复杂活性天然产物Cyclocitrinol的不对称全合成

The bioactive natural product family——Cyclocitrinols （24 compounds have been isolated by now）presents a formidable challenge to its total synthesis because of their special unique complex structure. They have a [7-7-6-5] tetracyclic framework which contains a strained bridged [4.4.1] bicyclic ring system and a bridgedhead double bond. Besides, it has 8 stereogenic centers. The total synthesis of cyclocitrinols is still not literature reported yet..In this project, it plan to utilize a novel intramolecular Type II [5+2] cycloaddition as the key reaction to rapid construct the core framework of the target natural prouduct, namely, the construction of the bridged seven membered ring system and the bridgehead double bond, introduction of several of the chiral centers could be realized in one step. Under sufficient consideration of taking full advantage of the chemical selectivity of substrate nature and the compatibility of the functional groups, the asymmetric total synthesis of cyclocitrinol is designed to be accomplished in just 10 steps starting from a commercial available known compound subsequently. The synthetic strategy described in this project is highly efficient, concise and universal. The synthesis of other members of cyclocitrinols and their analogues could be achieved by changing different side chains, which lays a soild foundation for rapid building small molecules for further drug development.

Cyclocitrinol类家族活性天然产物（24个分子被分离）具有新颖独特的复杂多环结构，给其全合成带来了很大挑战：具有共同的[7-7-6-5]四环核心骨架，包含张力很大的双环[4.4.1]桥环体系和一个桥头双键，8个手性中心。到目前为止，没有一例关于Cyclocitrinol家族分子的全合成文献报道。 .本项目拟利用新颖的分子内Type II [5+2]环加成反应，快速构建Cyclocitrinol桥接的七元环体系，同时构建桥头双键以及引入多个手性中心，高效地构建目标天然产物的核心骨架。随后，充分利用底物本身的化学选择性和官能团的兼容性，尽量少用保护基，以最少的官能团转化，由易得的原料出发经10步即可完成Cyclocitrinol的不对称全合成。整个合成路线高效简洁，普适性高，通过改变不同的侧链片段，可以合成该家族的其它天然产物及其类似物，为快速构建小分子库进行药物研发打下坚实的基础。

本项目所研究的cyclocitrinol天然产物是一类新型的甾体化合物，它的结构通过谱图、化学方法以及X 射线单晶衍射确定。到目前为止，该家族已经有超过24 个天然产物被分离报。cyclocitrinol家族天然产物具有大张力的含有桥头双键的A/B双环[4,4,1]骨架，目前合成这一骨架的方法非常有限，因而实现对天然产物cyclocitrinol的全合成具有很大的挑战。.在该项目中，从商业可得的原料6（维生素D2的降解产物）出发，以最长线性步骤18步完成了cyclocitrinol的首次不对称全合成。本项目通过分子内Type II [5 + 2]环加成反应高效、且非对映选择性地构建了，具有高度合成挑战的大张力桥头双键[4.4.1]双环A / B环系。此外，使用Li-EtNH2条件成功地实现了对底物40中的氧杂双环[3.2.1]辛烯的C-O键的选择性还原切断。同时，我们以简洁、高非对映选择性的方式构建了cyclocitrinol的八个手性中心。这项工作将为其他cyclocitrinol家族天然产物的不对称合成工作奠定基础。.在本项目的支持下，本研究小组也利用Type II [5 + 2]环加成反应作为关键反应，完成了活性天然产物cerorubenic acid-III的全合成以及开展了天然产物eurifoloid A的合成研究。