Total Synthesis Of Benzosceptrins And Delavatine A

Bioactive natural products(including Marine and terrestrial),whose various chemical structures and high biological compatibility offer a shortcut to medicinal chemists in their process of new drug discovery,have long been an important source of drug molecules.However,the poor biomass of natural resources and low content of natural product severely limit our further development of bioactive natural products.Hence,total synthesis of natural products,as a powerful alternative method to provide bioactive natural products,is of great significance to modern natural pharmaceutical chemistry.In this dissertation,two active natural products separated from the Marine and terrestrial plants were selected as synthetic objects,and their synthesis studies were carried out in order to solve the following problems: 1)the confirmation of their absolute configurations.Although the stereochemistry of two compounds were proposed by biosynthetic hypothesis,only the relative configurations could be confirmed by spectroscopic studies.Total synthesis was the essential means to solve the problem,which also provided a positive evidence of the verification of the biological hypothesis.2)The discovery and development of novel chemistry.Both alkaloids were new skeletal compounds,and we hoped to develop new chemistry in our unconventional synthetic process.3)Large scale synthesis of natural products.Concise and efficient synthetic strategies would offer a sufficient quantity of natural products for further biological studies,which made up for the shortage of natural resources.This dissertation focused on the total synthesis of two active alkaloids,including two parts: the first part was total synthetic of benzosceptrins,a kind of marine natural product with antibacterial activity;the second part was the solution of some key problems in the synthesis of anti-tumor alkaloid delavatine A.These two scalable synthetic works were completed in 12 and 13 steps(longest linear sequence),respectively.In the synthesis of benzosceptrins,we abandoned the conventional strategy of sequential functionalization of polysubstituted aromatic derivative,aiming to apply modified Ullmann coupling reaction mediated by CuTc to realize the homo-coupling of the functionalized imidazole iodide,and obtained the key intermediate.Then the synthesis of the benzocyclobutane core skeleton was achieved by the 8?-6? tandem electrocyclization reaction of unique imidazoletetraene,which expanded our understanding of the electrocyclic reaction.Meanwhile,during the research,we discovered that lewis acid had accelerated effect on the reaction,and enantioselective electrocyclic process can be achieved by a Br?nsted acid activated chiral oxazaborolidine.Then,we confirmed the relationship of absolute configuration of benzosceptrins and their circular dichroism(CD)spectrum through chiral resolution and identification of the stereostructure of intermediate compounds,so a method to identiy the absolute configuration of this three natural products based on CD spectrum was built.This work will help us to confirm the absolute configuration of benzosceptrins and further understand the biosynthesis of pyrrole-imidazole alkaloids.In additions,we could prepare a large amount of these compounds in this synthetic route,which established the foundation for the study of the biological activity of this natural products.In the synthetic research of delavatine A,we proposed a novel asymmetric hydrogenation of the non-functional tetra-substituted alkene to realize the chiral synthesis of this natural product,which avoided the conventional construct strategies.For this reason,we succeeded in developing the new methodology which enriched the research of asymmetric hydrogenation,and solving the synthesis problem.And it is first example of rhodiumcatalyzed asymmetric hydrogenation of tetrasubstituted unfunctionalized olefins.On the other hand,based on the anomalous results of the experiment,we independently discovered the stereoselective effect of the monoprotected amino acid on the C-H bond activated olefination of the substrate rac-3-39,and then developed a remarkable kinetic resolution of ?-alkyl phenylethylamine derivatives via palladium-catalyzed triflimide-directed C-H olefination,which provided another asymmetric synthesis method.Using this kinetic resolution,we synthesized the natural product along with three stereoisomers,and confirmed the absolute configuration of delavatine A by comparing the physical and chemical data including optical rotation,CD,HPLC retention time,which illustrated the origin hypothesis.Especially,to deserve to be mentioned,this reaction has a wide range of substrate,which can be used to synthesize various chiral bioactive lead compounds.What's more,the gramscale synthesis of delavatine A allowed us to conduct a wide range of biological studies.We have completed the total synthesis of two type of bioactive natural products,the marine pyrrole-imidazole alkaloid benzosceptrins A,B,C and the new framework terrestrial alkaloid delavatine A.These two synthesis solved the problems caused by natural resource deficiency and low content in natural pharmaceutical chemistry research.In the meantime,the new methodologies developed during the process of total synthesis studies would be instructive to the synthesis of other different kinds of natural products or industrial compounds.All of these showed the true value of total synthesis.