| DISCOVERY |
Dynamic combinatorial chemistry has been used to select and amplify a novel catalyst for the Diels-Alder reaction. “We used a compound that resembles the transition state of the reaction and screened a dynamic combinatorial library for receptors that recognize the compound,” explains Sijbren Otto, Royal Society research fellow at Cambridge University. 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 chemistry professor Jeremy K. M. Sanders [Angew. Chem. Int. Ed., 42, 1270 (2003)]. The chemists isolated two receptors from the library and studied their influence on the rates of the Diels-Alder reaction between acridizinium bromide and cyclopentadiene. The team found that the larger of the two receptors is catalytically active, whereas the smaller one binds only one of the starting materials without leaving enough room for further reaction. “To my knowledge, the paper represents the first example of catalyst discovery through dynamic combinatorial chemistry,” comments Alexey V. Eliseev, chief technology officer at Therascope AG, Heidelberg, Germany. “Application of dynamic libraries to catalysis adds one more important item to the list of its other rapidly developing applications in such areas as drug discovery, extraction processes, and materials science.” The Cambridge team identified the two receptors using a dynamic combinatorial library of water-soluble macrocyclic disulfides that the chemists had previously employed to prepare synthetic receptors (C&EN, Sept. 2, 2002, page 31). The library 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 members 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, Otto 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 analog resulted in the simultaneous selection 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 nonspecific shape recognition. “Our studies establish proof of principle,” he says. “We are currently trying to incorporate specific catalytically active centers such as metal ions into our building blocks, which should result in highly active catalysts for, for instance, hydrolysis reactions.” |
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