Asymmetric synthesis of a novel antinociceptive substance, incarvillateine

新型抗伤害物质incarvillateine的不对称合成

• 批准号: 14572011
• 负责人: KIBAYASHI Chihiro
• 金额: $ 2.69万
• 依托单位: Tokyo University of Pharmacy and Life Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572011/
• 关键词: non-opioid; analgestic agent; incarvilateine; incavilline C; monoterpene alkaloids; three-component coupling; Heck reaction; photodimerization; モノテルペンアルカロイド; Incarvillateine; Incarvine C; Monoterpene Alkaloid; Antinociceptive Activity; Total

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.

基于使用 6-epi-incarvilline 作为共同前体的策略，我们开发了用于组装 6-epi 的策略，首次全合成了新型强效镇痛单萜生物碱 incarvillateine 及其同源生物碱 incarvine C 和 incarvilline。 -incarvilline涉及通过三组分偶联反应构建适当的三取代环戊酮(S)-4-甲硅烷氧基环戊烯酮使用由(E)-甲锡烷基和碘甲烷原位生成的有机锌试剂，得到2,3,4-三取代的环戊烷作为单一立体异构体，随后闭环得到八氢环戊[c]吡啶。该反应是在甲酸存在下使用钯(II)催化剂通过还原赫克反应进行的。由此得到6-Epi-incarvilline，通过C6差向异构化和(+)-incarvilline C与阿魏酸的Mitsunobu缩合，成功实现了(-)-incarvillateine的全合成。 6- 表-因卡维林与 α-truxillic 酸，通过 O-甲苯磺酰的头尾光二聚化制备阿魏酸的衍生物。