Syntheses of Chiral Fluorinated Amino Acids and Peptides

The replacement of hydrogen atoms by fluorine in organic molecules has become a very important and powerful tool in various fields of research, mainly because of the fact that such a modification usually has a very dramatic effect on the physical, chemical, biological, and medical properties of these compounds. One class of fluorine containing compounds that has attracted a lot of interest for biomedical applications are fluorine containing amino acids and peptides. However, it is fair to say that the synthesis of chiral fluorinated amino acids or peptides still represents a major synthetic challenge. In this project plan to overcome this current limitation by establishing novel catalytic synthesis strategies to access chiral fluorinated - and -amino acid derivatives or peptides. Once successful, this project should thus deliver new powerful synthesis tools that will be of interest to organic and medicinal chemists and will finally give access to compounds that were not accessible with the existing state of the art methods. Mario Waser1

The replacement of hydrogen atoms by fluorine in organic molecules has become a very important and powerful tool in various fields of research. Although H and F do not differ too much with respect to their steric demand, these modifications usually have a very dramatic effect on the physical, chemical, biological, and medical properties of these compounds. Among different classes of fluorine-containing organic molecules, enantiomerically-enriched fluorinated amino acids and peptides turned out to be especially promising lead compounds for numerous (biological) applications. As a consequence, the development of new efficient asymmetric synthesis methods to access these valuable targets from simple starting materials is an important task. Accordingly, the primary goal of this project was to introduce novel (asymmetric) methods allowing for the synthesis of fluorinated a- and b-amino acids (AA). Our main focus was on the following three (conceptually overlapping) targets: a) Synthesis of a-fluoro-a-amino acids and derivatives thereof; b) synthesis of fluoroalkylated a-amino acids and derivatives; and c) a-F and a-fluoroalkylated b-amino acid derivatives. We have carried out very detailed investigations in all of these three subtopics and developed a variety of new strategies to access the targeted amino acids. In addition, we have gathered a detailed understanding about the scope and limitations of the different methods as well as the sometimes problematic stabilities of the herein introduced derivatives. Furthermore, some of the observations made herein led to interesting side-projects either, thus opening new paths for future research directions as well.