also present.  The reaction is heated to about 40 °C for 12 hours.  We had a reaction time of about 20 hours this week, but the R_f was much less than we had previously seen, and there still appeared to be starting material (or something with a similar mobility) in the reaction lane.  We decided to add more lutidine and TBDMSOTf and run again.  The only thing that I can think of is that the trifluoromethanesulfonate was from a bottle that had been previously used.  Can anyone think of other problems?

[rolnor]

You dont need this long reaction time, monitor the reaction. Its a very reactive reagent, risc of byproducts. Also, I would use 5eq., not 7.6.

[Babcock_Hall]

I noticed yesterday and again today that a bilayer is present.  I do not recall seeing this in previous reactions.  It might be unreacted aldehyde, or it might be lutidinium trifluoromethanesulfonate, or conceivably both.  Lindner, Jean-Pierre and Studer, Armido, Chemistry - A European Journal, 17(15), 4090-4094 did a similar reaction and used 6 moles of TBSOTf per mole of glycoside.

[rolnor]

6 is better than 7,6. There is no reason for this large excess. The stm is dry so why? Its a straightforward reaction. Its a lot of steric bulk but the reagent is potent.  I think its complete in 1hour. I have protected many carbohydrates with many PG-s, its usually fast.

[Babcock_Hall]

We chose 7.6 because we were following one particular protocol (whether or not it was the best protocol is not easy to determine).  There are a total of five forms of the glycoside, corresponding to 0-4 TBDMS groups, a fact which makes monitoring the reaction more challenging.  Someone mentioned to me that the TBDMS groups all go axial, which if true might explain the need for the trifluoromethanesulfonate leaving group.

I looked at a fresh TLC plate today, and I saw a spot with the expected R_f.  It is much less intense than other spots, the ones with less mobility, but free lutidine is in much higher concentration, and lutidinium trifluoromethanesulfonate is also present and should not move at all.

[rolnor]

With som much reagents in the mixture TLC-interpretation gets harder. I dont see where the excess reagent will end up, why is it necessary? You can easily set up 3-4 small-scale experiments with different amounts if reagent, 10mg-runs.
Tedious comment/advise from me is, LC-MS…

[Babcock_Hall]

If we scrape the bottle, we might come up with a few more milligrams of material.  We will use a copper sulfate wash to pull out the lutidine.  The unreacted TBSOTf may become an ether: TBSOTBS.  We hope to remove this by stripping with toluene and applying a high vacuum.  I don't have access to routine LC/MS.

[rolnor]

Thats not good news. If you dont have material+time+resources there is slim chance of success, then you need luck. It can not became an ether without water present?

[Babcock_Hall]

We successfully carried out the first two steps of this 3-step synthesis three times and the third step twice, but we seem to be running into a patch of bad luck.  After the reaction, we wash the DCM solution with aqueous copper sulfate and brine, then use rotary evaporation and high vacuum to remove the volatiles.  Our hypothesis is that unreacted TBSOTf becomes (TBS)₂O during the aqueous work-up.

[rolnor]

Yes, thats possible. Is that a problem? Did it became acidic?

[rolnor]

You can quench the reagent with MeOH+TEA before workup. But now uts to late I guess.

[Babcock_Hall]

On one unsuccessful synthesis about a year ago, there was a miscalculation, and too much TBSOTf was added, more than the amount of lutidine (contrary to the protocol).  My best guess is that the molecule decomposed at some point, owing to hydrolysis of the glycosidic bond.  There was a broken flask in the most recent synthesis, but we recovered some spilled material.  We will run a silica column to see how much pure compound we can obtain, but it is a roll of the dice.

[rolnor]

I prey for you.

[billnotgatez]

Prey and pray are homophones: they belong to a category of words in which two words sound alike, but have different meanings, origins, or spellings.

[rolnor]

Sorry, I sm not a native. Prey is what carnivors eat?