Library synthesis substrate-based approach

In no time the concept of combinatorial chemistry has become a valuable tool in the process of drug discovery. The popularity of this approach is based on the possible synthesis and screening of libraries containing millions of compounds. In the field of asymmetric catalysis, combinatorial methods could help to discover new efficient catalysts as the number of possible metal-ligand combinations is immense. In an ideal case a substrate would be screened against a library of catalysts or a library of substrates against one catalyst to find out the most efficient conditions for the reaction in question. Up to now this has been essentially a utopian idea, but the first examples of the efficient detection of new catalysts and their reactions using combinatorial methods were recently described in the literature [1]. 

A variety of small-molecule inhibitors of protein geranylgeranyltransfer-ase type-I (GGTase-I) have been developed over the years. In this chapter, we describe our approach to obtain novel inhibitors of GGTase-I (GGTIs). We screened a library of compounds derived from phosphine-catalyzed annulation reactions of allenoates and A-sulfonyl arylamines and obtained hits, P3-E5 and P5-H6, which exhibited specific inhibition of GGTase-I. Further derivatization of P5-H6 based on the C-terminal sequence of the GGTase-I protein substrates led to the synthesis of P61-A6 that has... 

A similar approach has been used for the synthesis of 3-lH-pyrazolo[3,4-fc]pyridyl-indole ° and 2-aminochromene libraries, the latter being performed solvent free using a clay as a support and base. In addition, a library of over 100 derivatized substituted 2-pyridones (21 x 5 members) has been prepared by the reaction of 1,3-cyclohexane-diones, dimethylformamide dimethylacetal, and various cyanoacetamides (Scheme 4.10). The outcome of the reaction could be controlled to furnish different products by changing the basicity of the medium to involve either the amide or nitrile functionality of the cyanoacetamide substrate during the 2-pyridone ring-formation step. 

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