The synthesis of 5-(4-pyridyl)benzo [c][2,7]naphthyridin-4-one (4), an intermediate previously employed in a total synthesis of the marine alkaloid, amphimedine (2), is reported. The route comprises the Pd-catalyzed Suzuki cross coupling of pyridylborane 21 with 2-iodoaniline to give the azabiaryl 22, which upon LDA-mediated cyclization and inflation leads to benzonaphthyridine 5. Stille cross coupling of 5 with pyridylstannane 24 affords the pyridylbenzonaphthyridine 25, which upon BBrs treatment leads to the target molecule 4. Pyridine directed ortho metalation chemistry leading to halonicotinate ester 12 and amides 14a,b and cross coupling to benzonaphthyridinones 17, 18 (one-pot procedure) and azabiaryls 20a,b are also reported.The discovery, during the last decade, of a number of marine alkaloids with highly condensed tetra-and pentaheterocyclic nuclei, coupled with their significant and diverse biological activity (Ca-releasing, antiviral, antimicrobial, cytotoxic to L1210 murine leukemia cells) has prompted considerable interest in the synthetic community.* 1 Of the more than 30 alkaloids reported to date, the dominant structural feature is the pyrido[2,3,4-feZ]acridine (dibenzo[/,ZJ][2,7]naphthyridine) nucleus as indicated in the representative members ascididemine (1), amphimedine (2), and the cystodytins (3) (Scheme l).la The highly compact nature of these groups of alkaloids together with annoying variations have demanded innovative synthetic approaches.1®'2 Syntheses of the pyridoacridine ring systems prior to the discovery of the natural products tended to be classical and specific according to the particular isomer prepared.lb In the context of combined directed ortho metalation-cross coupling strategies under current development in our laboratories,3 we developed a new route to phenanthridines and phenanthridinones by coupling of o-N-t-+ Instituí National des Sciences Appliquées de Rouen.

A methodical investigation on functionalization by carbonylated groups in position 4 and 5 of the benzo[c][2,7]naphthyridine skeleton has been undertaken. In particular the study has shown the complex influence of these two sites on each other. A careful choice of both substituents in 4 and 5 permitted the synthesis of an interesting pyrido[2,3,4‐kl]acridone tetracyclic structure through an intramolecular Mukayama aldolisation reaction. The structure is supposed to be a potential precursor to various marine alkaloids of the pyridoacridine family.

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