News and Publications
The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998
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
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
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,
Yudin, A.K., Sharpless, K.B. Bis(trimethylsilyl) peroxide extends
the range of oxorhenium catalysts for olefin epoxidation. J. Am. Chem. Soc. 119:11536,