Evidence for a Trianion Intermediate in the Metalation of 4-Hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic Acid. Methodology and Application to Racemic 5,5′-Didesisopropyl-5,5′-dialkylapogossypol Derivatives

Abstract

The metalation of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid (8) affording trianion 6 is presented and applied to the regioselective efficient construction of a series of 5,5'-didesisopropyl-5,5'-dialkylapogossypol derivatives 3 that are potent pan-active inhibitors of antiapoptotic Bcl-2 family proteins.

ortho-Lithium/Magnesium Carboxylate-Driven Aromatic Nucleophilic Substitution Reactions on Unprotected Naphthoic Acids

“…The 1,1′-binaphthyl unit has enjoyed extensive use in the design and syntheses of chiral catalysts for carbon–carbon or carbon–hydrogen bond-making reactions and of chiral reagents for reducing ketones to optically active alcohols . Gossypol, which is based on the 2,2′-binaphthalene system, is a major constituent of cottonseed pigment which displays multiple pharmacological applications , …”

Selectivity in C-alkylation of dianions of protected 6-methyluridine

“…It has also been proposed that poor reactivity of lithiated carbanions toward alkyl halides may result from steric hindrance [24,27]. Recently, the lateral lithiation of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid was applied to the regioselective efficient construction of a series of 5,5'-didesisopropyl-5,5'-dialkylapogossypol derivatives that are potent pan-active inhibitors of anti-apoptotic Bcl-2 family proteins [28]. …”