Aranotin

The dihydroxyoxepine moiety is a part of a fungal metabolite such as aranotin acetate exhibiting an antiviral activity. To prepare the 4,5-dihydroxyoxepines 546, the Cope rearrangement of the corresponding divinylepoxides 545 was used (equation 215)267-269. 

N-arylation has also formed the basis of the synthesis of analogs of aranotins (77JOC948). In this case, the N,N-bis-arylated product (37) has been obtained in 32% yield from piperazine-2,5-dione (Cu2I2, K2C03, CH3CN). 

Arene oxides and their oxepin tautomers play a role in the biosynthesis of some microbial metabolites, e.g., the sulfur-containing antibiotics gliotoxin (345),188 dehydrogliotoxin (346),189 apoarontin (347),190 aranotin (348),191... 

Aranotins and Sirodesmin.—ctc/o-(l Phenylalanyl-L-seryl) is an efficient and intact precursor for gliotoxin (114) (cf. Vol. 10, p. 27). Bisdethiobis(methylthio)-acetylaranotin (115) is related to gliotoxin in the biosynthesis of this metabolite, it is believed that ring-opening of an arene oxide las (116)1 occurs, followed by further epoxidation and cyclization, as in the biosynthesis of gliotoxin (114).2... 

Chaetocin70" (75a) and verticillin A70b (75b), metabolites of Chaetomium minutum and a species of Verticillium from Coltricia cinnamomea respectively, are closely related dimers (Scheme 29) with S2-bridged diketopiperazine systems reminiscent of gliotoxin, sporidesmin, and aranotin. 

Incorporation of phenylalanine into these metabolites would reasonably proceed by a pathway involving 2,3-epoxidation of the aromatic ring, shown in Scheme 6 for gliotoxin (46) additionally, rearrangement of the appropriate 2,3-epoxide would give the oxepin rings found in the aranotins. 

Several metabolites in which phenylalanine participates as a component of the diketopiperazine ring have been isolated from Aspergillus species. Other possible components of the diketopiperazine skeleton are serine (gliotoxin), phenylalanine (aranotin and emestrin), and glycine (aspirochlorine). It is interesting that all of these metabolites possess two-four sulfur atoms in the molecule. These inhibit bacterial growth and are rather toxic to mammalian cells. 

Acetylation of aranotin (65), C2oHigN207S2, mp 198-200°C, affords another metabolite, acetylaranotin (66), C22H2oN20sS2> 201-215°C, which has a... 

Scheme 13. Conversion of aranotin (65) to acetylaranotin (66), BDA (67), and 70. Reaction conditions a, Raney Ni b, NaBH4 c, CH3l-CHCl3/MeOH.

Cyclo(L-[U- C]phenylalanyl-L-phenylalanine) is incorporated into BDA in 19.9% yield, in cultivation for 48 hr in Asp. terreus (141). In contrast, the cyclo L,D and D,D isomers are not incorporated. Further, the isolation of cis-3,6-bibenzyl-3,6-bis(methylthio)piperazine-2,5-dione (71), mp 291-293°C, [a]54g — 122°, from Asp. terreus (142) suggests that the sulfur atoms are introduced in an early stage of aranotin biosynthesis, as in gliotoxin biosynthesis. 

A few other aranotin-related metabolites have been noted. Epicorazine A has been isolated from Epicoccum nigrum (143). Bipolaramide was found in Bi-polaris species (144). 

Gross U, Nieger M, Brase S (2010) A Unified Strategy Targeting the Thiodiketopiperazine Mycotoxins Exserohilone, Gliotoxin, the Epicoccins, the Epicorazines, Rostratin A and Aranotin. Chem Eur J 16 11624... 

Aranotin 47, a diketopiperazine containing the oxepine nucleus, is a metabolite from Arachniotus aureus and showed antiviral activity. The structure and the stereochemistry of 47 appear to represent a biogenetic transformation of a benzene ring into the oxepine nucleus. 

Gliotoxin, aranotin, and sporidesmin are the principal members of a group of fungal metabolites characterized by having an epidithiodioxopiperazine moiety as a unique structural feature. Though somewhat toxic to mammals, several... 

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