Guanidine library

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.

A second method of incorporating phase into the selection process is to immobilize the target. Essentially an affinity chromatographic method, this allows nonbound library constituents to be washed away, leaving the selected compound(s) bound to resin. Eliseev s guanidine resin and Still s peptide-bearing beads, both discussed above in the context of exchange reactions, are examples of these. 

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. 

The triazene T2 linker14 and the improved T2 linker57 systems offer a unique approach to the formation of guanidines in which all three substituents can be varied to a wide extent. Starting from disubstituted triazene on the T2 linker, deprotonation using NaH/DMF and subsequently acylation by the addition of isothiocyanates (Scheme 12) yielded a library of resin-bound thioureas. For the reaction of the thioureas with amines, the use... 

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.

A small library of di- and trisubstituted pyrimidines was prepared by condensation of amidines and guanidines with a range of alkynones. The reaction could be performed under conventional conditions (reflux in acetonitrile, ca. 82 °C), albeit 2 hours was required for the reaction to go to completion. Microwave dielectric heating in sealed vessels at 120 °C (ca. 38 °C above the boiling point of acetonitrile) diminished the reaction time to 40 min [120,121] (Scheme 46). 

Finally, two polycyclic systems were built. First, the cyclic guanidine embedded into the 2-aminobenzimidazole nucleus 9.20a-f was used to buM the tricyclic library L9 (7680 members. Fig. 9.13) then a complex spiro-piolyheterocycle library LIO... 

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. ... 

Sulfonyl resins (23) have been developed to prepare indoles via a palladium-catalyzed cyclization. Cleavage was carried out with TBAF with excellent yields and purities (85-100%) [78]. Likewise, a library of bivalent ligands (including guanidine, pyridinium and carboxylic and sulfonic acids constituents) for a protein receptor was prepared on nitrobenzenesulfonamide resin 24. Cleavage was achieved with sodium sulfide [79]. 

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... 

Other advantageous reaction sequences enable the preparation of complex libraries of thiourea or guanidine via an analogous catch and release process. This strategy, although very efficient, is nevertheless closely related to SPS, and limited to only one step. 

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