Regioselective synthesis of natural and unnatural (Z)-3-(1-alkylidene)phthalides and 3-substituted isocoumarins starting from methyl 2-hydroxybenzoates

(Z)-3-(1-Alkylidene)phthalides and 3-substituted isocoumarins, which include compounds bearing a substituent on their benzene ring, have been selectively and efficiently synthesized by a new protocol which involves: (i) the conversion of methyl 2-hydroxybenzoates into the corresponding nonaflates; (ii) Pd-catalyzed alkynylation reactions of these derivatives; (iii) the conversion of the so obtained methyl 2-(1-alkynyl)benzoates into the corresponding carboxylic acids followed by a transition metal-catalyzed heteroannulation reaction. This procedure has been used to prepare either natural products such as senkyunolide B, senkyunolide C, 3-propylisocoumarin and artemidin, or the MEM-ether of senkyunolide E. The regioselectivity of the transition metal-catalyzed cyclization reactions of 2-(1-alkynyl)benzoic acids has proven to be affected either by the catalyst used or the type of 1-alkynyl group present in these carboxylic acids. (C) 2000 Elsevier Science Ltd. All rights reserved.