Synthese von biologisch aktiven Dihydropyrimidinderivaten

In the framework of this project we have elaborated novel and efficient methodology to synthesize and characterize so-called dihydropyrimidines, a family of synthetic compounds which known interesting biological properties. In order for synthetic chemistry to fulfill its role in the 21st century, novel techniques are need to supply large numbers of synthesized compounds in an efficient way. This is particularly important in the context of the drug discovery and development process, where thousands of new compounds are required per day, in order to screen available biological targets derived by biochemical methods (genomics, proteomics). Traditional organic synthesis is orders of magnitude to slow to fulfill this need. Therefore, new techniques have been invented that allow the efficient production of synthetic compounds. One of the methods used, is to apply so-called multicomponent reactions in the synthesis process. In multicomponent reactions, three or more components are reacted at the same time in the same reaction vessel in order to provide a single reaction product. The great advantage of a multicomponent process is that "diversity" can be readily introduced in a single step by variation of the e.g. three building blocks. One such multicomponent process is the so-called Biginelli dihydropyrimidine synthesis, dating back to 1893. Here, three components are condensed to give a highly functionalized dihydropyrimidine scaffold which demonstrated pharmacological efficiency. Unfortunately, under the classical reaction conditions, the synthesis of more complex analogs is difficult. One part of our project was therefore devoted to develop better, more efficient ways to synthesize those substances. We have succeeded in doing so, by employing new technologies such as solid-phase synthesis, or microwave-assisted chemistry. Therefore, large numbers of dihydropyrimidine derivatives can now be prepared very rapidly and efficient and submitted for biological screening. In another part of the project we have dealt with the issue of "chirality". Due to their special structural features, all substances of this type are in fact mixtures of two isomers. Although such mixtures have virtually the same physical properties, the biological activities of these two isomers can be fundamentally different, i.e. one isomer being highly active, the other one toxic. It was therefore necessary to develop methods to separate the two isomers. This was achieved by both physical (chromatographic) methods and by chemical means (biocatalysis). A process was developed to prepare an orally active antihypertensive agent using the latter method. In various spin- off projects other synthetic modifications of those substances were pursued in order to develop more active biologically active compounds or to increase the understanding on how those drugs interact with their biological targets. In short, the main result of this project is that the long-neglected Biginelli dihydropyrimidine synthesis was successfully revived has now become an efficient method in the toolbox of synthetic organic chemists to synthesize interesting molecules.