Synthesis of Bicyclic Analogs of Artemisinin, an Antimalarial Natural Product

Discovery of the peroxy natural products artemisinin (1) has engendered a renewed interest in chemotherapeutic agents to treat malaria. The unusual array of oxygen functionality in 1, a mechanism of action unrelated to that of the more traditional antimalarials, and the possibility for rational drug design have motivated our study of the chemistry of compounds related to 1.

Compounds such as 2 and 3 are proposed for synthesis. A variety of side-chains may be incorporated: lipophilic chains, carboxylate chains, and/or chains with "handles" for further functionalization.

Our route to compounds of these types involves preparation of a suitably functionalized pyran or oxepane precursor. Students will either purchase the starting dihydropyran or prepare them by hetero Diels-Alder reaction. The pyrans can then be alkylated using butyllithium to install the group R'. Hydroboration gives the hydroxypyran and mesylation, treatment with hydrazine and hydrogen peroxide/sodium peroxide yields the corresponding hydroperoxide. Cyclization under acidic conditions forms the bicyclic artemisinin analog 2. Similar steps are planned for the formation of analogs similar to 3.

Techniques and reactions in organic synthesis that student researchers will learn include Diels-Alder reactions, use of strong bases (butyllithium), handling of air-sensitive reagents, running reactions under an inert atmosphere, extractive work-ups, chromatography, working with oxidants, and characterizing new compounds (1H and 13C NMR, MS, IR, elemental analysis).

Additional Information

Dee Ann Casteel
Associate Professor
Department of Chemistry,
Bucknell University

e-mail: casteel@bucknell.edu
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phone: 570-577-3675
fax: 570-577-1739