How is a hemiacetal formed
- Protonated aldehyde + alcohol
- Intramolecular cyclisation
What is observed for orientation of substituted Me, OR, OMe, OAc, Cl at anomeric carbon
- A preference for alkoxy (OR) and acetyl groups to reside in the axial position was noticed
- Alkyl substituted cyclohexanes prefer equatorial orientation over axial
- Alkyl substituted tetrahydropyrans show this same preferences
- D-glucopyranose shows preferences for an equatorial orientation but surprising amount is axial
- If OH is converted to OMe at the anomeric carbon however it then shows preference for the axial
- Substitution with more electronegative groups (OAc/Cl) change the observed ratio to a greater extent - anomeric effect
What is responsible for the anomeric effect
- Hyperconjugation stabilises axial conformation
- Bond between anomeric carbon and O in the ring is shorter than expected as some C=O bond character
- Lone pair of O in ring donates into empty antibonding orbital of OR bond causing bond to elongate
- Only in axial, not right orientation when in equatorial (beta) position
Why are protecting groups needed for sugars
- Only functional group on a sugar are -OH groups
- There are 3 different hydroxyl environments with different steric accessibility- primary, secondary and anomeric alcohol
- Needs to selectively activate and protect alcohols
- In glucose all secondary alcohols are equivalent (either all axial or equatorial)
- The anomeric position determines if alpha or beta sugar
What is used to protect the anomeric alcohol and how is it added
- Methyl protecting group
- MeOH added with HCl
- Goes to alpha position- axial
How is the anomeric alcohol deprotected
- H+, H2O
- Acidic so can’t do acidic chemistry unless you want PG to be removed
- Easy to take off and put on- mild conditions
Describe features of protecting the C6 -OH group
- Primary alcohol so more sterically available and nucleophilic
- Mono-protection possible
- Big bulky groups
What can be used to protect the C6 -OH group
- Trityl (triphenylmethyl) PG
- Tosylate
- Silyl ether
Describe Trityl (triphenylmethyl) as a PG for the C6 -OH group
- Added using trityl chloride -(Ph)3CCl and a weak base (Et3N) in an SN1 type reaction-
- Weak base is used to mop up H+ once trityl has attached not other way round
- Typically remove with weak acid (HCl, TsOH, BF3)
- But can be tricky to remove in practice
- Then Methoxytrityl ethers are used instead - make more acid labile so easier to remove
Describe how tosylate can be used as a protecting group for C6 -OH and how it can be used to selectively carry out a reaction on C6 -OH
- Add TsCl + base e.g Et3N to mop up H+
- Can then Add Ac2O to acetylate all the other -OH
- Then could use NaI + acetone to replace tosylated C6 with I -SN2
- Good way of only carrying out reaction on C6 -OH
Describe how silyl ether can be used as a protecting group
- R3SiX with tertiary amines
- E.g t-BuMe2SiCl and pyridine
- Very stable protecting group
- Removal with TBAF, BF3KF, Pyridine-HF- Unusual removal is good as doesn’t interact with other chemistry
What can be used to protect every OH in a sugar
- Acyl or benzoyl
- Add Ac2O and pyridine
- Protects every OH
- Removed using NaOMe in MeOH
What can be added to a sugar with al OHs protected with AcO group to change just the anomeric OH
- HBr- Change to Br
- BnNH2 - change to OH
- H2NNH2-HOAc- change to OH
- S-nucleophile - Change to SH
What is the neighbouring group effect
- Stereochemical outcome of glycosylation reactions may be affected by type of protecting group at position 2 of glycosyl donor
Give example of neighbouring group effect
- A participating group e.g. carboxyl group present –> Beta- glycoside
- Anomeric carbon reacts with Position 2 =O protecting bottom face
- Therefore HO-R comes in from top face- Beta-glycoside
What position of a glycoside is favoured if there are no participating groups at position 2
- Prefers to attack at bottom face and produce alpha-glycoside due to anomeric effect
Describe difference in cyclohexane and tetrahydropyran in equatorial bs axial
- In cyclohexane ring sterics dominates and the equatorial position dominates
- In tetrahydropyran ring a heteroatom stabilises the axial position via hyperconjugation
What can be used to prevent the neighbouring effect
- Benzyl protecting group
- No stabilisation by neighbouring group coordination so get favoured axial alpha-glycoside product
What are good methods for protecting 1,2 and 1,3 diols
- Cyclic acetal formation
- Acetone/H+
- Benzaldehyde/H+
- Can be used in regioselective protection of polyol compounds
What size rings do acetyl and benzaldehyde prefer to form
- Dimethyl (acetone) derived acetals tend to form 5 membered rings - kinetically favourable
- benzylidene (benzaldehyde) derived acetals tend to form 6 membered rings -thermodynamically favourable
What is best for protection of 1,3 diols
- Benzaldehyde to form benzylidene
Describe Benzaldehyde as a protecting group
- Prefers to give 6-membered ring with Ph group equatorial
- To add use an acid catalyst e.g. TsOH, PPTS or ZnCL2
- Stable to basic conditions
- Mild acid for removal or H2, Pd/C
What can the 1,3-diol intermediate formed with benzaldehyde be used for
- A range of selectively protected carbohydrate derivatives
What is the best method for protecting 1,2 diols
- Isopropylidene- reaction with acetone
- Add acid e.g H2SO4
- Steric hindrance gives the furanose form
- Cyclic hemiacetal ring adopted by a given ring structure is not constant
