Stereoselective Synthesis of [5-[4,4,4,4′,4′,4′-Hexafluoro-N-(2-hydroxyethoxy)-D-valine]]- and [5-[4,4,4,4′,4′,4′-Hexafluoro-N-(2-hydroxyethoxy)-L-valine]cyclosporin A

✍ Scribed by Marcel K. Eberle; Reinhart Keese

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: German
• Weight: 284 KB
• Volume: 93
• Category: Article
• ISSN: 0018-019X
• DOI: 10.1002/hlca.201000175

✦ Synopsis

Addition of various amines to the 3,3-bis(trifluoromethyl)acrylamides 10a and 10b gave the tripeptides 11a -11f, mostly as mixtures of epimers (Scheme 3). The crystalline tripeptide 11f 2 was found to be the N-terminal (2-hydroxyethoxy)-substituted (R,S,S)-ester HOCH 2 CH 2 O-d-Val(F 6 )-MeLeu-Ala-O t Bu by X-ray crystallography. The C-terminal-protected tripeptide 11f 2 was condensed with the Nterminus octapeptide 2b to the depsipeptide 12a which was thermally rearranged to the undecapeptide 13a (Scheme 4). The condensation of the epimeric tripeptide 11f 1 with the octapeptide 2b gave the undecapeptide 13b directly. The undecapeptides 13a and 13b were fully deprotected and cyclized to the [5-[4,4,4,4',4',4'-hexafluoro-N-(2-hydroxyethoxy)-d-valine]]-and [5-[4,4,4,4',4',4'-hexafluoro-N-(2-hydroxyethoxy)-l-valine]]cyclosporins 14a and 14b, respectively (Scheme 5). Rate differences observed for the thermal rearrangements of 12a to 13a and of 12b to 13b are discussed. Scheme 1. Cleavage Reaction of Cyclosporin A (1a)