Selective synthesis of natural and unnatural 5,6-disubstituted 2(2H)-pyranones via iodolactonization of 5-substituted (Z)-2-en-4-ynoic acids Fabio Bellina, p Matteo Biagetti, Adriano Carpita and Renzo Rossi p Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy Received 7 November 2000; revised 11 January 2001; accepted 25 January 2001 Abstract ÐReaction of 5-substituted (Z)-2-en-4-ynoic acids with iodine and NaHCO 3 in CH 3 CN or with ICl in CH 2 Cl 2 affords mixtures of (E)-5-(1-iodoylidene)-2(5H)-furanones and 6-substituted 5-iodo-2(2H)-pyranones in which these last compounds are the major products. The 5-iodo-2(2H)-pyranones, which are easily separated chromatographically from the corresponding regioisomers, are able to undergo Stille-type reactions with a variety of organotin compounds to give 5,6-disubstituted 2(2H)-pyranones in moderate to good yields. One of these compounds, i.e. 5-(1-butynyl)-2(2H)-pyranone, has been used as direct precursor to two substances produced by fungal culture LL-11G219, which function as androgen ligands, i.e. (Z)-5-(1-butenyl)-6-methyl-2(2H)-pyranone and 5-butyl-6-methyl-2(2H)-pyranone. q 2001 Elsevier Science Ltd. All rights reserved. 2(2H)-Pyranones are useful intermediates for the synthesis of a variety of carbo- 1 and heterocyclic compounds 2 and occur as structural subunits in a large number of natural products, which display a wide range of biological activities including antimicrobial, 3 androgen like, 4 phytotoxic, 5 cardiotonic, 6 antifungal 7 and pheromonal effects. 8 As a consequence, much attention has been paid to the synthesis of 2(2H)-pyranone derivatives either by the traditional approaches 9 or by procedures involving transition metal- catalyzed reactions. 10 Nevertheless, despite the plethora of these synthetic processes it is rather disappointing to note that no general procedure has been developed so far for the regioselective synthesis of natural and unnatural unsymmetrically 5,6-disubstituted 2(2H)-pyranones. Recently, we began an investigation on this subject and we found that treatment of (Z)-2-en-4-ynoic acids 1 with aryl halides 2 in the presence of K 2 CO 3 and a catalytic quantity of Pd(PPh 3 ) 4 provides mixtures of 6-substituted 5-aryl- 2(2H)-pyranones 3 and stereode®ned 5-[(1,1-unsymmetri- cally disubstituted)methylidene]-2(5H)-furanones 4 in which, however, these last compounds are the major products (Scheme 1). 11 More recently, in continuation of our studies on the synthe- sis of oxygen-containing heterocycles by approaches which involve intramolecular additions of carboxylic acids to alkynes, 12 we developed a new and convenient procedure for the synthesis of 5,6-disubstituted 2(2H)-pyranones of general formula 5 (Fig. 1). We now wish to report that, under suitable reaction condi- tions, 5-iodo-2(2H)-pyranones 6 can be obtained as major products by iodolactonization of (Z)-2-en-4-ynoic acids 1 and that these heterocyclic iodides, which represent a not previously reported class of organic electrophiles, are useful precursors to compounds 5. In fact, we found that compounds 6 are able to undergo palladium-catalyzed reac- tions with organostannanes 8 such as tetramethylstannane, vinyltributylstannane, aryl- and 1-alkynyltributylstannanes Tetrahedron 57 (2001) 2857±2870 Pergamon TETRAHEDRON 0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(01)00139-9 Scheme 1. (a) Pd(PPh 3 ) 4 (5 mol%), K 2 CO 3 (4 equiv.), CH 3 CN, 70±808C. Keywords: heterocycles; iodine; cross-coupling; organometallic compounds; natural products. p Corresponding authors. Tel.: 139-50-918214; fax: 139-50-918260; e-mail: rossi@dcci.unipi.it