Polymer-supported combinatorial chemistry: Small organic compound library synthesis and detection

A solid-phase split-mix organic synthesis method was developed to convert polymer-bound functionality into libraries of synthetic organic compounds. Step one consisted of dividing the polymer-bound functional group into equal portions in separate flasks. The polymer in each flask was reacted with slightly different building block compounds to produce a series, or sublibrary, of analogous polymer-bound compounds. The polymer beads were mixed and then again equally divided into separate flasks; each treated with a new building block reagent. This procedure repeated multiple times yields a large number of compounds with high efficiency whose chemical diversity could be harnessed to search for biologically active molecules. Prior to a recombination step, small molecule products could be liberated from the polymer for analysis. GC-MS was used in each library generated to established that each sub-library contained the anticipated analogues. In addition, GC analysis illustrates that, while there were no purification steps involved in this solid-phase analogous organic synthesis save bead washings between steps, the desired products are obtained in excellent purity. To establish that there was one compound per bead, a single bead of polymer (200-400 mesh) was selected from a library, treated to cleave the product, and analyzed by GC-MS. This methodology was used to generate a nine-compound library. Further, a 27-compound library was constructed and analyzed for antioxidative efficiency in a polymer-free (ferric thiocyanate assay) deconvolutive assay. A third, 64-compound library was delivered by iterative application of nitrile oxide 1,3-dipolar-cycloaddition producing polymer-bound triisoxazoline pseudopeptide analogues.