三萜spirochensilides的仿生合成

Genus Abies consists of 50 species that distribute in the highlands of Asia, European, North and Middle America, and North Africa. There are over 250 terpenoids from this genus have been isolated. The class of triterpenoids has broad spectrum of bioactivities, such as antiinflammatory, antibacterial, anticancer, antifungal and antihypertensive. As such, the plants have been employed traditionally as the sources to treat different symptoms. Of note, ablesenonic acid methyl ester prepared from triterpenoid abieslactone inhibited tumor promoter-induced phenomena both in vitro and vivo. In 2015, the Gao group reported the isolation of spirochensilides A and B, two new rearranged triterpenoids from Abies chensiensis, together with a known biogenetically related lanostane lactone. Spirochensilides feature two spirocycles and five quarternary centers. At this point, total synthsis or synthetic study of spirochensilides remains unreported. We were fascinated by spirochensilides’ biogenesis and thus rationalized a modified biosynthetic pathway. We will complete total synthesis of spirochensilides guided by the modified biosynthesis. We hope total synthesis herein may not only afford a supply for further extensive bioactivities test, but also serve as a tool to explore the biogenesis of the class of triterpenoids, although isotopic labeling and gene cluster identification are indeed needed to fully verify the mechanism.

Abies属是一类广泛分布的植物，迄今已有250多种萜类化合物从Abies属分离出来，其中大部分是三萜。这一类三萜的活性广泛，例如消炎、抗菌、抗肿瘤和治疗高血压等。因此被当地人作为治疗上述各种症状的药物使用。例如ablesenonic甲酯被发现不论体内或体外都有抑制肿瘤生长的作用。2015年，Gao组分离出两个三萜spirochensilides A和B，同时分离出已知天然产物lanostane lactone (被认为是spirochensilides的生源合成前体)。Spirochensilides包含有2个螺环结构，多个相邻的季碳手性。这些特点对它的合成研究是很大挑战。迄今为止，spirochensilides的全合成或合成研究还没有报道。我们希望通过spirochensilides改进的生源合成来指导、并高效完成它的全合成、从而来验证生源假说。 并为进一步的活性测试提供充足的原料。

重排类甾体化合物是一类重要的天然产物，生源上，他们可能是经过甾体的基本骨架，发生氧化，键的断裂，或者重排得到。例如，重排类甾体天然产物spirochensilides, dankasterones A, B和periconiastone A从生源上分析，都可以由甾体的基本骨架在合成的后期，发生特定化学键的迁移，重排得到。在spirochensilides的合成研究中，其中的Sp3 C-H氧化关环反应难以实现，由此启发我们运用金属作用的氢原子转移反应 （MHAT）构建甾体的[6.6.6.5]基本骨架。（1）首先高效构建了A环片段，随后应用了 Stille 偶联/氧化构建了 C/D 环片段。两个片段的连接拿到关环前体；（2）利用Fe或者Co引发的 HAT 反应，自由基环化合成甾体的四环骨架；（3）区域选择性的烯丙位氧化，自由基重排反应构建13(14→8)abeo-8-ergostane 重排骨架；（4）引入侧链完成天然产物dankasterones A, B的合成，分子内aldol反应完成periconiastone A的合成。本部分工作发表于Angew. Chem., Int. Ed. 2021, DOI: 10.1002/ anie.202013881。本项目采用的MHAT反应为甾体基本骨架的构建提供了新的思路，是对传统方法例如多烯环化，Diels–Alder反应, Cope 重排的有效补充，这一方法将有可能在甾体合成中有更为广泛的应用。