Fungal Tetronic Acids

Before its true nature as a vitamin deficiency disease was firmly established, a connection was made between the incidence of pehagra and the consumption of mouldy maize. Several Penicillium species were isolated from this source. Examination of one of these, P. charlesii, by Raistrick between 1933 and 1935 led to the isolation of a series of acidic metabohtes that were derivatives of tetronic acids and exemplified by L-y-methyltetronic acid (6.11), carolic acid 

Biosynthetic studies have shown that the butyric acid portion and the carbon 

A group of metabolites have been isolated, particularly from lichens, that may arise by condensation between the activated a-methylene of a fatty acid and the carbonyl group of oxaloacetate. Another example is agaricic acid from Polyporus officinalis, a metabolite with antibiotic properties associated with the agaricum of the Romans (see Chapter 1). 

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Not all fungal tetronic acids are derived by this pathway. The biosynthesis of multicolic acid (6.17), a metabolite of P. multicolor, has been shown by carbon-13 labelling experiments to follow entirely a polyketide pathway. The proposed biosynthetic pathway (Scheme 6.2) involves the intermediacy of a 6-pentylresorcylic acid (6.16) and the cleavage of an aromatic ring. 

The biosynthesis of the fungal tetronic acids penicillic acid (185) and carolic acid (76 a), which are closely related structurally to patulin and multicolic acid, have also been studied extensively. Early work with " C-labelled precursors has clearly demonstrated the polyketide origin of penicillic acid, and also the intermediacy of orsellinic acid... 

The biosynthesis of the fungal tetronic acid carolic acid (76 a) in Penicillium charlesii is markedly different from that of patulin, multicolic acid and penicillic acid. Carbon-14 work has demonstrated that the carbon sub-unit C-3, C-4, C-9 in the acid is derived from a C-4-dicarboxylic acid such as succinate, whereas the remaining six carbons (C-1, C-2, C-5, C-6, C-7, C-8) are derived from two malonate units (C-5, C-6, C-7, C-8) and just one acetate unit (C-1, C-2) (Scheme 19) (775). It is proposed then that the biosynthesis of carolic acid proceeds from a C4-dicarboxylic acid first to either y-carboxymethyltetronic acid (196) or to carlosic acid (77 b) hydroxylation of carlosic acid then gives rise to carlic acid (77 a) which on decarboxylation produces carolic acid 176). 

The fungal metabolites patulin (10) and multicolic acid (79) are derived in nature via oxidative cleavages of polyketide derived aromatic intermediates a similar pathway has been established for the tetronic acid penicillic acid (185). By contrast, the biosynthesis of carolic acid (76a) which is found with dehydrocarolic acid (75) in P. charlesii, has been shown to occur from Krebs cycle intermediates. 

A number of fungal 5-substituted 3-acyl tetronic acid metabolites, as shown in Scheme 1.19, have attracted significant attention during the development of new synthetic protocols in the field of tetronic acids. 

Syntheses, published in 1976, of naturally occurring tetronic acids include those of (S )-carlosic acid (75) and the related (/ )-carolic acid and of fungal pigments based on the pulvinone e.g. 76) and pulvinic acid e.g. 77) structures. 

Substituted tetronic acids (89) can be obtained by condensation between the magnesium complex of ethyl hydrogen malonate and a-acetoxy-acid chlorides, followed by acid-catalysed lactonization in the presence of an alcohol (Scheme 15).The fungal metabolite derivative methyl (if)-O-methylmulticolanate (90)... 

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