Study On The Total Synthesis Of The Alkaloid Himalensine B

In 2016,Himalensine A and B are two new daphniphyllum alkaloids isolated from stems and leaves of the D.himalense plant by Yue Jianming’s group of the Shanghai In stitute of Materia Medica,Chinese Academy of Sciences.They belong to calyciphyllineA type and daphnicyclidin type alkaloids,respectively.Himalensine B is a triterpene alkaloid.It has a pentacyclic fused structure skeleton of 6/5/7/5/6 and eight chiral centers.The total synthesis of Himalensine B is very challenged.Preliminary biological activity tests show that the alkaloid possesses a certain inhibitory activity on PTP1B and IKK-β.Because of the unique structure and potential biological activity of himalensine B,the total synthesis research of himalensine B can not only lay the foundation for the total synthesis research of other alkaloids of daphnicyclidin type alkaloids,but also help the researchers to understand the basic theory of organic chemistry and improve their experimental skills.Based on the previous research’s achievement of our research group,the synthesis of Himalensine B was studied in this paper.Aiming at the construction of the most difficult seven-membered C ring in the himalensine B,herein,the research strategy of intramolecular decarboxylation radical Michael addition is the key reaction.Adjusting the structure of the reaction substrate to promote the reaction,we achieve the efficient and concise construction of the himalensine B’s core structure,and lay the foundation for the total synthesis of the himalensine B.We has carried out the following research work and achieved certain research results.(1)A large number of cis-2,3,4-trisubstituted pyrrolidine 116a prepared by our research group in the early stage as raw materials,through 8-11 steps,we synthesize three substrates for intermolecular decarboxylation Michael addition reaction.Uniformly,cis-2,3,4-trisubstituted pyrrolidine 116a as raw materials,through 11-13 steps,we also synthesize four substrates including BD ring in himalensine B for intramolecular decarboxylation Michael addition reaction.Researches of intermolecular decarboxylation Michael addition reaction have shown that although the reaction can worked,the yield is very low and the reaction has no practical value.The decarboxylated Michael addition reaction of the four intramolecular substrates don’t observed any Michael addition products,and only relevant decarboxylated products are obtained,which indicates that the three-dimensional spatial structure of the substrate may have a greater impact on the Michael addition reaction.(2)Based on the results of the previous research,we tried to promote the intramolecular free radical Micheal addition reaction by increasing the complexity of the spatial structure of the reaction substrate.Similarly,through 13-15 steps,we accomplish intramolecular decarboxylation Micheal addition substrate precursor 272 and 277 containing the ABD tricyclic skeleton of himalensine B from cis-2,3,4-trisubstituted pyrrolidine 116a.The synthesis of substrate 272 and 277 lay a substantial foundation for subsequent attempts on the key decarboxylation free radical Michal addition reaction.