Guanidine library synthesis

Fig. 8. Solid-phase synthesis of a trisubstituted bicyclic guanidine library.

Fig. 9. Solid-phase synthesis of an urea-tethered bicyclic guanidine library from resin-bound polyamines.

This very old synthesis of l,4-dihydropyrimidin-2-ones, which is analogous to the Hantzsch pyridine synthesis (8.14.1.2), is much used, particularly for library synthesis, and many variants of the reaction conditions have been described most often the condensation is acid or Lewis-acid catalysed. The products are important in their own right, but can also be dehydrogenated to give pyrimidin-2-ones. If guanidine is used instead of the urea component, 2-amino-1,4-dihydropyrimidines result. ... 

Dealing with the synthesis of dihydropyridopyrimidinones, the procedure was quite similar to the precedent, involving 2,6-diaminopyrimidin-4(3//)-one as enaminocarbonyl partner, various 1,3-dicarbonyl derivatives, and either aliphatic or aromatic aldehydes in water under microwave irradiations (Scheme 11). Interestingly, the guanidine system was unreactive, and a library of tri- and tetracyclic dihydropyridopyrimidinone derivatives was chemoselectively synthesized in high yields and short reaction times from this environmentally friendly procedure. 

A library containing several million beads can be screened in a single afternoon. Furthermore, the library is reusable, as it may be washed in 8 M guanidine hydrochloride and then re-screened using a different probe. This split synthesis approach displays the ability to generate peptide libraries of incredible variety, variety that can be further expanded by incorporation of, for example, D-amino acids or rarely occurring amino acids. 

Figure 15.21 Synthesis of geometrically varied mono-functionalized poly (amino)-guanidine building blocks ( Libraires trom libraries ) tor the synthesis of geometrically varied lipo-poly-guanidinium-amines.

Many biologically active compounds contain cyclic ureas, including inhibitors of human immunodeficiency virus (HIV) protease and HIV replication [70]. Kim et al. [71] presented an illustration of the synthesis of oligomeric cyclic ureas as nonnatural biopolymers. Applying the libraries from libraries [72] concept, triamines [65] such as those described earlier were used as templates for the generation of different heterocyclic compounds such as cyclic ureas, cyclic thioureas, and bicyclic guanidines [65]. The cyclizations to obtain the five-membered ring cyclic ureas and cyclic thioureas were... 

Similarly, this laboratory has recently described the synthesis of constrained peptidomimetics (118, Scheme 11.14) via intramolecular palladium-catalysed cinnamylation of a variety of amino acid side chains containing heteroatom nucleophiles (117, XH = amine, imidazole, phenol, carbo y). This procedure is remarkable for its scope and efficiency, proceeding rapidly and in high yield independent of the nature of the residues and chain length of the peptide. Further, protection of guanidine, alcohol and amide side chains was not required. These and similar templates would appear to be quite suitable for library investigations. 

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