Catalytic azide alkyne cycloaddition reactivity and application
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For more presentations and information visit http://www.pharmaxchange.info. CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION. PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY, VCU.

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CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION

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Catalytic azide alkyne cycloaddition reactivity and application

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CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION

PREET PAL SINGH SIDHU

GRADUATE STUDENT

DEPT.OF MEDICINAL CHEMISTRY

SCHOOL OF PHARMACY, VCU


Overview

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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


Introduction

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INTRODUCTION

  • Most suited reaction of CLICK CHEMISTRY

  • Selective reaction to form hetero-link.

Huisgen thermal 1,3-cycloaddition

∆H= -45 kcal/mol

CuAAC

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


Characteristic of cuaac

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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


Properties of reactants

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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.


Advantages of 1 2 3 triazole

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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


Mechanism

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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


Mechanism1

MECHANISM

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


Generation of cu i catalyst

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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).


Direct addition of cu i salt

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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.


Direct addition of cu i salt1

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DIRECT ADDITION OF Cu(I) SALT

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


Reduction of cu ii salt

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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.


Reduction of cu ii salt1

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REDUCTION OF Cu (II) SALT

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


Oxidation of cu metal

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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.


Oxidation of cu metal1

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OXIDATION OF Cu METAL

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


Comproportionation method

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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


Auxiliary ligands

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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.


Auxiliary ligand

AUXILIARY LIGAND

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Sulfonated bathophenanthroline

TBTA

Pybox


One pot multi step synthesis

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ONE POT MULTI-STEP SYNTHESIS

  • Overcome safety problem of low MW azide.

  • Azide is generated in-situ.


One pot multi step synthesis1

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ONE POT MULTI-STEP SYNTHESIS

Wang et al Tetrahedron Lett. 2005, 46, 2331


Microwave assisted cuaac

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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.


Microwave assisted cuaac1

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MICROWAVE-ASSISTED CuAAC


Reaction of sulfonyl azide

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REACTION OF SULFONYL AZIDE

  • Different product in different condition.

  • Amidine, Amide, Azetidin-2-imines and Triazole can be formed.


Reaction of sulfonyl azide1

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Amidine

Amide

Azetidinimine

Triazole

REACTION OF SULFONYL AZIDE


Reaction of sulfonyl azide2

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amine

REACTION OF SULFONYL AZIDE


When click chemistry fails

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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


Alkyne homocoupling

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ALKYNE HOMOCOUPLING

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


Cu i saturation

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Cu(I) SATURATION

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


Applications of cuaac

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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.


Synthesis of screening libraries

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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.


Synthesis of screening libraries1

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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.


Synthesis of screening libraries2

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SYNTHESIS OF SCREENING LIBRARIES

Wong et al ChemBioChem. 2003, 4, 1246


Synthesis of screening libraries3

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SYNTHESIS OF SCREENING LIBRARIES

4

1

1

2

3

4


Modification and biological profiling of natural products

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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.


Modification and biological profiling of natural products1

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MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS

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


Modification and biological profiling of natural products2

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MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS

11µg/ml

7µg/ml

13µg/ml

24µg/ml

10µg/ml


Synthesis of gylco conjugate

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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.


Synthesis of gylcoconjugate

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SYNTHESIS OF GYLCOCONJUGATE

Acetylene glycoside

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


Bioconjugation

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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.


Bioconjugation1

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BIOCONJUGATION

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


Synthesis of dendrimers

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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.


Synthesis of dendrimers1

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SYNTHESIS OF DENDRIMERS

Sharpless et al Chem. Commun. 2005, 5775


Conclusion

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CONCLUSION

  • Catalytic azide-alkynecycloaddition offers an alternate method for cycloaddition reactions


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