Total synthesis of 1,4a-di- epi-ent -pancratistatin, exemplifying a stereodivergent approach to pancratistatin isomers

The total synthesis of 1,4a-di- -pancratistatin, a novel stereoisomer of the anti-tumor alkaloid pancratistatin, was achieved in 14 steps starting from D-mannitol. The construction of the pancratistatin skeleton involved conjugate addition of organocuprate to a nitrosoolefin, which was generated from inosose oxime. This was followed by stereoselective reduction of the oxime to an amine and site-selective formylation. Biological evaluations revealed that the newly synthesized compounds exhibit cytotoxicity toward cancer cells and significant ferroptosis inhibitory activity. These compounds constitute a promising small-molecule library for the development of potent bioactive agents.