Regioselective Synthesis of Natural and Unnatural (Z)-3-(1-Alkylidene)phthalides and 3-Substituted Isocoumarins Starting from Methyl 2-Hydroxybenzoates Fabio Bellina, * Donatella Ciucci, Piergiorgio Vergamini and Renzo Rossi Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy Received 10 December 1999; revised 24 January 2000; accepted 10 February 2000 Abstract —(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.  2000 Elsevier Science Ltd. All rights reserved. Introduction (Z)-3-(1-Alkylidene)phthalides 1 represent an important class of naturally occurring lactones, 1 which are character- ized by interesting biological properties. In fact, compounds 1, which have been isolated from the rhizome of Cnidium species or Ligusticum wallichi, commonly known as Senkyu in Japan, are used in the treatment of anemia and women’s disease, 2 as cardiokinetics, antistenocardiacs, anti- arrhytmics, vasodilators and coronary artery dilators. 3 Moreover, antispasmodic activity has been observed for a series of synthetic compounds of general formula 1. 4 A wide range of biological and pharmacological activities are also displayed by 3-substituted isocoumarins of general formula 2, which correspond to regioisomers of compounds 1. 5,6 Thus, a number of methods have been reported for the synthesis either of compounds 1 7,8 or 2. 9 Tetrahedron 56 (2000) 2533–2545 Pergamon TETRAHEDRON 0040–4020/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(00)00125-3 Keywords: cross-coupling reactions; heteroannulation reactions; regioselectivity; transition metal catalysts. * Corresponding author. Tel.: +39-050-918275; fax: +39-050-918260; e-mail: bellina@dcci.unipi.it Scheme 1.