Anticancer agent synthesis designed by artificial intelligence: Pd(OAc)2-catalyzed one-pot preparation of biphenyls and its application to a concise synthesis of various diazofluorenes

Abstract We successfully synthesized the antitumor agent 1-methoxydiazofluorene via an artificial intelligence (AI)-proposed design. The pivotal biphenyl scaffold of 1-methoxydiazofluorene was constructed by applying Pd(OAc)2-catalyzed cycloaromatization, a method developed by our group. AI-proposed functional group conversion of the biphenyl intermediate provided 9-diazo-1-methoxy-9H-fluorene, which inhibits the proliferation of HeLa cells, was achieved in reasonable chemical yield. In addition, various diazofluorenes were synthesized using the above protocol and their antitumor effects were evaluated. As a result, several novel diazofluorenes, which have a stronger cytotoxic activity than cisplatin against various human epithelial cancer cells, were found.