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Dynamic Combinatorial Chemistry 3652 Chem. Rev. 2006, 106, 3652−3711 Dynamic Combinatorial Chemistry Peter T. Corbett, Julien Leclaire, Laurent Vial, Kevin R. West, Jean-Luc Wietor, Jeremy K. M. Sanders,* and Sijbren Otto* Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom Received February 20, 2006 Contents 6. Related Approaches 3702 6.1. Separation of Equilibration and Template 3703 1. Introduction 3652 Binding 1.1. History 3654 6.2. DCLs in Which Template Binding Is Followed 3704 1.2. Scope and Outline of the Review 3655 by an Irreversible Reaction 2. The Exchange Reactions 3656 6.3. Pseudo-Dynamic Combinatorial Chemistry 3705 2.1. Reactions Involving Covalent Bonds 3656 7. Prospects 3706 2.1.1. Acyl Exchange 3657 8. List of Abbreviations 3707 2.1.2. CdN Exchange 3660 9. Acknowledgments 3708 2.1.3. Acetal Exchange 3663 10. Notes and References 3708 2.1.4. Reversible Diels−Alder Chemistry 3664 2.1.5. Disulfide Exchange 3665 2.1.6. Alkene Metathesis 3665 1. Introduction 2.1.7. Alkyne Metathesis 3666 2.2. Reactions Involving Noncovalent Bonds 3667 Dynamic combinatorial chemistry is defined as combina- torial chemistry under thermodynamic control; that is, in a 2.2.1. Metal−Ligand Coordination 3667 dynamic combinatorial library (DCL), all constituents are 2.2.2. Hydrogen Bonding 3668 in equilibrium. This requires the interconversion of library 2.3. Dynamic Combinatorial Libraries Involving 3669 members into one another through a reversible chemical Multiple Exchange Processes process, which can involve covalent bonds or noncovalent 3. Experimental Considerations 3670 interactions including metal-ligand coordination (see section 3.1. Methods for Confirming That Equilibrium Has 3671 2). Been Reached Dynamic combinatorial chemistry is unique in that the 3.2. Building Block Concentrations and 3671 − composition of the library is determined by the thermody- Ring Chain Equilibria namic stability of each of the library members under the 3.3. Building Block Design and Library Diversity 3671 particular conditions of the experiment. This makes DCLs 4. Applications 3672 powerful tools in identifying thermodynamic minima, which 4.1. Synthetic Receptors 3672 is useful in a number of different contexts. 4.1.1. Linear Receptors 3672 One application is the identification of the most stable 4.1.2. Macrocyclic Receptors 3675 structure in mixtures of structures with different conforma- 4.1.3. Molecular Capsules and Related 3684 tional properties (foldamers) (Figure 1a). Those structures Structures that have the most favorable internal noncovalent interactions 4.2. Catalysts from Dynamic Combinatorial 3688 will be stabilized and formed in preference over those library Libraries members that lack such stabilization (see section 4.5). 4.3. Ligands for Biomolecules 3690 Stabilization of specific library members can also take 4.3.1. Targeting Peptides and Proteins 3691 place through intermolecular noncovalent interactions be- 4.3.2. Targeting Nucleic Acids 3693 tween library members, the library composition being biased 4.4. Dynamic Combinatorial Approaches to 3695 toward those members that form stable assemblies or Aggregation aggregates (Figure 1b). Although this approach has received 4.5. Dynamic Combinatorial Studies of Folding 3696 little attention (see section 4.4), it has real potential for the 4.5.1. Folding of Peptides 3696 discovery of self-assembling molecules including interlocked 4.5.2. Folding of Nucleotides 3697 architectures and new soft materials. 4.5.3. Folding of Synthetic Polymers 3697 Thermodynamic control in DCLs implies that changing the conditions of the experiment can induce changes in the 4.6. Sensors 3698 library composition; that is, dynamic combinatorial libraries 5. Theoretical Studies of Dynamic Combinatorial 3699 will respond to external influences. In principle, this respon- Libraries (DCLs) siveness can be exploited in numerous fashions: for instance, for the discovery of compounds with strongly temperature- * Telephone: +44 1223 336343. Fax: +44 1223 336017. E-mail ad- or pressure-dependent properties or compounds that respond dresses: [email protected] and [email protected]. to light or electric or magnetic fields. Giuseppone and Lehn 10.1021/cr020452p CCC: $59.00 © 2006 American Chemical Society Published on Web 08/10/2006 Dynamic Combinatorial Chemistry Chemical Reviews, 2006, Vol. 106, No. 9 3653 Peter Corbett was born in Ascot, England, in 1978. After finishing school, Laurent Vial was born in 1975 and was educated at the University Claude he went on to read Natural Sciences at the University of Cambridge, Bernard of Lyon (France). In 2003, he received his Ph.D. degree in graduating with an M.Sci. in 2001. His final year dissertation on “Dynamic chemistry from the University of Geneva (Switzerland), exploring the use Combinatorial Libraries of Disulphide-Linked Molecular Capsules” was of chiral salts in asymmetric chemistry under the supervision of Prof. supervised by Sijbren Otto and Jeremy Sanders. Since then he has stayed Je´roˆme Lacour. Since January 2004, he has been a Marie Curie on to study the behavior of dynamic combinatorial libraries of macrocyclic Postdoctoral Research Fellow in the laboratory of Jeremy Sanders and disulfides for a Ph.D.: “Dynamic Combinatorial Libraries in Theory and Sijbren Otto at the University of Cambridge. His current research interests Practice”. He is currently working as a Research Associate for Prof. P. include the selection and preparation of biomimetic catalysts and receptors Murray-Rust, studying the automated extraction of information from the from dynamic combinatorial libraries. chemical literature. Kevin West was born in Oxford, England, in 1980; his family returned to Julien Leclaire graduated from the Ecole Normale Supe´rieure in Lyon Edinburgh, Scotland, soon after, where he remained for his primary, and obtained his Ph.D. in Chemistry at the University of Toulouse in 2003 secondary, and tertiary education. He attended the University of Edinburgh working in the field of phosphorus dendrimers under the supervision of where he received his M.Chem. in chemistry with industrial experience in Prof. J.-P. Majoral. He studied as a postdoctoral researcher at the 2003. He is currently pursuing his Ph.D. at the University of Cambridge − University of Cambridge in 2003 2005 with Jeremy Sanders, investigating under the supervision of Sijbren Otto. The main focus of his research is anion recognition through dynamic combinatorial chemistry and multilevel on dynamic combinatorial libraries of disulfide capsules in water. exchange in solution. In 2005, he joined the Ecole Ge´ne´raliste d’Inge´nieur de Marseille and the Chirotechnologies laboratory as an assistant Templating can be used to select for species that act as hosts professor. or receptors (Figure 1c), as well as for the discovery of new guests or ligands (Figure 1d). These applications are reviewed reported one of the first demonstrations that dynamic libraries in detail in sections 4.1, 4.2, and 4.3. can respond to selection pressures other than molecular Ideally, amplification will be selective for the compound recognition, as illustrated by the adaptive behavior of a that binds the template most strongly. Or, more generally, library of imines to external stimuli in the form of a change the compound that is most stabilized through noncovalent in pH and temperature.1 In practice, the response of the interactions (either with the template, within itself, or with library to an added template has so far proven most valuable other library members) tends to be produced in preference (sections 4.1-4.3). over other library members. However, since DCLs strive for In the context of this review, a template influences the the lowest oVerall Gibbs energy, special cases can occur overall geometry or structure of the product rather than the where the final equilibrium distribution favors library intrinsic chemistry. In general, after a template has directed members other than the one that is, in isolation, the most the formation of the product(s), it can be removed.2 When a stable species. This behavior reflects the fact that DCLs are template binds to a specific library member, this species is complex molecular networks,7 in which library members are stabilized and the equilibrium will shift, normally resulting connected through a set of equilibrium reactions. Any change in an increase in the concentration of the selected library to the stability of one member will be “felt” by all others. member (thermodynamic templating3-6). This increase in the The final equilibrium distribution is determined by the sum concentration of selected species in response to the introduc- total of the thermodynamic stabilities of all species in the tion of a template is commonly referred to as “amplification”. mixture. Fortunately, it is in most cases possible to choose 3654 Chemical Reviews, 2006, Vol. 106, No. 9 Corbett et al. Jean-Luc Wietor was born in Luxembourg in 1980. In 1999, he went to Sijbren Otto received his M.Sc. (1994) and Ph.D. (1998) degrees cum Strasbourg to study chemistry at the Universite´ Louis Pasteur. In 2003, laude from the University of Groningen in The Netherlands. He worked he joined Jeremy Sanders’ research group as an Erasmus exchange on physical organic chemistry in aqueous solutions in the group of Jan student. After the completion of his Maıˆtrise in Strasbourg the same year, Engberts. In 1998, he moved to the United States for a year as a he started his Ph.D. work in the same group. His work is focused toward postdoctoral researcher with Steve Regen (Lehigh University, Bethlehem, DCLs of ligands for nucleotides. Pennsylvania) investigating synthetic systems mediating ion transport through lipid bilayers. In 1999, he received a Marie Curie Fellowship and moved to the University of Cambridge where he worked for two years with Jeremy Sanders, introducing the disulfide chemistry. He started his independent research career in 2001 as a Royal Society University Research Fellow at the same university. His current research interests involve molecular recognition at biomembranes and dynamic combinatorial chemistry in water.
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