Structural and Synthetic Investigations of Tanikolide Dimer, a SIRT2 Selective Inhibitor, and Tanikolide <i>seco</i>-Acid from the Madagascar Marine Cyanobacterium <i>Lyngbya majuscula</i>

Tanikolide <i>seco</i>-acid <b>2</b> and tanikolide dimer <b>3</b>, the latter a novel and selective SIRT2 inhibitor, were isolated from the Madagascar marine cyanobacterium <i>Lyngbya majuscula</i>. The structure of <b>2</b>, isolated as the pure <i>R</i> enantiomer, was elucidated by X-ray experiment in conjunction with NMR and optical rotation data, whereas the depside molecular structure of <b>3</b> was initially thought to be a <i>meso</i> compound as established by NMR, MS, and chiral HPLC analyses. Subsequent total synthesis of the three tanikolide dimer stereoisomers <b>4</b>, <b>5</b>, and <i>ent</i>-<b>5</b>, followed by chiral GC−MS comparisons with the natural product, showed it to be exclusively the <i>R</i>,<i>R</i>-isomer <b>5</b>. Tanikolide dimer <b>3</b> (= <b>5</b>) inhibited SIRT2 with an IC<sub>50</sub> = 176 nM in one assay format and 2.4 μM in another. Stereochemical determination of symmetrical dimers such as compound <b>3</b> pose intriguing and subtle questions in structure elucidation and, as shown in the current work, are perhaps best answered in conjunction with total synthesis.