Synthetic approaches to peptide analogues containing 4, 4-difluoro-L-proline and 4-keto-L-proline

An improved synthesis of 4, 4-difluoro-L-proline is described. A key step in this synthesis involves the fluorination of Z-4-keto-L-proline benzyl ester, using diethylaminosulfur trifluoride (DAST), to give the corresponding Z-4, 4-difluoro-L-proline benzyl ester. Preparation of dipeptide derivatives containing 4, 4-difluoro-L-proline has been accomplished by initial synthesis of the corresponding 4-keto-L-proline depeptide derivatives, which were then fluorinated with DAST. A one-step synthesis of Boc-4-keto-L-proline from Boc-4-hydroxy-L-proline by chromium trioxide oxidation is reported. These synthetic procedures should facilitate the preparation of a variety of peptide analogues containing 4, 4-difluoro-L-proline and 4-keto-L-proline.