Access to Natural and Unnatural 28-Norlupane Endoperoxides by Isayama-Mukaiyama Cobalt-Catalyzed Hydroperoxyl Silylation and Evaluation of Antiplasmodial Activity.

To synthesize a natural 28-norlupane endoperoxide previously isolated from an herbal source and displaying antiplasmodial activity, a four-step semisynthetic pathway was designed from natural betulinic acid and performed via Isayama-Mukaiyama cobalt-catalyzed hydroperoxyl silylation. The target 28-norlupane endoperoxide (2) was obtained along with its endoperoxide analogs (compd. 7-11) and other products (compd. 12-16). All products were identified by 1D and 2D nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS), and some were characterized by X-ray diffraction. All compounds were tested for their antiplasmodial activity against both Plasmodium falciparum chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains as well as for their cytotoxicity. Compound 2 presented broad-spectrum activity by inhibiting both chloroquine-sensitive (3D7) and -resistant (W2) P. falciparum strains. Compound 11, featuring a novel rearranged seven-membered ring scaffold, showed potent antiplasmodial activity with a favorable selectivity index, while compound 13 exhibited moderate activity. These findings highlight the potential of novel 28-norlupane endoperoxides as promising leads in antimalarial drug discovery.