# Regiosellective De Novo Synthesis of Phenolic Isoprenoids Grifolin and Neogrifolin
## 3 Results and Discussion  
In a preliminary study, we investigated the synthesis of 5-methyl-cyclohexane-1,3-dione (**7a**) from ethyl acetoacetate and ethyl crotonate via a possible one-pot cyclization reaction (Scheme 1) [22]. However, the reaction (using the condition of 0.2 equiv. _t_-BuOK in _t_-BuOH at 90 \({}^{\circ}\)C for 4 h) was stopped at the conjugate addition step, giving **9a** in 95% yield. Even under forced conditions with excessive base and prolonged reaction times, the Dieckman condensation of **9a** did not proceed. Decarboxylation was thus performed first (NaOH; HCl, reflux), followed by esterification (SOCI\({}_{2}\), MeOH) to give _e_-ketoester **11**, which readily cyclized to **7a** under common basic conditions (t-BuOK, _t_-BuOH, reflux). Ironically, this unexpected three-step sequence for **7a** allows us to propose a regioselective introduction of a farnesyl unit for terpenophenols. The introduction of a farnesyl unit via dianion alkylation at the \(\gamma\)-position of \(\beta\)-ketoester would produce **10b**, which would give rise to 1,3-cyclohexanedione **7b**, containing a 2-farnesyl group according to the cyclization process of **7a**. On the other hand, the introduction of a farnesyl unit at the carbon with most acidic proton of **9a** would produce **9c** that would ultimately provide 1,3-cyclohexanedione **7c** containing the 6-farnesyl group after the cyclization process to **7a**. The halogenative aromatization [23; 24; 25] of **7b** has been reported to yield grifolin **1**[20]. Similarly, the aromatization of **7c** would afford neogrifolin **2**. Although alkylation at the 2-position of cycloalkane-1,3-dione has been reported using Triton-B [26], hydrocalcite [27], and Pd catalysts [28], the direct allylation of 1,3-dione **7a** was problematic, as pointed out by [PERSON] in the synthesis of grifolin [20], resulting in _C,C_-diallylation as well as _O_-allylation with very low yields of the desired product. We thus turned our attention to the regioselective allylation of ethyl acetoacetate (see Scheme 1). The dianion of \(\beta\)-ketoester was generated by a well-known procedure using NaH and then _n_-BuLi [29] and reacted with _(E,E)_-farnesyl bromide, prepared from _(E,E)_-farnesyl, to yield the \(\gamma\)-allylation product **10b** in 75% yield (Scheme 2). The conjugate addition of the \(\alpha\)-anion of **10b** to ethyl crotonate in the presence of catalytic (0.2 equiv.) _t_-BuOK in _t_-BuOHat 90 \({}^{\circ}\)C for 2 h produced **9b**, which was further reacted with a stoichiometric amount of _t_-BuOK at 90 \({}^{\circ}\)C for 16 h to complete the Dieckman condensation, producing **12b** in 86% yield. A trivial decarboxylation process through (1) saponification, (2) protonation, and (3) thermolysis provided 2-farnesyl-5-methyl-cyclohexane-1,3-dione (**7b**) in 67% yield (6:1 keto/enol forms), which completed a formal synthesis of grifolin **1** in a total 43% yield from ethyl acetoacetate. DFT calculations (using B3 LYP function and 6-31G basis set) predicted the keto (**7b**) and enol (**7b'**) equilibrium constant to be 0.047, whereas the actual ratio was calculated to be 0.17 by \({}^{1}\)H-NMR analysis in CDCl\({}_{3}\) solvent (see Supplementary Materials). Since diallylation was again a major problem in the \(\alpha\)-allylation of ethyl acetoacetate for neogrifolin synthesis, the reaction sequence was switched to avoid this problem. The farnesyl unit was introduced into the conjugate addition product **9a** between ethyl acetoacetate and ethyl crotonate. The most acidic and only \(\alpha\)-hydrogen of \(\beta\)-ketoester **9a** was deprotonated using NaH in DMF solvent, which led to smooth farnesylation to give **9c** in 71% yield. The Dieckman condensation of **9c** using stoichiometric _t_-BuOK in refluxing _t_-BuOH provided the cyclization product **12c** (91% yield), which was then subjected to the general decarboxylation condition to yield 6-farnesyl-5-methyl-cyclohexane-1,3-dione (**7c**) in 65% yield. No enol form was observed in \({}^{1}\)H-NMR spectrum.