AbstractA systematic and comprehensive study of the conformational spaces of the Cinchona alkaloids quinine, quinidine, cinchonine, cinchonidine, epiquinine, epiquinidine, epicinchonine, and epicinchonidine using the semiempirical PM3 method is described. The results were analyzed in terms of syn/anti and open/closed/hindered and α/β/γ conformations. Special emphasis was given to the torsion angles T1 (C4a′‐C4′‐C9‐C8), T2 (C4′‐C9‐C8‐N1) and T3 (H‐O9‐C9‐C8) that define the backbone and the hydroxy conformation, respectively. The results reveal the quasi‐enantiomeric relationships between quinine and quinidine and between epiquinine and epiquinidine, and the main structural differences that exist between the therapeutically active Cinchona alkaloids, quinine and quinidine, and their inactive epimers, epiquinine and epiquinidine. The lowest energy conformation of quinine and quinidine is anti‐closed‐α. The lowest energy conformations of epiquinine and epiquinidine are anti‐open‐β and anti‐open‐α, respectively. Low energy conformations with an intramolecular hydrogen bond (N1. . .H. . .O9) were found in epiquinine (the global minimum) and epiquinidine, but not in quinine and quinidine. Chirality 15:637–645, 2003. © 2003 Wiley‐Liss, Inc.