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

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Abstract
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 dipeptide 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.