Die Synthese von β,β-Diaryl-α-Aminosäurehybriden zur Modifikation von Peptidhormonen

This work covers the development of a synthetic access to α-amino acid hybrids composed of encoded α-amino acids. The sequential modification of the β-position of alanine using directed C–H activation mainly gave rise to hybrids of tryptophan and phenylalanin, among other derivatives. The anti-periplanar χ-space arrangement of the amino acid hybrids was defined through β-disubstitution, which allowed the pre-synthetic spacial planning of substituent orientation. Furthermore, new concepts were introduced to enable the mild and selective cleavage of amide-based, C-terminal directing groups. Using this new method, non-planar amides could successfully be used in unusual transamidation reactions and were characterized by crystallographic and in silico methods. Moreover, the altered amide geometry facilitated the C-terminal derivatization of the α- amino acid hybrids. In conclusion, the synthetic concepts of C–H activation were improved and the chemistry of amidebased directing groups was revisited to access gram-scale quantities of novel α-amino acid hybrids. These ready-to-use building blocks for automated peptide synthesis enabled the formation of tailored peptide hormones with distinct structural changes and unique biological profiles.