# Regiosellective 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 regiosomeric 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 \(\beta\)-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 regiosomeric cyclohexane-1,3-diones produced grifolin and neogrifolin, respectively. a +
Footnote †: journal: Applied sciences  
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Terpenophenolic natural products with relatively simple structures do not allow for a facile direct coupling reaction between orcinol and farnesol. Various approaches to their synthesis have been proposed and are summarized in Figure 1 and Table 1. In the first total synthesis attempted by [PERSON] in 1968, protected orcinol **3** (P = THP) and farnesyl bromide **4** (X = Br) were coupled by _n_-BuLi (entry 1) [12]. Deprotection was performed with weak oxalic acid, and the sequence required a total of five steps. Although not reported, the reaction yields were probably reduced due to poor coupling and/or further cyclization to a chroman ring, a common byproduct under acidic deprotection conditions. [PERSON] directly coupled orcinol **3** (P = H) and farnesyl chloride **4** (X = Cl) using metallic sodium, but this resulted in a mixture of grifolin **1** (23% yield) and neogrifolin **2** (42% yield), which was difficult to separate (entry 2) [13]. Similar direct couplings between orcinol **3** (P = H) and farnesol **4** (X = OH) were reported using CoCl\({}_{2}\) catalyst at 70 \({}^{\circ}\)C (entry 3) [14] or using Lewis acids including Al\({}_{2}\)O\({}_{3}\) (entry 4) [15] and BF\({}_{3}\)-OEt\({}_{2}\) (entry 5) [16], but all of these methods suffered from low yield and regioisomeric problems. To address the regichemical issue, [PERSON] used _n_-BuLi to selectively deprotonate MOM-protected orcinol, which was then formulated and chain-extended with the farnesyl unit. However, deprotection was performed under strongly acidic _p_-ToOH conditions, which allowed the synthesis of grifolin in seven steps with an overall yield of 8% (entry 6) [17]. \begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Entry** & **Ring (P)** & **Chain (X)** & **Reagent** & **\# Step** & **Tot. Y (\%)** & **Reference** \\ \hline
1 & **3** (THP) & **4** (Br) & _n_-BuLi & 5 & - & [PERSON] [12] \\
2 & **3** (H) & **4** (CI) & Na & 1 & 23 & [PERSON] [13] \\
3 & **3** (H) & **4** (OH) & CoCl\({}_{2}\) & 1 & 17 & [PERSON] [14] \\
4 & **3** (H) & **4** (OH) & Al\({}_{2}\)O\({}_{3}\) & 1 & 37 & [PERSON] [15] \\
5 & **3** (H) & **4** (OH) & BF\({}_{3}\)-OEt\({}_{2}\) & 1 & 24 \({}^{1}\) & [PERSON] [16] \\
6 & **3** (MOM) & geranyl acetone & _n_-BuLi & 7 & 8 & [PERSON] [17] \\
7 & **3** (OMe) & **4** (Br) & _n_-BuLi/CuCN & 4(1) & (82) \({}^{2}\) & [PERSON] [18] \\
8 & **6** & **5** (R = farnesyl) & 80 \({}^{\circ}\)C & 2 & 21–43 & [PERSON] [19] \\
9 & **7a** & **4** (O=C) & Hamtzsch ester, proline & 4 & 37 & [PERSON] [20] \\
10 & **8** & **4** (OH) & Pd\({}_{2}\)(dba)\({}_{3}\) & 7 & 30 & [PERSON] [21] \\ \hline \hline \end{tabular} \# Number of steps required to synthesize grifolin. \({}^{1}\) The yield of neogrifolin. \({}^{2}\) The yield of the coupling step only.  
\end{table}