Collective Total Syntheses Of The Plakortin Polyketides

Marine natural products represent a valuable resource for the discovery of new drugs and leading compounds.The Plakortin polyketides are a prominent class of marine natural products displaying remarkable structural and biological diversity,which has attracted considerable interest from synthetic community and medicinal chemists.While significant advancements have been made on the chemical synthesis of Plakortin polyketides,there is still some unmet challenge in this area.For examples,the present synthetic routes could only be applied to some specific targets of similar core skeleton,and thus a unified strategy enabling the access to all representative skeletons of this family remains unattainable.Besides,most of the biological studies are performed on a single natural product,lacking of a systematic SAR study.In this thesis,a unified strategy enabling the access to all representative skeletons of Plakortin polyketides has been established,based on the combination of biomimetic strategy and rationally designed synthetic methodologies.First of all,the Plakortin polyketides are divided into six subgroups according to their distinct core skeletons,including six-membered cyclic peroxides,furans,fivemembered cyclic peroxides,five-membered lactones,lacton[2,3-b]tetrahydrofurans,and complex polycyclic molecules.Next,the overall biosynthetic network of Plakortin polyketides is proposed,which indicates that the aforementioned six types of skeletons could be stem from a common linear 1,3-diene precursor.Inspired by this biosynthetic hypothesis,two generation of strategies have been developed,which pave the way to the collective total syntheses of over 10 Plakortin polyketides,including(+)-Hippolachnin A,Plakilactones,and Gracilioethers.The first generation of strategy allows to access three types of skeletons presented in the late stage of biosynthetic pathways of Plakortin polyketides,including furans,fivemembered lactones,and polycyclic molecules.The key elements of our synthesis include a series of rationally designed and biomimetic transformations.Initially,an organocatalytic asymmetric Mukaiyama-Michael reaction was developed,which enables the raid access of a chrial five-membered lactone.Starting from this key precursor,several congeners of Plakilactones were synthesized through side-chain extension.Furthermore,the first biomimetic synthesis of(+)-Hippolachnin A was also realized by a challenging [2+2]-photocycloaddition.Besides,an unprecedented HAT-triggered oxidation of vinylcyclobutane was developed to obtain(+)-Gracilioether A,(+)-11-epi-Gracilioether A,and(-)-Gracilioether E in one pot.Finally,the total synthesis of(-)-Gracilioether F was also accomplished through a [2+2]-cycloaddition followed by tandem oxidative cleavage of methyl ether/Baeyer-Villiger rearrangement.In the second generation of our synthesis,we achieved the biomimetic synthesis of two other subgroups of Plakortin polyketides,that is,the endoperoxide skeleton and furan skeleton.While these two types of skeletons seem relatively simple,they play key roles in the biosynthetic pathways of Plakortin polyketides.In practice,we first obtained the proposed biosynthetic linear precursor of Plakortin polyketides through Suzuki coupling reaction.Next,a biomimetic photo-[4+2]-cycloadditon of 1,3-diene with singlet oxygen was employed to forge the endoperoxide skeleton.Moreover,the biomimetic conversion of the endoperoxide skeleton to the furan skeleton was also realized,which led to the second-generation synthesis of(-)-Gracilioether B.In conclusion,we developed a unified strategy that enables the access of all representative skeletons presented in Plakortin polyketides.A dozen of natural products have been synthesized in less than 10 steps,highlighting its remarkable efficiency,novelty and diversity.Owing to its biomimetic nature,the current work provides informative evidence for deciphering the whole biosynthetic network of Plakortin polyketides.Meanwhile,it also paves the way to explore the biological function and SAR of this family of natural products.