Practical Synthesis of the Trisubstituted Naphthalene Carboxylic Acid from Neocarzinostatin Chromophore

Neocarzinostatin carboxylic acid (5) has been synthesized in 33% overall yield by a nine-step sequence which is operationally easy enough to be carried out by second-year chemistry students. 3,5-dimethylanisole was brominated in the para and in one benzylic position so that an S_N2 reaction with sodium cyanide led to the cyanated aryl bromide 15. Heck-coupling with ethyl acrylate gave the α,β-unsaturated ester 14. It was converted into the saturated diester 18 through dissolving-metal reduction, saponification of nitrile and ester groups, and re-esterification with MeOH. Dieckmann cyclization and dehydroaromatization furnished ester 19 whose hydrolysis to the title compound 5 has been known.

aromatization - Dieckmann cyclization - Heck coupling - naphthalene derivative