Total Synthesis of AGI-7 and Sescandelin from Enol Esters

A silver salt-mediated aerobic approach to access 4-acetyl 3-unsubstituted isocoumarins from the reaction of ortho-iodobenzoic acid and enol ester in the presence of a base has been presented. The reaction proceeds through the base mediated initial cleavage of the enol ester followed silver-mediated C-arylation reaction. Intramolecular annulation of the resulting intermediate followed by dehydration produces the 4-acyl isocoumarins. Selective demethylation of the 4-acylated isocoumarin affords biologically potent AGI-7, while selective reduction followed by demethylation enabled the sescandelin in good yield.

Automated summary

A silver salt-mediated aerobic approach has been developed for the synthesis of 4-acetyl 3-unsubstituted isocoumarins. The reaction involves the cleavage of enol ester mediated by a base followed by silver-mediated C-arylation. Intramolecular annulation and dehydration lead to the formation of 4-acyl isocoumarins. Selective demethylation and reduction followed by demethylation provide access to biologically potent AGI-7 and sescandelin in good yield.