![Page 1: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/1.jpg)
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
![Page 2: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/2.jpg)
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
![Page 3: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/3.jpg)
![Page 4: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/4.jpg)
Some Common Aldoses (Eukaryotes)
CHO
OHH
HHO
OHH
OHH
CH2OH
OHH
HHO
OHH
H
CH2OH
H OH
O
cis-alpha
trans-beta
![Page 5: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/5.jpg)
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.
![Page 6: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/6.jpg)
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
![Page 7: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/7.jpg)
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
![Page 8: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/8.jpg)
Glycoside Bond Formation
Glucoside
Donor
Glycone
Acceptor
Aglycone
![Page 9: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/9.jpg)
Glycoside Bond Formation
![Page 10: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/10.jpg)
Glycoside Bond Formation
![Page 11: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/11.jpg)
Glycoside Bond Formation
Synthesis of 2-deoxy glycosides
Glycals:
![Page 12: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/12.jpg)
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
![Page 13: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/13.jpg)
Glycoside Bond Formation
“Easy” glycosylation events: 1,2-trans glycosides
Neighboring group participation: Stereospecific reaction
![Page 14: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/14.jpg)
Glycoside Bond Formation
“Easy” glycosylation events: 1,2-trans glycosides
b-glucosides:
a-mannosides:
PFP = pentafluoropropionyl
![Page 15: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/15.jpg)
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
Non-participating group: Stereoselective reaction
![Page 16: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/16.jpg)
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
a-glucosides:
![Page 17: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/17.jpg)
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
a-glucosides:
![Page 18: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/18.jpg)
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
b-mannosides:
![Page 19: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/19.jpg)
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
b-mannosides:
![Page 20: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/20.jpg)
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
Intramolecular Aglycone Delivery (IAD):
![Page 21: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/21.jpg)
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
Intramolecular glycosylation: a-glucosides
![Page 22: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/22.jpg)
Glycoside Bond Formation
“Difficult” glycosylation events: 1,2-cis glycosides
Intramolecular glycosylation: b-mannosides
![Page 23: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/23.jpg)
Glycoside Bond Formation
“Other” saccharides: 2-deoxy-2-acetamidoglycopyranosides
Oxazoline method: b-2-acetamidoglucosides
Phthalimide group can also be used
![Page 24: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/24.jpg)
Glycoside Bond Formation
“Other” saccharides: 2-deoxy-2-acetamidoglycopyranosides:
Oxazoline method: b-2-acetamidoglucosides
![Page 25: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/25.jpg)
Glycoside Bond Formation
“Other” saccharides: 2-deoxy-2-acetamidoglycopyranosides:
Azide: a-galactosides
![Page 26: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/26.jpg)
Glycoside Bond Formation
“Other” saccharides: Sialic acids
![Page 27: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/27.jpg)
Chemical Synthesis of Glycans
![Page 28: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/28.jpg)
Chemical Synthesis of Glycans
![Page 29: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/29.jpg)
Chemical Synthesis of Glycans
![Page 30: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/30.jpg)
Chemical Synthesis of GlycansSolid Phase Synthesis: Automation
![Page 31: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/31.jpg)
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
![Page 32: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/32.jpg)
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
![Page 33: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/33.jpg)
Incorporation of Azido Tagged N-Acetylgalactosamineonto Cell Surfaces
Taken from Waldmann and Jannin, Chemical Biology, Learning through Case Studies.
![Page 34: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/34.jpg)
Incorporation of Azido Tagged Sialosides onto CellSurfaces
Taken from Waldmann and Jannin, Chemical Biology, Learning through Case Studies.
![Page 35: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/35.jpg)
Taken from Kiessling & Splain Ann. Rev. Biochem. 2010, 79, 619-653.
![Page 36: Carbohydrates in Nature: Structure and Synthesis · Carbohydrates in Nature: Structure and Synthesis • Structure and Nomenclature • Eukaryotes: glycans, glycoproteins, glycolipids](https://reader033.vdocument.in/reader033/viewer/2022051511/600a6ce6621cab29667568ea/html5/thumbnails/36.jpg)
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