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.