Total Synthesis Of Natural Product Asperterpene A And Formal Synthesis Of (±)-stelletin

Study on Total Synthesis of Asperterpene AAsperterpenes A,a 3,5-dimethylorsellinic acid-based meroterpenoid that contains a novel carbon skeleton,was obtained from Aspergillus terreus.Asperterpene A exhibited promising inhibitory activities against BACE1(IC50=78 nM),which are similar to that of LY2811376(IC50=260 nM)developed by Eli Lilly and company.Structurally,it contains a highly strained trans-syn-trans-fused perhydrophenanthrene skeleton and an unprecedented 1 2,13,1 6-trimethyl-15,1 7-dioxobicyclo[3.3.1]non-13-ene14-carboxylic acid moiety.By now there are no literatures about total synthesis of asperterpene A.The trans-syn-trans-fused perhydrophenanthrene skeleton was successfully constructed from commercial geranyl acetate through biomimetic cationic cyclization,Eschenmoser Claisen rearrangement,diastereoselective alkylation of nitrile and Dieckmann condensation.On this basis,steps such as Nazarov cyclization were used to install C12 quaternary chiral center.Subsequently,strategies such as enol lactone rearrangement,transannular Aldol condensation,intramolecular Michael addition and intramolecular Claisen condensation were explored to construct bridged ring,but none of them were successful.This may be due to the large steric hindrance between the methyl groups on C8 and C16 during the transition state.Then we adopted another synthetic route,using a semi-pinacol rearrangement strategy to successfully construct the bridged ring,and completed the synthesis of the key intermediate of Asperterpene A through oxidation.A preliminary exploration was conducted on the introduction of functional groups in the Dring using this key intermediate.This study provides the ideas for the total synthesis of structural analogues in the future.Formal synthesis of(±)-stelletin AStelletin A is an isomalabaricane-type triterpenoid which isolated from marine sponge.Stelletin A revealed significant cytotoxicity against murine leukemia P388 cell line with ED50 of 2.16 nM.Therefore,stelletins are considered as promising lead compound for the treatment of tumors.Isomalabaricanes are a group of tricyclic triterpenes bearing a 6/6/5 trans-syn-trans tricyclic core attached to a polyene side chain.We conducted the research about formal synthesis of(±)-stelletin A.Based on the new protocol for the synthesis of trans-syn-transperhydrophenanthrene skeleton established in the first part of the paper,we developed a novel,efficient and scalable synthesis of the ABC tricyclic triketone in a linear sequence of 18 steps,with a total yield up to 24.4%.Key reactions include a diastereoselective Eschenmoser-Claisen rearrangement,a highly diastereoselective alkylation of decalinnitrile,and an intramolecular[3+2]cycloaddition/N-O reductive bond cleavage.This approach has the advantages of simple operation and high reaction yield in each step,providing ideas for synthesizing the natural product analogues of stelletins and materials for comprehensive biological activity studies.