2003 Fiscal Year Final Research Report Summary
Asymmetric synthesis of a novel antinociceptive substance, incarvillateine
| Project/Area Number |
14572011
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Tokyo University of Pharmacy and Life Science |
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Principal Investigator |
KIBAYASHI Chihiro Tokyo University of Pharmacy and Life Science, Department of Pharmacy, Professor, 薬学部, 教授 (80057330)
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| Co-Investigator(Kenkyū-buntansha) |
ABE Hideki Tokyo University of Pharmacy and Life Science, Department of Pharmacy, Research Associate, 薬学部, 助手 (00328551)
AOYAGI Sakae Tokyo University of Pharmacy and Life Science, Department of Pharmacy, 薬学部, 助教授 (30212385)
AOYAGI Sakae Tokyo University of Pharmacy and Life Science, Department of Pharmacy, Associate Professor (30212385)
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| Project Period (FY) |
2002 – 2003
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| Keywords | non-opioid / analgestic agent / incarvilateine / incavilline C / monoterpene alkaloids / three-component coupling / Heck reaction / photodimerization |
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| Research Abstract |
The first total synthesis of a novel potent antinociceptive monoterpene alkaloid incarvillateine and its congenetic alkaloids incarvine C and incarvilline has been achieved based on the strategy using 6-epi-incarvilline as a common precursor. The strategy we have developed for assembling 6-epi-incarvilline involves the construction of an appropriately trisubstituted cyclopentanone via a three-component coupling reaction of (S)-4-siloxycyclopentenone using the organozinc reagent, generated in situ from (E)-stannylalkene, and iodomethane, affording the 2,3,4-trisubstituted cyclopentane as a single stereoisomer. Subsequent ring closure to the octahydrocyclopenta[c]pyridine was performed by means of a reductive Heck reaction using palladium(II) catalyst in the presence of formic acid. 6-Epi-incarvilline thus obtained was converted to (-)-incarvilline via C6 epimerization and (+)-incarvine C by Mitsunobu condensation with ferulic acid. The total synthesis of (-)-incarvillateine was successfully achieved by Mitsunobu condensation of 6-epi-incarvilline with the α-truxillic acid, prepared by head-to-tail photodimerization of the O-tosyl derivative of ferulic acid.
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