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Scientific Report 2008


Click Chemistry and Biological Activity

K.B. Sharpless, J. Culhane, J. Fotsing, S. Grecian, N. Grimster, J. Hein, T. Horneff, J. Kalisiak, K. Korthals, S.-W. Kwok, S. Pitram, J. Raushel, B. Stump, J. Tripp, C. Valdez, T. Weide

The driving forces in our research are the discovery and understanding of chemical reactivity, the harbingers of new discoveries in chemistry. Our goal is to develop chemical transformations that enable scientists to rapidly synthesize diverse compounds with desired properties; after all, it is the function of molecules that matters. The nature of the building blocks and the speed with which synthesis, screening for the desired function, and lead optimization can be performed are determining factors in the search for new compounds, whether the new entities are drugs, better plastics, or dyes. The greater the variety of scaffolds and functional groups that can be used in the rapid construction of candidate compounds, the more likely it is that new and useful function will be discovered. Because of the enormous number of compounds to explore (the number of small druglike molecules may be as high as 1064), the size of a given collection becomes much less important than the ability to rapidly probe the collection for a desired activity.

Several years ago, we proposed a minimalistic approach to synthesis that relies solely on the best reactions for assembly of new molecules. Inspired by the natural synthesis of the myriad functional molecules (nucleic acids, proteins, and carbohydrates) from just a handful of building blocks, we devised a fast, reliable, and highly modular style of organic synthesis, which we termed click chemistry. Click reactions fulfill the most stringent criteria of usefulness and convenience (Fig. 1); they are highly energetically driven, and the majority of them form carbon-heteroatom bonds. The reactions produce only the expected products and work regardless of which functional groups are present in the starting materials. Naturally, the number of reactions that meet these criteria is limited, but we contend that a wide variety of interesting and useful molecules can be easily made by using click chemistry and that the chances for achieving desirable biological activity with such compounds are at least as good as chances with the traditional target-guided approach.

Fig. 1. Click chemistry: molecular diversity from a handful of near-perfect reactions.

Recently, we realized that olefins are probably the most attractive starting molecules available to synthetic organic chemists. Olefins are readily accessible in large quantities and in many varieties, and processes for their selective oxidation provide convenient access to electrophilic intermediates such as epoxides, aziridines, aziridinium ions, and cyclic sulfates. These electrophilic intermediates are ideal for introduction of reactive "hot spots," such as azides and acetylenes, that can be used for the assembly of final structures via 1,3-dipolar cycloadditions.

The 1,3-dipolar cycloaddition of azides and alkynes, most extensively studied by R. Huisgen in the 1960s, and the copper- and ruthenium-catalyzed variants we developed with V.V. Fokin, Department of Chemistry, take a prominent place in click reactions. These transformations enable reliable assembly of complex molecules by means of the 1,2,3-triazole heterocycle.

Although both alkynes and azides are highly energetic, they are quite unreactive to a broad range of reagents, solvents, and other common functional groups. This inertness allows clean sequential transformations of broad scope without the need for protecting groups, even if the reactions are performed in aqueous solvent in the presence of atmospheric oxygen. The 1,2,3-triazoles have advantageous properties of high chemical stability (in general, they are inert to severe hydrolytic, oxidizing, and reducing conditions, even at high temperatures), strong dipole moment, presence of aromatic groups, and the ability to accept hydrogen bonds. Thus, they can interact productively in several ways with biological molecules. For example, 1,2,3-triazoles can replace the amide bond in peptides, preventing proteolytic degradation of the peptides.

Our focus on this powerful and underappreciated class of azoles led us back to the simple parent triazole (C2H3N3), which in solution is a rapidly equilibrating mixture of 2 tautomers (Fig. 2). The physical properties of the NH-triazole struck us as highly unusual and are, in fact, much like those of water. These properties include its weak acid-base character, high proton conductivity, and a liquid range spanning nearly 200 degrees. In addition, the NH-1,2,3-triazole is stable: it is insensitive to impact, friction, rapid heating, and even detonation. We studied the Michael reaction of NH-triazole with α,β-unsaturated ketones. The 1H-1,2,3-triazolyl-ketones were selectively generated when the triazole was combined with a variety of enones under solvent-free conditions. The use of aprotic solvents with a catalytic base gave the corresponding 2H-regioisomers. Together, these 2 protocols provide direct access to either the N1- or N2-substituted 1,3-triazolyl ketone regioisomers.
Fig. 2. Michael additions of NH-triazole.


Finn, M.G., Kolb, H.C., Fokin, V.V., Sharpless, K.B . Concept and applications of click chemistry from the standpoint of advocates. Kagaku to Kogyo 60:976, 2007.

Hawker, C.J., Fokin, V.V., Finn, M.G., Sharpless, K.B. Bringing efficiency to materials synthesis: the philosophy of click chemistry. Aust. J. Chem. 60:381, 2007.

Kalisiak, J., Sharpless, K.B., Fokin, V.V. Efficient synthesis of 2-substituted-1,2,3-triazoles. Org. Lett. 10:3171, 2008.

Kwok, S.-W., Hein, J.E., Fokin, V.V., Sharpless, K.B. Regioselective synthesis of either 1H- or 2H-1,2,3-triazoles via Michael addition to α ,β -unsaturated ketones. Heterocycles 76:1141, 2008.

Liu, Y., Dìaz, D.D., Accurso, A.A., Sharpless, K.B., Fokin, V.V., Finn, M.G. Click chemistry in materials synthesis, III: metal-adhesive polymers from Cu(I)-catalyzed azide-alkyne cycloaddition. J. Polym. Sci. A Polym. Chem. 45:5182, 2007.

Radi´c, Z., Manetsch, R., Fournier, D., Sharpless, K.B., Taylor, P. Probing gorge dimensions of cholinesterases by freeze-frame click chemistry. Chem. Biol. Interact. 175:161, 2008.

Sugawara, A., Sunazuka, T., Hirose, T., Nagai, K., Yamaguchi, Y., Hanaki, H., Sharpless, K.B., Omura, S. Design and synthesis via click chemistry of 8,9-anhydroerythromycin A 6,9-hemiketal analogues with anti-MRSA and -VRE activity. Bioorg. Med. Chem. Lett. 17:6340, 2007.

Van der Eycken, E., Sharpless, K.B. Click chemistry. QSAR Comb. Sci. 26:1115, 2007.

Vestberg, R., Malkoch, M., Kade, M., Wu, P., Fokin, V.V., Sharpless, K.B., Drockenmuller, E., Hawker, C.J. Role of architecture and molecular weight in the formation of tailor-made ultrathin multilayers using dendritic macromolecules and click chemistry. J. Polym. Sci. A Polym. Chem. 45:2835, 2007.

Yoo, E.J., Ahlquist, M., Bae, I., Sharpless, K.B., Fokin, V.V., Chang, S. Mechanistic studies on the Cu-catalyzed three-component reactions of sulfonyl azides, 1-alkynes and amines, alcohols, or water: dichotomy via a common pathway. J. Org. Chem. 73:5520, 2008.


K. Barry Sharpless, Ph.D.

Valery Fokin, Ph.D.
Associate Professor

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