N-Acyl-N-alkylsulfonamide und aktivierte Carbonsäuren als polymergestützte Reagenzien in der konvergenten Parallelsynthese

Main focus of the present studies was the polymer assisted parallel synthesis of leadstructure based amide libraries. Furthermore, the conceptional development of “naked-eye” detectable reactions on solid support was investigated. The applied strategy to prepare the desired amides may be divided into three major operational steps a-c. After the selection of several well-suited leadstructures, the required amino templates were synthesized in solution, utilizing established solution phase chemistry (a). Following a second route, various acyl residues were coupled onto a polymer support (b) and to some extent further modified on solid phase (b'). Linkage of the acyl moieties was achieved either employing a couple&release linker based on polymer bound 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid, or using the Kenner safety-catch linker modified by Ellman. The final transfer of polymer bound carboxylic acid equivalents onto the amino templates (c) yielded the desired amide libraries, that were successively probed in terms of biological activity through several collaboratores. Executing this convergent synthesis protocol, test compounds could be made available fast, in a quantitatively and qualitatively high-grade fashion, which could be exemplified applying eight different amino templates. The subsequent pharmacological evaluation of the obtained amide libraries focussed on the inhibition of human pathogenic protozoa such as Plasmodium falciparum, Trypanosoma brucei rhodesiense etc., or the D2/D3-dopaminereceptor selectivity and was conducted by our partners. The limited possibility to monitor proceeding reactions in polymer assisted chemistry represents a severe drawback in this field of synthesis. Common techniques often do not meet the special requirements of polymer bound reagents or afford serious monetary investments. Therefore the interest in simple “naked-eye” detectable principles such as colour tests, additionally polymer bound indicators or combination of polymers with both, indicator- and functional groups, increases year by year. Starting from the modified Kenner safety-catch linker, insertion of a phenylazo-moiety into the sulfur-benzene bond, led to a coloured species of the Kenner linker, that allowed for visual estimation of the loading level on the one hand, and furthermore rendered possible the observation of the linker integrity throughout the synthesis on the other hand. The coloured modification could be demonstrated to allow for comparably precise estimation of the loading level as well as to maintain its general functionality. The transfer of these linker types onto modern and economically priced PEI-resins (“Polyethyleneimine”) could be performed, but unfortunately it was not possible to preserve the outstanding attributes of this polymer material till today in a satisfying manner. Looking at a multistep synthesis on solid phase, a colour change of the polymer after every key step in the synthetic sequence seems to be desireable to facilitate the observation of the conversion progress. The Kenner safety-catch linker requires as a central element alkylation of the N-acylsulfamoylfunctionality prior to the transfer of the acyl residue onto a nucleophile. Due to the fact that O-alkylisoureas turned out to be reasonable alternatives for the often highly toxic reagents used in standard acitvation protocols, experiments were conducted applying coloured reagents. Initial results identified N',N-diisopropyl-O-(3,5-dinitrobenzyl)-isourea as the first reagent demonstrating the desired dyeing of the polymer after successful activation.