sugar chemistry & glycobiology
DESCRIPTION
Sugar Chemistry & Glycobiology. In Solomons, ch.22 (pp 1073-1084, 1095-1100) Sugars are poly-hydroxy aldehydes or ketones Examples of simple sugars that may have existed in the pre-biotic world:. Most sugars, e.g. glyceraldehyde, are chiral : sp 3 hybridized C with 4 different substituents - PowerPoint PPT PresentationTRANSCRIPT
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Sugar Chemistry & Glycobiology
• In Solomons, ch.22 (pp 1073-1084, 1095-1100)• Sugars are poly-hydroxy aldehydes or ketones• Examples of simple sugars that may have existed in the
pre-biotic world:
OHH
CH2OH
OHOH
O
OHCH2OH
OH
glyceraldehyde (chiral)
dihydroxyacetone(achiral)
Aldose KetoseAldose
glycolaldehyde(achiral)
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• Most sugars, e.g. glyceraldehyde, are chiral: sp3 hybridized C with 4 different substituents
The last structure is the Fischer projection:1) CHO at the top2) Carbon chain runs downward3) Bonds that are vertical point down from chiral centre4) Bonds that are horizontal point up5) H is not shown: line to LHS is not a methyl group
OH
OH
H
CHOCHO
OH
OHH
CHO
OH
OHH= =
(R)-glyceraldehyde
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• In (R) glyceraldehyde, H is to the left, OH to the right D
configuration; if OH is on the left, then it is L
• D/L does NOT correlate with R/S
• Most naturally occurring sugars are D, e.g. D-glucose
• (R)-glyceraldehyde is optically active: rotates plane
polarized light (def. of chirality)
• (R)-D-glyceraldehyde rotates clockwise, it is the (+)
enantiomer, and also d-, dextro-rotatory (rotates to the right-
dexter)
(R)-D-(+)-d-glyceraldehyde
& its enantiomer is: (S)-L-(-)-l-glyderaldehyde
(+)/d & (-)/l do NOT correlate with D/L or R/S
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• Glyceraldehyde is an aldo-triose (3 carbons)• Tetroses → 4 C’s – have 2 chiral centres
4 stereoisomers:
D/L erythrose – pair of enantiomers
D/L threose - pair of enantiomers• Erythrose & threose are diastereomers: stereoisomers that
are NOT enantiomers• D-threose & D-erythrose:
• D refers to the chiral centre furthest down the chain (penultimate carbon)
• Both are (-) even though glyceraldehyde is (+) → they differ in stereochemistry at top chiral centre
• Pentoses – D-ribose in DNA• Hexoses – D-glucose (most common sugar)
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Reactions of Sugars1) The aldehyde group:
a) Aldehydes can be oxidized
“reducing sugars” – those that have a free aldehyde (most aldehydes) give a positive Tollen’s test (silver mirror)
b) Aldehydes can be reduced
OH OOH
Ag(I) Ag(0)
NH3
Aldose Aldonic acid
OH OHHNaBH4 An alditol
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Biological Redox of Sugars:
OH
OH
OH
OOH
OH
OH
OH
OH
OH
Glyceraldehyde Glycerate
NAD+
NAD(P)H
Aldosereductase
Glyceraldehydedehydrogenase
NAD+
NAD(P)H
Glycerol
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c) Reaction with a Nucleophile
• Combination of these ideas Killiani-Fischer synthesis: used by Fischer to correlate D/L-glyceraldehyde with threose/erythrose configurations:
OH OHMeMgBr
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OH
OH OH
OH
CN
OH
OH
CN
OH
OH
CO2H
OH
OH
CO2H
OH
OH
CHO
OH
OH
CHO
-CN +
cyanohydrins(stereoisomers)
H3O+
+
aldonic acids
NaBH4
+
pair of homologousaldoses
Nu, (recallfrom base synthesis)
nitrile hydrolysis
(reduce)
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Reactions (of aldehydes) with Internal Nucleophiles
• Glucose forms 6-membered ring b/c all substituents are equatorial, thus avoiding 1,3-diaxial interactions
O
OHOH
OH
OH
OH
OH
OHOH
OH
O
OHH
O
OH
OH
OH
OH
OH
CH2OH D-glucose
H+
a "hemiacetal"D-glucopyranose
Derivative of pyran
1
2
3
4
5
6
12
3
45
6
=
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• Can also get furanoses, e.g., ribose:
O
H
OHOH
OHOH
OOH
OHOH
OH
O
ribofuranose
like furan
• Ribose prefers 5-membered ring (as opposed to 6) otherwise there would be an axial OH in the 6-membered ring
OOH
OHOH
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Why do we get cyclic acetals of sugars? (Glucose in open form is << 1%)
a) Rearrangement reaction: we exchange a C=O bond for a stronger C-O σ bond ΔH is favored
b) There is little ring strain in 5- or 6- membered rings
c) ΔS: there is some loss of rotational entropy in making a ring, but less than in an intermolecular reaction:1 in, 1 out.
H
O
H
MeO OMe
+ 2 MeOH+ H2O
3 molecules in 2 molecules out
** significant –ve ΔS! ΔG = ΔH - TΔS
Favored for hemiacetal
Not too bad for cyclic acetal
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Anomers
• Generate a new chiral centre during hemiacetal formation (see overhead)
• These are called ANOMERS– β-OH up (technically, cis to the CH2OH group)– α-OH down (technically, trans to the CH2OH group)– Stereoisomers at C1 diastereomers
• α- and β- anomers of glucose can be crystallized in both pure forms
• In solution, MUTAROTATION occurs
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O
OHOH
OH
OH
OH
OH
OHOH
OH
O
OHH
OH
OHOH
OH
OOH
HO
OHOH
OH
OHOH
-D-glucopyranose (19o)
-D-glucopyranose (112o)
Mutarotation
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In solution, with acid present (catalytic), get MUTAROTATION: not via the aldehyde, but oxonium ion
OOH
O+ O
OHH+
H2O
oxonium ion
• At equilibrium, ~ 38:62 α:β despite α having an AXIAL OH…WHY? ANOMERIC EFFECT
+112o ()[]D
+19o ()
+52.7o
at equilibrium
time
MUTAROTATION
We know which mechanism operates because the isotope oxygen-18 is incorporated from H2
18O
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O
OH
O+
-OH
O lone pair is antiperiplanar to C-O σ bond GOOD orbital overlap and hence stabilized by resonance form (not the case with the β-anomer)
oxonium ion
Anomeric Effect
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ProjectionsOH
OH
OH
OH
OH
CH2OH
OH
H
OH
OH
OH
CH2OH
O
OHO
H
OH
OH
OH
OH
O
OH
OH
OH
OH
OH
OH
1
2
3
4
5
6
turn on side
1
2
3
4
5
6
conventional Fischer
123
4
5
6
Haworth
O OH
OHOH
OH
Haworth of ribose
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More Reactions of Sugars
1) Reactions of OH group(s):a) Esterification:
b) Ethers:
O
OHOH
OH
OH
OH
O
OO
O
AcOAcO
OAc
O
AcO
Oacetic anhydride:
reactive acid derivative penta-O-acetyl--D-glucopyranose
BrPhR-OH +SN2
R-Ph
Benzyl ethers
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b) Ethers (con’t)
O OH
OHOH
OHO OH
OHOH
TrOPh3CBr
SN1
via stablecarbocation
(cf malachitegreen)
Tr = trityl = **SELECTIVE: steric hinderance only 1o reacts
c) Acetals
O OH
OHOH
TrOO
O OH
OO
TrO
H+
(eg. TsOH)
Acetonide: best for 5 - membered rings requires cis OH groups
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c) Acetals (con’t)
O
OH
OH
OH
OH
OMe
O
HPh O
O
OH
OH
O
OMe
H
Ph
OO O
R1
R2
TsOH
Benzaldehyde: prefers 6-membered ring the 2 OH's can be cis or trans (provided they are diequatorial)
WHY?
Me2CO: requires R2 (Me) to be axial in 6- membered ring
PhCHO: can have R1 = H & Ph can be equatorial * new stereocentre
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These reactions are used for selective protection of one alcohol & activation of another (protecting group chemistry)
O T
OH
TrOO T
OH
OH
O T
O
TrO
SO
O
O T
OH
TrO
O T
OMs
TrON N
+N O T
TrO
N3
O TOH
N3
TrCl
CH3SO2Clactivate 2o alcohol
H2O
inverts stereochemistryat C3
MeSO2Cl reactivate
SN2
HCl
remove Tr
1° alcohol is most reactive protect first
AZT
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e.g, synthesis of sucrose (Lemieux, Alberta)
O
PGOPGO
OPG
OH
PGOO
OPG
OPGOH OPG
PGO
Activate anomericcentre as oxoniumion
• Can only couple one way—if we don’t protect, get all different coupling patterns– YET nature does this all of the time: enzymes hold molecules
together in the correct orientation• Mechanism still goes through an oxonium ion (more on this
later)
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Selectivity of Anomer Formation in Glycosides
• Oxonium ion can often be attacked from both Re & Si faces to give a mixture of anomers.
• How do we control this?
O+ Si face
Re face
OOH
OHOH
OH
OHO
AcOAcO
AcO
OAc
AcO
OAcO
AcOAcO
AcO
Br
Ac2O
(Cf Exp 2)
HBr/AcOH
-bromide
-anomer is favoreddue to strongly e- withdrawing Br
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OAcO
AcOAcO
AcO
Br
O+
AcOAcO
O
AcO
O
OAcO
AcO
AcO
O O
OAcO
AcOAcO
AcO
OMe
MeOH
Ag2CO3
+
cis-fused dioxolenium ion---must be axial!
MeOH
-glycoside selectively
This reaction provides a clue to how an enzyme might stabilize an oxonium ion (see later)
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Examples of Naturally Occurring di- & oligo- Saccharides
Maltose:
2 units of glucose a β sugar α glycoside1,4-linkage
O
OHOH
OH
OH
OO
OH
OHOH
OHLactose (milk):
galactose + glucose a β sugar β glycoside1,4-linkage
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Sucrose (sugar):
glucose + fructofuranose a β sugar α glycoside
1,2-glycosidic bond
O
OH
OH
CH2OH
CH2OH
O
OOH
OHOH
OH
Amylopectin (blood cells):
an oligosaccharide
α-1,6-glycosidic bond
α-1,4-glycosidic bond