Peroxide Natural Products from <i>Plakortis zyggompha</i> and the Sponge Association <i>Plakortis halichondrioides</i>–<i>Xestospongia deweerdtae</i>: Antifungal Activity against <i>Cryptococcus gattii</i>

<i>Cryptococcus gattii</i> is a human pathogen and causative agent of a pernicious, sometimes fatal, disseminated fungal disease. Investigation of antifungal extracts of the marine sponge association <i>Plakortis halichondrioides</i>–<i>Xestospongia deweerdtae</i> and the sponge <i>Plakortis zyggompha</i> from the Bahamas led to the discovery and isolation of 6-<i>epi</i>-7,8-dihydroplakortide K (<b>1</b>), plakortide AA (<b>2</b>), and three new plakinic acids, N–P (<b>4</b>–<b>6</b>; unstable 1,2-dioxolanes bearing benzyl-substituted conjugated dienes), along with known plakinic acids L, K, and M. Chiroptical comparisons and DFT calculations of <sup>13</sup>C NMR chemical shifts were used to assign the absolute stereostructure of <b>4</b>. The stereospecific base-promoted rearrangement–saponification of <b>1</b> to <b>10</b> was briefly investigated and showed tight kinetic control and stereospecific formation of the new C-2 stereocenter with inversion at C-3. Plakinic acid M and plakortides <b>9</b> and <b>11</b> exhibited antifungal activity against <i>C. gattii</i> (MIC<sub>90</sub> = 2.4 to 36 μM), but plakinic acids N–P were inactive under the same conditions.