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.
Nicke, Lennart: Die Synthese von β,β-Diaryl-α-Aminosäurehybriden zur Modifikation von Peptidhormonen. : Philipps-Universität Marburg 2020-10-14. DOI: https://doi.org/10.17192/z2020.0491.
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