Desulfurization of epidithiodioxopiperazines. A mechanistic and chiroptical study

The chemistry and biology of the immunomodulating agent gliotoxin and related epipolythiodioxopiperazines

“…Further reaction gave the tetrasulfide. The trisulfide of sporidesmin (14,n=3) was photolytically converted to a mixture of di and tetrasulfides, and by using 35S as a tracer it was shown that the sulfur transferred from one S3 molecule to a second was the same one inserted Following an earlier observation on dehydrogliotoxin by Safe and Taylorz8, it was shown that desulfuration of the disulfide (28) with triphenylphosphine to yield the monosulfide (29) appears to occur with inversion of configuration at the bridgehead carbons based on crystal structure determination^. '^ However, corresponding desulfuration of the sirodesmin (30) occurs with retention, again based on crystal structure e~idence.~' The differences in behavior of triphenyl phosphine in these instances has been explained in terms of differing mechanisms and may depend on the nature of other substituents in the ETP ring.…”

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

“…11 At the M06-2X/6-311++G(d,p) level with a solvent model for dichloromethane, the optical rotation of ( R , R )- 8 was −169. Although the quantitative magnitude of this predicted value is different, the strong negative sign of the rotation is suggestive that the first eluted enantiomer has the ( R , R ) configuration.…”

“…Indeed, this regiochemical outcome is consistent with the experimental work of Ottenheijm and co-workers through trapping of a key intermediate ( Int2 ) with a methanol nucleophile. 11 The second unimolecular step via TS2 [or TS2 (iso)] corresponds to elimination of triphenylphosphine sulfide from Int1 to create the zwitterionic intermediate Int2 . Computational modeling of the geometry of such ionic intermediates has historically been difficult.…”

“…In 1979, Ottenheijm and co-workers reported the desulfurization of gliotoxin analogue 7 into monosulfide 8 (Figure 1 ). 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.…”

“… 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 .…”