具有镇痛活性的乌头类生物碱Aconicarmisulfonine A的合成研究

Aconitum carmichaelii Debx. belongs to the Ranunculaceae family and the plant has long been used as indispensable Chinese herbal medicine for the treatment of neuralgia, rheumatalgia, and cardianeuria. So far, about 300 diterpene alkaloids have been isolated from the Ranunculaceae family. Some of these alkaloids, such as Lappaconitine, 3-Aceylaconitine, Crassiculine, and Guan-fu base A, have been used for therapeutic treatment of long-term analgesia, postoperative pain, cancer pain, and rheumatalgia. Aconicarmisulfonine A, a novel sulfonated C20-diterpenoid alkaloid with significant analgesic activity, was isolated from an aqueous extract of the lateral roots of Aconitum carmichaelii by Shi and co-workers. This diterpene alkaloid exhibited potently antinociceptive (or analgesic) effect almost equilvalent to morphine. Structurally, it contains an unprecedented cage-like carbon skeleton possessing 6 rings and 8 stereocenters，the latter of which include 7 continuous stereocenters and one all-carbon quaternary carbon center. The congested structure poses considerable synthetic challenges. At present, we are eager to launch a research project focused on the total synthesis aconicarmisulfonine A through a convert synthetic strategy, in order to provide sufficient sample supply of the alkaloid for biological investigations. Key transformations include: (i) a cascade sequence involving a substrate-controlled intramolecular Michael addition followed by a catalytic asymmetric intermolecular Michael addition designed for rapidly constructing tricyclic intermediate 2-6; (ii) an intramolecular Diels−Alder reaction for assembling tetracyclic intermediate 2-4; and (iii) a transannular Mannich/aldol reaction sequence for efficiently forging the remaining three rings and providing the whole cage-like hexacyclic backone of aconicarmisulfonine A. The completion of the current project would hopefully lay a solid foundation for the identification of novel lead compounds for the development of innovative analgesic drugs.

乌头属植物具有治疗神经痛、风湿痛和心力不足等功效，从中已分离出约三百种生物碱，其中高乌甲素、乙酰乌头碱和Crassiculine和关附甲素已用于临床治疗长效镇痛、术后疼痛、恶性肿瘤疼痛和风湿痛等。Aconicarmisulfonine A是石建功研究员课题组从四川乌头中分离得到的磺酸化C20-二萜生物碱，镇痛活性和吗啡相当。该六环笼状分子共有8个立体中心，其中包含7个连续的立体中心和1个全碳季碳中心，该分子极具合成挑战性。我们拟以汇聚式合成策略对该生物碱展开不对称全合成探索。关键转化包括：底物控制的串联分子内Michael加成/催化不对称分子间Michael加成构筑三环中间体2-6；分子内Diels-Alder环加成构筑四环中间体2-4；分子内Mannich/Aldol反应构筑复杂笼状骨架。希望通过化学合成获取足量样品并进行相关构效关系研究，为最终发现创新镇痛药物的先导化合物奠定坚实基础。

2018年，石建功课题组从四川乌头中分离得到的磺酸化C20-二萜生物碱，其笼状结构含有8个立体中心，其中包含7个连续的立体中心和1个全碳季碳中心，该分子极具合成挑战性。小鼠模型研究发现aconicarmisulfonine A 具有和吗啡相当的镇痛效果，具有开发成为镇痛药物的潜在价值。鉴于其独特的化学骨架，有机合成化学家对该分子给予了一定关注。我们从易得原料开始对aconicarmisulfonine A进行合成研究，实现了aconicarmisulfonine A的关键三环骨架的高效构建，其关键步包含：Rupe重排构建环加成前体；分子间Diels-Alder反应构筑三环中间体2-4；生物碱liangshanone是Sakai研究小组1991年从梁山乌头(Aconitum liangshanium)根中发现分离的。属于异贝壳杉烯二萜生物碱中乌头碱家族中的一种，这种生物碱具有广泛的生物活性，包括抗炎、抗过敏、抗心律失常和抗焦虑作用。在结构上，它的骨架为六环体系，由一个对映贝壳杉烷型四环骨架和一个氮杂双环[3.2.1]辛烷部分组成。我们采用Fe催化的HAT环化等策略实现了liangshanone的关键三环骨架的高效构建，为此类天然产物的全合成提供了新的研究思路和方法。