COMBINE METALATION PALLADIUM-CATALYZED CROSS-COUPLING STRATEGIES - A FORMAL SYNTHESIS OF THE MARINE ALKALOID AMPHIMEDINE

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 al kaloid, amphimedine (2), is reported. The route comprises the Pd-catal yzed Suzuki cross coupling of pyridylborane 21 with 2-iodoaniline to g ive the azabiaryl 22, which upon LDA-mediated cyclization and triflati on leads to benzonaphthyridine 5. Stille cross coupling of 5 with pyri dylstannane 24 affords the pyridylbenzonaphthyridine 25, which upon BB r3 treatment leads to the target molecule 4. Pyridine directed ortho m etalation chemistry leading to halonicotinate ester 12 and amides 14a, b and cross coupling to benzonaphthyridinones 17, 18 (one-pot procedur e) and azabiaryls 20a,b are also reported.