Lecture 6- Carbohydrates 3 Flashcards
What is a general glycosylation reaction
- Glycone (sugar) + aglycone (alcohol) –> glycoside
- Reaction at anomeric position
What happens when you link two sugars together
- Glycosyl acceptor (Nucleophile) gives electrons from OH to glycosyl donor (electrophile) Carbon
- Opposite terminology then may be expected
- Forms a glycosidic bond
What do all glycoside reactions involve
- Oxonium intermediate
- charge on O in ring if no neighbouring group participation
- Or on O coming of C1 if there is neighbouring group participation
Which is major product if OH is added with no neighbouring participation
- Alpha is major due to anomeric effect
- Hyperconjugation or donation of lone pair into sigma* bonding orbital of OR group
What are the three methods used to generate a carbocation at position 1
- Fischer glycosylation
- Koenigs-Knorr Method
- Thioglycosides
Describe Fischer Glycosylation
- Formation of a glycoside by reaction of a sugar with an alcohol in the presence of an acid catalyst
- Carbohydrate is typically unprotected
- The alcohol is commonly the solvent
- SN1 style reaction
- Produces alpha carbon due to anomeric stability
How is Fischer glycosylation altered to form beta bond instead
- Fully acetyl protected sugars are used
- Get neighbouring group effects and more selective beta bond formation
Describe the Koenigs-Knorr glycosylation
- First must make glycosyl halide (typically Br) from fully protected acetyl sugar
- Silver salts (Ag2CO3 or Ag2O) are used as the promoter - both insoluble
- Driving force is formation of AgBr
How do you generate a thioglycoside
- Prepared from acetylated sugar
- Add strong LA e.g. BF3.OEt2 which cleaves of Ac
- RSH (R=Ph, Tol, Et)
How are thioglycosides used in glycosylation
- Use an electrophilic thiophilic promotor to generate S+ - activated
- This is cleaved to generate O+ in ring
- Then add R’OH
Give examples of electrophilic thiophilic promotors
- Hg salts: HgSO4, HgCl2
- Triflate salts: AgOTf, MeOTf, TMSOTf, Cu(OTf)2
What is another way to activate the thioglycoside
- Oxidise to sulphoxide with mCPBA
- Treat with triflic anhydride or TMS triflate to further activate
- Add aglycone to get glycoside
What is advantage of thioglycoside method
- Starting material is stable and protected
- Needs to be activated
What is iterative synthesis
- Start with 1 carbohydrate and add to it
What is chemoselective glycosylation
- Start with reactive thioglycoside and add less reactive ones on
- Starting material is all protected except for one OH
- Only activate more reactive thioglycoside - form glycosidic bond between C1 of more reactive and whichever contains free OH of less reactive
- Carries on
- Last one added has no SR group - terminal glycloside
What are disadvantages of chemoselective glycosylation
- Need to determine which thioglycoside is less reactive
- Time consuming and have to do prelim experiments
- Probably can’t get much longer than tetraglycoside
Describe orthogonal glycosylation
- Uses mixed linkers
- Start with C-F leaving group at C1 and add activator selective for F-
- React with thioglycoside then add activator selective for SR
- Then C-F one
- Then Thioglycoside etc
- Can keep going as long as correct protective sugars
- Better than chemoselective
What is another method of iterative glycosylation
- Pre-active the system- generate carbocation before addition to flask
- Depends how stable species is however
- Easy to get iterative glycosylation
- Don’t need to worry about selective activation
- But can get side reactions when it gets longer
What can methylation be used for with oligosaccharides
- Useful to help determine the structure of complex oligosaccharides
How do you methylate oligosaccharides
- Treat with MeI or dimethyl sulphate ((MeO)2SO2) to fully methylate all free OH groups (ones not involved in glycosidic bond)
- Break glycosidic bonds to give mixture of monosaccharides using 100 degrees, HCl/H2O
- Analyse by MS, NMR. Use other derivatisation methods to show location of glycosidic linkages
