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The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000

Click Chemistry

K.B. Sharpless, M. Andersson, M. Bartsch, B. Bender, K. Burow, J. Chiang, T.-H. Chuang, A. Converso, Z. Demko, R. Epple, V. Fokin, A. Gontcharov, L. Green, A. Marzinzik, M. Matsui, C. Nichols, D. Nirschl, W. Pringle, A. Ripka, E. Rubin, A. Thomas, A. Vaino, M. Winter, Z.-Y. Zhan

The aims of our research program in the past year were 2-fold. First, we continued to improve the olefin oxidation methods previously discovered in our laboratories, and on the basis of mechanistic insights, we searched for new efficient processes. Second, in addition to our traditional pursuit of developing novel synthetic transformations, we initiated efforts to apply the reactions we have developed to the synthesis of libraries of small druglike molecules. Empowered with robotics technology and using a uniquely practical approach, which we refer to as "click chemistry," we created diverse libraries of compounds, and through collaborations within the Scripps community, we discovered molecules with interesting and important biological functions.

With reliable methods for selective olefin oxidations available to us, our goal is to develop a set of powerful, highly reliable, and selective reactions that use "spring-loaded" intermediates (e.g., aziridines and epoxides) for rapid synthesis of useful new compounds and libraries of these compounds. With optimization for large-scale applications already built-in, these reactions are also useful tools for discovery driven by process chemistry. Such processes form the basis of the click chemistry approach. Click chemistry uses high-yielding and practical reactions (click reactions) that meet stringent criteria: the reaction must be modular, wide in scope, give very high yields, generate only trivial by-products that can be removed by nonchromatographic methods, and be stereospecific. Despite the apparent simplicity of click chemistry, quite complex molecules can be rapidly assembled.

By taking advantage of both the wide array of commercially available, inexpensive olefins and our expertise in selective olefin oxidations, we can tailor our click chemistry scaffolds. For example, with the aid of the current equipment in our robotics lab, which includes a weighing-dissolution station, liquid handlers, a variable temperature reaction block, a centrifuge/evaporator, and a solid-phase extractor, we prepared diverse libraries based on the aminohydroxylation, cyclodehydration, nucleophilic aziridine opening sequence shown in Figure 1. High-performance liquid chromatography was used for analysis and quality control; the resulting purity of the individual compounds was usually at least 85%. Libraries of novel compounds, each library with 100-400 members, have been prepared.

We are currently involved in a number of collaborations with colleagues at the Skaggs Institute and The Scripps Research Institute (TSRI), and our synthetic products are being tested for a wide range of activities. Examples include antibacterial activity, in our laboratory; inhibition of feline immunodeficiency virus, with J. Elder, TSRI; inhibition of the formation of amyloid fibrils, with J. Kelly, the Skaggs Institute; RNA binding, with J. Williamson, the Skaggs Institute; binding of viral capsids, with J. Johnson and G. Siuzdak, TSRI; and regulation of transcription, with P. Vogt, TSRI. Early results of screening have already yielded 4 types of new lead compounds. Representatives of 2 anti-infective classes and an inhibitor of the formation of amyloid fibrils are shown in Figure 2.

The discovery of compounds with interesting biological activity has highlighted an additional advantage of our click chemistry approach. Because of the simplicity and modularity of our synthetic processes, we have been able to quickly prepare analogs of the compounds for studies of the relationship between structure and activity and for optimization of lead compounds. The results have been the discovery of compounds with greater activity and a better understanding of the interactions between compounds and their biological targets.

With the goal of exploring new chemical approaches for the synthesis of the libraries, we continue to develop methods that take advantage of the unique reactivity of some olefins in oxidations catalyzed by transition metals. Discovery of highly efficient osmium-catalyzed aminohydroxylation of unsaturated carboxylic acid salts is one example.

The ready availability of the unsaturated acids from natural sources, the outstanding synthetic methods for the preparation of unsaturated acids, and the importance of the α,ß-hydroxyaminoacid derivatives obtained make them one of the most attractive olefin classes to date for the aminohydroxylation reaction. Similar to α,ß-unsaturated amides, maleamic acids, and Baylis-Hillman olefins in our previously described results, unsaturated acids undergo rapid and nearly quantitative aminohydroxylation with very low catalyst loading in the absence of cinchona alkaloid ligands and with only 1 equivalent of the haloamine salt. The reaction will proceed at high concentrations of substrate, and a range of solvents can be used (water/acetonitrile, water/tert-butanol). Most importantly, the reaction often proceeds just as well in water without any organic cosolvent. The only by-product of the reaction is sodium chloride.

Upon acidification, most products precipitate in pure form, making chromatography or recrystallization unnecessary. In instances in which formation of regioisomers occurs, separation of the isomers is usually quite easy. For example, the α-toluenesulfonamido-ß-hydroxy derivative of cinnamic acid is water soluble, whereas its regioisomer is not (Fig. 3).

This newly discovered transformation is of wide scope and can be easily performed on a large scale. For example, the N-tosylated hydroxyaspartic acid product was obtained in almost quantitative yield from fumaric acid (Fig. 4).

Thus, we now know of 4 classes of olefins from which we can produce high yields of racemic hydroxysulfonamides. We are exploring applications that take advantage of these exceptionally efficient processes to synthesize novel click chemistry scaffolds. The products from these reactions and their derivatives are also being tested for biological activity.


Chuang, T.-H., Sharpless, K.B. Applications of aziridinium ions: Selective syntheses of ß-aryl-α,ß-diamino esters. Org. Lett. 1:1435, 1999.

Demko, Z., Bartsch, M., Sharpless, K.B. Primary amides: A general nitrogen source for catalytic asymmetric aminohydroxylation of olefins. Org. Lett. 2:2221, 2000.

Gontcharov, A.V., Liu, H., Sharpless, K.B. tert-Butylsulfonamide: A new nitrogen source for catalytic aminohydroxylation and aziridination of olefins. Org. Lett. 1:783, 1999.

Thomas, A.A., Sharpless, K.B. The catalytic asymmetric aminohydroxylation (AA) of unsaturated phosphonates. J. Org. Chem. 64:8379, 1999.



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