Synthesis of highly functionalized naphthoate precursors to damavaricin D — Observation of kinetically stable benzocyclohexadienones in the bromination reactions of highly functionalized β-naphthol derivatives

Abstract

Selective syntheses of the highly substituted bromonaphthoates 4a, 4b, 19, and 22 are reported. These compounds were targeted as precursors to the naphthoquinone nucleus of damavaricin D; compound 22 ultimately was used in the successful total synthesis. The synthesis of 22 features the Diels–Alder reaction of the oxygenated diene 5 and 2,6-dibromo-3-methylbenzoquinone 6 to establish the core naphthalenic unit. The quinone was protected throughout this synthesis as a 1,4-bis-methoxymethyl-1,4-dihydroquinone (see 36). The C-2-carboalkoxy group of 22 was added by carboxylation of the aryllithium intermediate generated from 36, and protected as a β-trimethylsilylethyl ester. Finally, the C-8-Br substituent was introduced by NBS bromination of 38. This reaction proceeds by way of bromobenzocyclohexadienone 39. Related bromobenzo-cyclohexadienones 13 and 29 were observed in the NBS brominations of the highly functionalized β-naphthyl MOM ethers 11 and 28. The bromobenzocyclohexadienones 29 and 39 undergo facile substitution reactions with chloride ion and reduction with bromide ion at rates competitive with base-promoted aromatization. The surprising kinetic stability of these intermediates is attributed to a combination of steric and stereoelectronic factors.Key words: damavaricin D, naphthoate precursors, kinetically stable benzocyclohexadienones, aromatic bromination.