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

The stereochemistry of the desulfurization products of chiral natural and synthetic 3,6-epidithiodiketopiperazines (ETPs) is specified inconsistently in the literature. Qualitative mechanisms have been put forward to explain apparently divergent stereochemical pathways, however the quantitative feasibility of such mechanistic pathways has not been assessed. We report a computational study which reveals that desulfurization of ETPs should occur universally with retention of configuration. While the majority of stereochemically assigned and reassigned cases fit this model, until now desulfurization of a synthetic gliotoxin analogue (7) has remained assigned as proceeding via inversion of configuration. Through detailed chiroptical studies, comparing experimentally obtained optical rotation values, electronic circular dichroism spectra, and vibrational circular dichroism spectra to their computationally simulated counterparts, as well as using chemical derivatization studies, we have unambiguously demonstrated that, contrary to its current assignment in the literature, the desulfurization of a synthetic ETP (7) also proceeds with retention of configuration.