Enantioselective Synthesis of the Pyrrolidine Core of Endothelin Antagonist ABT-627 (Atrasentan) via 1,2-Oxazines

Diastereoselective syntheses of the pyrrolidine core 6a of the endothelin antagonist ABT-627 (Atrasentan) either as a racemic mixture or as an enantiopure compound are presented. The crucial steps of these syntheses utilized the highly diastereoselective conjugate addition of 1,3-benzodioxol-5-yllithium to racemic 6H-1,2-oxazine 3 or enantiopure 6H-1,2-oxazines 7 or 8, followed by trapping with ethyl cyanoformate (Mander′s reagent). The resulting 5,6-dihydro-4H-1,2-oxazines were transformed into the 2,3,4-trisubstituted pyrrolidine 6a. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)