Synthesis and Biological Evaluation of Epidithio‑, Epitetrathio‑, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-<i>epi</i>-<i>ent</i>-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial Agents

An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)­diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis­[bis­(trimethylsilyl)­amino]­trisulfide (<b>23</b>) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (<b>1</b>), 8,8′-<i>epi</i>-<i>ent</i>-rostratin B (<b>2</b>), gliotoxin (<b>3</b>), gliotoxin G (<b>4</b>), emethallicin E (<b>5</b>), and haematocin (<b>6</b>). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, and <b>61</b>) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, <b>58</b>, <b>61</b>, and <b>1</b>)