一叶萩类生物碱的仿生不对称全合成

The securinega alkaloids are a small family of plant metabolites with fascinating bridged tetracyclic structures. They display an impressive range of biological activity,and plants containing these compounds have been used in traditional Chinese herbal medicine for many years. The most widely studied pure alkaloid is securinine, which has been studied in the clinic for treatment in humans of paralysis following Bell's palsy and poliomyelitis, and in alleviating the symptoms of ALS and chronic aplastic anemia. Because the plant sources are limited, and these alkaloids are extracted from plant are cumbersome and expensive, the chemical synthesis of these alkaloids have important theoretical significance and practical value of economic. This project aims to establishment a general method of efficient and concise biomimetic asymmetric synthesis of the three representative Securinega alkaloids(securinine, norsecurinine, and securinol) and its analogues through 6-8 steps. The key steps of the synthesis include an enantioselective Pictet-Spengler reaction and oxa-Micheal addition reaction. In this project, biomimetic synthesis is its fundamental guiding ideology, atom economy is its starting point, ideal synthesis becomes an ultimate goal. This study can enrich the theory of modern organic synthesis, and provide realistic and feasible research method for an important physiological activity of a securinega alkaloids medicine application and structure-activity relationship study. More importantly, this study has a bright future for potential new drugs of securinega alkaloids.

一叶萩植物是我国传统中草药，其所含多种生物碱具有广泛的生物活性。其中 一叶萩碱为临床治疗面神经麻痹的常用药物。但由于该植物来源有限，从中提取这些生物碱的工艺繁琐和昂贵，因此化学合成这类生物碱具有重要的理论意义和经济实用价值。本项目以仿生全合成为基本指导思想，以"氧化还原经济性"(Redox Economy)为出发点，最终以实现"理想合成"(Ideal Synthesis)为目标，经过Pictet-Spengler 和Micheal加成等关键反应，以6－8 步合成这类生物碱；建立简洁高效地不对称合成三种经典一叶萩植物代表性生物碱及其类似物的通用方法，实现一叶萩碱、降一叶萩碱、一叶萩醇三种生物碱的仿生不对称全合成。开展本项目研究能丰富现代有机合成理论，为具有重要生理活性的一叶萩类生物碱的医药应用和构效关系的深入研究提供现实、可行的研究方法，为潜在的一叶萩类新药开发奠定基础。

一叶萩植物是我国传统中草药，其所含多种生物碱具有广泛的生物活性。一叶萩碱为临床治疗面神经麻痹的常用药物。但由于该植物来源有限，从中提取这些生物碱的工艺繁琐和昂贵，因此化学合成这类生物碱具有重要的理论意义和经济实用价值。本项目以仿生全合成为基本指导思想，以“氧化还原经济性”为出发点，最终以实现“理想合成”为目标，经过Pictet-Spengler 和Micheal加成等关键反应，建立简洁高效地不对称合成一叶萩碱及其类似物的通用方法。在本项目的资助下首先对一叶萩碱的仿生全合成进行了深入研究，通过不对称Pictet-Spengler反应引入了第一个手性中心。实验发现手性Brønsted acid能较好地诱导Pictet-Spengler环化的对映选择性。已经尝试了几种手性Brønsted acid，得到环化产物的ee值达86%。同时已经完成了后继反应步骤，尝试不同碱性条件下，发现当用6M的氢氧化钠溶液时，有较好的非对映选择性得到Micheal加成产物（dr = 5:2)，分别还原胺化完成Securinine和Allosecurinine的全合成。此外，还利用仿生的合成思想，将5-甲基-1，3-苯二酚与金合欢醛反应，经过串联的Aldol反应、6π电环化以及[4+2]环加成反应。仅仅经过一步反应高效地首次完成Citran类天然产物的全合成。开展本项目研究能丰富现代有机合成理论，为具有重要生理活性的一叶萩碱的医药应用和构效关系的深入研究提供可能的研究方法。