Bioinspired Total Syntheses Of Tetracyclic Diterpenoids And Quinic Acid Derived Meroterpenoids

Natural products are the source of searching for biologically active substances and practical medicines,as well as an important driving force for the discovery of new reactions,new concepts,and new catalysts.The development of natural medicinal chemistry has greatly promoted the progress of human society,especially in drug development,pharmaceutical chemists often regard natural products and their analogues as lead compounds,which are utilized as a basis for structural modification and target testing.The novel and variability of the framework structure,the complexity of the chiral environment,and the diversity of activities have made the total synthesis of natural products a hotspot in the fields of natural medicinal chemistry and chemistry.The total synthesis of natural products is an inseparable part of natural medicine chemistry.It is not only a single target compound molecule that can be used for pharmacological activity research and solve the problem of drug sources,but also confirms the true structure of the target molecule through modern analytical techniques and methods.Meanwhile,a large number of novel chemical reactions have been effectively developed during the synthesis process to promote the development of chemistry.Moreover,in the process of the target molecule synthesis,natural products with the same skeleton and similar functional groups are obtained,which provide more choices for the activity research of natural product molecules.Till now,total synthesis of natural products is one of the most active fields in organic chemistry,and has attracted long-term attention.Terpenoids are one of the secondary metabolites of plants,which were widely distributed in nature,with bactericidal,anti-inflammatory,anti-tumor and other physiological activities.With the development of natural medicinal chemistry in recent years,a large number of terpenoids with novel structures have been discovered.Many compounds are favored by pharmaceutical chemists because of their excellent biological activities,along with structural modification and transformation.They are designed as natural product derivatives with better activity and developed into clinical drugs.Furthermore,terpenoids are widely used in various intractable diseases.Among them,tetracyclic diterpenoids and meroterpenoids are two common terpenoids.Their inherent unique backbones and good pharmacological activity have aroused the interest of countless synthetic chemists and pharmacologists.Tetracyclic diterpenoids mainly refers to closely biogenetically related carbon skeletons derived from（-）-copalyl pyrophosphate（ent-CPP）,and they undergo intramolecular rearrangement reactions to achieve the skeleton mutual transformation.In chapter two,a bioinspired synthesis strategy was utilized.First of all,a Lewis acid catalyzed polyene cyclization to construct the A/B ring is performed.Followed by the ingenious design to construct precursor of the key De Mayo reaction.The[2+2]cycloaddition occurs smoothly under visible light,and the kaurane backbone,phyllocladane skeleton,and C9 isomeric kaurane skeleton are so obtained after Bronsted acid treatment.Subsequently,the nucleophilic cyclopropanation reaction occurs with high efficiency under weak acid conditions,which achieves the first efficient chemical conversion from kaurane to trachylobane type diterpenoids.Next,a chemoselective C12-C13 bond cleavage is achieved via nucleophilic attack by phenyl selenium reagent,realizing the transformation from trachylobane type to beyerane type framework.Finally,the conversion from trachylobane type to atiserane type diterpeniods is also realized under trifluoroacetic acid,via C13-C16 bond cleavage.The meroterpenoids,which also characterizes a unique and complex carbon skeleton,have attracted our attention due to its wide range of biological activities.For example,guignardones A-C,meroterpenes derives from 3-dehydroquinic acid,have very good antibacterial activity,and the homologous manginoids A-D,have a significant inhibitory effect on type 1 11-hydroxysteroid dehydrogenase,which is an anti-diabetic potential drug.In addition,the spiro-ring skeletons together with[3.2.1]bridged ring are highly appreciated by us.In Chapter three,this type of natural products are synthesized via a biomimetic and divergent manner.For the non-terpene part,we introduce the chirality through Sharpless asymmetric epoxidation.After a series classic manuscriptions,the vinyl bromide with a[2.2.2]ring system was achieved,and a Suzuki coupling reaction occurs with the known monoterpene boron derivative to get these two parts connected.Finally,a silica-gel promoted semi-pinacol rearrangement reaction is utilized to convert the[2.2.2]ring system into[3.2.1]bridged ring,thereby obtaining natural product precursors.After the screening of different acid catalysts,the quantitative conversion to guignardone A and guignardone C was achieved.From a chemist perspective,1,3-diketone substrates,which are easily oxidized into free radicals,can undergo the biogenic pathway of free radical cyclization and then be captured by intramolecular double bonds.A relatively stable free radical is generated on the tertiary carbon atom,and then reacts with the oxygen in the system to form a peroxygen molecule.By exposing the diketone intermediate to the air and sunlight or directly under the condition of trivalent manganese oxidant,spiro skeleton of manginoids natural products is successfully constructed.And manginoids A and C are so obtained by reduction and dehydration manipulations.In summary,using geraniol as the starting material,14-17 steps transformations,four types of tetracyclic diterpenoids are successfully synthesized via a bioinspired and divergent manner.Including kaurane,trachylobane,beyerane and atisane,and totally six natural products.Taking the De Mayo reaction as the key step,the bicyclo[3.2.1]bridged octane of kaurane is efficiently obtained.Conversion to enttrachylobane from ent-kaurane is achieved through nucleophilic cyclopropanation.Regioselective cyclopropane fragmentations of ent-trachylobane,furnishing entbeyerane and ent-atisane,are achieved through the nucleophilic attack and protonation of the cyclopropane ring,respectively.It is worth noting that,the natural products mentioned above were accomplished in an enantioselective manner,and the first total synthesis with high efficiency.Meanwhile,a similar strategy for the design of complex meroterpenoids is also achieved and furnishing the total syntheses of guignardones A and C.And manginoids A and C are realized through a free radical cyclization reaction,innovatively,which provides new ideas and research basis with pharmacologists from terpenoids for the drug potential development and exploration.