Solid-phase synthesis of 4H-2-(3-hydroxy-4-methoxyphenyl)- naphtho[1,2-b]pyran-1-one q Pablo Cironi, a,b Fernando Albericio a,c, * and Mercedes A ´ lvarez a,b, * a Barcelona Biomedical Research Institute, Barcelona Scientific Park-University of Barcelona, 08028 Barcelona, Spain b Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain c Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain Received 6 May 2004; revised 28 July 2004; accepted 3 August 2004 Available online 21 August 2004 Abstract—An effective solid-phase preparation of the pharmaceutically interesting 4H-2-(3-hydroxy-4-methoxyphenyl)-naph- tho[1,2-b]pyran-1-one system from an anchored bisarylacetylene is described. Ó 2004 Elsevier Ltd. All rights reserved. A Baeyer–Villiger 1 reaction is one of the key steps in the solid-phase synthesis of pentacyclic lamellarins, 2 as re- cently described by our group (Fig. 1). 3 This transfor- mation allows the use of the formyl group of a substituted benzaldehyde 2 to mask the required phenol, which in turn allows the introduction of a second ele- ment of diversity in a putative library. Diversity is fur- ther increased by the use of an iodophenol, the first building block anchored to the starting resin to give 1, and a dihydroisoquinoline. An intramolecular [3+2] cycloaddition then allows the formation on solid phase of the pentacyclic system that is characteristic of lamellarins. 4 The Baeyer–Villiger oxidation–transposition, which has few precedents in solid phase, gave good results using MCPBA and base. 3 However, the number of commer- cially available substituted benzaldehydes is relatively small and their preparation is tedious. With the aim of reducing the number of steps in solid phase and trans- forming the synthetic strategy into a more convergent route, we tested a Pd(0) cross-coupling reaction between the anchored 5-iodo-2-methoxyphenol (1) 5 with a hydroxynaphthylacetylene protected with the O-meth- oxymethyl (MOM) group (5). 6 The choice of MOM as a protecting group can be attrib- uted to its facile removal under mild acidic conditions, which are compatible with Merrifield resin, as well as the fact that basic conditions can be avoided altogether. The latter is relevant because base promoted nucleophi- lic addition can lead to the formation of condensed polycyclic systems if one of the aryl rings linked to the triple bond is deactivated or a p-deficient system. 7 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.08.012 Keywords: Solid-phase synthesis; Heterocycles; Naphthopyrones; Chromones. q This work was presented as an oral communication in the Twelfth FECHEM Conference on Heterocycles in Bio-organic Chemistry, June 20–24, 2004, Siena, Italy. * Corresponding authors. Tel.: +34 934 037 088; fax: +34 934 037 126 (F.A.); tel.: +34 934 037 086; fax: +34 934 037 126 (M.A ´ .); e-mail addresses: albericio@pcb.ub.es; malvarez@pcb.ub.es MeO O I MeO O O OMe OiPr O N MeO MeO I OHC OMe OiPr N O O OMe OH MeO HO MeO RO MeO O Z OMe OiPr + Lamellarin L R = H Lamellarin U R = Me 1 2 3 Z=CHO 4 Z=OH Baeyer-Villiger Figure 1. Solid phase synthesis of Lamellarins U and L. Tetrahedron Letters 45 (2004) 7311–7314 Tetrahedron Letters