4.1 General experimental procedures

Unless otherwise mentioned, all reactions were carried out under an argon atmosphere under anhydrous conditions, and all reagents were purchased from commercial suppliers without further purification. NMR spectra were recorded on Bruker ARX600, and calibrated using residual undeuterated solvent as an internal reference (CDCl3, δH 7.26 ppm 1H NMR, δC 77.0 ppm 13C NMR; Acetone-d6, δH 2.05 ppm 1H NMR, δC 206.3 ppm 13C NMR). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, b = broad, m = multiplet. High-resolution mass spectra (HRMS) were recorded on a Bruker Apex IV FTMS mass spectrometer using ESI (electrospray ionization).

4.1.1 (E)-tert-Butyldimethyl(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)phenoxy)silane (12)

To a two-necked 25 mL flask, 2,2,6,6-tetramethylpiperidine (TMP, 350 µL, 2.32 mmol, 4.0 eq.) and n-BuLi (1 M solution in hexane, 2.32 mL, 2.32 mmol, 4.0 eq.) were added at 0 °C. The resulting mixture was stirred for 10 min at the same temperature, followed by the dropwise addition of a solution of bis[(pinacolato)boryl]methane (466 mg, 1.74 mmol, 3.0 eq.) in anhydrous THF (0.7 mL). After an additional 10 min of stirring, the reaction mixture was cooled to – 78 °C and stirred for another 10 min. Then, a solution of 11 (153 mg, 0.58 mmol, 1.0 eq.) in THF (0.7 mL) was added dropwise to the mixture. The reaction was stirred for 2 h at –78 °C, after which excess reagents were quenched by the addition of saturated aqueous NH4Cl. The reaction mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to afford 11 as a colorless oil (94 mg, 42%). Rf = 0.5 (SiO2, hexane) This obtained material contained trace amounts of unidentified impurities and residual bis[(pinacolato)boryl]methane, as determined by 1H NMR analysis. 1H NMR (600 MHz, CDCl3) δ 7.04 – 7.01 (m, 2H), 6.75 – 6.73 (m, 2H), 6.68 (d, J = 17.9 Hz, 1H), 5.48 (d, J = 17.9 Hz, 1H), 2.66 (dd, J = 9.5, 6.6 Hz, 2H), 2.44 (ddd, J = 9.5, 5.0, 1.6 Hz, 2H), 1.27 (s, 12H), 0.97 (s, 9H), 0.18 (s, 6H); 13C NMR (151 MHz, CDCl3) δ 153.8, 153.8, 134.6, 129.3, 129.3, 129.3, 120.0, 120.0, 83.2, 83.2, 37.9, 33.9, 25.9, 25.9, 25.9, 24.9, 24.9, 24.9, 24.9, 18.3, − 4.3, − 4.3; HRMS (ESI): m/z [M + H]+ calcd for C22H37BO3Si: 388.2720; found: 388.2719.

4.1.2 (1E,4E)-1-(4-Hydroxyphenyl)-7-(4-methoxyphenyl)-1,4-heptadiene (Otteacumiene O (1))

To a mixture solution of 12 (48 mg, 0.23 mmol, 1.0 eq.), 5 (152 mg, 0.39 mmol, 1.7 eq.) and KF (34 mg, 0.59 mmol, 2.5 eq.) in anhydrous ethanol (5 mL) was added Pd(OAc)2 (15.7 mg, 0.07 mmol, 0.30 eq.) under an argon atmosphere. The reaction mixture was stirred for 24 h at 70 °C. After the reaction was confirmed to be complete by TLC monitoring, the mixture was quenched with water (5 mL) and extracted with dichloromethane (DCM, 2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and filtered. The organic solvent was completely removed by rotary evaporation. The solid residue was purified by column chromatography (DCM: EtOAc /100:1) to afford otteacumiene O (1) (43 mg, 63%) as a yellow oil. Rf = 0.45 (SiO2, DCM: EtOAc /100:1); 1H NMR (600 MHz, Acetone-d6) δ 7.31 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 6.31 (d, J = 15.9 Hz, 1H), 6.09 (dt, J = 15.8, 6.6 Hz, 1H), 5.59 – 5.45 (m, 2H), 3.78 (s, 3H), 2.84 (m, 2H), 2.59 (dd, J = 8.7, 6.7 Hz, 2H), 2.32 – 2.25 (m, 2H); 13C NMR (151 MHz, Acetone-d6) δ 159.9, 156.4, 133.5, 131.7, 131.3, 130.6, 130.2, 130.2, 129.4, 127.9, 127.4, 127.4, 115.9, 115.8, 114.7, 114.7, 55.5, 36.5, 35.8, 35.6; HRMS (EI): m/z [M]+ calcd. for C12H14O3: 294.1614; found: 294.1611.

4.1.3 (1E,4E)-1,7-Di(4-methoxyphenyl)-1,4-heptadiene (3)

To a stirred solution of 1 (30 mg, 0.1 mol, 1.0 eq.) and iodomethane (26 µL, 0.4 mmol, 4.0 eq.) in DMF (1 mL) was added K2CO3 (42 mg, 0.3 mmol, 3.0 eq.). The resultant suspension was heated at 60 °C for 4 h, then allowed to cool to room temperature and stirred overnight. The reaction mixture was filtered, and the solid residue was washed with EtOAc (10 mL). The combined filtrates were then washed with brine (3 × 10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane: EtOAc/20:1) to give (1E,4E)-1,7-di(4-methoxyphenyl)-1,4-heptadiene (3) (28 mg, 0.9 mmol, 90%) as white solid. Rf = 0.70 (SiO2, PE: EtOAc /5:1); 1H NMR (600 MHz, CDCl3) δ 7.27 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 7.4 Hz, 2H), 6.82 (d, J = 7.1 Hz, 2H), 6.28 (dt, J = 15.7, 1.6 Hz, 1H), 6.05 (dt, J = 15.8, 6.6 Hz, 1H), 5.56 – 5.51 (m, 1H), 5.51 – 5.47 (m, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 2.88 – 2.85 (m, 2H), 2.63 (dd, J = 8.8, 6.8 Hz, 2H), 2.33 – 2.30 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 158.7, 158.7, 157.7, 157.7, 134.2, 130.8, 129.6, 129.4, 128.6, 127.1, 127.0, 113.9, 113.9, 113.7, 113.7, 55.3, 55.2, 35.9, 35.0, 34.7; HRMS (EI): m/z [M]+ calcd. for C21H24O2: 308.1771; found: 308.1771.

4.1.4 1-(3-Bromo-4-methoxyphenyl)pent-4-en-1-ol (8)

To a solution of 10 (1291 mg, 6.03 mmol, 1.0 eq.) in THF (30 mL), 3-butenylmagnesium bromide solution (1 M, 15 mL, 15.0 mmol, 2.5 eq.) was added dropwise at 0 °C. The reaction was stirred at the same temperature until the starting aldehyde disappeared based on TLC analysis. The mixture was quenched by pouring it into saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (20 mL × 3). The organic extracts were washed with brine, dried over MgSO4, and then concentrated in vacuo. Silica gel column chromatography of the residue (hexane: EtOAc/10:1) gave 8 (1467 mg, 90%) as a white solid. Rf = 0.35 (SiO2, hexane: EtOAc/10:1); 1H NMR (600 MHz, CDCl3) δ 7.21 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.2 Hz, 2H), 5.83 – 5.75 (m, 1H), 5.16 – 5.11 (m, 2H), 4.67 (t, J = 6.6 Hz, 1H), 2.49 (t, J = 6.9 Hz, 2H), 0.98 (s, 9H), 0.19 (s, 6H); 13C NMR (151 MHz, CDCl3) δ 155.2, 136.8, 134.8, 127.1, 120.1, 118.3, 73.2, 43.9, 25.8, 25.8, 25.8, 18.3, − 4.3, − 4.3; HRMS (ESI): m/z [M + Na]+ calcd for C12H15BrO2: 293.0148; found: 293.0154.

4.1.5 (4E)-1-Hydroxy-1-(3-bromo-4-methoxyphenyl)-7-(4-hydroxyphenyl)-4-heptene (7)

A solution of 8 (74 mg, 0.28 mmol, 1.0 eq.) and 9 (76 mg, 0.28 mmol, 1.0 eq.) in DCM (5 mL) was degassed for 30 min under a flow of argon. The reaction mixture was heated at reflux using a glycerol bath. Then, Grubbs-II catalyst (10 mol %, 24 mg, 0.028 mmol, 10% eq.) was added in one portion. The reaction mixture was stirred at reflux for 16 h. Upon completion, the solvent was removed and the crude was purified on a flash column (hexanes:acetone/15:1) affording 7 (35 mg, 32%) as a solid. Rf = 0.2 (SiO2, hexanes:acetone/15:1); 1H NMR (600 MHz, CDCl3) δ 7.12 (dd, J = 8.3, 2.2 Hz, 1H), 7.07 (dd, J = 8.2, 2.5 Hz, 1H), 7.01 (dd, J = 8.2, 2.2 Hz, 1H), 6.94 (ddd, J = 7.7, 4.9, 2.3 Hz, 2H), 6.88 (d, J = 8.2 Hz, 1H), 5.43 (d, J = 2.1 Hz, 1H), 5.12 (ddd, J = 15.0, 9.1, 5.6 Hz, 1H), 4.95 (dt, J = 15.3, 5.9 Hz, 1H), 4.59 (dd, J = 6.8, 4.4 Hz, 1H), 3.97 (s, 3H), 2.93–2.88 (m, 1H), 2.70–2.64 (m, 1H), 2.42 (dd, J = 13.1, 5.8 Hz, 1H), 2.35 (dd, J = 8.8, 6.0 Hz, 1H), 2.10 (dt, J = 13.9, 9.6, 4.7 Hz, 2H), 1.83–1.76 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 155.4, 151.3, 147.6, 139.4, 136.7, 132.0, 131.6, 130.4, 129.2, 123.7, 123.0, 118.0, 115.3, 111.7, 72.2, 56.3, 38.8, 35.6, 34.8, 27.56; HRMS (ESI): m/z [M + Na]+ calcd for C20H22O3: 333.1461; found: 333.1464.

4.1.6 (E)-16-Methoxy-2-oxa-1(1,3),3(1,4)-dibenzenacyclo d-ecaphan-6-en-10-ol (6)

To a solution of 7 (71 mg, 0.176 mmol, 1.0 eq.) in anhydrous pyridine (3 mL) was added K2CO3 (209 mg, 0.878 mmol, 5.0 eq.). The mixture was heated to 90 °C, followed by the addition of CuO (70 mg; 0.878 mmol, 5.0 eq.). After heating for 48 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and neutralized by the addition of 10% aqueous NaHSO3 solution. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with 10% aqueous NaHSO3 solution, water, and brine, then dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (pentane: EtOAc/10:1) to provide 6 (39 mg, 71%) as a yellow oil. Rf = 0.25 (SiO2, pentane: EtOAc/10:1); 1H NMR (600 MHz, CDCl3) δ 7.12 (dd, J = 8.3, 2.2 Hz, 1H), 7.07 (dd, J = 8.2, 2.5 Hz, 1H), 7.01 (dd, J = 8.2, 2.2 Hz, 1H), 6.94 (ddd, J = 7.7, 4.9, 2.3 Hz, 2H), 6.88 (d, J = 8.2 Hz, 1H), 5.43 (d, J = 2.1 Hz, 1H), 5.12 (ddd, J = 15.0, 9.1, 5.6 Hz, 1H), 4.95 (dt, J = 15.3, 5.9 Hz, 1H), 4.59 (dd, J = 6.8, 4.4 Hz, 1H), 3.97 (s, 3H), 2.93 – 2.88 (m, 1H), 2.70 – 2.64 (m, 1H), 2.42 (dd, J = 13.1, 5.8 Hz, 1H), 2.35 (dd, J = 8.8, 6.0 Hz, 1H), 2.10 (dt, J = 13.9, 9.6, 4.7 Hz, 2H), 1.83 – 1.76 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 155.4, 151.3, 147.6, 139.4, 136.7, 132.0, 131.6, 130.4, 129.2, 123.7, 123.0, 118.0, 115.3, 111.7, 72.2, 56.3, 38.8, 35.6, 34.8, 27.6; HRMS (ESI): m/z [M + Na]+ calcd for C20H22O3: 333.1461; found: 333.1464.

4.1.7 (6E,9Z)-16-Methoxy-2-oxa-1(1,3),3(1,4)-dibenzenacyclo decaphane-6,9-diene (13)

A 10 mL 3-necked flask equipped with a magnetic stirring bar, stoppers, and a nitrogen inlet was charged with 6 (35 mg, 0.122 mmol, 1.0 eq.) dissolved in DCM (3 mL). Camphor-10-sulfonic acid (42 mg, 0.183 mmol, 1.5 eq.) was added and the reaction mixture was stirred at ambient temperature for 2.5 h, until TLC showed complete consumption of the alcohol. The reaction was concentrated and purified via flash column chromatography (pentane: EtOAc/20:1) to yield 13 as a white solid. (29 mg, 82%). Rf = 0.5 (SiO2, pentane: EtOAc/20:1);1H NMR (600 MHz, CDCl3) δ 7.17 – 6.98 (m, 4H), 6.88 (d, J = 8.2 Hz, 1H), 6.71 (dd, J = 8.3, 2.1 Hz, 1H), 6.26 (d, J = 11.4 Hz, 1H), 5.78 (d, J = 2.1 Hz, 1H), 5.55 (dt, J = 11.4, 9.2 Hz, 1H), 5.23 (dt, J = 15.3, 7.7, 2.1 Hz, 1H), 4.39 (dt, J = 15.4, 5.6, 1H), 3.98 (s, 3H), 2.77 (s, 2H), 2.63 (s, 2H), 2.34–2.08 (m, 2H); 13C NMR (CDCl3, 151 MHz, 25 °C) δ (four carbons signals were not detectable because of a coalescence at rt) 154.1, 150.8, 147.3, 139.7, 131.3, 129.7, 129.6, 129.5, 128.5, 122.5, 115.5, 111.7, 56.2, 35.7, 35.1, 30.4; HRMS (ESI): m/z [M + Na]+ calcd for C20H20O2: 315.1356; found: 315.1355.

4.1.8 (6E,9Z)-2-Oxa-1(1,3),3(1,4)-dibenzenacyclodecaphane-6,9-dien-16-ol (otteacumiene P (2))

To a solution of 13 (31 mg, 0.106 mmol, 1.0 eq.) in DMF (3 mL) was added EtSNa (30 mg, 0.35 mmol, 3.5 eq.). The reaction mixture was refluxed for 3.5 h. After cooling to 0 °C, 5% aqueous HCl solution was added, the aqueous layer was extracted with EtOAc, and the combined organic layers were successively washed with 5% aqueous HCl solution, H2O, and brine. The solution was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (pentane: EtOAc/8:1), yielding otteacumiene N (2) (29 mg, 67%) as a white solid. Rf = 0.40 (SiO2, pentane: EtOAc/8:1); 1H NMR (600 MHz, CDCl3) δ 7.09 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.26 (d, J = 11.5 Hz, 1H), 5.71 (d, J = 2.0 Hz, 1H), 5.54 (dt, J = 11.6, 9.2 Hz, 1H), 5.22 (dt, J = 15.4, 7.7, Hz, 1H), 4.41 (dt, J = 15.4, 5.6, 1H), 2.93–2.65 (m, 2H), 2.62 (s, 2H), 2.37–2.11 (m, 2H); 13C NMR (CDCl3, 151 MHz) δ (four carbon signals were not detectable because of a coalescence at rt) 153.6, 148.8, 143.7, 140.2, 131.3, 129.9, 129.5, 129.3, 128.2, 123.0, 115.2, 114.9, 35.7, 35.1, 30.3; HRMS (ESI); m/z [M + H]+ calcd for C19H18O2: 279.1380; found: 279.1386.