Total Syntheses Of Eight 5/10 Or 5/7/5 Skeleton-containing Stemona Alkaloids Including Parvistemoamide And Stemoamide And Study On Their Biotransformation

Medium-sized compounds(8-12 sized rings)are one of the important components of cyclic active molecules because of their unique rigid skeletons and three-dimensional structures.From the traditional Chinese medicine “Baibu”,over215 alkaloids have been isolated until now,among which the medium-sized ring-containing alkaloids are one of the important components.Nevertheless,there is no biological studies on medium-sized alkaloids,which limits the study on the substance basis of biological activities of “Baibu”.Therefore,realizing the collective total syntheses of Stemona alkaloids may play significant roles in the study toward biomimetic conversion of Stemona alkaloids as well as the study toward the substance basis of biological activities of “Baibu”.However,limited by the huge ring tension of these unique ring skeletons,it is a great challenge for the syntheses of medium-sized Stemona alkaloids;this seriously hinders the study on the bioactivity and the study on the biomimetic conversion of Stemona alkaloids,and further increases the difficulty of collective total syntheses of Stemona alkaloids.In this paper,we chose two of the most representative Stemona alkaloids,parvistemoamide and stemoamide as the research objects,realized their total syntheses and studied their biomimetic conversion relationship.Based on this biomimetic conversion relationship,further collective total syntheses of six stemoamide-type alkaloids such as Saxorumamide were completed.In conclusion,this paper consists of the following three parts:Chapter I: Review of medium-sized natural productsMedium-sized compounds have a wide range of biological activities due to their unique skeletons.In this part,we introduced medium-sized compounds with a wide range of biological activities,especially natural products that containing medium-sized lactones or lactams,and demonstrated the application of medium-sized compounds in total syntheses of other natural products.In addition,we briefly introduced the common ways to construct the medium-sized skeletons in the total syntheses of natural products.We found that although the construction methods toward the medium-sized skeletons have been made great progress in recent years,the total syntheses of natural products that containing the medium-sized rings are still lacking,which seriously affects the systematic exploration of their biological activities.Chapter II: Review of Stemona alkaloidsWe briefly introduced the bioactivities of Stemona alkaloids and the hypothesis of the biogenic conversion relationship between the medium-sized ring containing Stemona alkaloids and other Stemona alkaloids with the common pyrrolo[1,2-α]azepine nucleus.We further systematically reviewed the total syntheses of Stemoamide,and the progress on the total syntheses of pyrrolidone or pyrrole containing Stemona alkaloids based on the key [5/7/5] skeleton of Stemoamide.Chapter III: Total syntheses of Parvistemoamide,Stemoamide and other six alkaloids,and study on their biomimetic conversionParvistemoamide as one of the most representative structures in the [5/n](n>7)ring containing Stemona alkaloids,contains four consecutive chiral centers.Notably,the chirality of C-9a and C-10 positions have not been fully determined,and its total synthesis has not been accomplished.At the same time,there is an important biogenic conversion relationship between Parvistemoamide and Stemoamide.To verify the above biogenic hypothesis,we used the commercially available 1,4-butanediol as the starting material and completed the total synthesis of Stemoamide through simple 7steps;and based on this,we have done a systematic study on the first-generation biogenetic conversion relationship between Parvistemoamide and Stemoamide.We found the first biogenetic conversion relationship could not be successfully proceeded in experiment.The above results prompted us to propose the second-generation biogenetic hypothesis: Stemoamide may be biosynthesized from Parvistemoamide via C-N bond formation.In order to further explore the biogenic conversion relationship between Stemoamide and Parvistemoamide,we focused on accomplishing the total synthesis of Parvistemoamide through three routes.In the first-generation route to Parvistemoamide,we used 3-methyl-2-(5H)-furanone as the starting material and constructed the core skeleton of Parvistemoamide through a series of key reactions such as macrolactonization.However,we found that the incompatibility of functional groups leaded to the failure of this synthesis.In the second-generation route to Parvistemoamide,3-methyl-2-(5H)-furanone was also used as the starting raw material.In order to avoid the incompatibility of functional groups,the C-9a carbonyl group which was reduced and protected firstly was then subjected to construct the 10-membered lactam ring.However,this synthesis failed due to the problems of separation and purification.Based on the previous two generations of synthetic routes,we directly employed the methyl-free compound 3-22 as the starting material and firstly synthesized Parvistemoamide and three diastereomers through the key step of macrolactonization.On this basis,we confirmed the second-generation biogenic conversion relationship between Stemoamide and Parvistemoamide.Based on the second biogenic conversion relationship between Stemoamide and Parvistemoamide,we successively completed the collective total syntheses of Saxorumamide,Isosaxorumamide,Isoneostemocochinine,Neostemocochinine,Isoneostemocochinine-N-oxide,Neostemocochinine-N-oxide through the key thioamide intermediates.