Stipitatonic acid

The tropolone alkaloid of Liliaceae species, colchicine, is transformed by acetylation, alkaline cyclization, and dehydration into the tetracyclic pyrrolotropone acetyl anhydrocolchicine [77TL2977 83AX(C)1709]. When the dicarboxylic acid anhydride groups of puberulonic and stipitatonic acids (metabolites of Penicillium species) condense with o-phenylenediamine, another tetracyclic pyrrolotropone structure is formed (51JCS1139 59JCS2847). 

The fungal tropolones puberulic acid (4.29) and stipitatic acid (4.30) were isolated from P. puberulum and P. stipitatum by Raistrick in 1932 and 1942, respectively. Their structures were not established at that time despite extensive chemical degradation. The tropolone structure for stipitatic acid was proposed by Dewar in 1945 and that for puberulic acid in 1950 by Todd. These structural proposals played an important part in the development of ideas of aromaticity. The biosynthesis of these tropolones involves the ring expansion of an orsellinie aeid via stipitatonic acid (4.31). 

Another complex polyketide compound, stipitatonic acid (7), is derived from four C2 units (Fig. 5.9) (Weiss and Edwards, 1980). 

Polyketides of this group are either carbocyclic compounds (like 6-methyl-salicylic acid) hydroxylated acetophenones, or possess an 6-membered (asperlin, coniine) or 7-membered (stipitatonic acid) N- or 0-heterocyclic ring. Often dimeric compounds occur, e.g., lecanoric acid. 

A mono-oxygenase is also implicated in the biosynthesis of fungal tropolones, e.g. stipitatonic acid (3.52). Ring expansion of an aromatic ring could, as in colchicine biosynthesis, account for the formation of the tropolone ring (Section 6.3.7). This is strongly supported by the appropriate specific incorporation of labelled 3-methylorsellinic acid (3.51) into stipitatonic acid (3.52), and 02... 

The same research group has also re-investigated the biosynthesis of puberulonic (37) and puberulic acid (38) in P. aurantio-virens (NRRL 2138) and have shown that C-9 of (37) is derived from acetate. A common biosynthetic route has been suggested for the fungal tropolones (35)—(38), although attempts to demonstrate the conversion of stipitatonic acid (35) or 3-methylorsellinic acid (33) into puberulonic acid (37) were unsuccessful. ... 

The nature of the intermediates involved between the polyketide stage of biosynthesis and sepedonin was not specified, although an alkylated benzene derivative was rejected. In the light of more recent evidence from biosynthetic studies of other naturally occurring tropolones, particularly the splendid work of Battersby on colchicine and the equally elegant work of Scott on stipitatonic acid (7), a benzenoid aromatic precursor is a likely intermediate in sepedonin biosynthesis. The incorporation of radioactive 3-methylorselIinic acid (8) into... 

Stipitatonic Acid (75). The mechanism for the oxidative cleavage of 3-methyl-orsellinic acid (74) to afford the tropolone stipitatonic acid (75) in Penicillium stipitatum was very elegantly demonstrated with labelling. Two pathways were considered, the dioxygenase recyclization route. Scheme 20, and the mono-oxygenase ring-expansion route, Scheme 21. 

Since the mass spectra of the O-enriched stipitatonic acid and other tropo-lone metabolites isolated showed only M + 2 peaks and no A/ + 4 peak, which would have been required by the dioxygenase mechanism, the monooxygenase pathway was favoured. 

Among the tropolone compounds found in nature are four tropolone-carboxylic acids,obtained from mold cultures.Two ofthese,stipitatonicadd(CXIV,R = COOH) and stipitatic acid (CXIV, R = H) have been obtained from Penicillium stipitatum (Bentley and Thiessen, 1963). Puberulonic add (CXV, R = COOH) and puberulic acid (CXV, R = H) were obtained from P. aurantio-virens, P. puberulum and P.johan-nioli as well as from strains of the P. cyclopium-viridicatum series (sources quoted in this paper). The infrared spectrum of the sodium salt of the anhydride of stipitatonic... 

Bentley, R. Biosynthesis of tropolones in Penicillium stipitatum II. The degradation of C -labeled stipitatonic and stipitatic acids. J. Biol. Chem. 238, 1889 (1963 a). 

Bentley, R., and C. P. Thiessen Tropolone biosynthesis the enzymatic decarboxylation of stipitatonic and puberulonic acids. Nature 184, 552 (1959). 

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