carbohydrates in nature: structure and synthesis · carbohydrates in nature: structure and...
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Carbohydrates in Nature: Structureand Synthesis
• Structure and Nomenclature• Eukaryotes: glycans, glycoproteins, glycolipids & other glycoconjugates• Advantages of chemical synthesis of oligosaccharides• Glycans found in microbes: deoxy sugars & novel structures• Glycoside Bond Formation: Some “easy”, some difficult• Examples of chemical synthesis of glycans• Chemical glycobiology
Glycans Derived from Monosaccharides
1
25
6
3
4O
HOHO
OH
OH
OH
OHHOH
OHO
HOOH
O
HO
OH
OH
OH
2
1
3
45
6
!-pyranose "-furanose
HO
O
HO
OHHO
OH
OH
Haworth projection
Represtentations of D-glucose
Some Common Aldoses (Eukaryotes)
CHO
OHH
HHO
OHH
OHH
CH2OH
OHH
HHO
OHH
H
CH2OH
H OH
O
cis-alpha
trans-beta
Glycoside Bonds Lead to Oligo- and PolysaccharidesO
OHHO
HOOH
OH
!-D-Galactose (Gal)
O
OH
HOHO
OH
OH
!-D-Glucose (Glc)
+ H2O
hydrolysis
condensation
- H2O O
OHHO
HOOH
O
OH
OHO
OH
OH
!-D-galactopyranosyl-(1"4)-!-D-glucopyranose
Lactose
reducing endnon-reducing end
Eukaryotic glycoprotein biosynthesis abd cell-surface recognition of glycans. Taken fromKiessling & Splain Ann. Rev. Biochem. 2010, 79, 619-653.
O
OHHO
HOX O
O
OHHO
O
O
O
OH
HO
OH
O
OMe OH
OH
OH
X = NHAc Blood Group AX = OH Blood Group B
R
NH
O
HN
R = H or R = Me
Roles of Oligosaccharides in Recognition & Adhesion
Taken from Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000
(a) Glycoproteins or glycolipidson outer surface of plasmamembrane; (b) Viruses effectanimal cells, like influenza, bindto glycoproteins; (c) Bacterialtoxins like cholera bind toglycolipids; (d) Some bacteriaadhere and colonize; (e) Lectinsrecruit T lymphocyte at a site ofinflamation/infection.
Tumor Associated Antigen
O
O
HO
OH
O
O
O
O
O
OMe
Me
OHMe
HONMe2
Me
O
Me
HO
HO O
OMe
OMe
OHOHOOHHO
O
HO
O
OO
HO
MeO
Me
Me
O
Me
OH
OHO
MeO
O
O OH OOH
O
OH
O
O O
OH
MeO
Me
Me
OHOH
O O
OCl
Cl
NH
O
HN
OH
OH
HO
O HN
NH
OHN
O
H
HOOC
NH
OH
NH2
OO
NHMe
H
OH
H
HO
OO
OOH
HO
HO
MeOH
NH2
Me
OH OH OO
OMe OH
OH
OO
OOMe
HOHO
MeHO
OO
O
MeHO
O
Me
HOOHOMe
Me
HO
O
hibarimicin B
erythromycin A
vancomycin
mithramcycin
O
O
O
O
O
O
Me
HO
Me
HO
Me
O
OOMe
Cl
MeHO
Cl
Me
O
OO
O
OMe
Me
HO
OH
OMe
MeO
O
O
OMe
O
O
O
O O
O
O
Me
OMe
NO2
Me
O
O
HO
CH3
OH
everninomycin
Oligosaccharides as Components Microbial Metabolites
Glycoside Bond Formation
Glucoside
Donor
Glycone
Acceptor
Aglycone
Glycoside Bond Formation
Glycoside Bond Formation
Glycoside Bond Formation
Synthesis of 2-deoxy glycosides
Glycals:
Glycoside Bond Formation
Factors influencing course of reaction:
“Each oligosaccharide synthesis remains an independent problem
which resolution requires considerable systematic research and a good
deal of know-how. There are no universal reaction conditions for
oligosaccharide synthesis.”- Hans Paulsen, 1982
Nature of the donor
Leaving group
Protecting groups
Activator
Solvent
Nature of the acceptor
Glycoside Bond Formation
“Easy” glycosylation events: 1,2-trans glycosides
Neighboring group participation: Stereospecific reaction
Glycoside Bond Formation
“Easy” glycosylation events: 1,2-trans glycosides
b-glucosides:
a-mannosides:
PFP = pentafluoropropionyl
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
Non-participating group: Stereoselective reaction
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
a-glucosides:
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
a-glucosides:
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
b-mannosides:
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
b-mannosides:
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
Intramolecular Aglycone Delivery (IAD):
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
Intramolecular glycosylation: a-glucosides
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
Intramolecular glycosylation: b-mannosides
Glycoside Bond Formation
“Other” saccharides: 2-deoxy-2-acetamidoglycopyranosides
Oxazoline method: b-2-acetamidoglucosides
Phthalimide group can also be used
Glycoside Bond Formation
“Other” saccharides: 2-deoxy-2-acetamidoglycopyranosides:
Oxazoline method: b-2-acetamidoglucosides
Glycoside Bond Formation
“Other” saccharides: 2-deoxy-2-acetamidoglycopyranosides:
Azide: a-galactosides
Glycoside Bond Formation
“Other” saccharides: Sialic acids
Chemical Synthesis of Glycans
Chemical Synthesis of Glycans
Chemical Synthesis of Glycans
Chemical Synthesis of GlycansSolid Phase Synthesis: Automation
Advantage and Need of ChemicalApproaches to Glycobiology• Polysaccharides are the most abundant organic compounds on Earth• Half of all proteins are glycosylated• Genomic sequencing indicates approximately 1% of each genome, from
eubacteria to archea and eukaryotes, is dedicated to sugar-processingenzymes
• Genomic sequencing provides no structural information on glycans asglycan biosynthesis is not template directed
• Defined oligosaccharides and glycoconjugates are critical for unravelingthe structure and function of glycans.
• Examples of chemical approaches to glycobiology: glycan arrays,perturbation of protein-glycan recognition and development ofcarbohydrate-based vaccines.
• Bioorthogonal ligation reactions for imaging cell-suface glycans
Introduction of Chemical Reporter Groups byBioorthogonal Ligation Reactions for Imaging of Cell-Surface Glycans
• Unlike protein and nucleic acid biosynthesis, oligosaccharide synthesis isnot template driven or under transcriptional control but assembled step bystep in the endoplasmatic reticulum and Golgi apparatus
• Microheterogenity complicates analysis of structure and biologicalproperties
• To be defined: relationship between cellular glycosylation and diseases.For example cancer cell surface proteins incorporate highly branched andsialylated oligosaccharides
• Labeling and visualization of cell-surfaces require bioorthogonal ligationmethods
• Bertozzi and co-workers have developed a Staudinger ligation and appliedHuisgen cycloaddition chemistry to label cell surfaces
Incorporation of Azido Tagged N-Acetylgalactosamineonto Cell Surfaces
Taken from Waldmann and Jannin, Chemical Biology, Learning through Case Studies.
Incorporation of Azido Tagged Sialosides onto CellSurfaces
Taken from Waldmann and Jannin, Chemical Biology, Learning through Case Studies.
Taken from Kiessling & Splain Ann. Rev. Biochem. 2010, 79, 619-653.
Conclusions
• Glycans are important molecules in biological systems• Chemical synthesis of glycans remains a significant challenge (esp.
glycosylation and characterization of large glycans)• Characterization (structural & bioactivity) of glycans remains important• Many opportunities for chemical synthesis in the general area of
glycobiology
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