The Chemistry of Spiroketals

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Chapter Three Experimental

General Details

Unless otherwise noted, all reactions were performed under an oxygen-free atmosphere of nitrogen or argon. Tetrahydrofuran and diethyl ether were freshly distilled over sodium/benzophenone ketyl. Dichloromethane, acetonitrile, methanol and dimethylsulfoxide were freshly distilled from calcium hydride. Toluene was freshly distilled over sodium. Triethylamine and diisopropylamine were freshly distilled from calcium hydride and stored over potassium hydroxide. All other reagents were used as received unless otherwise noted.
Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials, unless otherwise stated. Reactions performed at low temperature were cooled either with an acetone/dry ice bath to reach −78 °C or an ice/water bath to reach 0 °C. Reactions were monitored by thin-layer chromatography (TLC) carried out on E. Merck silica gel plates using UV light as visualizing agent and an ethanolic solution of vanillin and ammonium molybdate and heat as developing agents. Kieselgel S 63-100 μm (Riedel-de-Hahn) silica gel was used for flash chromatography. Preparatory TLC was carried out on 500 μm, 20 × 20 cm UniplateTM (Analtech) silica gel thin layer chromatography plates.
NMR spectra were recorded at room temperature in CDCl3, CD3OD, (CD3)3CO, C6D6 or (CD3)SO solutions on either a Bruker DRX300 spectrometer operating at 300 MHz for 1H nuclei and 75 MHz for 13C nuclei or using a Bruker DRX-400 spectrometer operating at 400 MHz for 1H nuclei and 100 MHz for 13C nuclei. Chemical shifts are reported in parts per million (ppm) from tetramethylsiane (δ = 0) and were measure relative to the solvent in which the sample was analysed. Coupling constants, J, are reported in hertz (Hz). Multiplicities are reported as “s” (singlet), “br s” (broad singlet), “d” (doublet), “dd” (doublet of doublets), “ddd” (doublet of doublets of doublets), “t” (triplet) and “m” (multiplets). Where distinguishable from those due to a major rotamer or diastereomer, resonances due to minor rotamers or diastereomers are denoted by an asterix. Optical rotations were measured with an Autopol® IV automatic polarimeter, using the sodium-D line (589 nm), with the concentration measured in grams per 100 mL. Infrared (IR) spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer using a diamond ATR sampling accessory. Melting points were determined on a Kofler hot-stage apparatus and are uncorrected. Highresolution mass spectra (HRMS) were obtained using a VG70SE spectrometer or on a micrOTOFQ II mass spectrometer.

Synthesis of Phthalides (±)-177, (±)-179 and Alkenes 167, 194 and 195

Methyl 2,4,6-trihydroxybenzoate (96)
To a stirred solution of 2,4,6-trihydroxybenzoic acid monohydrate 169 (10 g, 53 mmol) in acetone (300 mL) was added K2CO3 (7.4 g, 53 mmol) and dimethyl sulfate (5.5 mL, 59 mmol) at room temperature. The solution was stirred for 16 h and then quenched with conc. aq. NH3 (40 mL) and stirred for a further 20 min. The reaction mixture was acidified to pH ~ 5 by the addition of aq. 2M HCl, concentrated in vacuo and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 3:1) afforded the title compound 96 (5.6 g, 30 mmol, 57%) as a white solid; m.p. 175-179 °C (lit. 177-178 °C)110; 1H NMR (400 MHz, ((CD3)2SO):  10.40 (2H, s, OH × 2), 10.18 (1H, s, OH), 5.85 (2H, s, H-3 and H-5), 3.84 (3H, s, OCH3); 13C NMR (100 MHz, (CD3)2SO): 
170.4 (C=O), 163.7 (C), 161.9 (C × 2), 95.1 (Ar-CH × 2), 94.3 (C), 52.0 (CH3). The spectroscopic data were in agreement with those reported in the literature.110
Methyl 4-(benzyloxy)-2,6-dihydroxybenzoate (172)
To a stirred solution of ester 96 (0.25 g, 1.4 mmol) in anhydrous acetone (6.8 mL) was added K2CO3 (0.19 g, 1.4 mmol), NaI (70 mg, 0.43 mmol) and benzyl bromide (0.16 mL, 1.4 mmol). The resultant mixture was heated at reflux for 3 h, cooled to room temperature and quenched with H2O (10 mL). The reaction mixture was extracted with EtOAc (3 × 15 mL), the combined organic extracts dried over MgSO4 and then concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 5:1) afforded the title compound 172 (0.23 g, 0.84 mmol, 62%) as a white solid; m.p. 110-112 °C (lit. 117-118 °C)227; 1H NMR (400 MHz, CDCl3):  7.41-7.31 (5H, m, Ar-H × 5),
6.13 (2H, s, H-3 and H-5), 5.04 (2H, s, OCH2), 4.00 (3H, s, OCH3); 13C NMR (100 MHz, CDCl3):  169.5 (C), 165.4 (C × 2), 162.4 (C=O), 135.9 (C), 128.5 (Ar-CH × 2), 128.1 (Ar-CH), 127.4 (Ar-CH × 2), 95.1 (Ar-CH × 2), 94.0 (C), 69.9 (CH2), 52.4 (CH3). The spectroscopic data were in agreement with those reported in the literature.227
Methyl 4-(benzyloxy)-2-hydroxy-6-methoxybenzoate (173)
To a stirred solution of ester 172 (4.4 g, 16 mmol), PPh3 (4.3 g, 16 mmol) and MeOH (0.98 mL, 24 mmol) in THF (120 mL) at 0 °C was added DIAD (3.2 mL, 16 mmol) dropwise. The solution was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with sat. aq. NH4Cl (40 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 8:1) afforded the title compound 173 (3.0 g, 10 mmol, 63%) as a colourless solid; m.p. 116-117 °C (lit. 106 °C)228; 1H NMR (400 MHz, CDCl3):  12.03 (1H, s, OH), 7.44-7.35 (5H, m, Ar-H × 5), 6.20 (1H, d, J = 2.4 Hz, Ar-H), 6.06 (1H, d, J = 2.4 Hz, Ar-H), 5.06 (2H, s, OCH2), 3.92 (3H, s, OCH3), 3.82 (3H, s, OCH3); 13C NMR (100 MHz, CDCl3):  171.7 (C=O), 165.9 (C), 164.5 (C), 162.2 (C), 136.0 (C), 128.7 (Ar-CH × 2), 128.3 (Ar-CH), 127.7 (Ar-CH × 2), 96.8 (C), 94.4 (Ar-CH), 92.2 (Ar-CH), 70.2 (CH2), 56.1 (CH3), 52.2 (CH3). The spectroscopic data were in agreement with those reported in the literature.
Methyl 4-(benzyloxy)-6-methoxy-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (168)
To a stirred solution of phenol 173 (1.4 g, 5.0 mmol) in CH2Cl2 (20 mL) was added NEt3 (1.3 mL, 9.9 mmol) and N-phenyltriflimide (2.5 g, 7.0 mmol). The resultant mixture was heated to reflux for 48 h. The reaction mixture was allowed to cool to room temperature, diluted with H2O (20 mL) and the layers separated. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL), the combined organic extracts dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 5:1) afforded the title compound 168 (2.1 g, 5.0 mmol, 99%) as a pale amber solid; m.p. 57-58 °C (lit. 71 °C)116 ;1H NMR (400 MHz, CDCl3):  7.36-7.26 (5H, m, Ar-H × 5), 6.52 (1H, d, J = 2.0 Hz, Ar-H), 6.48 (1H, d, J = 2.0 Hz, Ar-H), 5.02 (2H, s, OCH2), 3.85 (3H, s, OCH3), 3.75 (3H, s, OCH3); 13C NMR (100 MHz, CDCl3):  163.5 (C=O), 161.7 (C), 159.7 (C), 148.1 (C), 135.4 (C), 128.8 (Ar-CH × 2), 128.5 (Ar-CH), 127.6 (Ar-CH × 2), 125.1 (CF3, J = 315 Hz), 110.0 (C), 100.2 (Ar-CH), 99.2 (Ar-CH), 70.7 (CH2), 56.3 (CH3), 52.4 (CH3). The spectroscopic data were in agreement with those reported in the literature.228
(E)-Methyl 4-(benzyloxy)-6-methoxy-2-(prop-1-en-1-yl)benzoate (167)
To a solution of triflate 168 (1.9 g, 4.5 mmol) and LiCl (0.58 g, 14 mmol) in degassed THF (8 mL) was added Pd(PPh3)4 (0.26 g, 0.2 mmol) and allyltributylstannane (1.6 mL, 5.1 mmol). The reaction mixture was heated to 80 °C, stirred for 48 h and then allowed to cool to room temperature. THF (40 mL) and tBuOK (1.5 g, 13 mmol) were added and the reaction mixture heated to 45 °C with stirring for 8 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL). The layers were separated and the combined organic extracts washed successively with aq. NH3 (25% v/v, 25 mL), aq. HCl (1 M, 25 mL) and sat. aq. NaHCO3 (25 mL). The organic extract was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 5:1) afforded the title compound 167 (1.2 g, 3.8 mmol, 84%) as a colourless oil; 1H NMR (400 MHz, CDCl3):  7.43-7.31 (5H, m, Ar-H × 5), 6.67 (1H, d, J = 2.0 Hz, Ar-H), 6.42 (1H, d, J = 2.0 Hz, Ar-H), 6.36 (1H, dd, J = 15.6, 1.6 Hz, H-1′), 6.18 (1H, dq, J = 15.6, 6.5 Hz, H-2′), 5.10 (2H, s, OCH2), 3.89 (3H, s, OCH3), 3.76 (3H, s, OCH3), 1.85 (3H, dd, J = 6.5, 1.6 Hz, H-3′); 13C NMR (100 MHz, CDCl3):  168.4 (C=O), 160.3 (C), 157.8 (C), 137.7 (C), 136.4 (C), 129.0 (CH), 128.4 (Ar-CH × 2), 127.9 (CH), 127.5 (Ar-CH), 127.3 (Ar-CH × 2), 115.3 (C), 102.4 (Ar-CH), 97.9 (Ar-CH), 69.9 (CH2), 55.7 (CH3), 52.0 (CH3), 18.5 (CH3); IR (film) max 2950, 1724, 1599, 1427, 1260, 1155, 1097, 1039, 961, 700 cm-1; HRMS (ESI+) for C19H20O4 [M+Na]+ requires 335.1254 found 335.1240.
5-(Benzyloxy)-3-(1-hydroxyethyl)-7-methoxyisobenzofuran-1(3H)-one ((±)-175)
To a solution of alkene 167 (370 mg, 1.2 mmol) in acetone/H2O (1:1, 9.5 mL) was added NMO (150 mg, 1.3 mmol) and OsO4 (2.5% w/w in tBuOH, 0.31 mL, 0.024 mmol) and the resultant mixture stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (30 mL), the layers separated and the organic layer washed successively with sat. aq. Na2S2O4 (5 mL), H2O (5 mL) and sat. aq. NaCl (5 mL). The organic extract was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 1:1) afforded the title compound (±)-175 (310 mg, 0.98 mmol, 82%) as a white solid; m.p. 75-78 °C; 1H NMR (400 MHz, CDCl3):  7.49-7.31 (5H, m, Ar-H × 5), 6.64 (1H, s, Ar-H), 6.47 (1H, s, Ar-H), 5.19 (1H, d, J = 4.0 Hz, H-3), 5.08 (2H, ABq, ΔδAB = 0.02, JAB = 11.5 Hz, OCH2), 4.15-4.13 (1H, m, H-1′), 3.85 (3H, s, OCH3), 2.65 (1H, br s, OH), 1.23 (3H, d, J = 6.4 Hz, H-2′); 13C NMR (100 MHz, CDCl3):  168.3 (C=O), 165.6 (C), 159.4 (C), 151.9 (C), 135.5 (C), 128.6 (Ar-CH × 2), 128.3 (Ar-CH), 127.5 (Ar-CH × 2), 107.3 (C), 99.7 (Ar-CH), 99.3 (Ar-CH), 82.5 (CH), 70.6 (CH2), 68.2 (CH), 55.8 (CH3), 18.1 (CH3); IR (film) max 3452, 2935, 1716, 1603, 1347, 1317, 1213, 1161, 1064, 762, 689 cm-1; HRMS (ESI+) for C18H18O5 [M+Na]+ requires 337.1046 found 337.1060. 5-(Benzyloxy)-3-(1-(ethoxymethoxy)ethyl)-7-methoxyisobenzofuran-1(3H)-one ((±)-177)
To a stirred solution of phthalide (±)-175 (250 mg, 0.80 mmol) and DIPEA (1.1 mL, 6.4 mmol) in THF (7 mL) at 0 ºC was added EOMCl (0.75 mL, 8.0 mmol). The resultant solution was allowed to warm to room temperature and stirred for 48 h. The reaction was quenched with sat. aq. NaHCO3 (7 mL), and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with sat. aq. NaCl (10 mL), dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 3:1) afforded the title compound (±)-177 (290 mg, 0.77 mmol, 96%) as a colourless oil; 1H NMR (400 MHz, CDCl3):  7.40-7.30 (5H, m, Ar-H × 5), 6.65 (1H, s, Ar-H), 6.48 (1H, s, Ar-H), 5.27 (1H, d, J = 3.6 Hz, H-3), 5.10 (2H, s, OCH2), 4.63 (2H, ABq, ΔδAB = 0.06, JAB = 7.0 Hz, OCH2O), 4.18-4.14 (1H, m, H-1′), 3.87 (3H, s, OCH3), 3.48-3.39 (2H, m, OCH2), 1.12 (3H, t, J = 6.8 Hz, CH3), 1.01 (3H, d, J = 6.4 Hz, H-2′); 13C NMR (100 MHz, CDCl3):  167.9 (C=O), 165.3 (C), 159.3 (C), 151.8 (C), 135.5 (C), 128.5 (Ar-CH × 2), 128.2 (Ar-CH), 127.4 (Ar-CH × 2), 107.6 (C), 99.7 (Ar-CH), 99.5 (Ar-CH), 93.8 (CH2), 80.5 (CH), 72.4 (CH), 70.5 (CH2), 63.3 (CH2), 55.8 (CH3), 14.8 (CH3), 14.7 (CH3); IR (film) max 2976, 2934, 1756, 1604, 1450, 1326, 1211, 1157, 1019, 840 cm-1; HRMS (ESI+) for C21H24O6 [M+Na]+ requires 395.1465 found 395.1467.
5-(Benzyloxy)-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-7-methoxyisobenzofuran-1(3H)-one ((±)-178)
To a stirred solution of phthalide (±)-175 (100 mg, 0.32 mmol) in CH2Cl2 (2 mL) at −78 °C was added 2,6-lutidine (0.15 mL, 1.3 mmol) and tert-butyldimethylsilyl triflate (0.20 mL, 0.95 mmol). The resultant solution was stirred at −78 °C for 4 h, and then quenched by the addition of sat. aq. NaHCO3 (2 mL). Upon warming to room temperature, the layers were separated and the aqueous layer further extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography afforded the title compound (±)-178 (140 mg, 0.32 mmol, 100%) as a colourless oil; 1H NMR (400 MHz, CDCl3):  7.36-7.31 (5H, m, Ar-H × 5), 6.68 (1H, d, J = 2.0 Hz, Ar-H), 6.49 (1H, d, J = 2.0 Hz, Ar-H), 5.15 (1H, d, J = 3.7 Hz, H-3), 5.09 (2H, s, OCH2), 4.25-4.18 (1H, m, H-1′), 3.87 (3H, s, OCH3), 0.96 (3H, d, J = 6.6 Hz, H-2′), 0.82 (9H, s, CH3 × 3), 0.04 (3H, s, SiCH3), −0.02 (3H, s, SiCH3); 13C NMR (100 MHz, CDCl3):  168.2 (C=O), 165.3 (C), 159.4 (C), 152.2 (C), 135.7 (C), 128.7 (Ar-CH × 2), 128.3 (Ar-CH), 127.4 (Ar-CH × 2), 108.0 (C), 99.9 (Ar-CH), 99.5 (Ar-CH), 81.6 (CH), 70.4 (CH2), 68.2 (CH), 55.8 (CH3), 25.5 (CH3 × 3), 17.8 (C), 17.6 (CH3), −4.6 (CH3), −5.1 (CH3); IR (film) max 2953, 2929, 2856, 1755, 1602, 1471, 1322, 1210, 1154, 1021, 957, 833, 732 cm-1; HRMS (ESI+) for C24H32O5Si [M+Na]+ requires 451.1911, found 451.1897.
5-(Benzyloxy)-4-bromo-3-(1-(ethoxymethoxy)ethyl)-7-methoxyisobenzofuran-1(3H)-one ((±)-184)
To a stirred solution of phthalide (±)-177 (60 mg, 0.16 mmol) in CH2Cl2 (1.5 mL) at 0 ºC was added NBS (32 mg, 0.18 mmol) in three portions over 30 min. The resultant mixture was allowed to warm to room temperature, stirred for 16 h and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 3:1) afforded the title compound (±)-184 (68 mg, 0.15 mmol, 93%) as a colourless solid; m.p. 148-150 °C; 1H NMR (400 MHz, CDCl3):  7.43-7.34 (5H, m, Ar-H × 5), 6.51 (1H, s, H-6), 5.24 (2H, s, OCH2), 5.17 (1H, s, H-3), 4.72 (1H, q, J = 6.2 Hz, H-1′) 4.44 (1H, d, J = 7.2 Hz, OCH2O), 4.28 (1H, d, J = 7.2 Hz, OCH2O), 3.91 (3H, s, OCH3), 3.20 (1H, m, OCH2), 2.99 (1H, m, OCH2), 1.45 (3H, d, J = 6.4 Hz, H-2′), 1.01 (3H, t, J = 6.8 Hz, CH3); 13C NMR (100 MHz, CDCl3):  167.4 (C=O), 160.7 (C), 158.7 (C), 150.0 (C), 135.2 (C), 128.7 (Ar-CH × 2), 128.4 (Ar-CH), 127.0 (Ar-CH × 2), 109.4 (C), 97.7 (Ar-CH), 96.0 (C), 93.0 (CH2), 83.2 (CH), 71.5 (CH2), 68.8 (CH), 63.0 (CH2), 56.2 (CH3), 17.4 (CH3), 14.8 (CH3); IR (film) max 2976, 1760, 1601, 1358, 1202, 1183, 1028, 985 cm-1; HRMS (ESI+) for C21H23O6Br [M+Na]+ requires 473.0570 found 473.0562.
5-(Benzyloxy)-3-(1-(ethoxymethoxy)ethyl)-4-iodo-7-methoxyisobenzofuran-1(3H)-one ((±)-185)
To a stirred solution of phthalide (±)-177 (60 mg, 0.16 mmol) and silver trifluoracetate (53 mg, 0.24 mmol) in CH2Cl2 (3.2 mL) was added I2 (61 mg, 0.24 mmol) in CH2Cl2 (1.7 mL) over 30 min. The reaction mixture was stirred at room temperature for 30 min, then filtered through Celite®. Sat. aq. Na2S2O3 (1 mL) and NaOH (1M, 1 mL) were added to the filtrate with stirring. The layers were separated and the aqueous layer further extracted with CH2Cl2 (2 × 3 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by flash column chromtography (hexanes/EtOAc 2:1) afforded the title compound (±)-185 (77 mg, 0.15 mmol, 96%) as a colourless solid; m.p. 146-148 ºC; 1H NMR (400 MHz, CDCl3):  7.49-7.32 (5H, m, Ar-H × 5), 6.45 (1H, s, H-6), 5.24 (2H, s, OCH2), 5.06 (1H, d, J = 1.0 Hz, H-3), 4.82 (1H, qd, J = 6.5 Hz, 1.0 Hz, H-1′), 4.43 (1H, d, J = 7.6 Hz, OCH2O), 4.25 (1H, d, J = 7.6 Hz, OCH2O), 3.94 (3H, s, OCH3), 3.20-3.16 (1H, m, OCH2), 2.97-2.93 (1H, m, OCH2), 1.47 (3H, d, J = 6.5 Hz, H-2′), 1.00 (3H, t, J = 7.0 Hz, CH3); 13C NMR (100 MHz, CDCl3):  167.6 (C=O), 162.8 (C), 159.9 (C), 153.9 (C), 135.3 (C), 128.8 (Ar-CH × 2), 128.4 (Ar-CH), 127.0 (Ar-CH × 2), 110.3 (C), 97.0 (Ar-CH), 96.8 (CH2), 84.9 (CH), 71.6 (CH2), 68.8 (C), 68.7 (CH), 63.0 (CH2), 56.2 (CH3), 17.4 (CH3), 14.9 (CH3); IR (film) max 2969, 2928, 1744, 1592, 1439, 1241, 1199, 1181, 1021, 974, 844, 743 cm-1; HRMS (ESI+) for C21H23O6I [M+Na]+ requires 521.0432 found 521.0427.
5-(Benzyloxy)-4-bromo-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-7-methoxyisobenzofuran1(3H)-one ((±)-186)
To a stirred solution of phthalide (±)-178 (35 mg, 0.082 mmol) in CH2Cl2 (1 mL) at 0 °C was added NBS (16 mg, 0.090 mmol) in three portions over 30 min. The resultant solution was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched by the addition of H2O (1 mL) and the layers separated. The aqueous layer was further extracted with CH2Cl2 (3 × 3 mL), the combined organic extracts dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 10:1) afforded the title compound (±)-186 (38 mg, 0.075 mmol, 93%) as a colourless solid; m.p. 150-154 ºC; 1H NMR (400 MHz, CDCl3):  7.47-7.34 (5H, m, Ar-H × 5), 6.48 (1H, s, H-6), 5.26 (2H, ABq, ΔδAB = 0.03, JAB = 12.2 Hz, OCH2), 5.14 (1H, d, J = 1.0 Hz, H-3), 4.72 (1H, qd, J = 6.4, 1.0 Hz, H-1′), 3.89 (3H, s, OCH3), 1.44 (3H, d, J = 6.4 Hz, H-2′), 0.57 (9H, s, CH3 × 3), −0.06 (3H, s, CH3), −0.39 (3H, s, CH3); 13C NMR (100 MHz, CDCl3):  167.8 (C=O), 160.8 (C), 158.9 (C), 150.7 (C), 135.5 (C), 128.9 (Ar-CH × 2), 128.5 (Ar-CH), 127.1 (Ar-CH × 2), 110.1 (C), 98.1 (Ar-CH), 96.3 (C), 84.1 (CH), 71.7 (CH2), 65.7 (CH), 56.5 (CH3), 25.4 (CH3 × 3), 21.2 (CH3), 17.6 (C), −4.3 (CH3), −5.6 (CH3); IR (film) max 2954, 2929, 2856, 1751, 1600, 1441, 1361, 1203, 1047, 956, 835, 775, 728 cm-1; HRMS (ESI+) for BrC24H31O5Si [M+Na]+ requires 529.1016 found 529.1014.
5-(Benzyloxy)-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-iodo-7-methoxyisobenzofuran1(3H)-one ((±)-187)
To a stirred solution of phthalide (±)-177 (25 mg, 0.058 mmol) and silver trifluoroacetate (19 mg, 0.088 mmol) in CH2Cl2 (1.2 mL) was added I2 (22 mg, 0.088 mmol) in CH2Cl2 (0.6 mL) over 30 min. The resultant suspension was stirred at room temperature for 3 h and then filtered through Celite®. Excess I2 was scavenged by the addition of sat. aq. Na2S2O3 (0.5 mL). The layers were separated and the aqueous layer further extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography afforded the title compound (±)-187 (29 mg, 0.052 mmol, 90%) as a colourless solid; m.p. 170-173 ºC; 1H NMR (400 MHz, CDCl3):  7.49-7.35 (5H, m, Ar-H × 5), 6.43 (1H, s, H-6), 5.26 (2H, ABq, ΔδAB = 0.02, JAB = 12.3 Hz, OCH2), 5.02 (1H, s, H-3), 4.79 (1H, q, J = 6.5 Hz, H-1′), 3.90 (3H, s, OCH3), 1.45 (3H, d, J = 6.5 Hz, H-2′), 0.57 (9H, s, CH3 × 3), −0.06 (3H, s, CH3), −0.41 (3H, s, CH3); 13C NMR (100 MHz, CDCl3):  168.0 (C=O), 162.8 (C), 160.1 (C), 154.5 (C), 135.5 (C), 128.9 (Ar-CH × 2), 128.5 (Ar-CH), 127.1 (Ar-CH × 2), 111.0 (C), 97.3 (Ar-CH), 85.7 (CH), 71.8 (CH2), 69.1 (C), 65.6 (CH), 56.5 (CH3), 25.4 (CH3 × 3), 21.1 (CH3), 17.6 (C), −4.3 (CH3), −5.4 (CH3); IR (film) max 2928, 2855, 1760, 1594, 1358, 1180, 1043, 957, 837, 776 cm-1; HRMS (ESI+) for C24H31IO5Si [M+H]+ requires 555.1058 found 555.1058.

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Table of Contents
Abstract
Acknowledgements
Abbreviations
Chapter One: Introduction
1.1 The Virgatolides – Isolation, Structure and Biosynthesis
1.2 Benzannulated 6,6-Spiroketals in Nature
1.3 The Chemistry of Spiroketals
1.4 Synthesis of Spiroketals
1.5 Previous Syntheses of Structural Motifs Related to the Virgatolides
1.6 Aims of the Present Research
1.7 Aldol Reactions of Methyl Ketones
1.8 The Chemistry of α-Chiral β-Arylated Carbonyl Compounds
1.9 Retrosynthesis of Methyl Ketone 112
Chapter Two: Discussion
2.1 Synthesis of Phthalides (±)-177 and (±)-178 via a Stille  Cross-Coupling Approach
2.2 Synthesis of Spiroketal Precursor 247 via Suzuki Cross-Coupling
2.3 Attempted Synthesis of Virgatolide B (2) via a pH-neutral Deprotection Approach
2.4 Development of a Carbonylation Model system
2.5 Total Synthesis of Virgatolide B (2)
2.6 Towards the Total Synthesis of Virgatolide A (1)
Chapter Three: Experimental
3.1 General Details
3.2 Synthesis of Phthalides (±)-177, (±)-179 and Alkenes 167, 194 and 195
3.3 Synthesis of Trifluoroboratoamide 158
3.4 Synthesis of Halides 208 and 209
3.5 Synthesis of Aldol 247
3.6 Synthesis of Amide 273
3.7 Carbonylation Model Study
3.8 Synthesis of Virgatolide B (2)
3.9 Synthesis of Spiro γ-Lactones (±)-317 and (±)-340
3.10 Synthesis of Aldol 352
NMR Spectra of Novel Compounds
References

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Total Synthesis of Virgatolide B

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