Multistep convergent solution-phase combinatorial synthesis and deletion synthesis deconvolution

A solution-phase convergent versus linear, divergent solid-phase synthesis of chemical libraries is illustrated enlisting the 2-fold dimerization of iminodiacetic acid diamides ultimately incorporating eight variable groups. The first dimerization is conducted with omega-alkene carboxamide derivatives of iminodiacetic acid which sets up the second dimerization conducted with the olefin metathesis reaction. This latter reaction randomizes the linking tether length adding a ninth degree of diversification suitable for the discovery of receptor dimerization antagonists and their linkage into potential receptor dimerization agonists. Unlike the divergent synthesis of libraries which is amendable to solid-phase synthesis techniques, such convergent syntheses are especially suited for solution-phase synthesis and are precluded by conventional solid-phase techniques since the combining components typically would be on mutually exclusive phases. Two mixture libraries of 476 775 and 114 783 975 compounds were prepared in five steps from four w-alkene carboxamides and 10 or 20 amines, respectively. Deconvolution of the library mixtures by positional scanning or a complementary technique we introduce as deletion synthesis can be conducted up front for depository libraries subjected to multiple assays. For convergent dimerizations such as that illustrated herein, only deletion deconvolution can provide information on all components of the mixture including the unsymmetrical combinations.