5,6-Dihydropyrrolo[2,1-b]isoquinolines as scaffolds for synthesis of lamellarin analogues Christian A. Olsen, a,  Nu ´ ria Parera, a,à Fernando Albericio a,b, * and Mercedes A ´ lvarez a,c, * a Biomedical Research Institute, Barcelona Scientific Park, University of Barcelona, 08028 Barcelona, Spain b Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain c Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain Received 22 December 2004; revised 25 January 2005; accepted 26 January 2005 Abstract—Efficient modular synthetic routes to open chain marine alkaloids such as lamellarins have been developed. 5,6-Dihydro- pyrrolo[2,1-b]isoquinoline scaffolds were prepared, and protocols enabling regioselective bromination followed by Suzuki cross-cou- pling were established for the introduction of aryl groups onto the 2- and 3-positions. Ó 2005 Elsevier Ltd. All rights reserved. In the past decade we have witnessed a renaissance in the research of marine natural products. Several new compounds derived from natural products of the sea are now in the clinical pipeline. 1 Although, preliminary and preclinical research is usually carried out with com- pounds obtained directly by isolation from marine sources, late clinical phases require an efficient synthetic route. Accordingly, there is an increased need for the development of synthetic strategies for preparation of these kinds of important natural products. Pyrrole is the core skeleton of a large number of marine alkaloids such as ningalins, 2 lukianols, 3 polycitones, 4 purpurone, 5 and lamellarins. 6 A common feature for all of these alkaloids is that the pyrrole ring contains substituted aromatic rings on positions 3 and 4. Among the more simple compounds are the tetrasubstituted pyr- roles (e.g., lamellarins O and P) or the symmetrically pentasubstituted pyrroles (e.g., polycitons A and B). More complex structures contain a pyrrole ring con- densed to one or two oxazinone rings as observed for lukianol A and ningalin A, respectively. The pentacyclic lamellarins can be considered as even more complex compounds, because the pyrrole is con- densed to a benzooxazinone and to a substituted dihy- droisoquinoline or isoquinoline (Lamellarin D, Fig. 1). More than 30 natural lamellarins have been isolated from natural marine sources. 7 Natural as well as syn- thetic lamellarins should be excellent candidates for the development of new drugs due to their unique skele- tal structure and their important biological activities especially as antitumor agents. 7,8 As part of our synthetic studies concerning lamellarins, 9 we here report a concise and efficient route to scaffolds 1a and b, and their roles as synthetic precursors for open chain analogues of lamellarins (Fig. 1). Scaffolds 1a–b were obtained by N-alkylation of the pyrrole with a 2 phenylethyl p-toluenesulfonate derivative, followed by cyclization through a Heck reaction. Regioselective bro- mination of 1a–b followed by Suzuki cross-coupling ren- ders the open chain lamellarin analogues. The initial synthetic target was the model molecule 1a (R 1 =R 2 = H), which was obtained in two steps from methyl pyrrole-2-carboxylate. 10 N-Alkylation with the p-toluenesulfonate 11 3a in the presence of K 2 CO 3 and 18-crown-6 ether in DMF at 70 °C afforded 2a (50% yield). 12 The conditions described for N-alkylation of pyrrole in polycitone B 13 were unsuccessful for the methyl pyrrole-2-carboxylate. 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.01.145 Keywords: Marine alkaloids; Heterocycles; Cross-coupling reactions; Palladium. * Corresponding authors. Tel.: +34 93 403 70 86; fax: + 34 93 403 71 26; e-mail addresses: cao@dfuni.dk; nuriapar@chembio.chalmers.se; albericio@pcb.ub.es; malvarez@pcb.ub.es   Present address: The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark. à Present address: Chalmers University of Technology, SE-41296 Gothenburg, Sweden. Tetrahedron Letters 46 (2005) 2041–2044 Tetrahedron Letters