Solid-phase synthesis of lamellarins Q and O Marta Marfil, a,b Fernando Albericio a,c, * and Mercedes A ´ lvarez a,b, * a Barcelona Biomedical Research Institute, Barcelona Science Park, University of Barcelona, Josep Samitier 1, E-08028 Barcelona, Spain b Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Avda. Joan XXIII s/n, E- 08028 Barcelona, Spain c Department of Organic Chemistry, University of Barcelona, Martı ´ i Franque ´s 1, E-08028 Barcelona, Spain Received 16 January 2004; accepted 4 May 2004 Available online 14 August 2004 Abstract—An efficient solid phase synthesis of the pyrrole-based alkaloids lamellarins Q and O using Merrifield resin and N-protected methyl 3,4-dibromopyrrole-2-carboxylate as a scaffold is described. q 2004 Elsevier Ltd. All rights reserved. 1. Introduction An important group of marine natural compounds including lamellarins, 1 lukianols, ningalins, 2 and polycytones 3 have a pyrrole ring as a core component of their skeleton. These compounds are important on the basis of their biological activities and the novelty of their structures, which are without precedent. Lamellarins and related compounds have been isolated from invertebrates such as the prosobranch mollusc Lamellaria sp., ascidians such as Didemnum chartaceum and the sponge Dendrilla Cactos collected from different sea areas. The structures of these natural products are related because they probably have a common biogenetic origin. The common structural feature is a pyrrole ring substituted at positions 3 and 4 by polyhydroxy- or methoxyphenyl groups. Lamellarins Q and O (1, 2) are the simplest compounds in this family. The structure is present in more complex molecules such as polycytone A (3), which contains a symmetrically substituted pyrrole, and lukianol A (4) and ningaline A (5), in which new rings condensed to pyrrole are present due to lactonisation processes. Lamellarin A (6) possesses the most complex structure and is an example of a pentacyclic lamellarin that is characterised by a lactone and an isoquinoline both condensed to the pyrrole ring. This group of pentacyclic compounds contains the largest number of related natural products. A considerable number of these natural products possess important cytotoxic activities (Fig. 1). For example, lukianol A exhibits activity against a cell line derived from human epidermatoid carcinoma, 1c polycytone A inhibits the growth of SV 40 transformed fibroblast 3a at concentrations of 10 mg ml 21 , lamellarins O and P demon- strated antibiotic activity, 1c lamellarins D and C caused inhibition of cell division 1a and lamellarin N tested by the NCI in a 60 cell-line panel showed selectivity towards melanoma cell lines. 1f In addition, a select set of lamellarins exhibit equally potent cytotoxic activity against multidrug- resistant (MDR) cell lines arising over expression of P-glycoprotein and/or reverse MDR at noncyctotoxic concentrations, resensitising the resistant cell lines to conventional therapeutic agents. 4f A number of synthetic routes have been described for lamellarins, 4 lukianols, 4a,b,f,5 and ningalins 4f,6 but only one has been developed using the solid-phase approach. 7 Solid- phase combinatorial synthesis is one of the most useful techniques for the preparation of small libraries. This technique provides rapid access to larger collections of products that can possess great diversity and may incorpor- ate optimised physical and pharmacological properties associated with certain structures. Palladium-catalysed cross-coupling reactions are good methods for the preparation of bisaryl or heteroaryl derivatives. Our previous experience in Pd-catalysed heteroaryl coupling reactions 8 encouraged us to use this methodology for the solid phase preparation of the structurally least complex components of the group of compounds under investigation, namely lamellarins Q and O. The developed methodology will be used in the preparation of compound libraries in which elements of diversity would be introduced in the aromatic substituents at positions 3 and 4 and on the nitrogen of the pyrrole ring. For this reason it was important to develop a synthetic procedure that would be compatible with the sequential introduction of 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.05.110 Tetrahedron 60 (2004) 8659–8668 * Corresponding authors. Tel.: þ34-93-403-70-86; fax: þ34-93-403-71-26; e-mail addresses: malvarez@pcb.ub.es; albericio@pcb.ub.es Keywords: Solid-phase synthesis; Heteroaryl cross-coupling; Marine natural products; Cytotoxicity.