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.

本文首次以6-外-incarvilline为共同前体，合成了一种新型强效抗伤性单萜生物碱incarvillateine及其同源生物碱incarvine C和incarvilline。我们已经开发的组装6-外-incarvilline的策略包括通过(S)-4-硅氧烷环戊酮的三组分偶联反应构建适当的三取代环戊酮，使用有机锌试剂，由(E)-斯坦烯和碘甲烷原位生成，提供2,3,4-三取代环戊烷作为单一立体异构体。随后，在甲酸的存在下，用钯（II）催化剂进行了还原Heck反应，使八氢环五[c]吡啶闭合环。得到的6-外显红绒毛素经C6外显异构反应转化为(-)-外显红绒毛素，经Mitsunobu与阿魏酸缩合反应转化为(+)-外显红绒毛素。通过阿魏酸的O-tosyl衍生物的头尾光二聚化法制备α- truxilic酸，并与6-外因- incarvillatine进行Mitsunobu缩合，成功地合成了(-)- incarvillatine。