Click Chemistry

Ahmed Fazary PhD Student D9506804

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 chemistrya set of powerful, virtually 100% reliable, selective reactions for the rapid synthesis of new compounds via heteroatom links (C-XC)Click chemistry is integral now to all research within the Sharpless Lab. Borman, S. C & En. 2002, 80(6), 29.
2

Definitions

Strategy for the rapid and efficient assembly of molecules with diverse functionalityenabled 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 appealhigh 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.
3

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.
4

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.

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

18.1

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.
8

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.

Regioselectivity of Click Chemistry Alkyne activation

10

Click Applications in Macromolecules

Dendrimer Synthesis Solid Support Chemistry SPOS SPPS DNA functionalization

11

Dendrimer Synthesis
Divergent-Growth

Convergent-Growth

Tomalia, I. Polymer J. 1985, 17, 117. Frechet, J.; Hawker, C. J. Amer. Chem. Soc. 1990, 112, 7638.
12

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.

13

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

 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.
15

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 hydrolyze intermediate aza-ylide

required

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
30