Synthetic Studies And Total Synthesis Of Periconiasins A-E、Aspochalasin D And Aspergillin PZ

Periconiasins A-E,Aspochalasin D and Aspergillin PZ are representative members of a large family of natural compounds named cytochalasans.Owing to their remarkable biological profiles including anti-cancer,anti-bacterium and anti-viral activities,they have been employed as important chemical tools for biomedical studies and viewed as promising lead compounds for drug research.Besides their biological importance,cytochalasans display notable structural novelty,complexity and diversity.Based on their structural feature,cytochalasans could be divided into four distinct classes: bicyclic,tricyclic,polycyclic and oligomeric cytochalasans.Not surprisingly,owing to their appealing biological and chemical diversity,cytochalasans have stimulated extensive interest from synthetic community.So far,most of the total synthese and synthetic studies on the cytochalasans family have been focused on the commonly seen tricyclic cytochalasans,wherein two general synthetic strategies are adopted: 1)a biomimetic intramolecular Diels-Alder reaction to construct the n/6/5 tricyclic skeleton in a single step;2)an intermolecular Diels-Alder reaction to form the 6/5 bicyclic isoindolone core followed by the macrocyclic ring formation.This thesis will describe in detail the total synthesis of Periconiasins A-E,Aspochalasin D and Aspergillin PZ based on above two distinct strategies.The collective total syntheses of Periconiasins A-E were achieved via a series of rationally designed or bio-inspired transformations.The execution of this route depended on the invention of a tandem aldol condensation/Grob fragmentation to assembly the linear polyketide-amino acid hybrid precursor.Then an intramolecular Diels-Alder cyclization was carried out to form the six-membered isoindolone ring and the large macrocycle simultaneously.After late-stage functionalization,Periconiasins A-C were obtained.Starting from Periconiasins A and B,a transannular carbonyl-ene reaction forged the polycyclic framework of Periconiasins D and E.To build the 11/6/5 skeleton of Aspochalasin D,an intermolecular Diels-Alder reaction was utilized to form the isoindolone core and a macrocyclic RCM reaction was performed to generate the eleven-membered ring.Subsequently,selective dihydroxylation enables the incorporation of the C17 and C18 oxygen atoms.After several functional group transformations,the total synthesis of Aspochalasin D was completed.Finally,a transannular ene cyclization followed by esterification led to Aspergillin PZ.In brief summary,in this thesis we have completed the collective total synthesis of Periconiasins and Aspochalasins,two subgroups of the cytochalasans,through a series of rationally designed and biomimetic transformations.The current work enables the rapid access of not only the aforementioned targets,but also various related cytochalasan congeners,which paves the way to explore their full biological profiles.Moreover,in both cases the biomimetic conversion of the tricyclic cytochalasans to their polycyclic congeners have also been investigated,which provides convincing evidence to decipher the underlying biogenetic relationship of the two different skeletons of cytochalasan.