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 language | English |
|---|---|
| Pages (from-to) | 6833-6841 |
| Number of pages | 9 |
| Journal | Journal of Organic Chemistry |
| Volume | 64 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - Sep 3 1999 |
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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 journal › Article
}
TY - JOUR
T1 - Catalytic asymmetric synthesis of antimalarial alkaloids febrifugine and isofebrifugine and their biological activity
AU - Kobayashi, Shu
AU - Ueno, Masaharu
AU - Suzuki, Ritsu
AU - Ishitani, Haruro
AU - Kim, Hye-Sook
AU - Wataya, Yusuke
PY - 1999/9/3
Y1 - 1999/9/3
N2 - 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.
AB - 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.
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U2 - 10.1021/jo990877k
DO - 10.1021/jo990877k
M3 - Article
VL - 64
SP - 6833
EP - 6841
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
SN - 0022-3263
IS - 18
ER -