Malaria constitutes a major health risk for billions of people worldwide, emphasized by ca. 214 million cases in 2015 and an estimated 438.000 deaths. The most effective treatment against malaria is an artemisinin-based combination therapy (ACT). Recently, resistance of Plasmodium falciparum to artemisinin derivatives has been detected in the Greater Mekong subregion. Although the combination therapy is still efficacious in most cases, it is important to consider new lead candidates in order to treat malaria in the future. Cupacinoxepin, an onocerane triterpene isolated from the bark of Cupania cinerea, shows in vitro activity against the Plasmodium falciparum K1 strain with an IC50-value of 8.7 mM. The biological activity and the intriguing molecular structure in combination with a low natural abundance (7.1 mg from 1.21 kg bark) renders cupacinoxepin a challenging target. Herein, we present an eight-step synthesis of cupacinoxepin using readily available starting materials. The application of one-pot procedures facilitates the synthetic sequence and allows for the preparation of advanced intermediates on gram scale. Currently, the synthesis of derivatives for structure activity relationship studies is in our focus.

Synthesis of antimalarial onocerane triterpene cupacinoxepin

253rd National Meeting (2017)

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