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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

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