Templated Dynamic Libraries

A large amplification in terms of total yield of compound 14 was observed when equilibration of the system was carried out in the presence of the previously mentioned silver salt, added as a solid due to its low solubihty in chloroform solution (c. 0.2 mM). As an example, when the equihbration was carried out at 50 mM monomer concentration, the yield of 14 passed from 2% to about 70% after addition of the salt. 

A set of equilibration experiments was carried out in chloroform at 25° C at increasing total monomer concentration, all in the presence of excess sohd AgN(CF3S02)2- h was possible to measure the total (free and silver-bound) concentration of dimer 14 at the equihbrium in the different conditions of total monomer concentration, and again a saturation profile on increasing of the latter was observed. This result is in perfect accordance with Eq. [31], which is equivalent to Eq. [16] with i = 2 with the caveat that now EM2 is the apparent effective molarity of the overall cyclic dimer that depends on silver salt concentration according to Eq. [32], where EM2 is 

The new limit value reached by the total concentration of 14 when x tends to 1 is EM = 39 mM to be compared with the value in the absence of the template, EM2 = 0.30 mM. The presence of the undissolved silver salt in all the equihbration runs has two favourable consequences (1) the concentration of free salt in solution is constant and always the same in all experiments, (2) acting as an inexhaustible source of material, it allows each member of the DL to bind to as much silver as it can. In Fig. 11, a comparison between the total equihbrium concentration of 14 at varying total 

Although the CC for the templated DL cannot be precisely determined, comparison of the two profiles in Fig. 11 shows that the silver template increases CC from 80-100 mM (in the absence of silver salt) to no less than 400 mM. The difference between CC in the presence and absence of silver salt amounts to no less than 300 mM, corresponding to 3/4 of the monomeric units supphed. Only a fraction of this material, namely, 2 X 39 = 78 mM is accounted for by the formation of the silver-complexed dimer. Much more than 1/2 of the material supphed has been presumably transformed into silver-complexed high molecular we t species, but this has no influence on the amplification of 14 [see point (2)]. 

Interestingly, an unambiguous assessment of the thermodynamic template effect (tte) offered by a saturated solution of AgN(Cp3S02)2 in chloroform at 25°C to the dimer 14 can be given by the ratio in Eq. [33]. The tte turns out to be a pure number that gives a measure of the strength of the template in amplifying the selected receptor 

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The examples discussed in this section provide encouraging leads for the future development of DCLs. Since a large number of biologically relevant substrates (and receptors) involve hydrogen bonding, it is certain that more templates using such interactions to amplify the formation of specific compounds from a dynamic library, will be developed in the future. 

Template-directed synthesis has also been exploited for combinatorial purposes in which a reversible reaction and the use of thermodynamic templates have been used. Two different processes have been envisaged and validated, both of which consider the dynamic optimization of a receptor-ligand interaction where one of the partners is the template that drives the self-assembly of a reversible library of other partners from which the best binder for the template is selected (Fig. 8.53). If the receptor is a template, a library made using a reversible reaction is incubated with the receptor and... 

The two aldehydes Mi,i and Mi,2 produced the same relative amount of imines in the presence or absence of CAll, which implied that no interaction between these dynamic library members and the enzyme was observed. The relative abundance of imines fromMi,3 varied in the two libraries and the two amines 8.112 and 8.113 almost disappeared from L29 when compared to L30, while the formation of 8.114 and especially 8.115 was favored by the template (Fig. 8.55). These results were confirmed in four validation experiments in which the two amines were reacted with Mi,3 in the presence or in the absence of the enzyme. The results reported in Table 8.6 show how 8.115 was the favored library component in the template-assisted synthesis of the mixture. Further confirmation of the specificity of 8.115 toward the template was provided by adding the known CAII inhibitor 8.116 (Fig. 8.55) to a binary mixture... 

TABLE 8.6 Template-Assisted Selection of Schiff Bases from Binary Mixtures Derived from Dynamic Library L27... 

Such highly organized assemblies may also be used as templates for the synthesis of new nanostructures and biomaterials. For example, Sreenivasach-ary and Lehn recently prepared dynamic hydrogels by covalent modification of the 5 -sidechains that extend from stacked G-quartets. Reaction of a hydrogel A made from 5 -hydrazido G 2 with a mixture of aldehydes produced a family of acylhydrazone G-quartets (Figure 3). This dynamic library of acylhydrazones demonstrated preferential synthesis of the most stable hydrogel... 

Keywords Anion template Dynamic combinatorial library Molecular recognition ... 

The concept of dynamic combinatorial chemistry was pioneered by Sanders [16,17] and Lehn [15,18,19] in the 1990s. Since then, a wide range of reports have appeared in which different templates have been used to amplify specific components of a dynamic library. In most cases, the templates used are either cationic or neutral species leading to the amplification of the corresponding receptors for these types of species. Considering that anion templates have only started to be used recently in synthesis, it is not surprising that there are only a handful of examples where DCLs are amplified by anionic species. 

T 0 conclude this part on dynamic combinatorial chemistry, we will mention the use of a polymer bound N-methyl ammonium ion as a template. The library is generated from the pseudopeptide building block mPro, which gives a dynamic library of hydrazones (Fig. 23). Depending on the conditions, the following will be formed at equilibrium in the absence of a template, 85% of the cyclic dimer and 7% of the cyclic trimer in the presence of the template BTA, 47% of the dimer and 50% of the trimer and in the presence of the immobilized template. 40% of pure trimer can be isolated by washing the resin. 

Another example that uses the global response of dynamic libraries to a template is the application of DCLs as sensors [29-32]. The idea is that the pattern of change in the concentration of aU network members carries the signature of the template (i.e., analyte) to which the DCL is exposed. If the library members have different optical properties (i.e., different UV-visible absorption spectra) then the change in... 

In the formation of complexes via self-sorting, no external template is used. Instead, the molecular structure of the host can be considered as the template for the preparation of a host-guest complex. In this case, the ampHfication of the most stable complex takes place via intermolecular interactions, such as hydrogen bonding, metal coordination, or ionic interactions, between the different components in the mixture. Since the strength of these supramolecular interactions is known to be influenced by substituents, a dynamic library can be obtained-not... 

We recently reported on the application of combinatorial methods to selection of stable and chloroform-soluble Schiff-base metal complexes from a dynamic library in order to improve the extraction of metal ions (18). In this study, we built a dynamic library of Schiff-base complexes to capitalize on the reversible nature of metal-catalyzed imine bond formation. Library components were chosen to optimize stability and chloroform solubility of metal complexes. By utilizing the template effect, metal ions promote the assembly of a group of ligands, which then undergo a condensation reaction to form a metal complex. Therefore, aldehydes containing a metal ion-binding site were used to facilitate metal ion templated formation of the Schiff-base ligands (Fig. 1). 

The head-to-tail-coupling reactions described above are potentially useful in the design of dynamic combinatorial libraries. Features of these reactions include the rapid and reversible formation of carbon-carbon bonds, multifunctional ene-imine building blocks, and formation of stereo centers upon ene-imine linkage. Support for template-directed synthesis utilizing ene-imine building blocks is the formation of a poly ene-imine species that could recognize 3 -GGA-5 sequences of DNA.48 It is noteworthy that some polyene-imines are helical and could form a triple helix with DNA. 

Hydrogen-Bonding Templates in Dynamic Combinatorial Libraries 120... 

In the following sections, examples of hydrogen-bonding templates for the synthesis of macrocycles, cages, interlocked species, helicates and for the photochemical reaction of olefins will be discussed. The use of hydrogen-bonding templates in dynamic combinatorial libraries will also be presented. 

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). 

Scheme 40 Synthesis of receptor 80-S-S-80 from a dynamic combinatorial library based on 80-SH and 81-SH. The receptor is amplified in the presence of a tripeptide template...

Goral, V. Nelen, M. I. Eliseev, A. V. Lehn, J. M. Double-level orthogonal dynamic combinatorial libraries on transition metal template. Proc. Natl. Acad. Sci. U.S.A. 2001,98,1347-1352. 

Dynamic combinatorial chemistry has recently been used to investigate the process of templating nucleic acid library members to form interesting structures. To date, the templating process has included the development... 

Scheme 4.14 Formation of a dynamic imine library and Cu+ templated self-sorting.

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