Conformation of epicinchonine and cinchonine in view of their antimalarial activity: x-ray and theoretical studies

Abstract

X-ray structure analysis was carried out for a single crystal of 9-epi-10,11-dihydrocinchonine in the form of free base obtained by stereoselective interconversion of cinchonine via 9-O-tosylcinchonine. An intramolecular hydrogen bond was found between the carbinol hydroxyl group, -O12-H12, and the quinuclidine nitrogen atom, N1, with the parameters: O12...N1=2.688(3)A, O12-H12=0.84(4)A, N1...H12=2.11(4)A and O12-H12...N1=126(3) degrees. Theoretical calculations for isolated molecules of epicinchonine and cinchonine with the use of AM1 semiempirical method and comparative studies of the crystal structures have shown that the conformation of the alkaloid molecules with respect to the C8-C9 bond depends on the absolute configuration at C9. The conformation with respect to the C9-C16 bond depends on the protonation of N1 for threo but not for erythro alkaloids. It was established that the ability to form inter- or intramolecular hydrogen bonds is determined by the energetically preferred conformations of erythro and threo alkaloids, respectively. In most cases the conformations preferred for erythro alkaloids are energetically forbidden for their threo epimers and vice versa. The differences in conformation and capability to form intramolecular hydrogen bonds may explain why their antimalarial activities are incomparable.