New Trends in Solution-Phase Combinatorial Synthesis

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 

SYNTHETIC ORGANIC LIBRARIES SOLUTION-PHASE LIBRARIES 

2 An Example Synthesis and Screening of a Reversible Imine Library 

Hasenkopf et al. (306) reported the synthesis of a dynamic 12-member, template-directed imine library L27 obtained from the reversible condensation of three aldehydes (monomer set Mi, Fig. 8.54) with four primary amines (monomer set M2, Fig. 8.54) in buffered aqueous conditions followed by irreversible reduction to amines L28 with sodium cyanoborohydride. The library was prepared in the presence of a large excess of M2, to prevent further condensation of an aldehyde onto the secondary amine product. A template-driven imine library L27 was prepared in the presence of the metalloenzyme carbonic anhydrase 11 (CAll). After the template-assisted, reversible dynamic reaction was complete, the reducing agent was added and the amine library L28 was produced (Fig. 8.54). Without any template the unbiased, equilibrated imine mixture L29 was then reduced to the mixture of amines L30 (Fig. 8.54). The different abundance of library components L28 and L30, reflecting the affinity of library components for CAll, was determined by comparing the HPLC traces of the stable amine mixtures. 

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 

---