Neoaspergillic acid

An alternative approach applicable both to the synthesis of racemic aspergillic acid428 and neoaspergillic acid is illustrated by the synthesis (Scheme 50) of neoaspergillic acid (8).429 The initial reaction of dl-leucine anhydride (235) with phosphoryl chloride produces, in addition to the required monochloro compound (236), some dichloro compound (237), and flavacol (4). Reaction of the latter compound with a mixture of phosphoryl chloride and phosphorus pentachloride yields further 2-chloro-3,6-diisobutylpyrazine (236). The remaining steps of the synthesis involve reactions discussed previously in this review, with the exception that the hydroxamic function is protected by diazomethane methylation and finally regenerated by ethanolic hydriodic acid treatment.429... 

Neoaspergillic acid (// 187), I -hydroxy-3,5-diisobutyl-2(l//)-pyrazinone, an Aspergillus sp metabolite [5021-35-2],... 

C12H20N2O2, Mr 224.30, pale yellow needles, mp. 97-99 C, [a]o+13.3° red complex with Fe, green Cu(ll) salts. Toxic, antibacterial metabolite from Af-pergillus flavus, A. sojae, and A. quercinus, LD50 (mouse p.o.) 4-5 mg/kg. A. is formed from leucine and isoleucine. Other amino acids can be built-in by specific feeding during the fermentation, e.g., neoaspergillic acid (2 mol. leucine). 

Leucine is known to be a precursor of neoaspergillic acid and pulcherriminic acid, and MacDonald s results would seem to rule out a role of the N-hydroxyamino acids as intermediates in the biosynthesis of these hydroxamates, although direct experiments using the hydroxylamino acids as substrates would be desirable. In the aspergillic acid family, it thus appears that the amino acid nitrogen undergoes substitution by carbon prior to its oxidation (oxygenation ). 

Neoaspergillic acid can be chemically degraded to the cyclic dipeptide of leucine, cyclo leucyl-leucyl, which in turn can be hydrolyzed to leucine (Micetich and MacDonald, 1965). This would suggest that leucine may be the precursor of neoaspergillic acid, and evidence to this effect will be discussed below. 

The reviewer finds that the conditions necessary for the biosynthesis of neoaspergillic acid or neohydroxyaspergillic acid in cultures of A. sclerotiorum have not been investigated systematically, and that it is not known whether modifications in the media or in the strain of the organism would affect the production of these antibiotics. In any case, the conditions described for the production of these antibiotics gives one no clue as to their routes of biosynthesis. 

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