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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,

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Presentation on theme: "1 CATALYTIC AZIDE-ALKYNE CYCLOADDITION: REACTIVITY AND APPLICATION PREET PAL SINGH SIDHU GRADUATE STUDENT DEPT.OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY,"— Presentation transcript:

1 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.pharmaxchange.infohttp://www.pharmaxchange.info

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

3 3 INTRODUCTION Most suited reaction of CLICK CHEMISTRY Selective reaction to form hetero-link. Sharpless et al. Angew. Chem. Int. Ed. 2001, 40, 2004 Huisgen thermal 1,3-cycloaddition CuAAC H= -45 kcal/mol For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

4 4 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 10 7 faster than uncatalyzed. High regioselectivity. Minimal work-up and purification. Least affected by temperature and pH. Fokin et al. Aldrichimica Acta, 2007,40,7 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

5 5 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

6 6 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 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

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

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

9 9 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). For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

10 10 DIRECT ADDITION OF Cu(I) SALT Examples: CuI, CuBr, and coordination complexes like Cu(CH 3 CN) 4 PF 6, (EtO) 3 P·CuI. Thermodynamically unstable. Nitrogen type donors prevent degradation. Reliable catalyst in presence of base. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

11 11 DIRECT ADDITION OF Cu(I) SALT Wong et al J. Am. Chem. Soc. 2002, 124, 14397 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

12 12 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

13 13 REDUCTION OF Cu (II) SALT Fokin et al Angew. Chem. Int. Ed. 2002, 41, 2596 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

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

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

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

17 17 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

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

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

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

21 21 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

22 22 MICROWAVE-ASSISTED CuAAC For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

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

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

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

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

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

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

29 29 APPLICATIONS OF CuAAC Synthesis of small molecule screening libraries. Synthesis of glycoconjugate. Modification and biological profiling of natural products. Bioconjugation. Synthesis of functional dendrimers. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

30 30 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. Doesnt require inert atmosphere. Results in cleaner isolated product. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

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

32 32 SYNTHESIS OF SCREENING LIBRARIES Wong et al ChemBioChem. 2003, 4, 1246 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

33 SYNTHESIS OF SCREENING LIBRARIES HIV PR6±0.51.7±0.113±0.54±0.5 V82F19±110±0.524±113±0.5 G48V39±122±117±19.7±0.5 V82A46±227±152±230±1 EnzymeIC 50 [n M ]K i [n M ]IC 50 [n M ]K i [n M ] 1 1 2 3 4 4 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

34 34 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

35 35 MODIFICATION AND BIOLOGICAL PROFILING OF NATURAL PRODUCTS Zhang et al Org. Lett. 2005, 7, 1513 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

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

37 37 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

38 38 SYNTHESIS OF GYLCOCONJUGATE Groothuys et al, Org. Lett. 2004, 6, 3123 Acetylene glycoside For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info

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

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

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

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

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


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