Studies in the biochemistry of micro-organisms. 85. Cyclopolic and cyclopaldic acids, metabolic products of Penicillium cyclopium Westling.

The genus PeniciUium has been separated by Raper & Thom (1949) in their Manual of the Penicillia into fourmajor sections, Monoverticillata, Asymmetrica, Biverticillata-Symmetrica and Polyverticillata. The section Asymmetrica is further divided into five subsections: Divaricata, Velutina, Lanata, Funiculosa and Fasciculata. The subsection Asymnietrica-Fasciculata, in its turn, is subdivided into ten series, one of which, the P. cycloqpium series, contains four accepted species and one variety, i.e. P. cyclkpium Westling, P. cyclopium West. var. echinuk&tum Raper & Thom, P. puberulum Bainier, P. martensii Biourge, and P. aurantio-viren.s Biourge. The P. cyclopium series has proved to be of considerable biochemical interest. In 1913, Alsberg & Black isolated from laboratory cultures of P. puberulum a metabolic product which they. na-med penicillic acid. Birkinshaw, Oxford & Raistrick (1936) isolated from Westling's type strain of P. cyclopium considerably larger yields of penicillic acid and established its molecular structure (structure I). Birkinshaw & Raistrick (1932), working with Alsberg & Black's strain of P. puberulum, showed that, after almost 20 years in laboratory culture, this strain now gave much smaller yields of penicillic acid than were reported by Alsberg & Black. In addition, however, two new metabolic products, puberulic and puberulonic acids, were isolated. The same two acids were also isolated by Birkinshaw & Raistrick (1932) from P. aurantio-virena and by Oxford, Raistrick & Smith (1942b) from P. johannioli Zaleski (=P. mnwrtensii Biourge). Penicillicacid,-puberulicacidandpuberulonic acid have significant antibacterial activity, particularly against Gram-positive bacteria (Oxford, Raistrick & Smith, 1942 a, b). Birkinshaw & Raistrick (1932) and Barger & Dorrer (1934) prepared a number of derivatives and breakdown products of puberulic and puberulonic acids but were unable to advance plausible structural formulae for them. Dewar (1945), in a novel attempt to interpret this experimental evidence and additional evidence on stipitatic acid (Birkinshaw, Chambers & Raistrick, 1942), suggested that puberulic acid might contain a seven-carbon ring and be in fact a derivative of what he proposed to call tropolone (cycloheptatrienolone or hydroxycycloheptatrienone), at that time unknown, puberulic acid thus becoming a dihydroxytropolonecarboxylic acid of undetermined orientation. Corbett, Johnson & Todd (1950a) have confirmed this view and have shown that puberulic acid has structure (II). The structure of puberulonic acid, vvhich on heating with dilute sulphuric acid loses a molecule of carbon dioxide and is converted into puberulic acid (Corbett, Hassall, Johnson & Todd, 1950), seems now to be satisfactorily settled. Three possible structural formulae were advanced by Corbett et al. (1950a), but doubt was thrown on these formulae by Aulin-Erdtman (1950) who prefers structure (III) (see also Cook & Loudon, 1951). This structure has been confirmed by AulinErdtman & Theorell (1950) and has now been accepted by Johnson, Sheppard &. Todd (1951).