Solution-phase synthesis of mixed amide libraries by simultaneous additionof functionalities (SPSAF) to a diketopiperazine tetracarboxylic acid scaffold monitored by GC analysis of isobutyl alcohol

A symmetric diketopiperitzine scaffold 2 has been prepared in a very simple two-step procedure from 1-aspartic acid dimethyl ester. This product (a te tracarboxylic acid equally protected at the two symmetric positions) has be en employed as a template for the synthesis of mixed amide libraries in the solution phase using the SPSAF (simultaneous addition of functionalities) strategy. By judicious choice of the amines employed, it is possible to pre pare parallel libraries containing hundreds of products using just a small number of different amines. We have also developed a simple method for moni toring the required conversion of the acid into amides based on an assay of the amount of iBuOH (determined by GC) formed during the coupling mediated by isobutyl chloroformate. We have observed that a conversion higher than 90% (iBuOH by GC) guarantees correct formation of the desired amides. This indirect method for assessing the conversion in a combinatorial reaction em ploying mixed reactants (SPSAF) can conveniently be used for the routine de termination of libraries prepared in the solution phase. In a broader persp ective, the present results contribute as a further step in the development of new and simple systems for monitoring the progress and evolution of com binatorial reactions.