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Topic: Schmidt glycosylation problems  (Read 4976 times)

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Offline Babcock_Hall

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Re: Schmidt glycosylation problems
« Reply #15 on: June 06, 2022, 05:45:47 PM »
https://doi.org/10.1016/S0040-4039(00)73209-6

So far I have found two methods to oxidize a sulfide to a sulfone in the presence of a 1° alcohol.  One used buffered Oxone, and the other used sodium tungstate, phenyl phosphonic acid, hydrogen peroxide, and methyltrioctylammonium hydrogensulfate.  I plan to keep searching.
« Last Edit: June 06, 2022, 06:03:30 PM by Babcock_Hall »

Offline rolnor

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Re: Schmidt glycosylation problems
« Reply #16 on: June 07, 2022, 01:43:16 AM »
These are all OK, Oxone does not affect alcohols.
You can even use alcohols as solvent when doing oxone-chemistry:


https://en.wikipedia.org/wiki/Potassium_peroxymonosulfate

Offline Babcock_Hall

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Re: Schmidt glycosylation problems
« Reply #17 on: June 07, 2022, 10:49:07 AM »
Yes, we have used water/methanol as the solvent when we used Oxone to make other sulfides into sulfones; I just forgot.

Offline Babcock_Hall

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Re: Schmidt glycosylation problems
« Reply #18 on: June 07, 2022, 04:09:36 PM »
To oxidize sulfides to sulfones, we often use the recipe in Blumenkopf T. 1986 Synthetic Communications 16 139-146.  This paper uses a slight excess of Oxone in the presence of 4:3 methanol/water.  Just today I found a protocol that uses one equivalent each of sodium periodate and potassium permanganate, Purrington ST and Glenn AG 1985 Organic Preparations and Procedures International 17(3):227-30.  According to the authors the periodate oxidizes the sulfide to a sulfide, and the permanganate oxidizes the sulfide to a sulfone.  A number of other functional groups are not affected, including alkenes, 1° alcohols, and amides.  The solvent was a mixture of acetone and water, and the yields were moderate to excellent. 
« Last Edit: June 07, 2022, 04:26:34 PM by Babcock_Hall »

Offline rolnor

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Re: Schmidt glycosylation problems
« Reply #19 on: June 07, 2022, 11:41:13 PM »
The sulfide is very easy to oxidize so this explains why alcohols survive KMnO4. Your product will offcourse be very very hydrophilic. Maybe H2O2 could be used so you get only volatile byproducts? I think you mean sulphoxide, not sulphide in your reply?
« Last Edit: June 08, 2022, 02:00:54 AM by rolnor »

Offline Babcock_Hall

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Re: Schmidt glycosylation problems
« Reply #20 on: June 08, 2022, 09:33:28 AM »
Yes, I meant to say sulphide to sulphoxide, then sulphoxide to sulphone.  The hydrophilicity of the product is of some concern in extractions and purifications.  We usually remove methanol and extract the aqueous layer versus DCM, but we usually do not run a column after the Oxone step.  I was toying with the idea of switching out the DCM for EtOAc.  I think that H2O2 with Na2WO4 is a plausible alternative.  Many years ago when we used to use hydrogen peroxide without a catalyst or promoter on water-soluble sulfides, the second oxidation was always sluggish in our hands.  I have seen tungstate used for this transformation, but I have not seen it discussed in terms of chemoselectivity.
« Last Edit: June 08, 2022, 09:44:39 AM by Babcock_Hall »

Offline rolnor

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Re: Schmidt glycosylation problems
« Reply #21 on: June 08, 2022, 10:39:19 AM »
Yes, EtOAc is a good choice, but even this takes several extractions. You could probably use 30% H2O2 and a very small dropp of sulphuric acid, that gives you some Caros acid and some real kick.

Offline Babcock_Hall

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Re: Schmidt glycosylation problems
« Reply #22 on: June 09, 2022, 03:51:39 PM »
Oxone worked well; thank you for that suggestion.  We are planning to couple by the Schmidt method.  If we ultimately fail using this method, we will try to couple using protected thioglycosides or bromoglycosides.

Offline rolnor

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Re: Schmidt glycosylation problems
« Reply #23 on: June 11, 2022, 06:24:56 AM »
Nice!

Offline Babcock_Hall

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Re: Schmidt glycosylation problems
« Reply #24 on: June 15, 2022, 04:49:26 PM »
The purified product was still a mixture having roughly 40% of the presumed product and some other compound.  Even if the compound were pure, the yield would have been low.  We are going to try boron trifluoride etherate as the promoter.  Is it possible that small amounts of water hurt the reaction more when TMSOTf is used than if the etherate is used?  Sieves are present in either case.

Offline rolnor

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Re: Schmidt glycosylation probl
« Reply #25 on: June 16, 2022, 07:21:57 AM »
Maybe the reaction was not complete? The product is extremely hydrophilic so workup is critical.
I am not sure sieves  are good, they can react with some reagents. DCM is usually very dry if you use that as solvent and you can co-evaporate the stm with toluene if you are worried about moisture.

Offline Babcock_Hall

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Re: Schmidt glycosylation problems
« Reply #26 on: June 16, 2022, 10:20:00 AM »
We generally follow the reaction by TLC using loss of the alcohol as the criterion.  Why do you say that the product is extremely hydrophilic?  It has 4 acetyl esters but it does not have hydroxyl groups.  Most of the protocols that I have read use sieves, but the reason is not given in the papers themselves.
« Last Edit: June 16, 2022, 11:00:02 AM by Babcock_Hall »

Offline rolnor

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Re: Schmidt glycosylation problems
« Reply #27 on: June 16, 2022, 04:38:42 PM »
Sorry, I thought you meant the sulphone-alcohol, hi, hi.
So you managed to make the glycosylation?
Thats great, even if in low yield, fantastic!
Sieves are not inert, they are weak acid and contain oxy-groups so they can quench reagents like TMSOTf. Even the surface of glass is rapidply sililated by this very powerfull regent.
I made  Cope-elimination reactions and studied different water-scavengers, molsieves were useless, they reacted with something, the mixture became dark brown. Bis-trimethylsilyl acetamide was the best choice.

https://en.wikipedia.org/wiki/Zeolite
« Last Edit: June 16, 2022, 08:09:20 PM by rolnor »

Offline Babcock_Hall

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Re: Schmidt glycosylation problems
« Reply #28 on: June 16, 2022, 09:12:33 PM »
When we were working with the sulfide-alcohol, we saw small amounts of product.  I thought that moving to the sulfone would help; I can't say that it hurt.  We will see how well the boron trifluoride etherate idea worked out.

Offline rolnor

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Re: Schmidt glycosylation problems
« Reply #29 on: June 17, 2022, 12:32:24 AM »
It seems to me that both TMSOTf and BF3 would  react/form adduct with the alcohol and this would quench the reagent. I dont understand how this can work really. Maybe you mix  the Lewis acid and the glycosyl-donor first, then add the alcohol?

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