Selective Synthesis Of Tert-butyl Sulfone Macrolide Drug Skeleton

Macrolides have a good effect on infectious diseases,respiratory diseases,digestive system diseases,cardiovascular diseases and so on.Alkenes with different configurations(E or Z)usually have a great influence on biological activity.The large hindered sulfone compound showing good performance in the rate of drug metabolism has become a very important structural unit in drug design and development.Therefore,this thesis is devoted to exploring a synthesis method that contains both tert-butyl sulfone group and internal olefin macrolide.1.Synthesis of allyl palladium-based macrolide compounds.In this chapter,eleven allyl palladium substrates were synthesized through esterification and olefin cross-metathesis reactions.Then,the fifteen-membered ring substrate was taken as an example to explore the ring-closing conditions,and the optimal reaction condition was obtained.Finally,the allyl palladium-catalyzed substrate was subjected to ring closure reaction to complete the synthesis of nine to fifteen-membered rings and nineteen,twenty-two,twenty-five,and twenty-eight-membered ring macrolides2.Synthesis of macrolide compounds based on olefin ring-closing metathesis reaction(RCM).First,RCM substrates were synthesized,and the RCM ring-closing conditions were explored with a 15-membered ring as an example.The optimal reaction conditions for E-selective and Z-selective RCM reactions were determined.Syntheses of nine-to fifteen-membered rings with E-and Z-olefins,and nineteen,twenty-two,twenty-five,and twenty-eight ring macrolides were finished,further validating the configuration issue existing in the allyl palladium-based macrolide synthesis3.Research on the mechanism of allyl palladium catalysis.First,the ring closing mechanism of the eight-membered allyl palladium complex substituted with tert-butyl sulfone and methyl ester was investigated,and it proved that the cis ?-allyl palladium complex turned into trans ?-complex,and then transferred to an eight-membered ring product after conversion.Next,the ring closure reaction of the eight-membered ring substrate substituted with tert-butyl sulfone group was tracked by NMR,and then the ring closure reaction mechanism of the ten-membered allyl palladium complex substituted with tert-butyl sulfone group was investigated.Later,we also studied the performance of the tertiary sulfone substituted seven-membered ring substrate in the ring closure reaction,and successfully obtained the five-membered ring.