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Click Chemistry

Click Chemistry. Ahmed Fazary PhD Student D9506804. Definitions .

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Click Chemistry

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  1. Click Chemistry Ahmed Fazary PhD Student D9506804

  2. Definitions Click Chemistry is a general term that identifies a class of chemical transformations with a number of attaractive features including excellent functional-group tolerance, high yields and good selectivity under mild experimental conditions. As defined by K. B. Sharpless – “‘Click’ chemistry…a set of powerful, virtually 100% reliable, selective reactions for the rapid synthesis of new compounds via heteroatom links (C-X-C)…Click chemistry is integral now to all research within the Sharpless Lab.” Borman, S. C & En. 2002, 80(6), 29.

  3. Definitions “Strategy for the rapid and efficient assembly of molecules with diverse functionality…enabled by a few nearly perfect reactions, it guarantees reliable synthesis of the desired products in high yield and purity…” Brik, A.; Muldoon, J.; Lin, Y.; Elder, J. Goodsell, D. Olson, A.; Fokin, V.; Sharpless, B.;Wong, H. Chem. Bio. Chem. 2003, 4, 1246. “Designing powerful and selective reactions for an efficient synthesis of interesting compounds and combinatorial libraries through heteroatom links…” The Huisgen 1,3-dipolar cycloaddition of azides and alkynes is regarded as the ‘cream of the crop’ of concerted reactions…” Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753. “Synthetic appeal…high yields, simple reaction conditions, tolerance of oxygen and water, and simple product isolation...” Helms, B.; Mynar, J; Hawker, C.; Frechet, J. J. Am. Chem. Soc. 2004, 126, 15020.

  4. History Click chemistry is a concept introduced by K. Barry Sharpless in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining small units together as nature does. In biochemistry, proteins are made from repeating amino acid units and sugars are made from repeating monosaccharide units. The connecting units are based on carbon - hetero atom bonds C-X-C rather than carbon - carbon bonds. In addition, enzymes ensure that chemical processes can overcome large enthalpy hurdles by division into a series of reactions each with a small energy step. Mimicking nature in organic synthesis of new pharmaceuticals is essential given the large number of possible structures.

  5. In 1996 Guida calculated the size of the pool of drug candidates at 1063, based on the presumption that a candidate consists of less than 30 non-hydrogen atoms, weights less than 500 daltons, is made up of atoms of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine and bromine, and is stable at room temperature and stable towards oxygen and water. Click chemistry in combination with combinatorial chemistry, high-throughput screening and building chemical libraries speeds up new drug discoveries by making each reaction in a multistep synthesis fast, efficient and predictable.

  6. NESTLED Model of inhibitor in the active site of acetylcholinesterase, similar to one formed experimentally using in situ click chemistry.

  7. 18.1

  8. Classes of ‘Click’ Reactions • Nucleophilic opening of highly strained rings – SN2 ring opening reactions – Epoxides, aziridines, cyclic sulfates, cyclic sulfamidates, aziridinium ions • “Protecting Group” Reactions – Reversible carbonyl chemistry – Acetals, ketals and their aza-analogs • Cycloaddition Reactions – Hetero Diels-Alder, 1,3 dipolar cycloadditions involving heteroatoms Kolb, H.; Finn, M.; Sharpless, B. Angew. Chem. Int. Ed. 2001, 40, 2004.

  9. Regioselectivity of “Click” Chemistry • Addition of Cu(I)-catalyst – “the champion “click” process…” Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, B. Angew. Chem Int. Ed. 2002, 41, 2596. Li, Z.; Seo, T.; Ju, J. Tetrahedron Lett. 2004, 45, 3143.

  10. Regioselectivity of “Click” Chemistry • Alkyne activation

  11. “Click” Applications in Macromolecules • Dendrimer Synthesis • Solid Support Chemistry – SPOS – SPPS • DNA functionalization

  12. Dendrimer Synthesis Divergent-Growth Convergent-Growth Tomalia, I. Polymer J. 1985, 17, 117. Frechet, J.; Hawker, C. J. Amer. Chem. Soc. 1990, 112, 7638.

  13. Dendrimer Synthesis Wu, P.; Feldman, A.; Nugent, A.; Hawker, C.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.; Sharpless, B.; Fokin, V. Angew. Chem. Int. Ed. 2004, 43, 3928.

  14. Wu, P.; Feldman, A.; Nugent, A.; Hawker, C.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.; Sharpless, B.; Fokin, V. Angew. Chem. Int. Ed. 2004, 43, 3928.

  15. • 4th generation dendrimer synthesis Wu, P.; Feldman, A.; Nugent, A.; Hawker, C.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.; Sharpless, B.; Fokin, V. Angew. Chem. Int. Ed. 2004, 43, 3928.

  16. “Click” Chemistry Using a Solid Support • Solid Phase Organic Synthesis (SPOS) • Solid Phase Peptide Synthesis (SPPS)

  17. SPOS: Solid Phase Organic Synthesis BAL Resin: "Click" Resin Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753.

  18. SPOS: Library of Tertiary Amines Lober, S.; Gmeiner, P. Tetrahedron, 2004, 60, 8699.

  19. SPOS: Library of Tertiary Amines • Triazolylmethyl acrylate (TMA) Resin Lober, S.; Gmeiner, P. Tetrahedron, 2004, 60, 8699.

  20. SPPS: Cu(I) catalysis on Solid Support Quantitative conversions & purities: 75-95% Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.

  21. “Click” Chemistry in Biology

  22. •Construction of fluorescent Oligo nucleotides for DNA sequencing •Biological Inhibitors •In-situ “Click” approach

  23. DNA Sequencing • Modified Oligonucleotides • Introducing additional functional groups in DNA – Staudinger reaction – Limitations: aqueous conditions required hydrolyze intermediate aza-ylide Seo, T.; Li, Z.; Ruparel H.; Ju J. J. Org Chem. 2003, 68, 609. Saxon, E.; Bertozzi C. Science, 2002, 287, 2007.

  24. • Fluorescent ss DNA sequencing Seo, T.; Li, Z.; Ruparel H.; J. Org Chem. 2003, 68, 609.

  25. Biological Inhibitors • HIV-1 protease (HIV-1 PR) Brik, A.; Muldoon, J.; Lin, Y.; Elder, J. Goodsell, D. Olson, A.; Fokin, V.; Sharpless, B.; Wong, H. Chem. Bio. Chem. 2003, 4, 1246.

  26. In Situ “Click” Chemistry PERFECT FIT Model of acetylcholinesterase inhibitor. Lewis, W.; Green, L.; Grynszpan, F.; Radic, Z.; Carlier, P.; Taylor, P.; Finn, M.; Sharpless, B. Angew chemie. Int. Ed, 2002, 41, 1054.

  27. • Enzyme Templating – Inhibitor for acetylcholinesterase Lewis, W.; Green, L.; Grynszpan, F.; Radic, Z.; Carlier, P.; Taylor, P.; Finn, M.; Sharpless, B. Angew chemie. Int. Ed, 2002, 41, 1054.

  28. Why “Click” Chemistry? • Functional group tolerance • Aqueous conditions • Shorter reaction time • High yield • High purity • Regiospecificity

  29. Thanks

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