Chemistry Forums for Students > Organic Chemistry Forum for Graduate Students and Professionals
synthesis of a glycosidic bond
Babcock_Hall:
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.
rolnor:
Is it not E1cb? The alphaprotons on the sulfone are acidic.
Babcock_Hall:
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.
rolnor:
Or use a Wittig reagent instead, they are much less basic.
Babcock_Hall:
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.
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