On the Determination of the Stereochemistry of Semisynthetic Natural Product Analogues using Chiroptical Spectroscopy: Desulfurization of Epidithiodioxopiperazine Fungal Metabolites

Abstract

Isolation and semisynthetic modification of the fungal metabolite chaetocin gave access to a desulfurized analogue of this natural product. Detailed chiroptical studies, comparing experimentally obtained optical rotation values, electronic circular dichroism spectra, and vibrational circular dichroism spectra to computationally simulated ones, reveal the desulfurization of chaetocin to unambiguously proceed with retention of configuration. Consideration of the plausible mechanisms for this process highlighted inconsistencies in the stereochemical assignment of related molecules in the literature. This in turn allowed the stereochemical reassignment of the natural product analogue dethiodehydrogliotoxin.

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

“…11 Ottenheijm and co-workers had assigned this stereoisomer to have ( R , R ) stereochemistry by qualitative comparison with the ECD spectra of the closely related gliotoxin. 20 Since correlative methods, which compare experimental chiroptical spectra of a given molecule to those acquired from related molecular frameworks, can lead to a significant chance of error 5,21 and ECD quantum-chemical simulations are generally less reliable than, for example, those for VCD and ROA, 22 we sought to confirm this assignment. The optical rotation of ( R , R )- 7 was calculated and compared to the experimental values.…”

“…We have previously employed this strategy to unambiguously determine the absolute configuration of a desulfurized analogue ( 2 ) of the 3,6-epidithiodiketopiperazine (ETP) natural product chaetocin ( 1 ) (Figure 1), 5 a nonspecific histone lysine methyltransferase inhibitor. 6−8 While the desulfurization of ETPs with triphenylphosphine has been known for decades, 9 the stereochemical course of this reaction has been contested in several papers (e.g., see Figure 1).…”

“…12 Through simulation of the ECD spectra of the two possible enantiomers of 6 ( R , R and S , S ), we found the assignment by Safe and Taylor to be erroneous and therefore reassigned this desulfurization reaction to also occur with retention of configuration. 5 …”

“…11 The stereochemical assignment of 8 was obtained by anomalous-dispersion X-ray crystallography (vide infra). While qualitative mechanistic scenarios have been reported to account for the apparent inversion of configuration for this isolated case, 5,11 we decided to computationally study the mechanistic course of this reaction in order to determine the feasibility of an inversion mechanism. In this paper, we report our results on this mechanistic study as well as the use of chiroptical methods and chemical derivatization to characterize the stereochemistry of compounds 7 and 8 .…”

Synthesis and anticancer activity of epipolythiodiketopiperazine alkaloids

“…Desulfurization of epidithiodiketopiperazine 26 was realized by treatment with triethylphosphite in THF to give epimonosulfide 25 in 63% yield. 35 The sulfur atoms were also capped with the S -acetyl and S -methylsulfane functional groupings to afford compounds that are potentially more labile under intracellular conditions. After reduction of the sulfur bridge of epidisulfide 26 , its treatment with an excess of acetyl chloride, methanesulfenyl chloride, or dimethyldisulfide afforded compounds 44, 45 and 46 , respectively, in good yields.…”