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1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY, VCU For more presentations and information visit http://www.pharmaxch

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Page 1: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND

APPLICATION

PREET PAL SINGH SIDHUGRADUATE STUDENTDEPT.OF MEDICINAL CHEMISTRYSCHOOL OF PHARMACY, VCU

For more presentations and information visit http://www.pharmaxchange.info

Page 2: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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OVERVIEW

Introduction Mechanism Source of catalyst Auxiliary ligands One pot synthesis Microwave assisted CuAAC CuAAC of sulfonyl azide Potential problems Applications Conclusion

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Page 3: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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INTRODUCTION

Most suited reaction of CLICK CHEMISTRY Selective reaction to form hetero-link.

Sharpless et al. Angew. Chem. Int. Ed. 2001, 40, 2004

R2

+NN -N

R1

+N

NN

R2

1,4

Cu catalystrt, mins-hours

R1N

NN

R2

R12

3

45

1

R2

+NN -N

R1

+N

NNN

NN

R2R2

R1R1

1,4 1,5

+60-120 0C

Hours-days

Huisgen thermal 1,3-cycloaddition

CuAAC

∆H= -45 kcal/mol

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Page 4: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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CHARACTERISTIC OF CuAAC

Not affected by steric and electronic properties of functional groups.

Can be carried out in both water and organic solvents.

Rate is 107 faster than uncatalyzed. High regioselectivity. Minimal work-up and purification. Least affected by temperature and pH.

Fokin et al. Aldrichimica Acta, 2007,40,7

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Page 5: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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PROPERTIES OF REACTANTS

Alkyne and azide is reactive and selective. Organic azides are stable and safe to use. Low molecular wt azides are unsafe to use. Electron deficient azides gives poor yield. Electron rich alkynes are not reactive.

R2

+NN -N

R1

+N

NN

R2

1,4

Cu catalystrt, mins-hours

R1

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Page 6: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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ADVANTAGES OF 1,2,3-TRIAZOLE

High chemical stability. Strong dipole moment (5.2-5.6D). Good hydrogen bond acceptor. An alternative for amide linkage.

Sharpless et al. Drug Discov. Today, 2003, 8, 1128

NN

N1

R2

R12

3

45

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Page 7: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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MECHANISM

Thermal cycloaddition occurs in concerted fashion

CuAAC occurs in stepwise. Cu(I) species is required. Reaction is second order in copper. Lower the activation barrier by 11 kcal/mol

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Page 8: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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MECHANISM

Maarseveen et al. Eur. J. Org. Chem. 2006, 1, 51

R2 H+

LnCu [LnCu]2

CumLnR2 H B B-H

LnCu2 R2

R1-N3

R2

CuILLCuI

1N-R1

+N

N3

L L

CuI1N

R1

N

N

R2

N3N1NR1

R2LnCu2

B-H B

N3N1NR1

R2H

CuI

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Page 9: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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GENERATION OF Cu(I) CATALYST

Direct addition of Cu(I) salts. Reduction of Cu(II) salts. Oxidation of Cu metal. Comproportionation of Cu(0) and Cu(II).

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Page 10: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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DIRECT ADDITION OF Cu(I) SALT

Examples: CuI, CuBr, and coordination complexes like Cu(CH3CN)4PF6, (EtO)3P·CuI.

Thermodynamically unstable. Nitrogen type donors prevent degradation. Reliable catalyst in presence of base.

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Page 11: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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DIRECT ADDITION OF Cu(I) SALT

Wong et al J. Am. Chem. Soc. 2002, 124, 14397

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Page 12: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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REDUCTION OF Cu (II) SALT

Example: Cu sulfate pentahydrate, Cu acetate etc.

Sodium ascorbate is used as reductant. No inert atmosphere requirement. Economical. Thermodynamically stable. High yield and purity.

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Page 13: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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REDUCTION OF Cu (II) SALT

Fokin et al Angew. Chem. Int. Ed. 2002, 41, 2596

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Page 14: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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OXIDATION OF Cu METAL

Require more Cu and long reaction time. Cu(0) nanosize activated powder can be used. Amine hydrochloride salts are used for

oxidative dissolution. Acid sensitive group need to be protected. Seven times costly.

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Page 15: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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OXIDATION OF Cu METAL

Sharpless et al J. Am. Chem. Soc. 2005, 127, 210

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Page 16: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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COMPROPORTIONATION METHOD

By comproportionation of Cu(II) and Cu(0). Just a piece of copper wire is added. Requires longer time. Convenient for high throughput synthesis of

screening library.

Fokin et al Angew. Chem. Int. Ed. 2002, 41, 2596

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Page 17: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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AUXILIARY LIGANDS

Examples: TBTA Sulfonated bathophenanthroline Pybox Accelerate the rate of CuAAC. Sequester copper ions and hence prevent

damage to bio-molecules. Best suited for bioconjugation process.

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Page 18: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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AUXILIARY LIGAND

TBTA

Sulfonated bathophenanthroline

N N

NaO3S SO3Na

Pybox

N

NN

N

NN

N

N

N N

Ph

Ph

Ph

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Page 19: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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ONE POT MULTI-STEP SYNTHESIS

Overcome safety problem of low MW azide. Azide is generated in-situ.

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Page 20: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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ONE POT MULTI-STEP SYNTHESIS

Wang et al Tetrahedron Lett. 2005, 46, 2331

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Page 21: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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MICROWAVE-ASSISTED CuAAC

CuAAC requires no heating but microwave reduces the time of reaction.

Reduces the undesired side reaction. Reduces the catalyst loading. Reduces the time of one pot synthesis to 15

min.

R2N

NN1

R2

R1

1,4

NaN3 +R X +Cu(0), CuSO4

BuOH, MW, 10-15 MIN

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Page 22: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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MICROWAVE-ASSISTED CuAAC

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Page 23: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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REACTION OF SULFONYL AZIDE

Different product in different condition. Amidine, Amide, Azetidin-2-imines and

Triazole can be formed.

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Page 24: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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REACTION OF SULFONYL AZIDE

Amidine

Amide

Azetidinimine

Triazole

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Page 25: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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REACTION OF SULFONYL AZIDE

amine

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Page 26: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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WHEN CLICK CHEMISTRY FAILS

Binding problem for highly electron deficient azide.

Alkyne homocoupling. Cu(I) saturation by polyalkyne.

Diederich et al Angew. Chem. Int. Ed. 2000, 39, 2632

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Page 27: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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ALKYNE HOMOCOUPLING

Diederich et al. Angew. Chem. Int. Ed. 2000, 39, 2632

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Page 28: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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Cu(I) SATURATION

Zhou et al. Org. Lett. 2005, 7, 1035

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Page 29: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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APPLICATIONS OF CuAAC

Synthesis of small molecule screening libraries.

Synthesis of glycoconjugate. Modification and biological profiling of

natural products. Bioconjugation. Synthesis of functional dendrimers.

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Page 30: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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SYNTHESIS OF SCREENING LIBRARIES

CuAAC is the ideal reaction for:

Synthesis of library for initial screening.

Structure-activity profiling.

What makes it ideal?

Works well in most of the solvents.

Doesn’t require inert atmosphere.

Results in cleaner isolated product.

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Page 31: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

SYNTHESIS OF SCREENING LIBRARIES

a) NaN3, EtOH/H20 60 °C, 2 h; b) 4 N HCl/dioxane; c) (S)-3-tetrahydrofuranyl N-oxysuccinimidyl carbonate, Et3N; d) i-BuNH2, MeOH; e) p-methoxybenzenesulfonyl chloride, K2CO3, CH3CN, 3 h; f) 4 N HCl/dioxane; g) TfN3, H2O/CH2Cl2/MeOH, RT.

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Page 32: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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SYNTHESIS OF SCREENING LIBRARIES

Wong et al ChemBioChem. 2003, 4, 1246

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Page 33: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

SYNTHESIS OF SCREENING LIBRARIES

HIV PR 6±0.5 1.7±0.1 13±0.5 4±0.5

V82F 19±1 10±0.5 24±1 13±0.5

G48V 39±1 22±1 17±1 9.7±0.5

V82A 46±2 27±1 52±2 30±1

Enzyme IC50 [nM] Ki [nM] IC50 [nM] Ki [nM]

11

2

3

4

4

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Page 34: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS

Many bioactive natural products have narrow therapeutic window.

Modification is viable approach to improve therapeutic index.

CuAAC is ideal reaction for last step derivatization of complex bioactive molecule.

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Page 35: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS

Zhang et al Org. Lett. 2005, 7, 1513

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Page 36: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS

11µg/ml

7µg/ml 13µg/ml

24µg/ml

10µg/ml

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Page 37: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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SYNTHESIS OF GYLCO-CONJUGATE

Act as a mediator of complex cellular events such as adhesion inflammation,etc.

N- or O- glycosidic linkage are sensitive to hydrolysis.

Alternative is stable and isosteric triazole linkage by CuAAC.

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Page 38: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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SYNTHESIS OF GYLCOCONJUGATE

Groothuys et al, Org. Lett. 2004, 6, 3123

Acetylene glycoside

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Page 39: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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BIOCONJUGATION

For investigation of protein structure and function in vivo.

Unnatural amino acid are incorporated into proteome which allow tracking of proteome dynamic to external stimuli.

Complement to gene labeling approach.

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Page 40: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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BIOCONJUGATION

Wang et al Org. Lett. 2004, 6, 4603

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Page 41: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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SYNTHESIS OF DENDRIMERS

Highly ordered, regularly branched, globular macromolecule.

Ideal for creating bioactive nanomaterials and for sensor application.

Currently 3rd generation are synthesized.

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Page 42: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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SYNTHESIS OF DENDRIMERS

Sharpless et al Chem. Commun. 2005, 5775

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Page 43: 1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,

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CONCLUSION

Catalytic azide-alkyne cycloaddition offers an alternate method for cycloaddition reactions

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