Scientific Report 2007

Chemistry

Organometallic Catalysis in Synthesis, Bioorganic Chemistry, and Materials Research

V.V. Fokin, B. Boren, A. Chanda, S. Chang, J. Fotsing, L. Krasnova, S.-W. Kwok, J. Raushel, T. Weide, M. Whiting

Our goals are to discover new reactivities and to develop their practical applications in organic synthesis, chemical biology, and materials science. Transformations catalyzed by transition metals are of particular importance, because they often have many variables that can be optimized to make the transformations useful on both laboratory and industrial scales. Although we often use automation techniques to screen extensive sets of catalysts, ligands, and conditions (often on the basis of just a hunch that 'it should work'), mechanistic studies of the initial reactivity are prominent in our research. Analysis of reaction kinetics, in situ infrared monitoring, microcalorimetry, and other physicochemical methods are routinely used to understand the mechanistic underpinning of the processes under investigation. This approach also offers excellent training opportunities for graduate students and postdoctoral researchers, preparing these scientists for successful careers in pharmaceutical and chemical industries.

Although high-throughput biology, genetics tools, robotics, and information technology have progressed with lightning speed since the late 1980s, the demands on the chemical methods made by these advances remain largely unmet. Many 'conventional' transformations have been successfully adopted to parallel synthesis of chemical libraries of significant size (but not necessarily of significant diversity), but reactions that allow selective manipulation of biological targets, both in vitro and in vivo, are still scarce. Indeed, the development of chemical tools to selectively address desired molecules in the complex biological milieu is still a formidable task: at the very least, the reactants must be tolerant to protic, nucleophilic, and electrophilic functional groups and must be reactive, yet tame, to perform efficiently, reliably, and selectively in the presence of water, oxygen, and proteins. Organic azides seem to fulfill most of these criteria.

Two reactions discovered in our laboratories, the copper- and ruthenium-catalyzed cycloadditions of azides and alkynes, provide ready access to 1,2,3-triazoles of various substitution patterns. The copper-catalyzed variant has become a premier click reaction and has been adopted by chemists working in organic synthesis, medicinal chemistry, chemical biology, and materials science. In addition to its excellent reliability and tolerance to a wide range of functional groups, the copper-catalyzed reaction has provided valuable insights into the unique and, until recently, unexplored reactivity of organic azides and in situ generated copper acetylides. The ruthenium-catalyzed reaction, although not yet as widely accepted as the copper-catalyzed one, enables 'fusion' of organic azides and both terminal and internal alkynes with a complementary regioselectivity and appears to proceed through a completely different mechanism (Fig. 1).

Fig. 1. Copper- and ruthenium-catalyzed azide-alkyne cycloadditions.

Both reactions and their applications to the synthesis of biologically active compounds and novel materials have been the subject of our intense attention during the past few years. We have investigated the mechanism of these processes and endeavored to develop new ligands to make the reactions more biocompatible. In addition, we have used the reactions to synthesize libraries of compounds for HIV protease inhibition (Fig. 2A), in collaboration with J.H. Elder and A.J. Olson, Department of Molecular Biology; β-secretase inhibition and nicotinic receptor agonists and antagonists, in studies with P. Taylor, University of California, San Diego; and polymeric materials and dendritic constructs for polyvalent display and imaging applications (Fig. 2B), in research with C. Hawker, University of California, Santa Barbara, and M.G. Finn, Department of Chemistry.

Fig. 2. A, New nicotinic acetylcholine receptor ligands (Kd <1 nm). B, Polyvalent fluorescent dendrimer.

Publications

Cassidy, M.P., Raushel, J., Fokin, V.V. Practical synthesis of amides from in situ generated copper(I) acetylides and sulfonyl azides. Angew. Chem. Int. Ed. 45:3154, 2006.

Fokin, V.V, Wu, P. Epoxides and aziridines in click chemistry. In: Aziridines and Epoxides in Organic Synthesis. Yudin, A.K. (Ed.). Wiley-VCH, Weinheim, Germany, 2006, p. 443.

Kade, M., Vestberg, R., Malkoch, M., Wu, P., Fokin, V.V., Finn, M.G. Sharpless, K.B., Hawker, C. A covalently bonded layer-by-layer assembly of dendrimers by ‘click' chemistry. Polymer Preprints (Am. Chem. Soc.) 47:376, 2006.

Narayan, S., Fokin, V.V., Sharpless, K.B. Chemistry ‘on water': organic synthesis in aqueous suspension. In: Organic Synthesis in Water: Principles, Strategies and Applications. Lindström, U.M. (Ed.). Blackwell Publishing, Oxford, England, 2007, p. 350.

Whiting, M., Fokin, V.V. Copper-catalyzed reaction cascade: direct conversion of alkynes to N-sulfonylazetidin-2-imines. Angew. Chem. Int. Ed. 45:3157, 2006.

Whiting, M., Tripp, J.C., Lin, Y.-C., Lindstrom, W., Olson, A.J., Elder, J.H., Sharpless, K.B., Fokin, V.V. Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization. J. Med. Chem. 49:7697, 2006.

Wu, P., Fokin, V.V. Catalytic azide-alkyne cycloadditions: reactivity and applications. Aldrichim. Acta 40:7, 2007.

Yoo, E.J., Ahlquist, M., Kim, S.H., Bae, I., Fokin, V.V., Sharpless, K.B., Chang, S. Copper-catalyzed synthesis of N-sulfonyl-1,2,3-triazoles: controlling selectivity. Angew. Chem. Int. Ed. 46:1730, 2007.