Mechanistic and chiroptical studies on the desulfurization of epidithiodioxopiperazines reveal universal retention of configuration at the bridgehead carbon atoms.

2,3,10,10-Tetramethyl-2,3-dihydro-1H-3,10a-epithiopyrazino[1,2-a]indole-1,4(10H)-dione (8). To a solution of gliotoxin analogue (7, 33 mg, 0.10 mmol) in dioxane (8 mL) was added PPh3 (33 mg, 0.16 mmol) and the resulting mixture was stirred overnight at room temperature. The solvent was then re-moved under reduced pressure and the pink residue was purified by column chromatography [PEEtOAc (100:0 to 95:5)] to afford a colorless oil (19 mg, 64%) which was recrystallized from CH2Cl2 to give a white solid: m.p. 58 60 C; IR (neat) 1720, 1456, 1387, 1288, 1134 cm-1; 1H NMR (400 MHz, CDCl3) 8.54 (app-d, J = 7.8 Hz, 1H), 7.25 (td, J = 7.8, 1.0 Hz, 1H), 7.20 (dd, J = 7.8, 1.0 Hz, 1H), 7.13 (td, J = 7.8, 1.0 Hz, 1H), 2.96 (s, 3H), 1.83 (s, 3H), 1.75 (s, 3H), 1.48 (s, 3H); 13C NMR (100 MHz, CDCl3) 172.5, 172.0, 139.7, 138.1, 128.1, 124.7, 122.4, 113.6, 86.6, 75.1, 43.5, 27.2, 26.3, 25.7, 13.3; MS (CI) m/z 289 (M+H)+, 306 (M+NH4)+; HRMS (CI) m/z calcd for C15H17N2O2S [(M+H)+] 289.1011, found: 289.1026. The obtained enantiomers could be separated by chiral HPLC (OD+ semiprep column, Hexane : Isopropanol, 90:10): First peak: [α]25D -47.5 (c 1.12, CH2Cl2), Second peak: [α]25D +34.4 (c 1.12, CH2Cl2).