Catalytic asymmetric synthesis of antimalarial alkaloids febrifugine and isofebrifugine and their biological activity

Antimalarial alkaloids febrifugine (1) and isofebrifugine (2) were efficien tly synthesized from simple achiral starting materials on the basis of the catalytic asymmetric synthesis. The first key reaction was performed using the tin(II)-mediated catalytic asymmetric aldol protocol to afford chiral a ldehyde 3 in high yield with high diastereo- and enantioselectivities. The second key step, a Mannich-type reaction, did not give satisfactory results according to the conventional methods. We then developed a novel aqueous M annich-type three-component reaction of an aldehyde, an amine, and a vinyl ether using a Lewis acid-surfactant combined catalyst (LASC), and the key i ntermediates 16 and 17 were obtained in high yields. The final coupling rea ctions of bromoacetone 14 with 4-hydroxyquinazoline were carried out using basic conditions, and successive deprotection gave 1 and 2, respectively, w ithout any isomerization. These unambiguous total asymmetric syntheses reve aled that the absolute configurations of febrifugine and isofebrifugine wer e not (2'S,3'R) and (2'R,3'R) as reported previously but (2'R,3'S) and (2'S ,3'S), respectively (1' and 2'). Finally, antimalarial activities of the sy nthesized febrifugine and isofebrifugine, and their antipodes, were examine d. It was revealed that the activities and selectivities of natural febrifu gine and isofebrifugine were much higher than those of the antipodes.