The non-proteinogenic amino acid (2S)-2-amino-3,3-bis(4-fluorophenyl)propanoic acid [(S)-1] is a key
intermediate required for the synthesis of Denagliptin (2a). Denagliptin is a dipeptidyl peptidase IV (DPP
IV) inhibitor that is being developed for the treatment of type-2 diabetes mellitus. A diastereoselective,
cost-efficient synthetic procedure for (S)-1 was developed by alkylating a Ni(II) glycine equivalent derived
from (S)-2-[(N-benzylprolyl) amino] benzophenone [(S)-BPB]. The alkylated product was then
decomposed to isolate the target amino acid (S)-1 (ee >99%) and ligand (S)-BPB, which can be reused in
subsequent reactions. The enantiomer (R)-1 and racemate (rac)-1 were synthesized from their corresponding
Ni(II) glycine equivalents. Denagliptin diastereomers (2), derived from the key intermediates
(S)-1, (R)-1, and (rac)-1 were synthesized, and their dipeptidyl peptidase IV inhibitory activities were
investigated. These findings are important in the design and synthesis of DPP IV inhibitors.