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, 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.
Department of Chemistry, Imperial College London , South Kensington Campus, London SW7 2AZ, U.K.
Fanny L
FL
Cherblanc
Ya-Pei
YP
Lo
Wouter A
WA
Herrebout
Patrick
P
Bultinck
Henry S
HS
Rzepa
Matthew J
MJ
Fuchter
D002244:Carbon / Q000737:chemistry*; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D011789:Quantum Theory; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D010879:Piperazines; D013438:Sulfhydryl Compounds; C583099:epidithiodioxopiperazine; D002244:Carbon