Regioselective De Novo Synthesis of Phenolic Isoprenoids Grifolin and Neogrifolin

Abstract

The total synthesis of biologically and pharmacologically important phenolic isoprenoids, grifolin and neogrifolin, was developed through simple allylation and cyclization procedures using only ethyl acetoacetate, ethyl crotonate, and farnesyl bromide as substrates. The regioisomeric terpenophenols, which consist solely of orcinol and farnesyl moieties, cannot be synthesized purely by direct coupling between the units. The regioselectivity issue was solved by controlling the timing of the allylation of β-ketoester with farnesyl bromide and the cyclization with ethyl crotonate. 2-Farnesyl-5-methyl-cyclohexane-1,3-dione and 6-farnesyl-5-methyl-cyclohexane-1,3-dione were prepared in a highly regioselective manner from ethyl acetoacetate in overall yields of 43% and 40%, respectively. The oxidative aromatization of the regioisomeric cyclohexane-1,3-diones produced grifolin and neogrifolin, respectively.

Keywords

• aromatization
• cyclization
• Dieckman condensation
• total synthesis
• phenol
• terpenoid