News and Publications

Catalysis Discovery

Discovery of new reactivity is our research mission. Past discoveries include metal-catalyzed oxidations of organic molecules, particularly olefins; examples include the asymmetric epoxidation, dihydroxylation, and aminohydroxylation reactions. Current goals include the development of practical, metal-catalyzed olefin epoxidation and aziridination reactions (Fig. 1).

Epoxides are among the most useful organic intermediates: their chemistry often combines the disparate qualities of great reactivity and excellent selectivity (Fig. 2). Although many chemists consider epoxidation a "solved" problem, existing methods often fail because of the epoxides' greatest weakness: acid sensitivity, both Lewis and Brønsted. The most common epoxidation reagents, peracids, are obviously acidic, whereas the catalysts in metal-catalyzed systems are strong Lewis acids. The most innocuous reagents, the dioxiranes, are also the most impractical. Recent results suggest that rhenium catalysts may have the ideal combination of reactivity and mildness.

The chemistry of aziridines, the nitrogen analogs of epoxides, is far less developed than that of epoxides, largely because of the lack of direct olefin-aziridination methods. The need for aziridination methods is evidenced in part by the myriad laboratories (our own included) engaged in the search for these methods. Our strategy is to use robotics.

Much effort in our previous searches for new reactions involved screening: running a reaction on a particular substrate while varying the catalyst, oxidant, solvent, temperature, and so on. Although this strategy has been successful, it does have drawbacks. It is boring and repetitive, the large number of failed reactions tends to be discouraging, and negative results tend not to be publishable.

Automating the manual-labor part of this process enables researchers to spend more time on the interesting and creative aspects of chemistry. In addition, more substrates, catalysts, and conditions can be screened with the automated system than can be screened manually; hence, the reaction variables and conditions can be mapped more completely. Finally, researchers' fatigue is reduced, reducing the likelihood that important results might be overlooked.

The direction of our future research hinges largely on the success of the automation program. Although many laboratories use robots to generate combinatorial libraries, reactivity screening is a new area for automation. Success with the aziridination project could lead to a new basis for our research, and use of the findings in future reactivity prospecting should accelerate the discovery process.

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., in press.

Reddy, K.L., Sharpless, K.B. From styrenes to enantiopure α-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.