Microbial Modification of Mycophenolic Acid

Abstract

On incubation with selected micro-organisms mycophenolic acid (1) has been found to undergo one or more of the following transformations: (a) oxygenation of the 4-methyl group giving an alcohol (5) and an aldehyde (6), (b) oxygenation of the 3′-methyl group and lactonisation giving a δ-lactone (31), (c) oxidation at C-3 giving a lactol (3), (d) loss of the double bond and oxidation at C-4′, giving a β-hydroxy-acid (18), a methyl ketone (14), a carboxylic acid (10), and, by further hydroxylation, a lactol (11), a benzyl alcohol (12), and a dihydrobenzofuran (29), (e) oxygenation of the double bond giving a hydroxy-lactone (21), (f) oxygenation and cyclisation of the terpenoid substituent giving dihydrobenzofurans (26) and (28), (g) oxidative cyclisation of the terpenoid substituent giving a chromen (30), and (h) combination of the carboxy-group with the amino-groups of glycine and alanine giving amides (15) and (16). Lactones (20) and (22) and diphenylmethane (32) were also obtained from mycophenolic acid fermentations but these compounds may have been artefacts generated during work-up. Fermentations of mycophenolic acid methyl ether (2) and of compound (9) gave the benzyl alcohols (7) and (5) respectively, and fermentations of dihydromycophenolic acid gave compounds (10), (11), and (29). The structures of the fermentation products have been established by spectroscopic methods and most of the compounds have been chemically related to mycophenolic acid. The biogenesis of the fermentation products is discussed and some preparations of cyclic ethers from mycophenolic acid derivatives are described.