Dynamic combinatorial libraries DCLs

Chemical templates are being increasingly employed for the development of dynamic combinatorial libraries (DCL) [94-98]. These (virtual) libraries of compounds are produced from all the possible combinations of a set of basic components that can reversibly react with each other with the consequent potential to generate a large pool of compounds. Because of the dynamic equilibria established in a DCL, the stabilization of any given compound by molecular recognition will amplify its formation. Hence the addition of a template to the library usually leads to the isolation of the compound that forms the thermodynamically more stable host-guest complex (see Scheme 37). 

A reversible Ugation technique was desired that would aUow the use of the mPE system in dynamic combinatorial libraries (DCL) in an effort to identify masterpiece sequences [81]. The imine bond metathesis is known to have an equilibrium constant close to unity, undergoes reactions at reasonable rates at room temperature, and has a geometry that is compatible with the phenylacetylene unit [82] therefore it was chosen as a component for mPEs. 

Using this approach, a dynamic combinatorial library (DCL) of rapidly equilibrating metal complexes was formed by incubating a series of salicylaldimines with the transition metal salt ZnCl in aqueous solution (Fig. 3.3). Divalent zinc was chosen as the transition metal for its known tetravalent coordination geometry with salicylaldimines [7] and its compatibility with DNA. (In retrospect, this was a somewhat naive view of both... 

For the purpose of organizing this stereoselecfion chapter, we will summarize the fiterature using the following taxonomy first divided by the nature of the guest and second by the nature of the dynamic combinatorial library (DCL) components. 

Dynamic combinatorial libraries (DCLs) are continuously interconverting libraries that evenmally evolve to an equilibrium distribution [61-65]. This approach has been used successfully in the discovery of stable supramolecular assemblies from mixtures. Due to the nearly endless possible peptide sequences that can potentially be synthesised, the DCL approach is attractive for the identification of supramolecular peptide interactions. Indeed, disulfide exchange between cysteine residues has been explored for this purpose [66, 67] as has peptide-metal binding [68]. We have recently demonstrated protease-catalysed amide exchange in this context, which allows for the evolution of the self-assembled peptide structures, and will therefore allow exploration of peptide sequence space for biomaterials design. 

In striking contrast with these two previous examples of 1,3-dipolar cycloaddition catalyzed by encapsulation, the EMs calculated for particular examples of Diels-Alder reactions catalyzed by Rebek s softball [25] or by Sanders [26] cyclophane, which was selected from a dynamic combinatorial library (DCL), are lower than the actual reactant concentration calculated from the volumes of the molecular cavities. Probably, the Diels-Alder reactions have more stringent orientational requirements than the 1,3-dipolar cycloaddition. The reactants of the Diels-Alder reactions, when encapsulated or included, spend a significant amount of time in ternary complexes displaying a non-productive mutual orientation. 

Complex dynamic and positive feedback between molecular/supramolecular partners in dynamic combinatorial libraries (DCLs) gives rise to emergent functional systems with a collective behavior. From the conceptual point of view, these systems express a synergistic constitutional self-reorganization (self-adaptation) of their configuration, producing an adaptive response in the presence of internal or external structural factors. 

Dynamic combinatorial chemistry (DCC) is founded on the study and the construction of mixtures of discrete constituents which are produced by reversible molecular or supramolecular associations [1, 2], The composition of a dynamic combinatorial library (DCL) is thermodynamically driven and, as such, is able to adapt itself to any parameter that - permanently or transiently - modifies its constitution/energy potential surface [3,4], Thus, in the presence of various internal or external parameters, the involved equilibria can be displaced toward the amplification of given products through an adaptation process that will occur through an in situ screening of these species. A schematic representation using Emil Fisher lock-and-key metaphora can be used to illustrate these concepts (Fig. 1). 

In a dynamic combinatorial library (DCL) the components of the library are not chemically static, but can interconvert through either covalent or noncovalent means. This is shown conceptually in Fig. 9a. The advantage of a dynamic combinatorial... 

ESI-MS/MS using an FT-ICR mass spectrometer also enables direct screening of dynamic combinatorial library (DCL) [106]. The protein-Ugand complexes are selectively trapped and dissociated to facilitate selective identification of the DCL ligands. 

The Diels-Alder reaction between acridizinium bromide and cyclopentadiene is typically catalyzed by cage compounds. In a seminal paper by Otto et al. [18], selection of catalysts was performed using the reaction product as a suitable TSA to select macrocycles from a dynamic library. Exposure of the dynamic combinatorial library (DCLs) based on dithiol building blocks to the product (as TSA) leads to the selection and the amplification of two hosts among all the constituents of the dynamic library (Figure 4.6). The selected cage compounds were applied as catalysts in separate experiments and, indeed, compound 7 was demonstrated to catalyze the Diels-Alder reaction between the two substrates. The reaction rate was... 

The basic concepts of selection experiments with dynamic combinatorial libraries (DCLs) were articulated more than 10 years ago (see Chapter 1). Since then, a number of applications have emerged. This includes the discovery new enzyme inhibitors, receptors, and catalysts, as well as the synthesis of novel materials such as responsive gels and polymers (see Chapters 2-5). A recent addition to the list of applications is the utilization of dynamic combinatorial chemistry (DCC) for analyhcal purposes. This chapter summarizes the main ideas and results in this area. 

It is evident from Chapters 3 and 5 that dynamic combinatorial libraries (DCLs) have indeed become popular and powerful tools for these purposes. The responsiveness of DCLs to external influences has also potential for other applications. First reports on the influence of electric flelds [9], light [10-12], and temperature and pH [13] have recently appeared, and it is our expectation that there is a great deal more to be discovered by using these and other external stimuli. The same applies to the use of DCLs for identifying catalysts (see Chapter 4). The dynamic combinatorial approach has not yet seriously entered this area of science and only the first examples have appeared that show proof-of-principle. It is possible to design procedures to select a catalyst from a dynamic mixture of candidate molecules. 

Dynamic combinatorial chemistry (DCC) has proven extremely useful in creating complex mixtures of interchanging compounds termed dynamic combinatorial libraries (DCL). Key to the formation of such DCLs is a reversible chemical process that allows the library members to interconvert. The formation of imines from aldehydes and amines is a prominent example for the creation of a DCL. Since the overall distribution of compounds is under thermodynamic control, external stimuli can be used to bias the DCL toward a specific member of the library. This approach has been exploited successfully in the search of potent receptors for molecules of pharmacological interest, the creation of supramolecular assemblies, and ligands for biomacromolecules. ... 

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