Studies On Total Synthesis Of The Bioactive Natural Products Daldinin A, B,C And Concentricolide

Background Concentricolide, a novel benzofuran derivative, was recently isolated from the fungal metabolites of Daldinia concentrica. Preliminary investigation showed that concentricolide exhibited good HIV-1inhibitory activity. Same to concentricolide, daldinin A, B and C, with benzofuran and phthalide pharmacophores, were also isolated the fungal metabolites of Daldinia concentrica. Studies on the total synthesis of concentricolide and its derivatives were necessary for providing a useful method for synthesis of the bioactive compounds with concentricolide skeleton. In this work, a venstile, facile and effective methodology for total synthesis of daldinins and concentricolide was perfectly established. Optically pure daldinin A, B, C and concentricolide were toatally synthesized by asmmetric transfer hydrogenationObjective Total synthesis of natural products is essential and important for research and development of new durgs. Studies on total synthesis of daldinin A, B, C and concentricolide are to provide the synthetic methodology for this new type of natural compounds.Method Reaction of1,3-acetonedicarboxylate with hex-2-ynal gave the dimethyl2-hydroxy-4-propylisophthalate, which afforded the aromatic ketone by phenolichydroxyl protection and subsequent oxidation. Treatment of the aromatic ketone with reducing agent gave the desired five-membered lactone. The other furan fragment was accomplished via Diekmann-condensation and Krapcho reaction in the following steps. Finally, daldinin A was synthesized by reduction of carbonyl of benzofuran with chiral reducing agent. Asymmetric synthesis of the daldinin B was sucessfully achieved by hydrogenation of daldinin A with Pd/C, and daldinin C was obtained by reduction daldinin B with LiAlH4. Concentricolide was obtained by elimination reaction of daldinin A.Results and Conclusion(1) From commercially available materials, daldinin A was totally synthsized in overall yield11.8%by a facile and efficient route in8steps. Total synthesis of daldinin B and C were also completed on basis of the same route.(2) Based on the synthesis of daldinin A, both (R) and (S)-concentricolide was obtained by elimination reaction in7.3%yield with97%ee and7.1%yield with98%ee, repectively. Their structure were charactered by NMR spectroscopy, and the structure of daldinin A was confirmed by single-crystal X-ray Diffraction. The natural concentricolide was determined as the S-enantiomer comparing with the synthetic (R)-concentricolide by HPLC.(3) A convenient and venstile synthestic route of the type of natural products with skeleton as6H-1,7-dioxa-as-indacen-8-one was established. It laid a solid foundation for the follow-up research of structure-activity relationship and biological activities.