具有连续桥头双季碳的活性天然产物的合成和生物活性的研究

The objective of this research proposal is to develop an asymmetric Rh-catalyzed [3+2] cycloaddition reaction for the construction of bicyclic ring systems bearing two quaternary carbon centres at their bridgehead positions by means of combination of computational and experimental chemistries, and to study the influence of bridgehead quaternary carbon on the entropy of natural products. To this end, we will carry out the following researches:.1) Developing new synthetic methods with asymmetric Rh-catalyzed [3+2] cycloaddition in the presence of chiral ligand;.2) Achieving the total synthesis of natural products crinipellin B、retigeranic acid and gascardic acid containing contiguous quaternary carbons, and their relevant 'single quaternary carbon' natural product analogues by using the above-developed asymmetric reaction,.3) Establishing new synthetic strategy for the total synthesis of daphniphyllum alkaloids bearing vicinal quaternary carbons on their 7-6 bicyclic scaffolds. .4) Using computational chemistry to study the influence of bridgehead quaternary carbon on the entropy of these natural products, thereby revealing their structure-activity relationships. Our ultimate goal is to develop rapid prediction program that could be used to guide drug design.

本项目以本课题组近期建立的铑催化［3+2］环化反应为基础，通过理论和实践化学相结合的研究方式，探索不对称铑催化［3+2］环化反应和研究桥头季碳对天然产物骨架熵的影响。并以此不对称［3+2］环化为关键步骤，设计合成具有连续桥头双季碳的天然产物和桥头“单季碳”的类天然产物。为此，我们将进行如下的研究：.1）研究手性配体诱导下，铑催化的不对称［3+2］环化反应；.2）利用上述反应，实现具有连续桥头双季碳的天然产物crinipellin B、retigeranic acid和gascardic acid以及相应 “单季碳”类天然产物的全合成；.3）建立基于7-6环系的具有连续桥头季碳的虎皮楠生物碱全合成新策略；.4）利用计算化学，研究桥头季碳季碳对天然产物骨架熵的影响，进而研究桥头季碳与生物活性之间的关系，尝试开发对药物设计有指导意义的快速预测和筛选方法。

相邻季碳结构骨架广泛存在于各种活性天然产物及药物分子中，而对于该类结构的快速一步构建一直都是合成化学家所面临的巨大挑战。虽然对于单个季碳中心的合成研究已经取得初步的进展，但对于相邻季碳的高非对映选择性一步构建方法却十分有限。目前绝大多数方法都是通过多取代双键的立体化学转移到相邻季碳结构，而关于过渡金属催化反应合成相邻季碳的报道，尤其是成功应用到天然产物合成中的方法学研究更是极为稀少。本课题组近期发展的铑催化［3+2］环化反应可以有效构建具有连续桥头双季碳的并环结构并成功应用于一些活性天然产物的全合成中，本项目把铑催化［3+2］环化反应发展成一个更加高效和通用的合成方法，并应用于一系列复杂天然产物的全合成中。