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CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION

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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  1. 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

  2. For more presentations and information visit http://www.pharmaxchange.info OVERVIEW • Introduction • Mechanism • Source of catalyst • Auxiliary ligands • One pot synthesis • Microwave assisted CuAAC • CuAAC of sulfonyl azide • Potential problems • Applications • Conclusion

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

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

  8. MECHANISM For more presentations and information visit http://www.pharmaxchange.info Maarseveen et al. Eur. J. Org. Chem. 2006, 1, 51

  9. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info DIRECT ADDITION OF Cu(I) SALT Wong et al J. Am. Chem. Soc.2002, 124, 14397

  12. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info REDUCTION OF Cu (II) SALT Fokin et al Angew. Chem. Int. Ed. 2002, 41, 2596

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

  15. For more presentations and information visit http://www.pharmaxchange.info OXIDATION OF Cu METAL Sharpless et al J. Am. Chem. Soc. 2005, 127, 210

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

  18. AUXILIARY LIGAND For more presentations and information visit http://www.pharmaxchange.info Sulfonated bathophenanthroline TBTA Pybox

  19. For more presentations and information visit http://www.pharmaxchange.info ONE POT MULTI-STEP SYNTHESIS • Overcome safety problem of low MW azide. • Azide is generated in-situ.

  20. For more presentations and information visit http://www.pharmaxchange.info ONE POT MULTI-STEP SYNTHESIS Wang et al Tetrahedron Lett. 2005, 46, 2331

  21. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info MICROWAVE-ASSISTED CuAAC

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

  24. For more presentations and information visit http://www.pharmaxchange.info Amidine Amide Azetidinimine Triazole REACTION OF SULFONYL AZIDE

  25. For more presentations and information visit http://www.pharmaxchange.info amine REACTION OF SULFONYL AZIDE

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

  27. For more presentations and information visit http://www.pharmaxchange.info ALKYNE HOMOCOUPLING Diederich et al. Angew. Chem. Int. Ed. 2000, 39, 2632

  28. For more presentations and information visit http://www.pharmaxchange.info Cu(I) SATURATION Zhou et al. Org. Lett. 2005, 7, 1035

  29. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info SYNTHESIS OF SCREENING LIBRARIES Wong et al ChemBioChem. 2003, 4, 1246

  33. For more presentations and information visit http://www.pharmaxchange.info SYNTHESIS OF SCREENING LIBRARIES 4 1 1 2 3 4

  34. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS Zhang et al Org. Lett. 2005, 7, 1513

  36. For more presentations and information visit http://www.pharmaxchange.info MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS 11µg/ml 7µg/ml 13µg/ml 24µg/ml 10µg/ml

  37. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info SYNTHESIS OF GYLCOCONJUGATE Acetylene glycoside Groothuys et al, Org. Lett. 2004, 6, 3123

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

  40. For more presentations and information visit http://www.pharmaxchange.info BIOCONJUGATION Wang et al Org. Lett. 2004, 6, 4603

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

  42. For more presentations and information visit http://www.pharmaxchange.info SYNTHESIS OF DENDRIMERS Sharpless et al Chem. Commun. 2005, 5775

  43. For more presentations and information visit http://www.pharmaxchange.info CONCLUSION • Catalytic azide-alkynecycloaddition offers an alternate method for cycloaddition reactions

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