News and Publications

Selective Catalysis and Organic Synthesis

K.B. Sharpless, H. Adolfsson, B. Bender, J. Chiang, T.-H. Chuang, C. Copéret, R. Dress, V. Fokin, A. Gontcharov, L. Goossen, V. Jeanneret, J. Jeong, L. Kolla, D. Lim, H. Liu, C. Nichols, D. Nirschl, W. Pringle, A. Ripka, E. Rubin, I. Sagasser, S. Seidel, E. Stevens, B. Tao, A. Thomas, A. Vaino, A. Yudin

The central theme of our research is the use of inorganic catalysts to uncover new and useful transformations for organic synthesis (Fig. 1). The primary goal is to discover unprecedented reactivity, the harbinger of all important new reactions. This discovery can be accomplished by design or, as often happens, serendipitously; in either case, a new type of transformation often reveals itself for the first time as a minor or trace product in a reaction mixture. When useful new reactivity is recognized in the formation of a minor product, shaping this embryonic reaction and nurturing its potential become the goals. Thus, our research is characterized by 2 distinct phases: the prospecting phase that leads to the discovery of new reactivity and the development phase that determines if the reactivity will become a useful new reaction or simply remain a curiosity.

Current research interests include development of new homogeneous catalysts for the oxidation of organic compounds, use of inorganic reagents to effect new transformations in organic chemistry, and studies of asymmetric catalysis involving both early and late transition metal--mediated processes.

Three discoveries from our laboratory, titanium-catalyzed asymmetric epoxidation, osmium-catalyzed asymmetric dihydroxylation, and osmium-catalyzed asymmetric aminohydroxylation, depend crucially on ligand-accelerated catalysis for their effectiveness. Part of our current effort is exploring this newly uncovered phenomenon and seeking to discover other systems driven by it.

During the past year, we began collaborations with several research groups here at TSRI. Each of these groups has developed one or more high-throughput screens for detecting important classes of biological response. The rate and importance of discoveries from such screening endeavors are naturally dependent on both the "quality" and the quantity of new, organic molecules tested.

Our catalyst screening program uses robots, which are ideal for generating libraries of small molecules. Our own catalytic olefin oxidation processes are among the best available tools for selective addition of nitrogen and oxygen heteroatoms to organic molecules. The number and placement of these heteroatoms in a carbon skeleton usually play a major role in determining the biological activity of the molecule.

We began these collaborations because they not only flourish in the TSRI environment but also complement our goal of finding ever better methods for the oxidation of olefins. No other type of reaction causes such a dramatic change in molecular properties as when an olefinic linkage, the most hydrophobic of organic functional groups, suddenly "sprouts" hydrophilic heteroatoms. The value of these powerful transformations is amplified by the fact that olefins are by far the most common and least expensive of available organic starting materials.

Therefore, using oxidative activation of olefins, we are creating diverse libraries of small molecules for biological testing. Our current collaborations involve screens for antibacterial, antiviral, antitumor, and antiinflammatory activity; assays for RNA binding; nuclear membrane transport phenomena; and formation of amyloid fibrils.

PUBLICATIONS

Copéret, C., Adolfsson, H., Chiang, J.P., Yudin, A.K., Sharpless, K.B. A simple and efficient method for the preparation of pyridine-N-oxides II. Tetrahedron Lett. 39:761, 1998.

Copéret, C., Adolfsson, H., Khuong, T.-A.V., Yudin, A.K., Sharpless, K.B. A simple and efficient method for the preparation of pyridine-N-oxides. J. Org. Chem. 63:1740, 1998.

DelMonte, A.J., Haller, J., Houk, K.N., Sharpless, K.B., Singleton, D.A., Strassner, T., Thomas, A.A. Experimental and theoretical kinetic isotope effects for asymmetric dihydroxylation: Evidence supporting a rate-limiting "(3 + 2)" cycloaddition. J. Am. Chem. Soc. 119:9907, 1997.

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.

Reddy, K.L., Sharpless, K.B. From styrenes to enantiopure /alpha/-arylglycines in two steps. J. Am. Chem. Soc. 120:1207, 1998.

Rubin, A.E., Sharpless, K.B. A highly efficient aminohydroxylation process. Angew. Chem. 36:2637, 1997.

Tao, B., Schlingloff, G., Sharpless, K.B. Reversal of regioselection in the asymmetric aminohydroxylation of cinnamates. Tetrahedron Lett. 39:2507, 1998.

Yudin, A.K., Sharpless, K.B. Bis(trimethylsilyl) peroxide extends the range of oxorhenium catalysts for olefin epoxidation. J. Am. Chem. Soc. 119:11536, 1997.