# Regiosellective De Novo Synthesis of Phenolic Isoprenoids Grifolin and Neogrifolin
## 2 Materials and Methods  
**General Procedure. ** Reactions were performed in a well-dried flask under an Argon atmosphere. Solvents for extraction and chromatography were of reagent grade and used as received. Solvents for the reaction were stored in molecular sieves, which were prepared by heating in a microwave for 1 min and then drying with a vacuum pump (this drying procedure was repeated three times). The column chromatography was performed with silica gel 60 (70-230 mesh) using a mixture of EtOAc/hexane as eluent. The \({}^{1}\)H- and \({}^{13}\)C-NMR spectra were, respectively, recorded on a 400 MHz and 100 MHz NMR spectrometer in deuterated chloroform (CDCl\({}_{3}\)) with tetramethylsilane (TMS) as an internal reference unless noted otherwise. **Experimental Procedures for the Synthesis of Grifolin 1**  
**Ethyl (6E,10E)-7,11,15-trimethyl-3-oxohexadeca-6,10,14-trienoate (10b). ** To a stirred solution of ethyl acetoacetate (10.41 g, 80.00 mmol) in THF (40 mL) at 0 \({}^{\circ}\)C under an argon atmosphere, NaH (60% in mineral oil, 3.84 g, 96.00 mmol) was carefully added in several portions. The mixture was stirred at 0 \({}^{\circ}\)C for 1 h; then, 1.6 M hexane solution of _n_-BuLi (55.0 mL, 88.00 mmol) was added. Stirring at 0 \({}^{\circ}\)C for 30 min, the mixture was treated with a THF solution (10 mL) of farnesyl bromide (21.95 g, 76.95 mmol). The reaction mixture was stirred at 0 \({}^{\circ}\)C for 4.5 h, and quenched with 1 M HCl. The mixture was extracted with EtOAc, dried over anhydrous Na\({}_{2}\)SO\({}_{4}\), filtered, and concentrated under reduced pressure to give the crude product (31.45 g), which was purified by SiO\({}_{2}\) flash column chromatography (3-20% EIOAc/hexane eluent) to produce the coupling product **10b** (19.20 g, 57.41 mmol) in 75% yield as yellow oil (a mixture of keto and enrol forms). Data for **10b**: R\({}_{f}\) = 0.65 (4:1 hexane/EtOAc); \({}^{1}\)H NMR (CDCl\({}_{3}\)) \(\delta\) = 1.28 (t, \(J\) = 7.2 Hz, 3H), 1.59 (s, 3H), 1.60 (s, 3H), 1.61 (s, 3H), 1.68 (s, 3H), 1.93-2.02 (m, 4H), 2.02-11 (m, 4H), 2.29 (dt, \(J_{d}\) = 6.8, \(J_{l}\) = 7.2 Hz, 2H), 2.57 (t, \(J\) = 7.2 Hz, 2H), 3.43 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 5.04-5.14 (m, 3H) ppm; \({}^{13}\)C NMR (CDCl\({}_{3}\), keto form) \(\delta\) = 14.2, 16.0, 16.1, 17.7, 22.2, 25.7, 26.6, 26.8, 39.7, 39.8, 43.1, 49.4, 61.4, 122.2, 124.1, 124.4, 131.3, 135.1, 136.8, 167.2, 202.6 ppm; IR v = 3469 (w), 2967, 2929, 1740, 1716, 1652, 1447, 1375, 1315, 1279, 1236, 1176, 1153, 1096, 1026, 843, 804, 750 cm\({}^{-1}\); HRMS (ESI) calcd for C\({}_{21}\)H\({}_{34}\)O\({}_{3}\)+Na 357.2406, found 357.2401. **Ethyl 4-hydroxy-6-methyl-2-oxo-3-((2E,6)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl) cyclohex-3-ene-1-carboxylate (12b). ** To a stirred solution of the coupling product **10b** (3.00 g, 8.97 mmol) and ethyl crotonate (1.02 g, 8.97 mmol) in \(t\)-BuOH (30 mL), \(t\)-BuOK (201 mg, 1.79 mmol) was added. The mixture was heated at 90 \({}^{\circ}\)C for 2 h, and the solution became cloudy. A stoichiometric amount of \(t\)-BuOK (1.01 g, 8.97 mmol) was added and the mixture was heated at 90 \({}^{\circ}\)C for 16 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The crude mixture was diluted with EIOAc, washed with 1 M HCl, dried over anhydrous Na\({}_{2}\)SO\({}_{4}\), filtered, and concentrated to give an orange oily product (3.76 g). The crude product was purified by SiO\({}_{2}\) flash column chromatography (20-40% EtOAc/hexane eluent) to produce the cyclized product **12b** (3.12 g, 7.76 mmol) in 86% yield as a light-yellow liquid (a mixture of diastereomers).