November 29, 2021, 03:48:19 AM
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Topic: synthesis of a glycosidic bond  (Read 455 times)

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Offline Babcock_Hall

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synthesis of a glycosidic bond
« on: November 23, 2021, 05:15:06 PM »
DOI: 10.1002/anie.200802036 Zhu and Schmidt Angewandte Chemie 2009
I am planning a synthesis of an O-glycoside bearing other functional groups.  I envision making an O-glycosidic bond, then oxidizing a sulfide to a sulfone with Oxone or MCPBA, then performing a Horner reaction, then deprotecting.  In my reading about protection of glycosides, I was surprised to learn that some, but not all, protecting groups affect the reactivity of the activated glycoside.  The review article above refers to the protecting groups that alter reactivity as "arming" or disarming."  How important is this issue in choosing the best protection/deprotection strategy?  Does anyone have another good review article on the synthesis of O-glycosides at their fingertips?
EDT
When I did a literature search, I obtained both good and bad news.  The good news was that oxidation of a sulfide to a sulfone by MCPBA in the presence of a benzoyl-protected glycoside is well precedented.  I also saw one example of acetyl protection.  The bad news is that when there is a two-carbon spacer between the sulfone and the oxygen, the sulfone and the two carbons are lost under basic conditions. LDA in THF will bring about this reaction, and so will sodium methoxide in methanol at 0 °C.  This turns the sulfur-containing portion of the molecule from a base-stable protecting group into a base-labile one.  The details of what happened were not given in this 1993 JCS Chem Comm paper (pp. 825-826): https://pubs.rsc.org/en/content/articlepdf/1993/c3/c39930000825. What is not clear is what would happen with a longer number of carbons, other than the cost of the synthesis going up.
« Last Edit: November 23, 2021, 07:05:23 PM by Babcock_Hall »

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #1 on: November 24, 2021, 03:01:58 AM »
Is it not E1cb? The alphaprotons on the sulfone are acidic.

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #2 on: November 24, 2021, 09:11:04 AM »
I was originally thinking about something akin to a Conant-Swan fragmentation, but now that you say E1cb, I think that you are probably right.  Our typical Horner conditions are 2 hours at room temperature, and one could try a weaker nitrogen base than DBU, like DIPEA.  But there is also the deprotection of the glycoside itself to consider.

If the spacing between O and S were 3-carbons, then I don't see how an elimination would happen. 
« Last Edit: November 24, 2021, 09:32:27 AM by Babcock_Hall »

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #3 on: November 24, 2021, 09:48:34 AM »
Or use a Wittig reagent instead, they are much less basic.

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #4 on: November 24, 2021, 02:55:01 PM »
On the sulfur of the sulfone is a benzyl group.  It was pointed out to me that the S-CH2-Ph hydrogen is more acidic than the hydrogen on the other side of the sulfone.  The person who pointed it out to me was wondering about the actual mechanism of fragmentation.  It may be not worth worrying about, but if I could understand better what was going on, I feel as though I have a better chance at preventing it.

I just now found a review article on protecting groups in oligosaccharide synthesis:   https://doi.org/10.1002/asia.201901621. The authors are Ghosh and Kulkarni, and the review covers 2009-2019.
« Last Edit: November 24, 2021, 03:12:24 PM by Babcock_Hall »

Offline phth

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Re: synthesis of a glycosidic bond
« Reply #5 on: November 24, 2021, 06:00:37 PM »
I do not understand why you are not using thioaryl glycosides to conduct the chemistry which is more precedented. The Kahne-Crich glycosylation is the most well known to work with stubborn alpha/beta ratios which was a significant problem with mannose.

However, I would try radical conditions. This pretty much sounds like the julia olefination https://www.organic-chemistry.org/namedreactions/julia-olefination.shtm

I remember danishefsky used a dissolving sodium reduction to deprotect benzyl groups because palladium chemistry failed to remove all ~20 of them in the final step of a large oligosaccharide; i.e. sodium metal in ammonia at -78. 10.1021/ja307628w and related references

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #6 on: November 24, 2021, 06:18:26 PM »
I may not have been clear, but the sulfone will be well away from the glycosidic portion of the molecule.  I am only just now looking at the various methods of making glycosidic bonds and protecting or deprotecting the alcoholic oxygen atoms.  I will look into the Kahne-Crich method.  Presently I was thinking in terms of making the glycosidic bond well in advance of making the vinyl sulfone.

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #7 on: November 25, 2021, 06:19:09 AM »
I think the problem with E1cb will persist even if you have the glycosidic bond early in the synthesis?

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #8 on: November 25, 2021, 12:51:44 PM »
At this point I am planning on a 3-methylene spacer between the oxygen of the glycoside and the sulfur of the sulfone.  The third carbon adds considerably to the cost of the starting material, but it is worth it if it does not eliminate.  I have yet to pick out a preferred method of making the glycoside, but I found the Handbook of Chemical Glycosylation edited by Demchenko, which might help.
https://onlinelibrary.wiley.com/doi/pdf/10.1002/9783527621644
« Last Edit: November 25, 2021, 01:21:31 PM by Babcock_Hall »

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #9 on: November 25, 2021, 04:51:27 PM »
OK. Is it important to control the stereochemistry in the glycosylation? I think if you use acetyl as PG you will get neighbouring group partiticipation and this will give you mainly one stereoisomere this may also be true uf you use benzoyl. Its not a difficult reaction, you can use a protected bromo-sugar and mild base and mix with your alcohol, its similar to protect a alcohol with a MEM-group. If you need you can make the bromo-sugar from the corresponding -OMe glycoside and TMSBr.

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #10 on: November 26, 2021, 09:46:03 AM »
It depends on the specificity of the putative enzyme that might hydrolyze.  I was thinking that I wanted a beta-linkage, but I need to continue my reading in this area.

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #11 on: November 26, 2021, 04:50:51 PM »
Maybe it would be good to make both alpha and beta? They can have very different biological properties. There are good ways to controll the stereochemistry in the glycosylation. I think this step will be trivial, its standard chemistry.

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