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The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999

Click Chemistry

K.B. Sharpless, M. Bartsch, B. Bender, K. Burow, J. Chiang, T.-H. Chuang, A. Converso, Z. Demko, R. Epple, V. Fokin, A. Gontcharov, L. Goossen, V. Jeanneret, H. Liu, A. Marzinzik, M. Matsui, C. Nichols, D. Nirschl, W. Pringle, A. Ripka, E. Rubin, I. Sagasser, S. Seidel, E. Stevens, A. Thomas, A. Vaino, M. Winter

The central theme of our research has traditionally been the discovery of practical catalytic transformations for organic synthesis. Recently, our focus shifted to the application of these reactions in the synthesis of molecular libraries. Through a uniquely practical approach to the synthesis of druglike molecules, which we refer to as "click chemistry," we have created diverse libraries of compounds, and through collaborations within the Scripps community, we have discovered molecules with interesting and important biological functions.

The number of "known" small organic molecules less than 500 amu is an infinitesimal fraction of the number of possible molecules, even given the molecular weight restriction. Therefore, it is reasonable to assume that many important biologically active compounds remain undiscovered. It is also reasonable to assume that a number of these undiscovered molecules are not structurally complex. Using click chemistry, we have begun to search for these undiscovered domains of biologically relevant molecules.

Click chemistry uses high-yielding and practical reactions (click reactions) that need no, or minimal, purification (i.e., approximately no by-products are produced). Versatility is another key characteristic of a click reaction. We strive to find and use reactions that are general and not confined to a few members of a class of nucleophiles--or even a single class of nucleophiles. An example of a click reaction we have exploited in the successful synthesis of diverse molecular libraries is the addition of heteronucleophiles to epoxides and aziridines. A generalized reaction sequence through which we have synthesized more than 1000 individual compounds is shown in Figure 1. Another key aspect of click chemistry is the brevity of the synthetic sequence used to create a library; we try to limit ourselves to fewer than 5 synthetic steps. In short, among the approximately infinite candidates of less than 500 amu, we aim to find the gems that are also simple to make.

By taking advantage of both the wide array of commercially available, inexpensive olefins and our expertise in olefin oxidations, we can tailor our click chemistry scaffolds. For instance, the widely available α,ß-unsaturated amides used as a starting material for the process depicted in Figure 1 undergo a remarkably efficient aminohydroxylation reaction, although this class of olefins is a poor substrate for our dihydroxylation, epoxidation, and aziridination protocols. Thus, we use the aminohydroxylation reaction, followed by a dehydrative cyclization, to form the aziridine scaffold, which is now ready for the click chemistry addition of a variety of nucleophiles. The library created through this process will contain druglike molecules with amine, amide, and sulfonamide functionalities. The modularity of this approach to compound synthesis also allows the easy incorporation of a desired pharmacophore into the final products--often brought in as the heteronucleophile. By automating these click chemistry reaction procedures, we have been able to multiply our productivity and thereby increase the likelihood of discovering compounds with interesting biological activities.

Of course, discovery of biologically relevant molecules requires the capacity to test compounds for biological activity. The Scripps scientific community, specifically our colleagues in the biological sciences, provides a world-class setting for collaborations and the opportunity to pursue many interesting biological targets. We are currently involved in multiple collaborations that explore a range of biological targets, from formation of amyloid fibrils to inhibition of feline immunodeficiency virus replication.

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 on the relationship between structure and activity, leading to the discovery of compounds with greater activity and a better understanding of the interactions between compounds and their biological targets.

Although catalysis is still an important focus in our research program, we recently began to explore the realm of molecular diversity. The reactions that we discovered, and continue to discover, are important tools in our syntheses of libraries of druglike compounds. Through the use of robotic technology, we have been able to accelerate our reaction discovery efforts and increase our output of novel compounds. The click chemistry approach to molecular diversity has already resulted in the discovery of compounds with unique biological activity.


Adolfsson, H., Converso, A., Sharpless, K.B. Comparison of amine additives most effective in the new methyltrioxorhenium-catalyzed epoxidation process. Tetrahedron Lett. 40:3991, 1999.

Dress, K.R., Goossen, L.J., Liu, H., Jerina, D.M., Sharpless, K.B. Catalytic aminohydroxylation using adenine-derivatives as the nitrogen source. Tetrahedron Lett. 39:7669, 1998.Goossen, L.J., Liu, H., Dress, K.R., Sharpless, K.B. Catalytic asymmetric aminohydroxylation with amino-substituted heterocycles as nitrogen sources. Angew. Chem. Int. Ed. 38:1089, 1999.

Gypser, A., Michel, D., Nirschl, D.S., Sharpless, K.B. Dihydroxylation of polyenes using Narasaka's modification of the Upjohn procedure. J. Org. Chem. 63:7322, 1998.

Jeong, J.U., Tao, B., Sagasser, I., Henniges, H., Sharpless, K.B. Bromine-catalyzed aziridination of olefins: A rare example of atom-transfer redox catalysis by a main group element. J. Am. Chem. Soc. 120:6844, 1998.

Kolb, H.C., Sharpless, K.B. Asymmetric aminohydroxylation. In: Transition Metals for Fine Chemicals and Organic Synthesis. Beller, M., Bolm, C. (Eds.). Wiley-VCH, New York, 1998, p. 243.

Kolb, H.C., Sharpless, K.B. Asymmetric dihydroxylation. In: Transition Metals for Fine Chemicals and Organic Synthesis. Beller, M., Bolm, C. (Eds.). Wiley-VCH, New York, 1998, p. 219.

Pringle, W., Sharpless, K.B. The osmium-catalyzed aminohydroxylation of Baylis-Hillman olefins. Tetrahedron Lett. 40:5151, 1999.

Reddy, K.L., Dress, K.R., Sharpless, K.B. N-Chloro-N-sodio-2-trimethylsilyl ethyl carbamate: A new nitrogen source for the catalytic asymmetric aminohydroxylation. Tetrahedron Lett. 39:3667, 1998.

Schlingloff, G., Sharpless, K.B. Asymmetric aminohydroxylation. In: Asymmetric Oxidation Reactions: A Practical Approach. Katsuki, T. (Ed.). Oxford University Press, New York, in press.



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