Gliotoxin analogs as inhibitors of reverse transcriptase. 2. Resolution and x-ray crystal structure determination

Publisher Website
Google Scholar
Abstract
A novel, simple and efficient method for the chemical resolution of epidithiodioxopiperazines was reported, which was based upon covalent formation of diastereomers. This method might be a general one for the resolution of chiral cyclic disulfides. Dithiol 5, prepared from 2 [an epipolythiodioxopiperazene] by reduction with NaBH4, was allowed to react with the disulfenyl chloride 8 [S,S-dichloro-2,3-O-isopropylidene-1,4-dithio-L-threitol] to yield 9 and 10, which were separated by short-column chromatography on silica gel. From these, the optically pure enantiomers 11 [2S,2aS)-9,9a-dihydro-1,2,9,9,-tetramethyl-2,9a-epidithio-3,10-diketopiperazino[1,2a]indole] and 12 [the 2R,9aR isomer of 11], respectively, were obtained by reduction with NaBH4, followed by reoxidation with I2-pyridine. In this way the precursor 7 of the resolving agent could also be recovered. The absolute configurations of 11 and 12 were derived from CD [circular dichroism] spectra. Kinetic asymmetric transformation of the gliotoxin analog 2 with the diphosphine 6 gave a 19% enrichment in 1 enantiomer of the starting material. Both enantiomers inhibited reverse transcriptase, the RNA-dependent DNA polymerase [Moloney mouse leukemia virus], to the same degree, indicating that there is no relation between this property of epidithiodioxopiperazines and their bridgehead configurations. From the X-ray crystal structure determination it can be seen that there is a considerable torsional and conformational strain in compound 2, which might enhance the ease of cleavage of the S.sbd.S bond. A possible relationship between this property and the biological activity of 2 is discussed.