Asymmetric synthesis of a novel antinociceptive substance, incarvillateine

基于6-epi-incarvilline作为共同前体的策略，首次实现了一种新的强效抗伤害单萜生物碱incarvillateine及其同源生物碱incarvine C和incarvilline的全合成。我们已经开发的用于组装6-epi-incarvilline的策略涉及通过（S）-4-甲氧基环戊烯酮的三组分偶联反应来构建适当的三取代环戊酮，所述偶联反应使用有机锌试剂，由（E）-甲锡烷基烯烃和碘甲烷原位生成，得到作为单一立体异构体的2，3，4-三取代环戊烷。随后的环闭合的八氢环戊二烯并[c]吡啶是通过还原赫克反应，使用钯（II）催化剂在甲酸的存在下进行。通过C6差向异构化将由此获得的6-差向-角蒿素转化为（-）-角蒿素，并且通过与阿魏酸的Mitsunobu缩合将（+）-角蒿素C转化。以阿魏酸的O-对甲苯磺酰基衍生物为原料，经光二聚反应得到α-曲克酸，再与6-表-恩卡维林发生Mitsunobu缩合反应，成功地合成了（-）-恩卡维坦。

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.