News and Publications
The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000
K.B. Sharpless, M. Andersson, M. Bartsch, B. Bender, K. Burow, J. Chiang,
T.-H. Chuang, A. Converso, Z. Demko, R. Epple, V. Fokin, A. Gontcharov, L. Green,
A. Marzinzik, M. Matsui, C. Nichols, D. Nirschl, W. Pringle, A. Ripka, E. Rubin,
A. Thomas, A. Vaino, M. Winter, Z.-Y. Zhan
The aims of our research program in the past year were 2-fold. First, we
continued to improve the olefin oxidation methods previously discovered in our
laboratories, and on the basis of mechanistic insights, we searched for new efficient
processes. Second, in addition to our traditional pursuit of developing novel
synthetic transformations, we initiated efforts to apply the reactions we have
developed to the synthesis of libraries of small druglike molecules. Empowered
with robotics technology and using a uniquely practical approach, which we refer
to as "click chemistry," we created diverse libraries of compounds, and through
collaborations within the Scripps community, we discovered molecules with interesting
and important biological functions.
With reliable methods for selective olefin oxidations available to us, our
goal is to develop a set of powerful, highly reliable, and selective reactions
that use "spring-loaded" intermediates (e.g., aziridines and epoxides) for rapid
synthesis of useful new compounds and libraries of these compounds. With optimization
for large-scale applications already built-in, these reactions are also useful
tools for discovery driven by process chemistry. Such processes form the basis
of the click chemistry approach. Click chemistry uses high-yielding and practical
reactions (click reactions) that meet stringent criteria: the reaction must be
modular, wide in scope, give very high yields, generate only trivial by-products
that can be removed by nonchromatographic methods, and be stereospecific. Despite
the apparent simplicity of click chemistry, quite complex molecules can be rapidly
By taking advantage of both the wide array of commercially available, inexpensive
olefins and our expertise in selective olefin oxidations, we can tailor our click
chemistry scaffolds. For example, with the aid of the current equipment in our
robotics lab, which includes a weighing-dissolution station, liquid handlers,
a variable temperature reaction block, a centrifuge/evaporator, and a solid-phase
extractor, we prepared diverse libraries based on the aminohydroxylation, cyclodehydration,
nucleophilic aziridine opening sequence shown in Figure 1. High-performance liquid
chromatography was used for analysis and quality control; the resulting purity
of the individual compounds was usually at least 85%. Libraries of novel compounds,
each library with 100-400 members, have been prepared.
We are currently involved in a number of collaborations with colleagues at
the Skaggs Institute and The Scripps Research Institute (TSRI), and our synthetic
products are being tested for a wide range of activities. Examples include antibacterial
activity, in our laboratory; inhibition of feline immunodeficiency virus, with
J. Elder, TSRI; inhibition of the formation of amyloid fibrils, with J. Kelly,
the Skaggs Institute; RNA binding, with J. Williamson, the Skaggs Institute;
binding of viral capsids, with J. Johnson and G. Siuzdak, TSRI; and regulation
of transcription, with P. Vogt, TSRI. Early results of screening have already
yielded 4 types of new lead compounds. Representatives of 2 anti-infective classes
and an inhibitor of the formation of amyloid fibrils are shown in Figure 2.
The discovery of compounds with interesting biological activity has highlighted
an additional advantage of our click chemistry approach. Because of the simplicity
and modularity of our synthetic processes, we have been able to quickly prepare
analogs of the compounds for studies of the relationship between structure and
activity and for optimization of lead compounds. The results have been the discovery
of compounds with greater activity and a better understanding of the interactions
between compounds and their biological targets.
With the goal of exploring new chemical approaches for the synthesis of the
libraries, we continue to develop methods that take advantage of the unique reactivity
of some olefins in oxidations catalyzed by transition metals. Discovery of highly
efficient osmium-catalyzed aminohydroxylation of unsaturated carboxylic acid
salts is one example.
The ready availability of the unsaturated acids from natural sources, the
outstanding synthetic methods for the preparation of unsaturated acids, and the
importance of the α,ß-hydroxyaminoacid derivatives obtained make
them one of the most attractive olefin classes to date for the aminohydroxylation
reaction. Similar to α,ß-unsaturated amides, maleamic acids, and
Baylis-Hillman olefins in our previously described results, unsaturated acids
undergo rapid and nearly quantitative aminohydroxylation with very low catalyst
loading in the absence of cinchona alkaloid ligands and with only 1 equivalent
of the haloamine salt. The reaction will proceed at high concentrations of substrate,
and a range of solvents can be used (water/acetonitrile, water/tert-butanol).
Most importantly, the reaction often proceeds just as well in water without any
organic cosolvent. The only by-product of the reaction is sodium chloride.
Upon acidification, most products precipitate in pure form, making chromatography
or recrystallization unnecessary. In instances in which formation of regioisomers
occurs, separation of the isomers is usually quite easy. For example, the α-toluenesulfonamido-ß-hydroxy
derivative of cinnamic acid is water soluble, whereas its regioisomer is not
This newly discovered transformation is of wide scope and can be easily performed
on a large scale. For example, the N-tosylated hydroxyaspartic acid product
was obtained in almost quantitative yield from fumaric acid (Fig. 4).
we now know of 4 classes of olefins from which we can produce high yields of
racemic hydroxysulfonamides. We are exploring applications that take advantage
of these exceptionally efficient processes to synthesize novel click chemistry
scaffolds. The products from these reactions and their derivatives are also being
tested for biological activity.
Chuang, T.-H., Sharpless, K.B. Applications of aziridinium ions: Selective
syntheses of ß-aryl-α,ß-diamino esters. Org. Lett. 1:1435,
Demko, Z., Bartsch, M., Sharpless, K.B. Primary amides: A general
nitrogen source for catalytic asymmetric aminohydroxylation of olefins. Org.
Lett. 2:2221, 2000.
Gontcharov, A.V., Liu, H., Sharpless, K.B. tert-Butylsulfonamide:
A new nitrogen source for catalytic aminohydroxylation and aziridination of olefins.
Org. Lett. 1:783, 1999.
Thomas, A.A., Sharpless, K.B. The catalytic asymmetric aminohydroxylation
(AA) of unsaturated phosphonates. J. Org. Chem. 64:8379, 1999.