Transcript Slide 1

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:
OH
H
H
O
H
OH
O
CH2OH
CH2OH
O
OH
glycolaldehyde
(achiral)
glyceraldehyde
(chiral)
dihydroxyacetone
(achiral)
Aldose
Aldose
Ketose
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•
Most sugars, e.g. glyceraldehyde, are chiral: sp3
hybridized C with 4 different substituents
HO
CHO
CHO
=
H
OH
H
OH
OH
CHO
=
H
OH
OH
(R)-glyceraldehyde
The last structure is the Fischer projection:
1) CHO at the top
2) Carbon chain runs downward
3) Bonds that are vertical point down from chiral centre
4) Bonds that are horizontal point up
5) H is not shown: line to LHS is not a methyl group
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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 rightdexter)
 (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 Sugars
1)
The aldehyde group:
a)
Aldehydes can be oxidized
Ag(0)
Ag(I)
H
NH3
O
O
HO
Aldose
Aldonic acid
“reducing sugars” – those that have a free aldehyde (most aldehydes)
give a positive Tollen’s test (silver mirror)
b)
Aldehydes can be reduced
H
H
O
NaBH4
OH
An alditol
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Biological Redox of Sugars:
Glyceraldehyde
dehydrogenase
Aldose
reductase
OH
H
O
NAD+
NAD+
OH
OH
Glycerol
OH
NAD(P)H
OH
Glyceraldehyde
NAD(P)H
HO
O
OH
OH
Glycerate
c)
Reaction with a Nucleophile
H
OH
O
MeMgBr
•
Combination of these ideas  Killiani-Fischer
synthesis: used by Fischer to correlate D/Lglyceraldehyde with threose/erythrose configurations:
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CN
CN
H
O
OH
-CN
HO
+
OH
OH
OH
Nu, (recall
from base synthesis)
cyanohydrins
(stereoisomers)
H3O+ nitrile hydrolysis
OH
+
HO
OH
pair of homologous
aldoses
CO2H
CO2H
CHO
CHO
NaBH4
OH (reduce)
OH
+
HO
OH
OH
aldonic acids
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Reactions (of aldehydes) with Internal Nucleophiles
O
H
1
2
HO
4
OH
5
OH
CH2OH
6
6
=
3
H+
OH
OH
OH
5
4
HO
HO
O
2
3
HO
1
H
D-glucose
OH
O
HO
HO
OH
HO
a "hemiacetal"
D-glucopyranose
Derivative of pyran
O
• Glucose forms 6-membered ring b/c all substituents are
equatorial, thus avoiding 1,3-diaxial interactions
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• Can also get furanoses, e.g., ribose:
OH
HO
O
O
OH
HO
H
HO
OH
HO
OH
ribofuranose
O
like furan
• Ribose prefers 5-membered ring (as opposed to 6)
otherwise there would be an axial OH in the 6-membered ring
O
OH
OH
OH
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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.
O
MeO
H
+
2 MeOH
+
H2O
H
2 molecules out
3 molecules in
** significant –ve ΔS!
OMe
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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Mutarotation
OH
OH
O
HO
HO
OH
OH
HO
HO
HO
O
HO
H
-D-glucopyranose (19o)
OH
OH
O
HO
HO
OH
HO
HO
HO
OH
H
HO
O
-D-glucopyranose (112o)
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In solution, with acid present (catalytic), get
MUTAROTATION: not via the aldehyde, but oxonium ion
O
O
OH
+
H2O
O
H+

oxonium ion

OH
We know which mechanism operates because the isotope oxygen-18 is
incorporated from H218O
+112o ()
[]D
+52.7o
at equilibrium
time
MUTAROTATION
+19o ()
• At equilibrium, ~
38:62 α:β despite α
having an AXIAL
OH…WHY?
ANOMERIC EFFECT
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Anomeric Effect
+
O

O
-OH
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
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Projections
O
H
OH
1
H
OH
2
HO
O
1
OH
2
3
HO
4
OH
5
OH
HO
3
O
OH
OH
4
5
CH2OH
OH
CH2OH
6
OH
6
HO
4
OH
HO
6
5
H
O
OH
OH

OH
O
OH
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Haworth of ribose
conventional Fischer
turn on
side
1
2
OH
OH
OH

Haworth
OH
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More Reactions of Sugars
1)
Reactions of OH group(s):
a)
Esterification:
O
O
OAc
OH
HO
HO
O
O
O
AcO
AcO
OH
HO
AcO
O
acetic anhydride:
reactive acid derivative
b)
O
penta-O-acetyl--D-glucopyranose
Ethers:
SN2
R-OH
+
Ph
Br
R-Ph
Benzyl ethers
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b) Ethers (con’t)
HO
O
Ph3CBr
OH
TrO
O
OH
S N1
OH
via stable
carbocation
OH
OH
OH
(cf malachite
green)
**SELECTIVE: steric hinderance
only 1o reacts
Tr = trityl =
c) Acetals
O
TrO
O
TrO
OH
O
OH
H+
OH
OH
(eg. TsOH)
Acetonide: best for 5 - membered rings
requires cis OH groups
O
O
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c) Acetals (con’t)
HO
O
O
O
Ph
H
OH
TsOH
OMe
OH
OH
H
O
Ph
OH
OMe
O
OH
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 6membered ring
R1
R2
O
O
O
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)
HO
O
TrO
T
O
TrCl
OH
T
OH
1° alcohol is most
reactive protect
first
TrO
O
TrO
T
O
H2 O
OH
activate 2o
alcohol
CH3SO2Cl
inverts stereochemistry
at C3
O
T
O
S
O
reactivate
MeSO2Cl
AZT
TrO
O
T
+
TrO
O
N N N
OMs
SN2
N3
HO
T
O
T
HCl
remove Tr
N3
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e.g, synthesis of sucrose (Lemieux, Alberta)
OPG
OPG
OPG
OH
O
PGO
PGO
OPG
OH
PGO
O
PGO
Activate anomeric
centre as oxonium
ion
• 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.
+
Si face
O
Re face
• How do we control this?
HO
HO
HO
O
HO
Ac2O
OH
(Cf Exp 2)
AcO
AcO
AcO
O
OAc
AcO
HBr/AcOH
AcO
-anomer is favored
due to strongly ewithdrawing Br
AcO
AcO
O
AcO
Br
-bromide
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AcO
AcO
AcO
MeOH
O
AcO
Br
Ag2CO3
AcO
AcO
AcO
O
O
AcO
+
O
O
AcO
AcO
O
O
+
cis-fused dioxolenium ion--must be axial!
MeOH
AcO
AcO
AcO
O
OMe
AcO
-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- & oligoSaccharides
Maltose:
2 units of glucose
a β sugar
α glycoside
1,4-linkage
Lactose (milk):
galactose + glucose
a β sugar
β glycoside
1,4-linkage
OH OH
O
HO
OH
OH
O
HO
O
OH
OH
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HO
Sucrose (sugar):
glucose + fructofuranose
a β sugar
α glycoside
1,2-glycosidic bond
HO
HO
O
OH OH
O
CH2OH
OH
O
CH2OH
α-1,6-glycosidic bond
Amylopectin (blood cells):
an oligosaccharide
α-1,4-glycosidic bond
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