Trabectedin and lurbinectedin are therapeutic antitumor pharmaceuticals approved by the Food and Drug Administration for treating soft tissue sarcomas and metastatic small cell lung cancer and have been facing synthes...Trabectedin and lurbinectedin are therapeutic antitumor pharmaceuticals approved by the Food and Drug Administration for treating soft tissue sarcomas and metastatic small cell lung cancer and have been facing synthesis challenges over the past three decades.In this report,the total synthesis of trabectedin,lurbinectedin,and renieramycin T were accomplished in 22-27 steps.The synthetic strategy features stereocontrolled Pictet-Spengler(PS)reaction leading to the multisubstituted tetrahydroisoquinoline fragment(DE ring),aldol condensation for C4-C10 bond formation,and a second PS cyclization with asymmetric oxomalonate for the fully substituted B ring,in which palladium complex-induced stereoselectivity is achieved via decarboxylative protonation anchoring the C1 stereocenter.The pentacyclic skeleton(A-E)was efficiently effectuated at a gramscale,displaying superior potential for further drug development.展开更多
基金the financial support provided by National Science Foundation of China(grant nos.22125103 and 21971065)Science and Technology Commission of Shanghai Municipality(grant nos.22JC1401000,20XD1421500,and 20JC1416800).
文摘Trabectedin and lurbinectedin are therapeutic antitumor pharmaceuticals approved by the Food and Drug Administration for treating soft tissue sarcomas and metastatic small cell lung cancer and have been facing synthesis challenges over the past three decades.In this report,the total synthesis of trabectedin,lurbinectedin,and renieramycin T were accomplished in 22-27 steps.The synthetic strategy features stereocontrolled Pictet-Spengler(PS)reaction leading to the multisubstituted tetrahydroisoquinoline fragment(DE ring),aldol condensation for C4-C10 bond formation,and a second PS cyclization with asymmetric oxomalonate for the fully substituted B ring,in which palladium complex-induced stereoselectivity is achieved via decarboxylative protonation anchoring the C1 stereocenter.The pentacyclic skeleton(A-E)was efficiently effectuated at a gramscale,displaying superior potential for further drug development.
