January 24, 2022, 06:19:33 AM
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Topic: synthesis of a glycosidic bond  (Read 1330 times)

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Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #15 on: November 29, 2021, 03:02:22 PM »
Based on conversations with various authors and the literature searching that I did, I think that the 3-carbon spacer between the glycosidic oxygen and the sulfonyl sulfur will not have the elimination issue seen with the 2-carbon spacer.  I also think that the presence of the glycoside will protect the oxygen against oxidation of the sulfide to the sulfone.  I need to research the deprotection, to make sure that the functional groups will survive it.

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #16 on: December 10, 2021, 09:46:29 AM »
https://doi.org/10.1016/j.tet.2005.01.015

Scheme 3 in this paper indicates that the 3-carbon spacer between the oxygen on C-1 of the glycoside and the sulfur of the sulfone is inert to base.  The 2-carbon spacer gives elimination, leading to loss of the glucose portion of the molecule.  In this paper there was a phenyl group on sulfur; therefore, there was only one acidic proton alpha to the sulfur.  The authors did not cite the paper that I did earlier in this thread (T-H Chan and C-H Fei, 1993 J Chem Soc Chem Comm, 825), suggesting that they were unaware of it.
« Last Edit: December 10, 2021, 10:06:28 AM by Babcock_Hall »

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #17 on: January 07, 2022, 09:23:14 AM »
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331121/
The β-trimethylsilylethoxymethyl (SEM) group, which can be added with 2-(Trimethylsilyl)ethoxymethyl chloride, came up in a different thread on glycosides.  "The trimethylsilylethoxymethyl group easily survives under bromination, basic hydrolysis, oxidation and other harsh conditions.[3]... In general, however, SEM deprotection from alcohols seems facile[9–14]..." This quote comes from the link above.

If I were to deprotect this group in the presence of a vinyl sulfone, does anyone foresee a problem in deprotection with, for example, magnesium bromide?  I did a quick SciFinder search to see if anyone had made a tetra-SEM glycoside, but I have not found one yet.  I did find two examples where SEM protected the O-1 oxygen and one example where the oxygen atoms of a disaccharide carried various orthogonal PGs, including one SEM.
« Last Edit: January 07, 2022, 09:37:48 AM by Babcock_Hall »

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #18 on: January 07, 2022, 10:03:34 AM »
Yes, for E1cb mechanism needs a labile group in the 2-position, if it is in the 3-position  you get no elimination.
Magnesium bromide sounds mild, but why not use some fluoride-reagent? Neutral or mild basic conditions sounds good if you have a glycoside, magnesium bromide is a weak Lewis acid, no?

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #19 on: January 07, 2022, 10:22:21 AM »
Fluoride sounds great, because we have previously used it in the presence of a vinyl sulfone without difficulty.  However, I am concerned that I have not found any examples of a tetra-SEM glycoside in the literature so far.  Possibly there is some difficulty of which I am unaware.

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #20 on: January 07, 2022, 05:37:04 PM »
In one of my proposed routes a primary alcohol bearing a sulfide linkage forms a glycosidic bond to an electrophilic, protected derivative of glucose. I wonder whether or not there will be a competition between the oxygen and the sulfur.  The sulfur would bear a positive charge if it attacked.  One way around this putative problem would be to oxidize the sulfur.

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #21 on: January 08, 2022, 03:50:55 AM »
No, there is actually a way of doing glycosylation where you have a methylthio glycoside and uses methyl triflate to activate this by forming a charged thio glycoside, the charged dimethyl sulfide act as a good leaving group. I dont think a sulfide will compete with the alcohol. The activated glycoside is a very hard electrophile and is attacked by the hard alcohol nucleophile, the sulphide is a very  soft nucleophile and does not go so well together with the activated glycoside.

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #22 on: January 08, 2022, 09:46:58 AM »
Fluoride sounds great, because we have previously used it in the presence of a vinyl sulfone without difficulty.  However, I am concerned that I have not found any examples of a tetra-SEM glycoside in the literature so far.  Possibly there is some difficulty of which I am unaware.
https://doi.org/10.1002/chem.201101163
I have now found one paper in which four SEM groups were used to protect the oxygen atoms at carbons 2-4 and 6 of a glycoside conjugated with a steroid.  I did not see a deprotection step in their supplemental, but I would assume that one would use a standard recipe.  Given that I have some concerns about the deprotection step if we used acetyl protection, protection with SEM looks potentially useful.

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #23 on: January 08, 2022, 01:14:14 PM »
Great!

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #24 on: January 13, 2022, 06:58:55 PM »
Our first glycosylation attempts will use the Schmidt glycosyl donor, a trichloroacetimidate.  The choice of base strongly influences the configuration of the trichloroacetimidate.  One thing that I am not yet sure about is what factors determine the configuration of the final product, the glycoside.  I have seen some schemes in which retention occurs and others in which inversion occurs, and my tentative view is that it depends on whether or not there is neighboring group participation, but it might also depend on the acidity of the catalyst.  As I learn more, I will post it here.
EDT
In the Handbook I mentioned in a previous comment, Schmidt wrote, "The anomeric stereochemistry is derived from the anomeric configuration of glycosyl trichloroacetimidates (inversion or retention), anchimeric assistance, the influence of solvents or thermodynamic or kinetic effects....In addition, the nature of the counteranion in catalysts is very influential in controlling the stereoselectivity of the Schmidt glycosidation, as reflected by comparing entries 1 and 2, or 3 and 4 in Table 3.1 [394], but how the anions work has not yet been understood."  Sounds like I will be burning the midnight oil.
« Last Edit: January 13, 2022, 07:38:25 PM by Babcock_Hall »

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #25 on: January 14, 2022, 01:03:35 AM »
I think the NGP-effect is strong so if you have acetyl-PG you get mostly beta.

Offline Babcock_Hall

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Re: synthesis of a glycosidic bond
« Reply #26 on: January 14, 2022, 06:21:05 PM »
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259426/
doi: 10.3390/molecules15107235

Hi Rolnor,

This is a 2010 review that is more focused on carbohydrate protecting groups.  After reading portions of it and looking at Scheme 1, I think I understand your comment a bit more clearly.  Thanks.

Offline rolnor

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Re: synthesis of a glycosidic bond
« Reply #27 on: January 15, 2022, 02:23:58 AM »
Good!

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