Synthetic Studies On Marine Brominated Alkaloid Atkamine And Several Tetracyclic Diterpenoids

Natural products are a major source of new compounds for drug discovery.Terpenoids widely distributed in nature,are isolated from not only terrestrial plants,but also marine organisms,and many of them have been used as drugs,such as the wellknown antimalarial drug artemisinin and antitumor drug taxol.The ocean is the most intrigued resources of new bioactive molecules for drug discovery which could serve as new tools for biological research.This dissertation describes the research progress on the total synthesis of brominecontaining marine alkaloid atkamine,hipposponlachnin,and five labdane-related diterpenoids.Specifically,it will be elaborated in the following three parts:a.In the synthetic studies toward atkamine:(1)A formal[5+2]annulation for the construction of the central azepene D ring on the simple substrate and an asymmetric Michael addition to couple the long-chain aldehyde fragment with β-nitrostyrene fragment to give chiral amino acetal have been achieved.(2)The substituent effects of amino acetal on formal[5+2]annulation were investigated in detail,and the cyclization principles of dihydropyrrole and azepane were determined.(3)The azepene D ring was constructed on trans-amino acetal substrate containing a benzohydrothiophene moiety.These results lay the foundation for the total synthesis of atkamine.b.In the synthetic studies toward hipposponlachnin,the two fragments were coupled by the Suzuki reaction and the 5-7-6 tricyclic system has been constructed through intramolecular ene reaction,and the methyl group was successfully introduced by 1,2-migrations of boronate to furnish the C1 quaternary carbon centers which is a meaningful exploration for the total synthesis of hipposponlachnin.c.Four diastereomers at C7 and C8 of 7-acetoxybetaer-13(17)-ene were synthesized,and the absolute configuration of the natural product was determined by NMR spectra and X-ray crystallography;late-stage C-H functionalizations on tetracyclic substrates have been achieved with favorable regioselectivity at C2 and C7 position and stereoselectivity through photochemistry and electrochemistry which provides methods for synthesis of natural products with oxidation states at these positions.d.The "Cut and Sew" ring system reorganization strategy by utilizing the structural characteristics of its ring system isomerism was developed and applied to the divergent total synthesis of four labdane-related diterpenoids.The skeletons of stemarene and betaerane were constructed through semi-pinacol rearrangement and aldol condensation or Criegee oxidation and consecutive aldol condensations and then four stemarene and betaerane diterpenoids including ent-stemara-13(14)-en-19-ol,entstemara-13(14)-en-18-ol,betaera-13(14)-en-19-ol,betaera-13(14)-en-18-ol,(-)oryzalexin S and(+)-stemarin and ent-kaurane diterpenoid 20-nor-cofaryloside I(proposed)were synthesized from chiral pool materials andrographolide or dehydroabietic acid and synthesized chiral starting materials.The structures of entstemara-13(14)-en-19-ol and ent-stemara-13(14)-en-18-ol have been revised based on total synthesis.This strategy provides an approach for the construction of the polycyclic labdane-related diterpenoids,which is expected to be widely used.