Development of an Anionic Multicomponent Reaction for Rapid Construction of Highly Functionalized Dearomatized Scaffolds

Biosynthetic dearomatization of 3,5-dimethyl orsellinic acid (DMOA) affords highly functionalized cyclohexadienone precursors for enzymatic polyene cyclization to produce numerous complex meroterpenoids. In particular, dearomatized scaffolds derived from 2,4-dihydroxyl-3,5-dimethylphathalide (DHDMP) are valuable synthons for synthetic access to meroterpenoids. Driven by a practical need to obtain scalable amounts of the requisite dearomatized motifs, herein we report an anionic, multicomponent reaction sequence for construction of such scaffolds from ester, Michael acceptor, and acyl chloride reaction partners. The reaction entails sequential Michael-Addition of an ester enolate, Acylation, and Dieckmann Annulation (MADA). The utility of the method is demonstrated through several examples and downstream derivatizations, including the synthesis of farnesyl-DHDMP, a key biosynthetic precursor to meroterpenoids.