Catalytic Asymmetric Synthesis of Antimalarial Alkaloids Febrifugine and Isofebrifugine and Their Biological Activity
- 19 August 1999
- journal article
- research article
- Published by American Chemical Society (ACS) in The Journal of Organic Chemistry
- Vol. 64 (18), 6833-6841
- https://doi.org/10.1021/jo990877k
Abstract
Antimalarial alkaloids febrifugine (1) and isofebrifugine (2) were efficiently 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 aldehyde 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 Mannich-type three-component reaction of an aldehyde, an amine, and a vinyl ether using a Lewis acid−surfactant combined catalyst (LASC), and the key intermediates 16 and 17 were obtained in high yields. The final coupling reactions of bromoacetone 14 with 4-hydroxyquinazoline were carried out using basic conditions, and successive deprotection gave 1 and 2, respectively, without any isomerization. These unambiguous total asymmetric syntheses revealed that the absolute configurations of febrifugine and isofebrifugine were 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 synthesized febrifugine and isofebrifugine, and their antipodes, were examined. It was revealed that the activities and selectivities of natural febrifugine and isofebrifugine were much higher than those of the antipodes.Keywords
This publication has 40 references indexed in Scilit:
- Catalytic Asymmetric Synthesis of Both Syn- and Anti-β-Amino AlcoholsJournal of the American Chemical Society, 1998
- A Novel Chiral Catalyst System, Tin(II) Triflate, a Chiral Diamine, and Tin(II) Oxide, in Asymmetric Aldol ReactionsChemistry Letters, 1994
- Use of lanthanide(III) ions as catalysts for the reactions of amines with nitrilesThe Journal of Organic Chemistry, 1987
- Trifluoromethylsulfonates of tinInorganic Chemistry, 1977
- Human Malaria Parasites in Continuous CultureScience, 1976
- Stereochemistry of febrifugine. II. Evidence for the trans configuration in the piperidine ringThe Journal of Organic Chemistry, 1973
- Streptomyces Antibiotics. XXII. Configuration of Streptose and StreptobiosamineJournal of the American Chemical Society, 1949
- Alkaloids of Dichroa Febrifuga Lour.Journal of the American Chemical Society, 1948
- Antimalarial Constituents of Chinese Drug, Ch'ang Shan, Dichroa febrifuga LourJournal of the American Chemical Society, 1948
- AN ALKALOID WITH HIGH ANTIMALARIAL ACTIVITY FROM DICHROA FEBRIFUGA1Journal of the American Chemical Society, 1947