Total Synthesis Of Trabectedin,Lurdinectedin And Renieramycin T

Trabectedin and Lurbinectedin are anti-tumor pharmaceuticals approved by FDA for treating soft-tissue sarcomas and metastatic small cell lung cancer.Among them,the antiproliferative activity of trabectedin is 10-1000 folds higher than taxol in vivo.Lurbinectedin is also in Phase III clinical study as a breast cancer treatment.Their structure features densely functionalized bistetrahydroisoquinoline skeleton(A-E),a fragile 10-membered sulfur-containing lactone and seven stereocenters.Due to the synthetic demand and challenge,trabectedin and lurbinectedin attracted great attentation from the chemistry community in the past three decades.Our synthetic studies toward trabectedin,lurbinectedin and renieramycin T are mainly devided into three parts.Part 1.The synthesis of chiral fragment and exploration of fragments connection methods.(1)Using L-tyrosine as the chiral raw material,the selective functionalization reaction of phenol was explored to construct the multi-substituted amino acid chiral fragment shared by these molecules.(2)Using cysteine derivatives and glycine ester Schiff base as the key synthons,the connection of fragment and the construction of contituous chiralty were achieved through intermolecular Pummerer rearrangement and then the construction of core pentacyclic skeleton was explored.Part 2.Advanced pentacyclic intermediates with benzyl ether structral units were constructed diastereoselectively.Based on this structure,the synthesis of fully substituted B-ring and the construction of C1 chirality were discussed.The chiralty of the benzylic position will be reversed with the prolongation of the reaction time,and it was found that the configuration of the benzylic stereocenter determines whether the Pictet-Spengler cyclization of the B ring can take place.Finally,the construction of the B ring was achieved but the chirality of the C1 position was opposite and the chiralty of C1 inversion could not be achieved.Part 3.Using Garner aldehyde and unsymmetric malonate as Pictet-Spengler cyclization partners,two tetrahydroisoquinoline rings were successfully constructed and connected through twice efficient Pictet-Spengler cyclization and intermolecular aldol condensation.Palladium complex induced diastereoselectivity via decaboxylative protonation was achieved for the C1 stereocenter.Finally,the total synthesis of trabectedin,lurbinectedin and renieramycin T were accomplished in 22-27 linear steps in a concise and practical manner.