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Home , Glycoside

in Nature: Structure and Synthesis

• Structure and Nomenclature

• Eukaryotes: , , & other

• Advantages of chemical synthesis of • Glycans found in microbes: deoxy & novel structures

• Bond Formation: Some “easy”, some difficult

• Examples of chemical synthesis of glycans

• Chemical glycobiology Glycans Derived from

Represtentations of D- HO OH O OH OH O HO HO OH OH HO OH HO OH OH 6 4 6 5 O 1 5 OH O 4 2 HO 3 2 OH OH HO H 3 OH 1 OH

!-pyranose "-furanose

Some Common Aldoses (Eukaryotes)

CHO H OH H OH HO H H OH cis-alpha HO H O H OH trans-beta H OH H OH H CH2OH CH2OH Glycoside Bonds Lead to Oligo- and

OH OH HO condensation HO OH OH O O non-reducing end reducing end OH HO OH - H2O O O OH HO HO HO O OH OH + H O HO 2 OH OH !-D-Galactose (Gal) !-D-Glucose (Glc) !-D-galactopyranosyl-(1"4)-!-D-glucopyranose Lactose

Eukaryotic biosynthesis abd cell-surface recognition of glycans. Taken from Kiessling & Splain Ann. Rev. Biochem. 2010, 79, 619-653. Roles of Oligosaccharides in Recognition & Adhesion

OH HO OH O HO OH NH O HO O HO O X O O OH O R O OH HN OH O Me OH R = H or R = Me X = NHAc Blood Group A X = OH Blood Group B Tumor Associated Antigen

(a) Glycoproteins or glycolipids on outer surface of plasma membrane; (b) Viruses effect cells, like influenza, bind to glycoproteins; (c) Bacterial toxins like cholera bind to glycolipids; (d) Some bacteria adhere and colonize; (e) Lectins recruit T lymphocyte at a site of inflamation/infection.

Taken from Nelson & Cox, Lehninger Principles of , 3rd ed., 2000 Oligosaccharides as Components Microbial Metabolites

HO OH O Me HO OH O NH2 O Me OMe OH HO Me Me NMe2 O OHO O OH HO HO O O O O O Me Cl HO O O O O OH O OH OH OH O O O OMe HO Cl HO Me H O Me Me O H H Me O O N N N O HOO O OH O NH HO O N NHMe Me Me H H NH O H O erythromycin A O H HO mithramcycin H O NH HOOC 2 OH vancomycin Me Me OH OMe O HO O Me HO Cl O O O O O Me HO O OMe HO Me O HO OMe O O Me Cl O HO O O Me O OH O Me O OH OH NO2 O Me O O O Me Me Me HO O HO HO OH O OMe O OH OH Me HO OMe Me O O MeO OH CH3 O OH O OH H O OH O HO O MeO O O Me O O hibarimicin B O O OH OH O O O Me O O OMe OMe

everninomycin Glycoside Bond Formation

Donor Acceptor Glycone Aglycone Glycoside Bond Formation Glycoside Bond Formation Glycoside Bond Formation

Glycals:

Synthesis of 2-deoxy Glycoside Bond Formation

Factors influencing course of reaction:  Nature of the donor  Activator  Leaving group  Solvent  Protecting groups  Nature of the acceptor

“Each 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 Glycoside Bond Formation

“Easy” events: 1,2-trans glycosides Neighboring group participation: Stereospecific reaction Glycoside Bond Formation

“Easy” glycosylation events: 1,2-trans glycosides

b-:

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- Glycoside Bond Formation

“Other” saccharides: Sialic Chemical Synthesis of Glycans Chemical Synthesis of Glycans Chemical Synthesis of Glycans Chemical Synthesis of Glycans

Solid Phase Synthesis: Automation Advantage and Need of Chemical Approaches 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 -processing

• Genomic sequencing provides no structural information on glycans as biosynthesis is not template directed

• Defined oligosaccharides and glycoconjugates are critical for unraveling the structure and function of glycans.

• Examples of chemical approaches to glycobiology: glycan arrays, perturbation of protein-glycan recognition and development of -based .

• Bioorthogonal ligation reactions for imaging cell-suface glycans Introduction of Chemical Reporter Groups by Bioorthogonal Ligation Reactions for Imaging of Cell- Surface Glycans

• Unlike protein and nucleic biosynthesis, oligosaccharide synthesis is not template driven or under transcriptional control but assembled step by step in the endoplasmatic reticulum and Golgi apparatus

• Microheterogenity complicates analysis of structure and biological properties • To be defined: relationship between cellular glycosylation and diseases. For example cancer cell surface proteins incorporate highly branched and sialylated oligosaccharides

• Labeling and visualization of cell-surfaces require bioorthogonal ligation methods

• Bertozzi and co-workers have developed a Staudinger ligation and applied Huisgen cycloaddition to label cell surfaces Incorporation of Azido Tagged N-Acetylgalactosamine onto Cell Surfaces

Taken from Waldmann and Jannin, Chemical Biology, Learning through Case Studies. Incorporation of Azido Tagged Sialosides onto Cell Surfaces

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 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