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CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION

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Presentation on theme: "CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION"— Presentation transcript:

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

2 OVERVIEW Introduction Mechanism Source of catalyst Auxiliary ligands
For more presentations and information visit OVERVIEW Introduction Mechanism Source of catalyst Auxiliary ligands One pot synthesis Microwave assisted CuAAC CuAAC of sulfonyl azide Potential problems Applications Conclusion

3 INTRODUCTION Most suited reaction of CLICK CHEMISTRY
For more presentations and information visit 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

4 CHARACTERISTIC OF CuAAC
For more presentations and information visit 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

5 PROPERTIES OF REACTANTS
For more presentations and information visit 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.

6 ADVANTAGES OF 1,2,3-TRIAZOLE
For more presentations and information visit ADVANTAGES OF 1,2,3-TRIAZOLE High chemical stability. Strong dipole moment ( D). Good hydrogen bond acceptor. An alternative for amide linkage. Sharpless et al. Drug Discov. Today, 2003, 8, 1128

7 MECHANISM Thermal cycloaddition occurs in concerted fashion
For more presentations and information visit 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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MECHANISM Maarseveen et al. Eur. J. Org. Chem. 2006, 1, 51

9 GENERATION OF Cu(I) CATALYST
For more presentations and information visit 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).

10 DIRECT ADDITION OF Cu(I) SALT
For more presentations and information visit 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.

11 DIRECT ADDITION OF Cu(I) SALT
For more presentations and information visit DIRECT ADDITION OF Cu(I) SALT Wong et al J. Am. Chem. Soc. 2002, 124, 14397

12 REDUCTION OF Cu (II) SALT
For more presentations and information visit 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.

13 REDUCTION OF Cu (II) SALT
For more presentations and information visit REDUCTION OF Cu (II) SALT Fokin et al Angew. Chem. Int. Ed. 2002, 41, 2596

14 OXIDATION OF Cu METAL Require more Cu and long reaction time.
For more presentations and information visit 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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OXIDATION OF Cu METAL Sharpless et al J. Am. Chem. Soc. 2005, 127, 210

16 COMPROPORTIONATION METHOD
For more presentations and information visit 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

17 AUXILIARY LIGANDS Examples: TBTA Sulfonated bathophenanthroline Pybox
For more presentations and information visit 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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AUXILIARY LIGAND Sulfonated bathophenanthroline TBTA AUXILIARY LIGAND Pybox

19 ONE POT MULTI-STEP SYNTHESIS
For more presentations and information visit ONE POT MULTI-STEP SYNTHESIS Overcome safety problem of low MW azide. Azide is generated in-situ.

20 ONE POT MULTI-STEP SYNTHESIS
For more presentations and information visit ONE POT MULTI-STEP SYNTHESIS Wang et al Tetrahedron Lett. 2005, 46, 2331

21 MICROWAVE-ASSISTED CuAAC
For more presentations and information visit 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.

22 MICROWAVE-ASSISTED CuAAC
For more presentations and information visit MICROWAVE-ASSISTED CuAAC

23 REACTION OF SULFONYL AZIDE
For more presentations and information visit REACTION OF SULFONYL AZIDE Different product in different condition. Amidine, Amide, Azetidin-2-imines and Triazole can be formed.

24 REACTION OF SULFONYL AZIDE
For more presentations and information visit REACTION OF SULFONYL AZIDE Amidine Amide Azetidinimine Triazole

25 REACTION OF SULFONYL AZIDE
For more presentations and information visit REACTION OF SULFONYL AZIDE amine

26 WHEN CLICK CHEMISTRY FAILS
For more presentations and information visit 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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ALKYNE HOMOCOUPLING Diederich et al. Angew. Chem. Int. Ed. 2000, 39, 2632

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Cu(I) SATURATION Zhou et al. Org. Lett. 2005, 7, 1035

29 APPLICATIONS OF CuAAC Synthesis of small molecule screening libraries.
For more presentations and information visit APPLICATIONS OF CuAAC Synthesis of small molecule screening libraries. Synthesis of glycoconjugate. Modification and biological profiling of natural products. Bioconjugation. Synthesis of functional dendrimers.

30 SYNTHESIS OF SCREENING LIBRARIES
For more presentations and information visit 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.

31 SYNTHESIS OF SCREENING LIBRARIES
For more presentations and information visit 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.

32 SYNTHESIS OF SCREENING LIBRARIES
For more presentations and information visit SYNTHESIS OF SCREENING LIBRARIES Wong et al ChemBioChem. 2003, 4, 1246

33 SYNTHESIS OF SCREENING LIBRARIES
For more presentations and information visit SYNTHESIS OF SCREENING LIBRARIES 1 4 1 Enzyme IC50 [nM] Ki [nM] HIV PR 6±0.5 1.7±0.1 13±0.5 4±0.5 V82F 19±1 10±0.5 24±1 G48V 39±1 22±1 17±1 9.7±0.5 V82A 46±2 27±1 52±2 30±1 2 3 4

34 MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS
For more presentations and information visit 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.

35 MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS
For more presentations and information visit MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS Zhang et al Org. Lett. 2005, 7, 1513

36 MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS
For more presentations and information visit MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS 11µg/ml 7µg/ml 13µg/ml 24µg/ml 10µg/ml

37 SYNTHESIS OF GYLCO-CONJUGATE
For more presentations and information visit 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.

38 SYNTHESIS OF GYLCOCONJUGATE
For more presentations and information visit SYNTHESIS OF GYLCOCONJUGATE Acetylene glycoside Groothuys et al, Org. Lett. 2004, 6, 3123

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

41 SYNTHESIS OF DENDRIMERS
For more presentations and information visit SYNTHESIS OF DENDRIMERS Highly ordered, regularly branched, globular macromolecule. Ideal for creating bioactive nanomaterials and for sensor application. Currently 3rd generation are synthesized.

42 SYNTHESIS OF DENDRIMERS
For more presentations and information visit SYNTHESIS OF DENDRIMERS Sharpless et al Chem. Commun. 2005, 5775

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


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