Mechanistic and Chiroptical Studies on the Desulfurization of Epidithiodioxopiperazines Reveal Universal Retention of Configuration at the Bridgehead Carbon Atoms

Abstract

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, but the quantitative feasibility of such mechanistic pathways has not been assessed. We report a computational study revealing 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 the synthetic gliotoxin analogue shown 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 chemical derivatization studies, we have unambiguously demonstrated that contrary to its current assignment in the literature, the desulfurization of this synthetic ETP also proceeds with retention of configuration.

Resistance is not futile: gliotoxin biosynthesis, functionality and utility

“…Amongst others, these include sirodesmin A, sporidesmin A, chaetocin, aranotin, and chetomin [13]. Studies on the biosynthetic mechanism of ETPs, particularly gliotoxin, are also serving to inspire new synthetic chemistry approaches for ETP synthesis and desulfurization, which are somewhat beyond the scope of the present review [13,14].…”

“…Amongst others, these include sirodesmin A, sporidesmin A, chaetocin, aranotin, and chetomin [13]. Studies on the biosynthetic mechanism of ETPs, particularly gliotoxin, are also serving to inspire new synthetic chemistry approaches for ETP synthesis and desulfurization, which are somewhat beyond the scope of the present review [13,14].In addition to studying how gliotoxin contributes to organismal virulence, it has also been deployed to explore and reveal novel biochemistry within both fungal and animal cells [15,16]. Thus, we contend that it is the ability of gliotoxin to interfere with so many cellular processes that makes it such a useful tool to access the many important, although occluded, systems interactions within fungi.…”

Recent advances in the use of vibrational chiroptical spectroscopic methods for stereochemical characterization of natural products

“…Compound 189 was found to adopt a bracelet-type structure in inert solvents, while a propeller-type structure was suggested in polar solvents. 194 Furthermore, a combination of chiroptical spectroscopic methods was successfully applied to two new dimeric epipolythiodiketopiperazines, preussiadins A (191) and B (192), obtained from the mycelia of a Preussia typharum isolate. It was found that the most populated conformer does not exhibit C 3 symmetry, and is different from that present in the crystal and the NMR-derived strucuture.…”

Structural Analysis Using Chiroptical Spectroscopy: Insights and Cautions

“…The errors in the literature ACs can be traced back to varying sources, which are detailed in the footnotes to Table . For detailed discussions on individual cases, the reader is encouraged to refer to the cited references …”