Synthesis of fluorine-containing α-amino acids in enantiomerically pure form via homologation of Ni(II) complexes of glycine and alanine Schiff bases

Development of synthetic methodology for preparation of enantiomerically pure fluorine containing amino acids (FAAs) is one of the most actively pursued areas of fluoroorganic chemistry. This review provides a comprehensive treatment of literature data dealing with asymmetric synthesis of FAAs via homologation of chiral and achiral Ni(II) complexes of glycine and alanine Schiff bases using fluorinated electrophilic reagents. The homologation approaches include: (1) alkyl halide alkylations; (2) aldol; (3) Michael and (4) Mannich addition reactions. Furthermore, Ni(II) complexes of Schiff bases of FAAs can be used for deracemization of racemic FAAs and (S) to (R) interconversion, providing additional synthetic opportunities for preparation of enantiomerically pure FAAs. Particular attention is given to the mechanistic considerations where fluorine can significantly influence the stereochemical outcome of the asymmetric transformation, as compared with the reactions of fluorine-free substrates. Aspects of practicality, cost-structure and large-scale synthesis of FAAs using this methodology are critically discussed.