Autor: Daniel Wachtendorf

The present work deals with the synthesis of novel scaffolds from β-oxoesters that are commercially available or readily accessible. The dissertation is divided into four projects that were worked on during the course of the PhD. In the first project, an optically active octahydrocyclopenta[c]pyridine scaffold ent-100 was prepared from a commercially available piperidone derivative 115 in five steps and fused to an indole derivative. The secondary amino function of the compound was then further functionalized. Thus, six derivatives of the new scaffold could be synthesized. All of these are of interest in medicinal chemistry. Interesting and important synthetic steps are the asymmetric allylation and the Fischer indole synthesis. In the next project, the enantiospecificity of the eight-membered lactam synthesis developed in the Christoffers group was observed. In this way new insights into the mechanism of ring expansion could be gained. For this purpose, an optically active precursor ent-103 was first synthesized from the indanone-derivative 104. This was then converted into the eight-membered ring lactam rac-102 in the bismuth-catalyzed reaction. In the major part of the work, an improved synthetic route to the scaffold of the active pharmaceutical ingredient Cebranopadol, was developed. Starting from benzald-ehyde, the β-oxoester 121 could be synthesized in four steps. Decarboxylation of ester 121 and a subsequent oxa-Pictet-Spengler reaction resulted in the scaffold trans-107a-d. From this it was possible to synthesize cebranopadol by an Eschweiler-Clarke methylation as well as seven derivatives of the active compound by further functionalizations. In contrast to the new method, the original synthetic route of the biologically active compound does not offer the possibility of derivatizing the amine at the end of the synthetic route, since the dimethylamine function is already installed at the beginning of the synthesis. Key steps here are the decarboxylation of the oxoester 121 and the oxa-Pictet-Spengler reaction. The last thing that was dealt with was the novel quinazoline scaffold. Based on the findings of the Christoffers working group, a decaline derivative rac-114 was constructed from benzaldehyde 108 in seven steps. The benzo[g]quinazoline rac-98h could be prepared by a Vilsmeier reaction to the carbaldehyde rac-126, followed by a condensation with acetamidine).