An Epitetrathiodioxopiperazine with 3S,6S Configuration from Hyalodendron sp.

Abstract

Can. J. Chem. 53,295 (1975).(3S,6S)3-Benzyl-6-hydroxymethyl-1,4dimethyl-3,6-epitetrathiopiperazine-2,5-dione has been isolated from cultures of Hynlodendron sp. The same compound is produced when hyalodendrin is heated with methanol -hydrochloric acid. The fungitoxic epidithiodioxopiperazine hyalodendrin, 1, and the corresponding di(methy1-thio) ether, 2, both with 3S,6S configuration have recently been isolated from culture filtrates of Hyalodendron sp. (1-3). Metabolites 1 and 2, and the trisulfide 3, of undetermined absolute configuration, were obtained from cultures of an unidentified fungus (NRRL 3888) (4). The metabolite 1, with R configuration at positions 3 and 6, and compounds 2 and 4, evidently belonging to the same stereochemical series, are produced by Penicillium turbatum (5). Gliovictin, a metabolite of Helminthosporium victoriae also has structure 2 (6) and is likewise enantiomeric (3R,6R) with the corresponding Hyalodendron product.We record here some observations made during a study of the 3S,6S tetrasulfide 4, isolated from fermentations of Hyalodendron sp. This compound, Cl,H16N,0,S,, was present in chloroform extracts of the filtered culture medium in amounts which ranged up to 3% of the yield of pure hyalodendrin. It was slightly more polar than the latter, and could be separated and purified by preparative-layer chromatography, followed by crystallization. Comparison of the spectral characteristics of 4 (see Experimental section) with those of its co-metabolites 1 and 2 leave no doubt as to its constitution. Comparison of the circular dichroism curve of the Hyalodendron tetrasulfide (see Experimental section) with that published for the Penicillium metabolite (5) establishes that these compounds are enantiomeric at positions 3 and 6. A detailed discussion of the geometry of the tetrasulfide system of 4 is deferred at this stage, although it is noted that the synthetic compound N,N1 -dimethyl -3,6 -epitetrathiopiperazine -2,5-dione and sporidesmin G have been shown by X-ray analysis to be structurally similar with respect to the epitetrathiodioxopiperazine moiety (7,8).A tetrasulfide, identical in all respects (including c.d. spectrum) with the Hyalodendron tetrasulfide, was obtained in modest yield when hyalodendrin was refluxed in methanolic hydrochloric acid until no starting material remained (t.1.c.). By-products from this transformation, depleted in sulfur, resisted preliminary purificaCan. J. Chem. Downloaded from www.nrcresearchpress.com by 34.214.212.150 on 05/12/18For personal use only.

Epidithiodioxopiperazines. occurrence, synthesis and biogenesis

“…22 The same fungus was later shown to produce the bis(methylthio) derivative ( 29 ) 23 and epitetrasulfide 28 . 24 Epitrithiohyalodendrin ( 27 ) has only been observed as a product of the unidentified fungus NRRL 3888, along with 3 and 29 . 25 Not surprisingly, hyalodendrin and the epitri- and epitetrasulfide derivatives exhibit antibacterial activity, while the bisdethiodi(methylthio) analogue is inactive against fungi and bacteria and relatively non-toxic to mice.…”

“…16 Evidence suggests that gliotoxin and other epidithiodioxopiperazines are also capable of forming mixed disuldes with free thiol groups in cells. 17,18 Following incubation with radiolabelled gliotoxin, cells were shown to contain protein-bound [ 35 S]-gliotoxin (24). 3 This result could be reversed if cells were treated with both gliotoxin and excess reducing agent (dithiothreitol), suggesting a covalent interaction.…”

“…25 Not surprisingly, hyalodendrin and the epitri-and epitetrasulde derivatives exhibit antibacterial activity, while the bisdethiodi(methylthio) analogue is inactive against fungi and bacteria and relatively non-toxic to mice. [22][23][24][25] Interestingly, it was observed that hyalodendrin could be converted to epite-trasulde 28 in the presence of HCl with heating in methanol and the culture medium. Racemic tetrasulde was isolated when HCl was omitted from the same conditions.…”

Natural Products Containing Hydrogen Sulfide Releasing Moieties

“…38 Much like gliotoxin, the parent hyalodendrin contains a disulfide bridge, but trisulfide hyalodendrin-S 3 (38) and tetrasulfide hyalodendrin-S 4 (39) have also been isolated and demonstrate antibacterial activity. 39 Elaborating the complexity of the epidithiodioxopiperazines, sirodesmins contain a spiro-fused tetrahydrofurancyclopentapyrrolidine core; they were first isolated from Sirodesmium diversum in the 1970s. 40 Much like gliotoxins…”