Total Synthesis and Biological Evaluation of 22-Hydroxyacuminatine and the Related Natural Products Norketoyobyrine and Naucleficine

Aromathecin compounds-which contain the same indolizine core structure as camptothecin-like compounds-are expected to show anticancer activity. Among them, 22-hydroxyacuminatine-which has a substituent on the E-ring of the pentacyclic scaffold-exhibits topoisomerase 1 inhibitory activity; therefore, the development of efficient methods for its synthesis has been actively pursued. Herein, we report a versatile synthetic methodology for introducing various substituents on the E-ring, leading to the total synthesis of 22-hydroxyacuminatine as a model compound of the aromathecin family. The synthesis comprises the following key steps: the synthesis of an isoquinoline <i>N</i>-oxide via the thermal cyclization of 2-alkynylbenzaldehyde oxime, the subsequent Reissert-Henze-type reaction to yield an isoquinolone, and the construction of the indolizine moiety (CD-ring) through C-N bond formation via the Mitsunobu reaction. Consequently, a pentacyclic benz[6,7]indolizino[1,2-<i>b</i>]quinolin-11(13<i>H</i>)-one framework is obtained. Using this methodology, the total synthesis of the natural products norketoyobyrine and naucleficine and an intermediate of the latter, which are indoloquinolizidine-type alkaloids, was achieved, and their antiproliferative activity against HCT-116 human colon cancer cells and HepG2 human liver cancer cells was assessed. Naucleficine and its intermediate exhibited moderate antiproliferative activity against HCT-116 cells, with IC₅₀ values of 55.58 and 41.40 μM, respectively.