Autoxidation of a C2-Olefinated Dihydroartemisinic Acid Analogue to Form an Aromatic Ring: Application to Serrulatene Biosynthesis

Dihydroartemisinic acid (DHAA) is a plant natural product that undergoes a spontaneous endoperoxide-forming cascade reaction to yield artemisinin in the presence of air. The endoperoxide functional group gives artemisinin its biological activity that kills Plasmodium falciparum, the parasite that causes malaria. To enhance our understanding of the mechanism of this cascade reaction, 2,3-didehydrodihydroartemisinic acid (2,3-didehydro-DHAA), a DHAA derivative with a double bond at the C2-position, was synthesized. When 2,3-didehydro-DHAA was exposed to air over time, instead of forming an endoperoxide, this compound predominantly underwent aromatization. This olefinated DHAA analogue reveals the requirement of a monoalkene functional group to initiate the endoperoxide-forming cascade reaction to yield artemisinin from DHAA. In addition, this aromatization process was exploited to illustrate the autoxidation process of a different plant natural product, dihydroserrulatene, to form the aromatic ring in serrulatene. This spontaneous aromatization process has applications in other natural products such as leubethanol and erogorgiaene. Due to their similarity in structure to antimicrobial natural products, the synthesized compounds in this study were tested for biological activity. A group of the tested compounds had minimum inhibitory concentration (MIC) values ranging from 12.5 to 25 μg/mL against the bacterial pathogen Staphylococcus aureus and the fungal pathogen Cryptococcus neoformans.