Practical Synthesis of Fluorinated Amino Acids: Process Optimization toward Improved Sustainability

Chiral Ni(II) complexes have emerged as powerful platforms for the synthesis of noncanonical amino acids. Recent advances have enabled gram-scale access to structurally diverse fluorinated amino acids. Nevertheless, the process reported earlier still suffers from practical limitations, including multistep manipulations, prolonged reaction times, and substantial solvent consumption. In this work, we streamline existing methodologies by developing an operationally simple, time-efficient, and sustainability improved protocol. Using an (R)-glycine Schiff base Ni(II) complex as the chiral auxiliary, we successfully prepared a series of Fmoc-protected fluorinated (R)-amino acids for the first time. This strategy provides a practical route for accessing fluorinated numerous new building blocks and facilitates their broader application in peptide synthesis.