Oosponol

It is shown that contrary to most isocoumarins the antibiotic compound oosponol from the fungus Gloeophyllum abietinum reacts instantaneously with nucleophilic agents like thiol compounds. The reason for this high reactivity is due to the vinylogous acid anhydride character of the compound which is produced by a single oxidation step of the non toxic biological precursor oospoglycol. One must assume that reactions of oosponol with HS-groups of polypeptides form the basis for its toxicity. The ring-opening reactions were studied in detail with the synthetic analogue 4-acetyl-isocoumarin. The structures of some reaction products have been analysed mainly with H-1 and C-13 NMR spectroscopy.

The cyclization of heteroatom-containing alkynes with π acidic metal salts is an attractive method to prepare heterocycles because the starting materials are readily available and the organometallic compounds are useful synthetic intermediates. A new organometallic species in the heterocyclization provides an opportunity to synthesize heterocycles that are difficult to obtain. Herein, we describe a novel cyclic oxymetalation of 2-alkynylbenzoate with indium or gallium salts that proceeds with an unusual regioselectivity to give isocoumarins bearing a carbon-metal bond at the 4-position. This new type of metalated isocoumarin provided 3-unsubstituted isocoumarins that have seldom been investigated despite their important pharmacological properties. Indium and gallium salts showed high performance in the selective 6-endo cyclization of terminal alkynes while boron or other metals such as Al, Au, and Ag caused 5-exo cyclization or decomposition of terminal alkynes, respectively. The metalated isocoumarin and its reaction intermediate were unambiguously identified by X-ray crystallographic analysis. The theoretical calculation of potential energy profiles showed that oxyindation could proceed via 6-endo cyclization under thermodynamic control while previously reported oxyboration would give a 5-membered ring under kinetic control. The investigation of electrostatic potential maps suggested that the differences in the atomic characters of indium, boron and their ligands would contribute to such a regioselective switch. The metalated isocoumarins were applied to organic synthetic reactions. The halogenation of metalated isocoumarins proceeded to afford 4-halogenated isocoumarins bearing various functional groups. The palladium-catalyzed cross coupling of organometallic species with organic halides gave various 4-substituted isocoumarins. A formal total synthesis of oosponol, which exhibits strong antifungal activity, was accomplished.

Oosponol [4-(hydroxyacetyl)-8-hydroxy-1H-2-benzopyran-1-one], a toxic metabolite of the basidiomycete Gloeophyllum abietinum, and some synthetic analogues were studied to clarify the molecular basis of their fungicidal, bactericidal, and phytotoxic effects. The antibiotic activity was due to a strong inhibition of RNA and protein synthesis in target cells.