促神经生长活性天然产物Scabronine A的高效全合成

Neurodegenerative diseases is a catchall term for the neural diseases of central neural system, include Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, etc. Neurodegenerative diseases currently affect approximately 10 million people in China, bringing stupendous suffering and enormous amount of healthcare cost. Unfortunately, research into the underlying cause of neurodegeneration is far from complete and no cures for these diseases have been found. Due to its superior pharmacokinetic profile, neurotrophic small molecule natural products have distinct advantage and great potential as drug leads for the treatment of neurodegenerative diseases. A natural cyathane diterpene, scabronine A, was isolated from Chinese mushroom Sarcodon scabrosus in 1998. It possesses a complex, caged, tetracyclic scaffold and six contiguous stereocenters on its seven-membered ring. More importantly, scabronine A was found to have potent neurotrophic activity which makes it a novel drug lead for the treatment of neurodegeneration. Due to its challenging chemical structure and promising bioactivity, herein we propose a novel and highly efficient strategy for the total synthesis of scabronine A and its natural analogues. The key steps would include an organocatalyzed 1,6-addition, a one-pot 1,4-addition/cyclopropanation, an oxidative ring expansion and a radical cyclization. This work would allow us to develop a highly efficient synthetic strategy for cyathane diterpenes. This project would not only be of significant interest to chemical science, but would also lay solid foundation for further neurobiological studies of scabronines as well as drug discovery for the treatment of neurodegenerative diseases.

在中国，约千万患者正承受包括阿尔茨海默病，帕金森症和肌萎缩侧索硬化症等在内的神经退行性疾病带来的痛苦和巨额医疗费用。此类疾病虽至今无法治愈，但促神经生长活性小分子天然产物在治疗该类疾病方面有着独特优势和巨大潜力。Scabronine A是从一种中国蘑菇中分离得到的鸟巢烷类二萜天然产物，具有复杂的四环笼状结构，并且其七元环上有着六个连续的立体中心。更重要的是scabronine A拥有出色的促神经生长活性，很有希望成为治疗神经退行性疾病的一类新型先导药物。由于其复杂的骨架结构和优秀的生物活性，本课题计划发展出一条针对scabronine A的创新高效合成路线，分别利用有机催化的1,6-共轭加成、一锅法1,4-共轭加成/环丙烷化、氧化扩环反应及自由基环化反应作为环系构建关键步骤，为该类重要天然产物探索出一种高效合成策略，对推动有机合成科学发展有着重要意义，并为后续生物学和药物研究奠定坚实基础。

天然萜类化合物长期以来是小分子创新药物的最重要来源之一。其中有代表性的包括二萜类化合物紫杉醇、倍半萜类化合物青蒿素等。我们的项目针对有着神经修复活性的鸟巢烷二萜、有着复杂化学骨架和潜在生物活性的二倍半萜、有着植物抗旱活性的红花菜豆酸开展了高效率的合成研究。本项目不仅发展了一条高效、对映选择性的鸟巢烷类二萜三环核心结构合成策略，同时也顺利开展了二倍半萜和红花菜豆酸的高效合成工作，目前已经完成罕见二倍半萜Astellatol的国际首次全合成工作，以及Phaseic acid目前已知的最简单不对称合成工作。我们的研究不仅有着较好的科学意义，也为这些小分子的生物研究和可能的医学临床应用和农业产业化应用提供了良好的基础。