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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on March 31, 2022, 04:07:30 PM
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We prepared the trichloromethylimidate of tetraacetylglucopyranoside (the Schmidt donor) and an alcohol with the intent of forming a glycosidic bond. We followed a protocol that had used BF3-etherate as the Lewis acid promoter and ran the reaction in the presence of 4 angstrom sieves. Dry DCM was the solvent. Following the suggestion of a colleague, we worked on a small scale and tried to isolate the steps of the reaction: quenching, extraction, and purification. We followed the disappearance of the Schmidt donor by TLC. There was a small excess of alcohol to Schmidt donor. We initially stored the reaction at -80 °C, then we quenched with TEA, which was the only deliberate deviation from the protocol that we were following. Those authors used aqueous sodium bicarbonate as the quench (other workers used TEA). The reason that we used TEA was to isolate the quench step from the extraction step; however, if I had this to do over again, I would just go with bicarbonate and not worry about isolating the quench step from the extraction step.
We removed the solvent and dried in vacuo. We took H-1 and P-31 NMR data. The H-1 suggested that the integral in the acetyl methyl region was about 1/3 of the expected value. In the starting material, the hydrogen at C-1 is a doublet near 6.6 ppm. We saw a broad signal in the same area. The NH signal of the Schmidt donor is no longer present. There are two populations of triplets in the general vicinity of where I would expect OCH2CH3 to show up. The P-31 NMR data suggested the presence of three populations of molecules.
In my informal survey of conditions in various papers, I found large variations in temperature, time, and mole ratios of Schmidt donor to alcohol to BF33-etherate. I am not sure about what to try next. I can supply more details if that would be helpful.
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The Schmidt-donor will dissapear even if it does not react with the alcohol beacause you have BF3 present so this is no good way to monitor the reaction. Have you considered that you can get a mixture of alpha and beta coupling?
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How would you monitor the reaction? Is there any point in doing a mini-extraction on what we have and taking another NMR?
There are two populations of triplets (presumably -OCH2CH3) separated by 0.15 ppm. In the presumed product they are 10 atoms away from C-1 of the glucopyranoside. Their combined area is twice that of the four CH3C(O)- protecting groups, when their area should be half. One possible explanation is that we had poor control of stoichiometry, owing to small masses or other reasons.
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You could look at the dissapering of the alcohol. The raction can probably take some time, you have steric bulk from PG-s and low temperature. If it is working as intended I think TLC would give a clear result, mainly the product.
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We attempted a second, small-scale Schmidt reaction with BF3-etherate as the acid promoter, monitoring the loss of the alcohol acceptor. I do not recall anything unusual about the TLC results. We checked the product by NMR. The P-31 NMR suggested one major and one minor product. The H-1 NMR was disappointing. The signal from the acetyl methyl groups was only about half of what we expected, based on the integral of the methyl groups from the alcohol.
We are continuing to review the literature. We plan to perform a reaction in the presence of TMSOTf as the acid promoter.
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TMSOTf is good, its not really a Lewis acid so sensitive groups are spared.
Are you planning to use LC-MS? You are potentially wasting time, effort and money by running only TLC…
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For our first reaction, our use of TLC was suboptimal because we followed the donor, not the acceptor. For our second reaction we followed the acceptor (the alcohol). We don't have walk-up LC/MS, but we might be able to run it on a more limited basis. What is the advantage of LC/MS over TLC, and would you follow the reaction this way by quenching a small portion of the reaction to generate the LC/MS sample?
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Well the advantage is that you see mass of the product and can better identify whats going on. I would do the quench for LCMS just for the sake of preventing column damage
For the TLC... dont you spot all stuff thats in the reaction?
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Yes, but in the past we chose TLC conditions to observe the loss of one reactant or the other. We could run two plates, choosing the best solvent to observe each reactant, if that is what you are thinking. One problem that we have to overcome is that the ratio between the trichloroacetimidate (the glycosyl donor) and the alcohol (the acceptor) varies a good deal from one protocol to the next. Although frequently the ratio is close to 1:1, either reactant can be limiting.
I think that our initial choice to follow the glycosyl donor might have been misleading; perhaps the donor reacted with the acid promoter (BF3-etherate) but not necessarily the acceptor. Our latest attempt used TMSOTf as the acid promoter, and the TLC looked promising. However, we won't know until next week some time.
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Update: We have been running several small scale reactions. We have been trying variations in temperature or the mole ratio of TMSOTf. We have yet to see obvious signs of success. I am obtaining review articles on Schmidt chemistry.
Using NMR to study the pooled fractions from one reaction and purification, we found a small amount of product and a large amount of something else, that may be the ether created from two molecules of alcohol. I consulted with someone much more knowledgeable about carbohydrate chemistry than I am, and he thought that this side product was the the ether, but the two hydrogen atoms that are closest to the central oxygen atom of a putative ether in our molecule are more downfield than they should be if we were making this ether. However, I have been unable to come up with an entirely satisfactory alternative structure. The -OCH2- group apparently overlaps with a signal from another part of the molecule, and it has a chemical shift that is more consistent with being part of an ester.
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You can have a thio-glycoside and activate this with methyl triflate, I think thats even more selective than Schmidt. It would be really nice to see your compounds structure to be able to give you advise. I guess I need to sign som documents of secrecy for that, as I understand this is commercial research.
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Our donor is the trichloroacetimidate of 2,3,4,6-tetraacetylglucopyranoside. In the acceptor there is a phosphorus that is distant to the primary alcohol group, and we can see small differences in the P-31 shifts of various pools. The alcohol is not hindered.
EDT
One way to explain the H-1 NMR data is if an acetyl group somehow migrated onto the alcohol. I don't know what the mechanism would be.
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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.
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There are two other potential nucleophiles on our 1° alcohol, a sulfide and the oxygen from a phosphonate. I am working out alternative synthetic paths. We may also try a simpler alcohol to see that our conditions are good, as per a suggestion at ChemPros.
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Yes, the sulphide could be a problem, oxidize it to sulphone, use NaIO4/MeOH/H2O. The phosphonate oxygen is not nucleopphilic.
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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.
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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
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Yes, we have used water/methanol as the solvent when we used Oxone to make other sulfides into sulfones; I just forgot.
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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.
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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?
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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.
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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.
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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.
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Nice!
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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.
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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.
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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.
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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
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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.
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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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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.
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Sounds good.
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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.
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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.
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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.
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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.
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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.
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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.
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Is there something in particular about the brominated derivative that you think makes it a good choice?
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Chloride is also fine.
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Why are either the chloride or bromide preferable to the trichloromethylimidate?
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You dont need Lewis acid for the halides.
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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.
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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.
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The oxidation and purification went successfully.
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[Applause]