Enantioselective synthesis of encecaline-derived potent antimalarial agents.
The high antiplasmodial activity of racemic benzylamines rac-1 and rac-2 stimulated the synthesis of pure enantiomers. Ellman's chiral sulfinamides (S)-6 and (R)-6 were used as chiral auxiliaries. Condensation of prochiral ketone 5 with enantiomerically pure sulfinamides (S)-6 and (R)-6 and subsequent NaBH4 reduction provided predominantly unlike configured diastereomers (S,R)-8 and (R,S)-8 (ratio unlike-8:like-8 = 90:10). The same transformation of phenol 4 led to the diastereomeric sulfinamides (S,R)-12 and (S,S)-12 in the ratio 60:40. Acid hydrolysis of the diastereomerically pure sulfinamides followed by monobenzylation yielded the enantiomerically pure benzylamines (R)-1, (S)-1, (R)-2 and (S)-2. The enantiomeric purity of the products was proven by chiral HPLC and the absolute configuration by CD-spectroscopy. Generally, benzylamines with (R)-configuration show higher antiplasmodial activity than their corresponding (S)-configured enantiomers. Phenol (R)-2 represents a very potent lead against P. falciparum, with an IC50 value of only 0.026 μM against the NF54 strain. The very high eudismic ratio of 34 indicates the enantioselective interaction of phenol (R)-2 with a particular target protein of P. falciparum.
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany. wuensch@uni-muenster.de.
Dipak
D
Harel
Dirk
D
Schepmann
Reto
R
Brun
Thomas J
TJ
Schmidt
Bernhard
B
Wünsch
D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects; D013237:Stereoisomerism; D013379:Substrate Specificity; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects
C588172:6-(1-(benzylamino)ethyl)-2,2-dimethyl-2H-chromen-7-ol; D000962:Antimalarials; D001578:Benzopyrans; D001596:Benzylamines; D007659:Ketones; C588171:N-benzyl-1-(7-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethanamine; D010636:Phenols; C030796:benzylamine