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72 APPENDIX
SUPPORTING INFORMATION
Synthesis of 198: To a solution of boronic ester 145 in THF:H2O = 10:1, was added NaIO4 (4.54
g, 21.2 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 20 minutes, until homogeneous. HCl (1.0 M in water, 20 mL) was then added, and the mixture was stirred for 2 h. The resulting mixture was extracted with DCM (3 x 50 mL), dried over anhydrous MgSO4, and
concentrated in vacuo to yield boronic acid 198 (3.10 g, 13.8 mmol, 98% yield) as a colorless solid. Product was used without further purification.
Rf = 0.15 (SiO2, hexanes:EtOAc = 1:1, UV). m.p. = 155.5–157.5 °C.
1H NMR (500 MHz, Methanol-d
4) δ 7.40 (s, 1H), 6.81 (s, 1H), 6.05 (s, 2H), 3.89 (s, 3H).
13C NMR (126 MHz, Methanol-d
4) δ 169.4, 153.4, 149.5, 127.2, 110.8, 109.6, 103.4, 52.9.
HRMS (ESI-TOF, m/z) calcd. For C27H22B3O15 [Anhydride+H]+ calc.: 618.1274 ; found:
618.1334.
IR (ATR, neat, cm-1): 3378 (br w), 2957 (w), 1702 (m), 1609 (w), 1505 (w), 1425 (m), 1372 (s),
73
Synthesis of 199: To a stirred solution of MTAD (523 mg, 4.46 mmol, 2 equiv.) in DCM (50 mL) was added benzyl bromide (3.51 g, 22.3 mmol, 10 equiv.). The mixture was cooled to –78 °C under an atmosphere of nitrogen, and was then irradiated with visible light LEDs. Once the pink color of the reaction had dissipated (2 days) the lights were turned off, and a solution of NMO (505 mg, 4.46 mmol, 2 equiv.) and OsO4 (0.2 M in DCM, 1.12 mL, 10 mol%) in acetone (10 mL)
was added. A solution of 198 (500 mg, 2.23 mmol, 1.0 equiv.) in acetone (10 mL) was then added. The mixture was stirred overnight while slowly warming to –20 °C. The mixture was then warmed to room temperature and quenched with Na2S2O3 (10% in water, 40 mL). Reaction was extracted
with DCM (3 x 40 mL), dried over MgSO4, and concentrated in vacuo. Purification of the resulting residue by flash column chromatography (silica gel, EtOAc:hexanes 1:1) gave boronic ester 199 as a colorless solid (708 mg, 1.44 mmol, 64% yield).
Rf = 0.14 (SiO2, hexanes:EtOAc = 1:1, UV). m.p. = 257–259 °C. 1H NMR (500 MHz, CDCl 3) δ 7.32 (s, 1H), 6.79 (s, 1H), 6.68 (ddd, J = 6.1, 2.3, 0.7 Hz, 1H), 6.05 (d, J = 1.3 Hz, 1H), 6.04 (d, J = 1.3 Hz, 1H), 5.25 (dd, J = 4.2, 2.3 Hz, 1H), 5.15 (dd, J = 6.1, 3.9 Hz, 1H), 5.10 (dd, J = 7.0, 4.2 Hz, 1H), 5.00 (ddd, J = 7.0, 3.9, 0.7 Hz), 3.93 (s, 3H), 3.07 (s, 3H). 13C NMR (126 MHz, CDCl 3) 169.3, 157.2, 156.8, 152.0, 148.9, 127.7, 127.2, 118.7, 110.7, 108.3, 102.0, 75.3, 74.5, 60.1, 54.4, 53.2, 26.0.
HRMS (ESI-TOF, m/z) calcd. For C18H16BBrN3O8 [M+H]+ calc.: 492.0212 ; found: 492.0265.
IR (ATR, neat, cm-1): 2955 (w), 1777 (w), 1709 (s), 1604 (w), 1447 (m), 1394 (m), 1379 (m), 1309 (m), 1277 (m), 1200 (m).
74
Synthesis of 195: To a dry pressure tube charged with boronic ester 199 (492 mg, 1.0 mmol) and Pd(dppf)Cl2 (37 mg, 0.05 mmol, 5 mol%) was added a mixture of THF and water (9:1, 10 mL).
To this was then added Et3N (0.726 mL, 670 mmol, 5 equiv) was added. The tube was sealed and
heated to 70 °C for 4 h. The reaction was cooled and quenched with HCl (1.0 M in water, 10 mL), then extracted with DCM (3 x 5 mL). The combined DCM layers were dried over MgSO4. To
this solution was then added 2,2-dimethoxypropane (2 mL) and catalytic PPTS then the mixture stirred for 12 h. The reaction was quenched with sat. aq. NaHCO3 (10 mL) and extracted with
DCM (3 x 5 mL). The combined organic layers were then dried over MgSO4 and concentrated in
vacuo. Purification of the resulting residue by flash column chromatography (silica gel, EtOAc:hexanes 1:2) gave acetonide 195 as a white solid (245 mg, 0.555 mmol, 55% yield). Rf = 0.22 (SiO2, hexanes:EtOAc = 2:1, UV).
m.p. = 134.1–136.1 °C. 1H NMR (500 MHz, CDCl 3) δ 7.20 (s, 1H), 6.91 (s, 1H), 6.03 (d, J = 1.4 Hz, 1H), 6.02 (d, J = 1.4 Hz, 1H), 6.00 (ddd, J = 5.8, 2.0, 0.9 Hz, 1H), 5.09 (dd, J = 4.0, 2.0 Hz, 1H), 5.06 (dd, J = 5.8, 3.8 Hz, 1H), 4.71 (dd, J = 6.8, 4.0 Hz, 1H), 4.64 (ddd, J = 6.8, 3.8, 0.9 Hz, 1H), 3.71 (s, 3H), 3.08 (s, 3H), 1.39 (s, 3H), 1.35 (s, 3H). 13C NMR (126 MHz, CDCl 3) δ 166.8, 158.0, 157.9, 150.4, 147.2, 138.9, 134.3, 124.2, 123.7, 112.4, 110.0, 109.0, 102.2, 74.3, 74.1, 56.9, 52.1, 51.8, 25.8, 25.7, 25.5.
HRMS (ESI-TOF, m/z) calcd. For C21H20N3O8 [M+H]+ calc.: 444.1401 ; found: 444.1409.
IR (ATR, neat, cm-1): 2953 (w), 1777 (w), 1714 (s), 1487 (m), 1459 (m), 1382 (m), 1249 (m), 1209 (m), 1126 (m), 1071 (m).
75
Synthesis of 196: To a stirred solution of acetonide 195 (690 mg, 1.56 mmol) in i-PrOH (20 mL) was added KOH (843 mg, 15.6 mmol, 10 equiv.). The mixture was refluxed for 12 hr under N2.
The reaction mixture was then neutralized with glacial acetic acid and concentrated in vacuo. The residue was dissolved in H2O (30 mL). To this solution was added CuCl2·2H2O (530 mg, 3.1
mmol, 2.0 equiv.), and the solution was then treated with NH4OH (5.0 M in water) and extracted
with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo, giving diene 196 as a beige solid (440 mg, 1.39 mmol,
89% yield). Product was used without further purification. Rf = 0.45 (SiO2, hexanes:EtOAc = 1:1 + 2% AcOH, UV). m.p. = 154.5–156.5 °C. 1H NMR (500 MHz, CDCl 3) δ 7.46 (s, 1H), 6.74 (s, 1H), 6.06 (s, 2H), 5.95 – 5.87 (m, 2H), 5.77 (dt, J = 3.9, 1.2 Hz, 1H), 4.83 (dd, J = 8.9, 3.9 Hz, 1H), 4.74 (dd, J = 8.9, 3.2 Hz, 1H), 1.47 (s, 3H), 1.44 (s, 3H). 13C NMR (126 MHz, CDCl 3) 169.8, 151.5, 147.3, 139.9, 137.4, 127.8, 123.9, 121.9, 121.2, 110.9, 110.6, 105.5, 102.3, 71.2, 70.2, 27.o, 25.3.
HRMS (ESI-TOF, m/z) calcd. For C17H16NaO6 [M+Na]+ calc.: 339.0839 ; found: 339.0816.
IR (ATR, neat, cm-1): 2912 (w), 1694 (s), 1614 (w), 1504 (m), 1485 (s), 1381 (w), 1250 (s), 1132 (w), 1036 (s), 931 (w).
76
Synthesis of 4-((triisopropylsilyl)oxy)aniline: To a stirred solution of 4-aminophenol (2.0 g, 18 mmol) in DCM (200 mL) was added TIPSCl (5.88 mL, 27.5 mmol, 1.5 equiv.) and imidazole (2.5 g, 37 mmol, 2.0 equiv.). The mixture was stirred for 12 h, then quenched with saturated aqueous NaHCO3 (30 mL). The mixture was extracted with DCM (3 x 30 mL), dried over MgSO4, and
concentrated in vacuo. The residue was purified by vacuum distillation (0.5 torr, 95 °C) to yield 4-((triisopropylsilyl)oxy)aniline as a colorless oil (4.56 g, 17.2 mmol, 94% yield).
Rf = 0.14 (SiO2, hexanes:EtOAc = 9:1, UV). 1H NMR (500 MHz, CDCl
3) δ 6.70 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 1.21 (hept, J =
7.3 Hz, 3H), 1.08 (d, J = 7.3 Hz, 18H). 13C NMR (126 MHz, CDCl
3) δ 148.9, 140.1, 120.6, 116.5, 18.1, 12.8.
HRMS (ESI-TOF, m/z) calcd. For C15H28NOSi [M+H]+ calc.: 266.1935 ; found: 266.1921.
IR (ATR, neat, cm-1): 2944 (m), 2892 (w), 2866 (m), 1508 (s), 1463 (w), 1248 (s), 910 (m), 883 (m), 829 (w), 685 (m).
77
Synthesis of 197: To a stirred solution of 4-((triisopropylsilyl)oxy)aniline (1.0 g, 3.8 mmol) in DCM (200 mL) was added a solution of Oxone® (4.63 g, 7.53 mmol, 2 equiv.). The mixture was
stirred vigorously for 2 h. The organic phase was then separated and the aqueous layers extracted with DCM (2 x 20 mL). The combined organic layers were then dried over MgSO4 and
concentrated in vacuo. Product was used without further purification. Rf = decomp. 1H NMR (500 MHz, CDCl 3) δ 7.86 (d, J = 9.2 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 1.33 (hept, J = 7.4Hz, 3H), 1.12 (d, J = 7.4 Hz, 18H). 13C NMR (126 MHz, CDCl 3) δ 164.1, 163.6, 120.0, 18.0, 12.9.
HRMS (ESI-TOF, m/z) calcd. For C15H26NO2Si [M+H]+ calc.: 280.1727 ; found: 280.1726.
IR (ATR, neat, cm-1): 2946 (m), 2893 (w), 2868 (m), 1644 (w), 1595 (m), 1502 (s), 1278 (s), 1111 (s), 904 (m), 687 (m).
78
Synthesis of 200: To a stirred solution of diene 196 (20 mg, 63 µmol) in THF (2 mL) was added a solution of nitroso 197 (18 mg, 63 µmol) in THF (1 mL). The mixture was stirred for 48 h at room temperature. Powdered zinc (83 mg, 1.26 mmol, 20 equiv.) and acetic acid (36 µmol, 0.63 mmol, 10 equiv.) were added, and the mixture stirred at room temp for 8 h. Reaction was quenched with saturated aqueous NaHCO3 (5 mL), and extracted with EtOAc (5 x 10 mL). The combined
organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo.
Residue was purified by column chromatography (silica gel, hexanes:EtOAc 1:1) to yield lactam 200 as a beige oil (22 mg, 38 µmol, 60% yield).
Rf = 0.39 (SiO2, hexanes:EtOAc = 1:1, UV). 1H NMR (500 MHz, CDCl 3) δ 7.60 (s, 1H), 7.10 (d, J = 8.7 Hz, 2H), 7.01 (s, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.32 (t, J = 3.1 Hz, 1H), 6.01 (s, 2H), 4.67 (dt, J = 6.0, 3.1 Hz, 1H), 4.33 (dd, J = 7.8, 6.0 Hz, 1H), 4.19 (dt, J = 7.7, 3.1 Hz, 1H), 3.90 (d, J = 7.8, 7.7 Hz, 1H), 1.26 (hept, J = 7.4, 3H), 1.18 (s, 3H), 1.10 (d, J = 7.4 Hz, 18H), 1.05 (s, 3H). 13C NMR (126 MHz, CDCl 3) δ 162.4, 155.3, 151.8, 148.6, 133.8, 129.5, 128.5, 128.2, 124.9, 121.4, 120.0, 110.4, 108.1, 102.0, 101.1, 79.1, 78.9, 72.1, 62.7, 27.0, 24.7, 18.1, 18.0, 12.8. HRMS (ESI-TOF, m/z) calcd. For C32H42NO7Si [M+H]+ calc.: 580.2725 ; found: 580.2708.
IR (ATR, neat, cm-1): 3411 (br, w), 2944 (w), 2867 (w), 1647 (w), 1601 (w), 1507 (s), 1479 (m), 1259 (s), 1221 (m), 1062 (m).
79
Synthesis of 191: To a stirred solution of lactam 200 (29 mg, 50 µmol) in THF (0.5 ml) cooled to 0 °C was added a solution of TBAF·3H2O (24 mg, 75 µmol, 1.5 equiv.) in THF (0.3 mL). The
mixture was stirred at 0 °C for 20 minutes, then quenched with saturated aqueous NH4Cl (0.5 mL).
The mixture was extracted with EtOAc (3 x 1 mL), and the combined organic layers washed with brine (1 mL), dried over MgSO4, and concentrated in vacuo. The residue as purified by column
chromatography (silica gel, hexanes:EtOAc 1:2) to yield phenol 201 as a brown solid (19.8 mg, 48 µmol, 93% yield).
Rf = 0.18 (SiO2, hexanes:EtOAc = 1:2, UV) 1H NMR (500 MHz, DMSO-d 6) δ 9.32 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 6.53 (t, J = 3.1 Hz, 1H), 6.12 (dd, J = 4.1, 0.9 Hz, 2H), 5.70 (d, J = 5.7 Hz, 1H), 4.74 – 4.69 (m, 1H), 4.26 (dd, J = 7.4, 7.2 Hz, 1H), 4.11 – 4.06 (m, 1H), 3.83 (dd, J = 7.4, 7.2 Hz, 1H), 1.04 (s, 3H), 1.01 (s, 3H). 13C NMR (126 MHz, DMSO-d 6) δ 161.1, 155.8, 151.3, 147.8, 132.9, 129.8, 128.7, 127.8, 127.2, 120.8, 114.6, 108.7, 106.5, 101.9, 101.7, 79.0, 78.8, 70.5, 61.9, 26.8, 24.8, 17.7.
HRMS (ESI-TOF, m/z) calcd. For C23H22NO7 [M+H]+ calc.: 424.1391 ; found: 424.1366.
IR (ATR, neat, cm-1): 3349 (br, m), 2936 (w), 1638 (m), 1595 (m), 1513 (s), 1571 (s), 1257 (s), 1218 (s), 1061 (m), 1036 (s).