SCIENCE & TECHNOLOGY
DYNAMIC SEARCH FOR CATALYSTS Technique screens library for compounds that show affinity for transition-state analog
D
chemistry professor Jeremy Κ. Μ. Sanders [Angew. Chem. Int. Ed., 42,1270 (2003)}. The chemists isolated two receptors from the library and studied their in fluence on the rates of the Diels-Alder reaction between acridizinium bromide and cyclopentadiene. T h e team found that the larger of the two receptors is catalytically active, whereas the smaller one binds only one of the starting mate rials without leaving enough room for further reaction.
YNAMIC COMBINATORIAL CHEM-
istry has been used to select and amplify a novel catalyst for the Diels-Alder reaction. "We used a compound that re sembles the transition state of the reac tion and screened a dynamic combinator ial library for receptors that recognize the compound," explains Sijbren Otto, Royal Society research fellow at Cambridge Uni versity He carried out the work with Swiss exchange student Barbara Brisig, who is now a Ph.D. student at the University of Basel, in Switzerland, and Cambridge
Strong binders in the library are amplified at the expense of the poor binders.
SELECTION PROCESS Product of Diels-Alder reaction resembles transition state.
CCD-û
Br Acridizinium Cyclopentadiene bromide
ο Transition state
Product
. so it's used to screen dynamic combinatorial library for catalyst COoH
COoH
COoH
Dithiol building blocks
Dynamic combinatorial library of macrocycles Diels-Alder product COoH
COoH COoH
Catalyst
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C & E N / MAY 1 2 , 2 0 0 3
"To my knowledge, the paper represents the first example of catalyst discovery through dynamic combinatorial chem istry," comments AlexeyV. Eliseev, chief technology officer atTherascope AG, Hei delberg, Germany 'Application ofdynamic libraries to catalysis adds one more im portant item to the list of its other rapid ly developing applications in such areas as drug discovery, extraction processes, and materials science." The Cambridge team identified the two receptors using a dynamic combinatorial li brary of water-soluble macrocyclic disul-
fides that the chemists had previously em ployed to prepare synthetic receptors (C&EN, Sept. 2 , 2 0 0 2 , page 31). The li brary is prepared by mixing equimolar amounts of three dithiol building blocks in water. The macrocycles are constructed by reversible covalent chemistry from the building blocks. Reversibility ensures that the library is in thermodynamic equilibrium. When exposed to a molecular target, such as a transition-state analog, library mem bers that bind to it are stabilized and the equilibrium shifts, with the result that the strong binders in the library are amplified at the expense of the poor binders. To create the molecular target, Ot to and coworkers "focused on the Diels-Alder reaction, for which the product of the reaction makes a good transition-state analog," Otto says. "Exposure of the library to the ana log resulted in the simultaneous se lection and amplification of two macrocycles. We then synthesized the two receptors in good yield from a second, biased library containing the selected building blocks in the right ratio." He points out, however, that the larger receptor exhibited only modest activity because it is based on non specific shape recognition. "Our studies establish proof of principle," he says. "We are current ly trying to incorporate specific cat alytically active centers such as met al ions into our building blocks, which should result in highly active catalysts for, for instance, hydrolysis reac tions."—MICHAEL FREEMANTLE HTTP://WWW.CEN-ONLINE.ORG
