Imines library formation

Linking the ketone and carboxylic acid components together in an Ugi reaction facilitates the synthesis of pyrrolidinones amenable to library design. The three-component condensation of levulinic acid 30, an amine and isocyanide proceeds under microwave irradiation to give lactams 31 [65]. The optimum conditions were established by a design of experiments approach, varying the equivalents of amine, concentration, imine pre-formation time, microwave reaction time and reaction temperature, yielding lactams 31 at 100 °C in poor to excellent yield, after only 30 min compared to 48 h under ambient conditions (Scheme 11). 

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

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. 

As we have already mentioned, the ability of imine formation to serve as a useful reaction in templated systems was observed by Lynn et al. in the early 1990s. Use of imine metathesis in DCC was first described by Hue and Lehn in 1997 in a library targeting the production of carbonic... 

Imine metathesis has continued to be a popular exchange reaction for DCLs. Various groups have found novel systems in which the reaction can be applied, as well as interesting ways to halt the equilibration. For example, Wessjohann and coworkers have demonstrated that Ugi reactions can efficiently halt equilibration of an imine DCL, combining an irreversible diversification process with areversible library selection [24]. Xu and Giusep-pone have integrated reversible imine formation with a self-duplication process [25], and Ziach and Jurczak have examined the ability of ions to template the synthesis of complex azamacrocycles [26]. The mechanistically related reactions of hydrazone [27] and oxime [28] exchange have also been explored as suitable foundations for DCL experiments. 

One can in principle combine different exchange reactions in the same system in order to further increase the structural diversity accessed by the library. However, as this compounds the problem of selectivity (i.e., one now has two or more reactions that must exclusively involve one pair of functional groups), there are very few examples thus far of the practical implementation of this concept. An early, highly intriguing example was described by Lehn and coworkers in 2001 [68]. In this system, imine exchange (acyl hydrazone formation) and reversible metal coordination were employed in library generation. 

Figure 3.4 Multistage imine formation and metal complexation produces a diverse library of amine-, salicylaldehyde- and salicylaldimine-zinc complexes.

Figure 3.19 Schematic of the DCC SELEX system. Upper left A library of random 2 -amino RNAs are allowed to equilibrate via imine formation with aldehydes in the presence of target. Bottom left Modified RNAs are bound to the target. Bottom center Modified RNAs bound to the target are separated from unbound RNAs. Bottom right Selected RNAs are eluted and reverse transcribed and amplified to corresponding double-stranded DNA. Upper right The selected double-stranded DNA is transcribed to the 2 -amino RNAs. The selection process is repeated n-cycles and selected conjugated aptamers are identified.

The Zr-catalyzed asymmetric alkylation shown in Eq. (2) [8] illustrates two important principles (1) The catalytic asymmetric protocol can be readily applied to the synthesis of non-aryl imines to generate homochiral amines that cannot be prepared by any of the alternative imine or enamine hydrogenation protocols. (2) The catalytic amine synthesis involves a three-component process that includes the in situ formation of the imine substrate, followed by its asymmetric alkylation. This strategy can also be readily applied to the preparation of arylamines. The three-component enantioselective amine synthesis suggests that such a procedure maybe used to synthesize libraries of homochiral amines in a highly efficient and convenient fashion. 

A small library of isoxazole fused azepines 39 was synthesised by the acid catalysed conjugate addition of 3,5-dimethyl-4-nitroisoxoazole 36 to a,p-unsaturated ketones 37 yielding the adduct 38 followed by tin(II) chloride reduction of the nitro group and imine formation <07ARK266>. 

Along these lines and as a proof of principle, reversible imine formation was implemented in 1997 for the generation of enzyme (carbonic anhydrase) inhibitors from a dynamic covalent library [43] and reversible covalent selection approaches to catalytic systems were presented [44]. 

A dynamic combinatorial library of six components can be generated under thermodynamic control by imine formation and exchange combined with non-covalent bonding within the enzyme binding site and DCL was evaluated for their relative affinities toward the physiologically relevant human carbonic anhydrase hCA I and hCA II isozymes [66]. 

This example clearly demonstrates that it is possible to self-amplify one product in a DCL, namely the one that can self-complementarily direct its own formation. It was shown that the expression of the components in the library evolves along both kinetic and thermodynamic biases that both lead to the amplification of the best duplicator. Importantly, because of the double reversibility of the system (supra-molecular H-bonds and molecular imine condensation), the competition is ruled not only by the differential rates of formation of the components, but also by the possible takeover of the building blocks of the antagonistic competitors, thus leading to the decrease of their absolute concentration. Such a system illustrates the spontaneous screening and selection of the most efficient self-duplicator by the destruction of the entities which are not (or less, such as Al, Am2) able to duplicate themselves. 

In 1992, Goodwin and Lynn reported the first example of template-directed synthesis of DNA analogs via formation of a reversible imino linkage [21]. Five years later, Hue and Lehn described the first use of the reaction of imine condensation for the selection, by DCC, of carbonic anhydrase inhibitors from a library of amines and aldehydes [8], Upon addition of the enzyme, the formation of one library component was strongly amplified when compared to a similar reaction carried out in the absence of template. Since then, imine exchange reaction has been applied... 

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... 

Although cyclization can take place in many ways, according to Kallen [11] the most preferred pathway involves imine formation followed by intramolecular cyclization. During the course of cyclization a new chiral center at C-2 is created thereby giving rise to a diastereomeric mixture namely 2R, 4R and 2S, 4R. An interesting situation arises when the reactant aldehyde is also chiral. The stereochemistry at the newly formed center is controlled by the stereochemistry of the aldehyde [12]. In view of the biological importance of thiazolidine, Patek et al. reported a solid-phase synthesis protocol (Scheme 4) [13]. This enables the synthesis of compound libraries for quick lead optimization. 

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