Total Synthesis of Trabectedin, Lurbinectedin, and Renieramycin T

Trabectedin and lurbinectedin are therapeutic anti-tumor 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 gram scale, displaying superior potential for further drug development (Figure Presented).