Supporting Information
Sylvain A. Jacques, Bhavesh H. Patel, Anthony G. M. Barrett*
aDepartment of Chemistry, Imperial College, London SW7 2AZ, United Kingdom
Contents
General Methods 2
1. Synthesis of 2-(N-Methyl 2-(trimethylsilyl)ethylsulfona-mido) acetic acid (17) 3
2. Synthesis of dioxinone keto-esters 10a and 10b 4
2.1 tert-Butyl 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (10a)1 4
2.2 Methyl 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (10b) 5
3. Synthesis of Dihydroxy-Isoindolinone-Carboxylates 8a and 8b 6
3.1 tert-Butyl 7-Hydroxy-2,2-dimethyl-5-((N-methyl-2-(trimethylsilyl)ethyl sulfonamido)methyl)-4-oxo-4H-benzo[d][1,3]dioxine-6-carboxylate (8a) 6
3.2 Methyl 7-Hydroxy-2,2-dimethyl-5-((N-methyl-2-(trimethylsilyl)ethyl sulfonamido)methyl)-4-oxo-4H-benzo[d][1,3]dioxine-6-carboxylate (8b) 7
3.3 1-tert-Butyl 3-Methyl 4,6-dihydroxy-2-((N-methyl-2-(trimethylsilyl)- ethylsulfonamido)methyl)isophthalate (18a) 8
3.4 Dimethyl 4,6-Dihydroxy-2-((N-methyl-2-(trimethylsilyl)ethylsulfonami- do)methyl)isophthalate (18b) 8
3.5 tert-Butyl 5,7-Dihydroxy-2-methyl-1-oxoisoindoline-4-carboxylate (7a) 9
3.6 Methyl 5,7-Dihydroxy-2-methyl-1-oxoisoindoline-4-carboxylate (7b) 9
Proton and Carbon NMR Spectra 10
General Methods
All reactions were carried out in flame-dried or oven-dried glassware in an atmosphere of dry N2 or Ar unless otherwise stated. Prolonged periods of vessel cooling were attained by the use of a CryoCool apparatus. All solvents and reagents were obtained from commercial suppliers and used without further purification unless otherwise stated. The following reaction solvents were distilled under nitrogen: THF from Na/benzophenone ketyl, CH2Cl2 and MeOH from CaH2. H2O refers to distilled H2O. Flash column chromatography was performed using silica gel unless otherwise stated. Thin layer chromatography (TLC) was performed on pre-coated aluminum backed plates, visualization was accomplished under UV light (254 nm) or by staining with acidic vanillin.
Melting points were obtained using a melting point apparatus and are uncorrected. IR spectra are given with adsorptions (lmax) reported in wave numbers (cm-1). Proton magnetic resonance spectra (1H NMR) were recorded at 400 or 500 MHz with chemical shifts (d) quoted in parts per million (ppm). Coupling constants (J) recorded in Hertz (Hz). Carbon magnetic resonance spectra (13C NMR) were recorded at 100 or 125 MHz with chemical shifts (d) quoted in ppm.
1.
2.
1. Synthesis of 2-(N-Methyl -2-(trimethylsilyl)ethylsulfona-mido) acetic acid (17)
Sarcosine 16 (1.59 g, 17.8 mmol, 1.0 equiv) was suspended in CH2Cl2 (35 mL) and TMSCl (2.26 mL, 17.8 mmol, 1.0 equiv) was added. The resulting mixture was heated at reflux for 3 h and was allowed to cool to room temperature. Et3N (4.97 mL, 35.6 mmol, 2.0 equiv) and Me3SiCH2CH2SO2Cl (3.58 g, 17.8 mmol, 1.0 equiv) in CH2Cl2 (10 mL) were added and the reaction mixture was stirred for 12 h at room temperature. MeOH (50 mL) was added and the reaction mixture was concentrated under reduced pressure. H2O (50 mL) was added and the pH was adjusted to 8 using saturated aqueous Na2CO3. The aqueous layer was extracted with Et2O (2 x 25 mL) and the combined organic layers were discarded. The aqueous layer was acidified to pH 1 using 1 M HCl and was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give SES-protected sarcosine 17 (3.20 g, 71%) as an off-white solid which was used without any further purification: Rf 0.62 (EtOAc); mp (Et2O) 68 °C; IR (film) 1731, 1403, 1325, 1246, 1168, 1132, 1029, 830 cm-1; 1H NMR (400 MHz, CDCl3) d 10.78 (br s, 1H), 4.14 (s, 2H), 3.04 – 2.99 (m, 2H), 3.02 (s, 3H), 1.09 – 1.04 (m, 2H), 0.05 (s, 9H); 13C NMR (100 MHz, CDCl3) d 173.5, 50.6, 48.7, 35.9, 10.1, -2.0 (3C); MS (ES) m/z 252 [M – H]-; HRMS (ES) calculated for C9H18NO4SSi [M – H]- 252.0730. Found: 252.0726. Anal. Calcd. for C8H19NO4SSi: C, 37.92; H, 7.56; N, 5.53; S,12.65. Found: C, 38.04; H, 7.63; N, 5.45; S,12.60.
2. Synthesis of dioxinone keto-esters 10a and 10b
3.
2.1 tert-Butyl 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (10a)1
Oxalyl chloride (4.0 mL, 46.7 mmol, 1.33 equiv) and DMF (5 drops) were added sequentially with stirring to carboxylic acid 13 (5.6 g, 35.1 mmol, 1.0 equiv) in CH2Cl2 (16 mL) at 0 °C. After 15 min, the mixture was allowed to warm up to room temperature and further stirred for 2 h. Rotary evaporation gave the corresponding acid chloride 14a as a yellow oil. n-BuLi (2.5 M in hexanes, 50.5 mL, 126.4 mmol, 3.6 equiv) was added with stirring to (Me3Si)2NH (26.3 mL, 105.3 mmol, 3.6 equiv) in THF (206 mL) at -78 °C. After 30 min, dioxinone 15 (14.9 g, 105.3 mmol, 3.0 equiv) in THF (45 mL) was added dropwise and the resulting mixture was further stirred for 1 h at - 78 °C. Acid chloride 14a (6.2 g, 35.1 mmol, 1.0 equiv) in THF (20 mL) was added dropwise and the reaction mixture was further stirred for 3 h at - 78 °C. The reaction was quenched at - 78 °C by addition of saturated aqueous NH4Cl (150 mL) and was allowed to warm up to room temperature. The aqueous layer was acidified to pH 3 with 1 M HCl and was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), rotary evaporated and chromatographed (hexanes : EtOAc, 100 : 1, 10 : 1, 5 : 1, 4 : 1, 3 : 2) to give dioxinone keto-ester 10a (7.6 g, 76%) as an off-white amorphous solid: Rf 0.48 (hexanes : EtOAc 1 : 1); mp 44 ºC; IR (film) 1732, 1715, 1635, 1392, 1370, 1315, 1267, 1252, 1206, 1165, 1130, 1055 cm-1; 1H NMR (400 MHz, CDCl3) d 5.36 (s, 1H), 3.48 (s, 2H), 3.42 (s, 2H), 1.72 (s, 6H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) d 196.0, 165.5, 163.7, 160.5, 107.3, 97.0, 82.7, 50.4, 46.9, 27.9 (3C), 24.9 (2C); MS (CI) m/z 285 [M + H]+; HRMS (CI) calculated for C14H21O6 [M + H]+ 285.1345. Found: 285.1338. Anal. Calcd. for C14H20O6: C, 59.14; H, 7.09. Found: C, 59.18; H, 7.10.
2.2 Methyl 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (10b)
n-BuLi (2.5 M in hexanes, 6.75 mL, 16.8 mmol, 3.6 equiv) was added with stirring to (Me3Si)2NH (3.52 mL, 16.8 mmol, 3.6 equiv) in THF (28 mL) at - 78 °C. After 30 min, dioxinone 15 (2.0 g, 14.0 mmol, 3.0 equiv) in THF (5 mL) was added dropwise with stirring. After 1 h at - 78 °C, acid chloride 14b (0.5 mL, 4.68 mmol, 1.0 equiv) in THF (2 mL) was added dropwise and, after a further 3 h at - 78°C, reaction was quenched at - 78 °C by addition of saturated aqueous NH4Cl (20 mL) and the resulting mixture was allowed to warm up to room temperature. The aqueous layer was acidified to pH 3 with 1 M HCl and was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), rotary evaporated and chromatographed (hexanes : EtOAc, 100 : 1, 10 : 1, 5 : 1, 4 : 1, 3 : 2) to give dioxinone keto-ester 10b (395 mg, 35%) as a yellow oil: Rf 0.36 (hexanes : EtOAc 1 : 1); IR (film) 1724, 1637, 1438, 1391, 1332, 1273, 1204 cm-1; 1H NMR (400 MHz, CDCl3) d 5.37 (s, 1H), 3.76 (s, 3H), 3.53 (s, 2H), 3.49 (s, 2H), 1.71 (s, 6H); 13C NMR (100 MHz, CDCl3) d 195.5, 166.7, 163.4, 160.4, 107.4, 97.1, 52.6, 48.8, 46.9, 24.9 (2C); MS (ES) m/z 243 [M + H]+; HRMS (ES) calculated for C11H15O6 [M + H]+ 243.0868. Found: 243.0869. Anal. Calcd. for C11H14O6: C, 54.54; H, 5.83. Found: C, 54.65; H, 5.75.
3. Synthesis of Dihydroxy-Isoindolinone-Carboxylates 8a and 8b
4.
3.1 tert-Butyl 7-Hydroxy-2,2-dimethyl-5-((N-methyl-2-(trimethylsilyl)ethylsulfonamido)methyl)-4-oxo-4H-benzo[d][1,3]dioxine-6-carboxylate (8a)
Oxalyl chloride (0.2 mL, 2.36 mmol, 1.2 equiv.) and DMF (2 drops) were added sequentially with stirring to SES-protected sarcosine 17 (500 mg, 1.97 mmol, 1.0 equiv.) in CH2Cl2 (2 mL) at 0 °C. After 15 min, the mixture was allowed to warm to room temperature and, after 2 h, concentration under reduced pressure gave acid chloride 11a (505 mg, 95%) as a slightly yellow oil, which was used without any further purification: 1H NMR (400 MHz, acetone-d6) d 4.67 (s, 2H), 3.12 – 3.07 (m, 2H), 3.04 (s, 3H), 1.03 – 0.99 (m, 2H), 0.07 (s, 9H). MgCl2 (273 mg, 2.87 mmol, 2.0 equiv) and pyridine (0.3 mL, 3.87 mmol, 2.7 equiv) in CH2Cl2 (20 mL) were stirred for 5 min at 0 °C, when dioxinone keto-ester 10a (408 mg, 1.43 mmol, 1.0 equiv) was added. After 30 min at 0 °C, acyl chloride 11a (505 mg, 1.86 mmol, 1.3 equiv) in CH2Cl2 (3 mL) was added dropwise and the resulting mixture was further stirred for 2.5 h at 0 °C. The reaction was quenched with saturated aqueous NH4Cl (10 mL) at 0 °C and the mixture was allowed to warm up to room temperature. The aqueous layer was acidified to pH 3 using 1 M HCl and was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried (MgSO4) and rotary evaporated to give dioxinone diketo-ester 9a, which was used without any further purification: Rf 0.37 (hexanes : EtOAc 1 : 1); 1H NMR (400 MHz, CDCl3) d 5.36 (s, 1H), 4.57 (s, 2H), 3.75 (s, 2H), 3.02 – 2.98 (m, 2H), 2.99 (s, 3H), 1.70 (s, 6H), 1.55 (s, 9H), 1.09 – 1.04 (m, 2H), 0.05 (s, 9H). Et3N (4.0 mL, 28.7 mmol, 20.0 equiv) was added with stirring to crude dioxinone diketo-ester 9a (745 mg, 1.43 mmol, 1.0 equiv) in CH2Cl2 (17 mL). After 12 h at 30 °C, the mixture was allowed to cool down to room temperature, when saturated aqueous NH4Cl (20 mL) was added and the aqueous layer was acidified with 1 M HCl and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (MgSO4), rotary evaporated and chromatographed (hexanes : EtOAc 10 : 1, 7 : 1, 5 : 1, 3 : 1) to give the resorcylate 8a (345 mg, 49% over 3 steps) as a colorless oil: Rf 0.52 (hexanes : EtOAc 1 : 1); IR (film) 1727, 1666, 1605, 1461, 1328, 1251, 1168 cm-1; 1H NMR (400 MHz, CDCl3) d 10.96 (s, 1H), 6.54 (s, 1H), 5.26 (s, 2H), 3.01 – 2.95 (m, 2H), 2.65 (s, 3H), 1.72 (s, 6H), 1.68 (s, 9H), 1.06 – 1.02 (m, 2H), 0.06 (s, 9H); 13C NMR (100 MHz, CDCl3) d 168.7, 165.7, 159.9, 159.7, 143.7, 114.4, 107.1, 105.3 (2C), 86.6, 46.5, 44.0, 34.5, 28.1 (3C), 25.6 (2C), 9.4, -1.9 (3C); MS (ES) m/z 502 [M + H]+; HRMS (ES) calculated for C22H36NO8SSi [M + H]+ 502.1938. Found: 502.1931.
3.2 Methyl 7-Hydroxy-2,2-dimethyl-5-((N-methyl-2-(trimethylsilyl)ethylsulfonamido)methyl)-4-oxo-4H-benzo[d][1,3]dioxine-6-carboxylate (8b)
Oxalyl chloride (0.37 mL, 4.30 mmol, 1.3 equiv.) and DMF (3 drops) were added sequentially with stirring to SES-protected sarcosine 17 (827 mg, 3.26 mmol, 1.0 equiv.) in CH2Cl2 (3.5 mL) at 0 °C. After 15 min at 0 °C, the mixture was allowed to warm to room temperature and, after a further 2 h, evaporation under reduced pressure gave acyl chloride 11a, which was used without any further purification. MgCl2 (311 mg, 3.26 mmol, 2.0 equiv) and pyridine (0.35 mL, 4.40 mmol, 2.7 equiv) were stirred together in CH2Cl2 (25 mL) at 0 °C. After 5 min, dioxinone 10b (395 mg, 1.63 mmol, 1.0 equiv) was added and the resulting mixture was stirred for 30 min at 0 °C. Acid chloride 11a (880 mg, 3.26 mmol, 2.0 equiv) in CH2Cl2 (3 mL) was added dropwise and the resulting mixture was further stirred for 2.5 h at 0 °C. The reaction was quenched with saturated aqueous NH4Cl (15 mL) at 0 °C and the mixture was allowed to warm up to room temperature. The aqueous layer was acidified to pH 3 using 1 M HCl and was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (MgSO4) and rotary evaporated to give diketo-ester dioxinone 9b, which was used without any further purification: Rf 0.35 (hexanes : EtOAc 1 : 1). Et3N (4.5 mL, 28.7 mmol, 20.0 equiv) was added with stirring to crude diketo-ester dioxinone 9b (778 mg, 1.63 mmol, 1.0 equiv) in CH2Cl2 (20 mL). After 12 h at 30 °C, the mixture was allowed to cool down to room temperature, when saturated aqueous NH4Cl (20 mL) was added and the aqueous layer was acidified with 1 M HCl and was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (MgSO4), rotary evaporated and chromatographed (hexanes : EtOAc 10 : 1, 5 : 1, 3 : 1) to give resorcylate 8b (223 mg, 30% over 3 steps) as an orange oil: Rf 0.32 (hexanes : EtOAc 1 : 1); IR (film) 1762, 1673, 1604, 1462, 1433, 1328, 1252, 1231, 1150 cm-1; 1H NMR (400 MHz, CDCl3) d 11.10 (s, 1H), 6.57 (s, 1H), 5.37 (s, 2H), 4.03 (s, 3H), 2.97 – 2.92 (m, 2H), 2.62 (s, 3H), 1.73 (s, 6H), 1.09 – 1.04 (m, 2H), 0.07 (s, 9H); 13C NMR (100 MHz, CDCl3) d 170.3, 166.4, 160.3, 159.9, 145.0, 111.9, 107.5, 105.5, 105.4, 53.5, 46.7, 44.2, 34.2, 25.7 (2C), 9.5, -1.9 (3C); MS (ES) m/z 460 [M + H]+; HRMS (ES) calculated for C19H30NO8SSi [M + H]+ 460.1447. Found: 460.1461.