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

Shu Kobayashi, Masaharu Ueno, Ritsu Suzuki, Haruro Ishitani, Hye-Sook Kim, Yusuke Wataya

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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.

Original languageEnglish
Pages (from-to)6833-6841
Number of pages9
JournalJournal of Organic Chemistry
Volume64
Issue number18
DOIs
Publication statusPublished - Sep 3 1999

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Antimalarials
Bioactivity
Alkaloids
Aldehydes
Lewis Acids
Tin
febrifugine
Enantioselectivity
Isomerization
Surface-Active Agents
Amines
Catalysts

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Catalytic asymmetric synthesis of antimalarial alkaloids febrifugine and isofebrifugine and their biological activity. / Kobayashi, Shu; Ueno, Masaharu; Suzuki, Ritsu; Ishitani, Haruro; Kim, Hye-Sook; Wataya, Yusuke.

In: Journal of Organic Chemistry, Vol. 64, No. 18, 03.09.1999, p. 6833-6841.

Research output: Contribution to journalArticle

Kobayashi, Shu ; Ueno, Masaharu ; Suzuki, Ritsu ; Ishitani, Haruro ; Kim, Hye-Sook ; Wataya, Yusuke. / Catalytic asymmetric synthesis of antimalarial alkaloids febrifugine and isofebrifugine and their biological activity. In: Journal of Organic Chemistry. 1999 ; Vol. 64, No. 18. pp. 6833-6841.
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