Patulin structure

Woodward then moved across town in Cambridge to devote a year of postgraduate study at Harvard University. At the end of that year, he accepted an appointment to the Harvard chemistry faculty, a post he held for most of the rest of his life. One of his great interests at Harvard was the synthesis of large, complex molecules, the first of which was quinine in 1944. He followed that work with the elucidation of other molecular structures and the development of synthetic methods for each. Included among these molecules were penicillin (1945), patulin (1948), cholesterol and cortisone (1951), oxytetracycline (1952), strychnine (1954), lysergic acid (1954), reserpine (1956), chlorophyll (1960), colchicine (1963), cephalosporin C (1965), and vitamin (1971). 

Owing to the varied structures of various food dyes, they can often be differentiated from one another by their characteristic ultraviolet/visible absorbance spectra. Using HPLC coupled with a diode array detector (HPLC-DAD) it is possible to collect a compound s absorbance spectrum as it elutes from the HPLC column, which greatly assists in identification. At Reading Scientific Services Ltd (RSSL) this type of detector is routinely used in a range of analyses of such substances as patulin, a mycotoxin found in apple juice, and in the analysis of colours and vitamins, which allows a more certain assignment of a particular peak to a specific compound to be made. 

Patulin is an excellent example of an acetate-derived structure synthesized from an aromatic substrate via oxidative cleavage and subsequent modifications (Figure 3.44). Patulin is a potent carcinogen produced by Penicillium patulum, a common contaminant on apples. If mould-infected apples find their way into food products, e.g. 

By contrast, Woodward s synthesis6 of the supposed structure 36 of the antibiotic patulin, which later turned out to have the isomeric structure 35, required intermediate 37 drawn both to resemble 36 and in a more normal way. Woodward then made the correct structure 35. 

Fig. 4. Structure of patulin showing the closed-ring tautomeric form. 

Representative Compounds Aflatoxins Citrinin Ergot alkaloids Fumonisins Ochratoxin A Patulin Trichothecenes Zearalenone Stachybotrys toxin Chemical Formula C17H12O6 (Aflatoxin Bi) Chemical Structure Aflatoxin Bi... 

Fliege, R. and Metzler, M. 2000. Electrophilic properties of patulin. Adduct structures and reaction pathways with 4-bromothiophenol and other model nucleophiles. Chem. Res. Toxicol. 13, 363-372. Florianowicz, T. 2001. Antifungal activity of some microorganisms against Penicillium expansum. Eur. Food Res. Technol 212, 282-286. 

It is interesting to speculate how quickly the structure might have been determined had NMR spectroscopy been in widespread use at the time. Indeed infrared correlations, which were being developed at the time of Woodward s proposal for the structure of patulin, were in accord with the structure. The presence of the enol of a ketone and a ketal in the structure also play an important part in the biological activity of patulin. 

This indicated that the two ethylenic linkages in the side chain of pyrethrolone were in conjugation. Similar results were obtained18 by the curve subtraction method with the absorption curves of the semicarbazones of pyrethrolone and tetrahydropyrethrolone. Woodward and Singh19 proposed the structure of patulin as XIX, with the C=C—C=C—C=0 unit, only because of the fact that it absorbs at 276 m/x (e 17,000). 

By contrast, in Woodward s synthesis of the supposed structure (35) of the antibiotic patulin, analysis of intermediate (36) by the standard 1,3-dicarbonyl disconnection reveals reactive non-enolisable (37) and unsym metrical ketone (38), required to enolise at the methyl group. Condensation in base ensured kinetic control (page 154). 

This synthesis showed that (35) was not the correct structure for patulin, and Woodward then made (39), the correct structure. 

C11H14O5, Mr 226.23, cryst., mp. 97-99°C, racemic. An antibiotic isolated from cultures of Lachnum pa-pyraceum (Ascomycetes), structurally related to other 5-membered cyclic lactones such as patulin and pen-icillic acid. P. acts as a fibrinogen antagonist. 

The microbial culprit organisms found to produce this environmental toxin are mostly Penicillium, Aspergillus, and Byssochlamys species (286-288) including P. patulum (289), P. urticae (290), P. claviforme (291), and P. expansum (292). While patulin (348) possesses antibiotic properties (293), it has not been investigated fully in this respect due to its toxic effects against mammals and plants (294). The chemical identity of patulin (348) was proposed initially incorrectly in 1948 (295), with the structure corrected by Woodward and Singh the following year to the structure shown (348, Fig. 7.1). 

Patulin (348) is a quite small natural product, but it nonetheless has a diverse complement of potent chemical functionality cyclic hemiacetal (the natural product is racemic) and allylic acetal moieties are present, and the molecule potentially can react with the nucleophihc residues of biomolecules as either a 1,4- or 1,6-Michael acceptor (see Fig. 7.1). Neopatulin (349) (296), ascadiol (350), and penicillic acid (351) are structurally related ylidenebutenolides, as are also metabolites of tetronic acid (352). 

The line between catabolic and anabolic activity is as nebulous as that between primary and secondary metabolism. The mycotoxins aflatoxin and patulin give every appearance of being catabolic in nature (Haslam, 1986). Many secondary metabolites possess elements of structure that directly parallel those observed in the catabolism of primary metabolites such as a-amino acids (Haslam, 1986). 

A compound that serves as an intermediate in the biosynthesis of patulin (6), phyllostine (also known as epoxydon) (55), (Fig. 5.7) has been identified as a phytotoxin from a Phyllosticta species that is pathogenic to red clover (Ballio, 1981). Patulin also has been reported to possess phytotoxic activity (Stoessl, 1981). Further, several structurally related compounds from a number of different fungal species seem to be involved in phytotoxicity (Stoessl, 1981). 

The structure of 6-methylsalicylic acid and orsellinic acid, themselves formed from acetate (Birch et al., 1955 Mosbach, 1%0 Birkinshaw and Gowlland, 1962), indicates that they may be the immediate precursors of more complex metabolites. Indeed, whole-cell studies have confirmed that 6-methylsalicylic acid may be metabolized, after decarboxylation, to terreic acid, a quinone epoxide (XXXI), in Aspergillus terreus (Read et al., 1%9) or m-hydroxybenzaldehyde (XXXII) and gentisaldehyde (XXXIII) en route to patulin (XII) in P. patulum (Forrester and Gaucher, 1972a). Moreover, orsellinic acid is readily converted to trihydroxytoluene (XIII) and further hydroxylated products in A. fumigatus (Packter, 1%6, 1968). These inter-... 

The ylidenebutenolide patulin (10) occupies a somewhat special place in organic chemistry. This structurally simple molecule, which is produced by the mold Penicillium urticae (synonym, P,patulum, P.flexuosum) was isolated independently by several groups of workers during the early 1940 s. It aroused immediate and widespread interest because of its potent antibiotic properties, but this interest evaporated almost as... 

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 but-2-enolide (1) and tetronic acid (2) ring systems constitute important structural features in a wide range of biologically important natural products, e.g. vitamin C (222), the cardenolide digitoxigenin (223), and strigol (224), the germination stimulant for the plant parasite Striga (192, 193). Two of the first 4-ylidenebutenolides to be found in natiu-e were protoanemonin (5) and patulin (10). These molecules aroused... 

Roquefortine C was often accompanied by a structurally related mycotoxin isofumigaclavine A (12-98). P. roqueforti molds may occasionally produce patulin, citrinin (12-99), penicillic acid (12-100), the so-called PR-toxin (12-101) and certain other toxins that have been implicated in incidents of mycotoxicoses. However, PR toxin is not stable in cheese and breaks down to the less toxic PR imine (12-101). Other secondary metabolites ofP. roqueforti found in blue cheeses are andrastins A-D with skeletons of ent-5a,lA -androstane. In European blue cheeses, the content of andrastin A (12-102) ranged from 0.1 to 3.7 mg/kg and contents of andrastins B, C and D were on average five times lower. The most significant biological activity of adrastins is the ability to inhibit the enzyme farnesyltransferase, an enzyme that catalyses the transfer of farnesyl residue from farnesyl diphosphate to proteins. It is a part of the apparatus carrying post-translational modification of proteins in... 

FIGURE 4.1 Structure of the cardiac glycosides digitoxin and digoxin and of patulin as examples of biologically active natural products containing a butenolide in their structure. 

Several chemical properties of the antibacterial substances have been assembled in Table III. The division into the groups of acidic substances, neutral substances, and basic substances has been maintained. The empirical formulas are those given by one of the authors cited in the references and represent usually results of analysis of the pure substance. A few of the structures, and, hence, the empirical formulas, also, have been proved by synthesis. Several formulas, citrinin, gliotoxin, and patulin, for example, are based upon analytical results and a consideration of degradation products. Probably several of these formulas will be revised after more work has been done with the compounds. The approximate stability of the compounds in acid, neutral, and alkaline solutions are given. Many of... 

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