Four New Pairs of MetO-Containing Diketopiperazine Enantiomers: Isolation, Synthesis and Potential Anti-Parkinson’s Disease Activity

Four new methionine sulfoxide-containing diketopiperazines, (+)-dysidmetsulfoxide A [(+)-<b>1</b>], (+)-dysidmetsulfoxide B [(+)-<b>2</b>], (+)-dysidmetsulfoxide C [(+)-<b>3</b>] and (-)-dysidmetsulfoxide C [(-)-<b>3</b>], were isolated from the South China Sea sponge <i>Dysidea</i> sp. These compounds represented the first example of diketopiperazines possessing the unit of methionine sulfoxide (MetO) isolated from marine sponges. As it was difficult to determine the configuration of chiral sulfur atom in the thionyl group, the structures with absolute configurations of these compounds were elucidated by spectroscopic analyses and total synthesis. It was noteworthy that the purchased synthetic precursors, Fmoc-<i>L</i>- and Fmoc-<i>D</i>-MetO, were mixtures of epimers, respectively, due to the stereogenic sulfur atom in MetO, which were separated to prepare the optically pure isomers via the method of supercritical fluid chromatography (SFC). In addition, the other four optical isomers [(-)-<b>1</b>, (-)-<b>2</b>, (+)-<b>4</b> and (-)-<b>4</b>] were also synthesized. Furthermore, (+)-<b>1</b>, (-)-<b>1</b>, (+)-<b>3</b>, (+)-<b>4</b> and (-)-<b>4</b> showed potential anti-Parkinson's disease activities in an in vivo zebrafish model.