| Summary: | An efficient synthesis of <i>rac</i>-6-desmethyl-5β–hydroxy-<span style="font-variant: small-caps;">d</span>-secoartemisinin <b>2</b>, a tricyclic analog of <i>R</i>-(+)-artemisinin <b>1</b>, was accomplished and the racemate was resolved into the (+)-<b>2b</b> and (−)-<b>2a</b> enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer <i>R</i>-(−)-<b>2a</b>. Several new compounds <b>9</b>–<b>16</b>, <b>19a</b>, <b>19b</b>, <b>22</b> and <b>29</b> were synthesized from <i>rac</i>-<b>2</b> but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of <b>2</b>, a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of <i>Plasmodium falciparum</i>. Several of the analogs had moderate activity in comparison to the natural product <b>1</b>. Iron (II) bromide-promoted rearrangement of <b>2</b> gave, in 50% yield, the ring-contracted tetrahydrofuran <b>22</b>, while the 5-ketone <b>15</b> provided a monocyclic methyl ketone <b>29</b> (50%). Neither <b>22</b> nor <b>29</b> possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.
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