Small substituted heterocycles are an exceptionally diverse class of compounds, showing a wide spectrum of biological activity. These include antibacterials, antifungals (thiazolidinones, b-lactams), antihistamines and anti-inflammatory compounds (thiazolidinones), antihypertensives (dihydropyridines, pyrrolidines), antiepileptics (hydantoins), anxiolytics and reverse transcriptase inhibitors (benzodiazepines). The usefulness of heterocycles as scaffolds for library generation has not gone unnoticed. A wide variety of heterocyclic compound libraries have been synthesized by solid phase methods (Thompson and Ellman, Chem. Rev., 1996, 96, 555-600; Fruchtel and Jung Angew., Chem. Int. Ed. Engl., 1996, 35, 17-42). These include benzodiazepins, pyrrolidines, hydantoins, 1,4-dihydropyridines, isoquinolinones, diketopiperazine, benzylpiperazines, quinolones, dihydro- and tetrahydroisoquinolines, 4-thiazolidinones, b-lactams, benzisothiazolones, pyrroles and imidazoles. Some solution phase heterocylic libraries have also been generated (Holmes, C. P. et. al., J. Org. Chem.,1995, 60, 7328-7333). Many biologically active compounds have been discovered from these libraries, including a potent tyrosine kinase inhibitor from a benzodiazepin library, a neurokinin-2 receptor antagonist from a diketopiprazine library, and an angiotensin-converting enzyme inhibitor from a pyrrolidine library, to name a few.
Given the large number of potential heterocyclic templates, how can we evaluate the most appropriate scaffolds for the problem at hand? How can we make use of the pseudo dilution effect on solid phase to carry out heterocyclic chemistry that is difficult or impossible to do in solution? Given the demonstrated usefulness of NMR and IR methods on resin bound compounds, would solid phase be a good medium to investigate heterocyclic reaction mechanisms?
Finally, the use of combinatorial chemistry is not limited to medicinal chemistry. For example, a pyrrolidinemethanol library has been generated by Liu and Ellman for asymmetric catalyst development and optimization (J. Org. Chem., 1995, 60, 7712-7713). To what extent would such non-therapeutically oriented heterocyclic combinatorial libraries find utility in other areas of science?
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