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was added LiOH·H2O (100 mg, 2.73 mmol, 5.8 equiv). After 4 h at
room temperature the reaction mixture was acidified with 15.0 mL
1N HCl and extracted with CH2Cl2 (3ꢂ20.0 mL). The combined or-
ganic layer was dried (Na2SO4) and evaporated under reduced pres-
sure to yield 187 mg of carboxylic acid that was used without fur-
ther purification. To a solution of the carboxylic acid (187 mg,
0.47 mmol, 1.0 equiv) in 10 mL dry CH2Cl2 was added HATU (1-[bis-
(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-
oxide hexafluorophosphate) (215 mg, 0.57 mmol, 1.2 equiv), dime-
thylamine (0.7 mL, 2.0m in THF, 1.41 mmol, 3.0 equiv) and triethyl-
amine (0.23 mL, 167 mg, 1.65 mmol, 3.5 equiv). After 12 h at room
temperature the reaction mixture was diluted with 30 mL CH2Cl2
and washed with brine (3ꢂ25 mL). The organic layer was dried
(Na2SO4) and the solvent was removed under reduced pressure.
Silica gel chromatography (25–40% EtOAc in hexanes) gave 37
1-enecarboxamide 39: A solution of 38 (100 mg, 0.17 mmol,
1.0 equiv), selenium dioxide (23 mg, 0.21 mmol, 1.2 equiv) and
acetic acid (21 mg, 0.35 mmol, 2.0 equiv) in 10.0 mL dry dioxane
was heated to reflux for 30 min. After cooling to room temperature
the solvent was removed under reduced pressure. The residue was
dissolved in 20.0 mL CH2Cl2 and the insoluble salts were removed
by filtration. The CH2Cl2 solution was washed with brine (2ꢂ
20.0 mL), dried (Na2SO4) and the solvent was removed under re-
duced pressure. Silica gel chromatography (40–50% EtOAc in hex-
anes) gave 39 (73 mg, 78%) as a white solid. ½aꢂ2D0 =ꢀ1928 (c=
0.98, CHCl3, 98.5:1.5 e.r.); m.p.: 1208C (decomp); 1H NMR (CDCl3,
500 MHz): d=7.21–7.09 (m, 5H), 6.97 (d, J=9.0 Hz, 2H), 6.55 (d, J=
9.0 Hz, 2H), 6.31 (dd, J=13.5, 2.4 Hz, 1H), 6.13 (dd, J=2.6, 1.3 Hz,
1H), 5.24 (s, 1H), 4.23 (s, 1H), 3.95 (s, 3H), 3.77 (s, 3H), 3.69 (s, 3H),
3.21 (s, 3H), 3.14 (s, 3H), 2.87 ppm (s, 3H); 13C NMR (CDCl3,
126 MHz): d=167.7, 162.2, 160.6, 160.4, 160.3, 159.7, 159.6, 158.2,
156.7, 138.5, 130.9, 130.6, 129.5, 129.4, 127.3, 126.8, 111.7, 109.8,
107.0, 96.2, 94.6, 94.3, 88.9, 88.9, 84.6, 64.0, 58.4, 55.9, 55.5, 55.0,
37.8, 34.6 ppm; IR n˜max (film): 3424, 1721, 1638, 1512, 1496, 1336,
1
(145 mg, 73% over 2 steps, 89:11 e.r.) as a pale-yellow oil. H NMR
(CDCl3, 500 MHz): d=7.01–6.95 (m, 3H), 6.89 (d, J=8.8 Hz, 2H),
6.81–6.76 (m, 2H), 6.57 (d, J=8.8 Hz, 2H), 5.84 (ddt, J=17.1, 10.4,
5.2 Hz, 1H), 5.26 (dq, J=17.2, 1.8 Hz, 1H), 5.11 (dd, J=10.5, 1.6 Hz,
1H), 4.48 (s, 1H), 4.04 (s, 3H), 4.03–3.98 (m, 1H), 3.87–3.79 (m, 1H),
3.67 (s, 3H), 3.06 (s, 3H), 2.86 (s, 3H), 2.80 ppm (s, 3H); 13C NMR
(CDCl3, 126 MHz): 200.4, 165.3, 158.8, 149.8, 138.2, 136.5, 134.7,
129.4, 129.3, 127.8, 127.6, 127.0, 116.0, 113.0, 85.4, 66.0, 58.4, 58.3,
55.1, 38.6, 37.6, 34.4 ppm; IR n˜max (film): 1713, 1680, 1639, 1513,
1336, 1122, 730 cmꢀ1; ESI-MS: m/z calculated for C25H27NNaO5
[M+Na+]: 444.1787, found 444.1781.
1216, 1097 cmꢀ1
; ESI-MS: m/z calculated for C30H32FNNaO7
[M+Na+]: 560.2061, found 560.2070.
(3R,3aR,8bS)-8b-Hydroxy-1,6,8-trimethoxy-3a-(4-methoxyphen-
yl)-N,N-dimethyl-3-phenyl-3a,8b-dihydro-3H-cyclopenta[b]benzo-
furan-2-carboxamide 40: To a solution of 39 (50 mg, 0.093 mmol,
1.0 equiv) in 5.0 mL dry THF was added potassium tert-butoxide
(52 mg, 0.47 mmol, 5.0 equiv). After 15 min at room temperature
the reaction was quenched by addition of saturated aq. NH4Cl and
extracted with EtOAc (3ꢂ10.0 mL). The combined organic layer
was dried (Na2SO4) and the solvent was removed under reduced
pressure to yield 40 (43 mg, 89%) as a white solid. ½aꢂ2D0 =ꢀ2068
(3S,4R,5R)-4-(Allyloxy)-3-(2-fluoro-4,6-dimethoxyphenyl)-3-hy-
droxy-2-methoxy-4-(4-methoxyphenyl)-N,N-dimethyl-5-phenylcy-
clopent-1-enecarboxamide 38: To a solution of 1-fluoro-3,5-dime-
thoxybenzene (207 mg, 0.17 mL, 1.33 mmol, 4.0 equiv) in 3 mL THF
was slowly added nBuLi in hexanes (0.48 mL, 2.4m, 1.16 mmol,
3.5 equiv) at ꢀ788C. After 1 h at ꢀ788C, a solution of LaCl3·2 LiCl
(1.94 mL, 0.6m, 1.16 mmol, 3.5 equiv) was added dropwise. The
temperature was maintained at ꢀ788C for 1 h and a solution of 37
(140 mg, 0.33 mmol, 1 equiv) in 2.0 mL THF was added. The reac-
tion mixture was allowed to warm to ꢀ308C over 45 min before
being quenched by the addition of saturated aq. NH4Cl. The pH
was adjusted to 4–5 with 1N HCl. The mixture was extracted with
EtOAc (3ꢂ20.0 mL). The combined organic layer was washed with
brine, dried (Na2SO4) and the solvent was removed under reduced
pressure. Silica gel chromatography (30–40% EtOAc in hexanes)
yielded 38 (167 mg, 87%, 89:11 e.r.) as white solid. Recrystalliza-
tion: 167 mg of 38 (89:11 e.r.) was dissolved in 1.5 mL CH2Cl2 at
room temperature 4.5 mL hexanes was slowly added and the re-
sulting solution was left undisturbed at room temperature for 12 h.
125 mg 38 (98.5:1.5 e.r.) was recovered (75% recovery). M.p.:
183.6–185.08C (98.5/1.5 e.r.). Chiral HPLC analysis of 38 on a Chira-
cel OD-H column: 20% iPrOH/hexanes, 1 mLminꢀ1, 254 nm. t=
8.15 min (+)-38, t=9.5 min (ꢀ)-38, 98.5:1.5 e.r.; ½aꢂ2D0 =ꢀ1398 (c=
0.75, CHCl3, 98.5:1.5 e.r.); 1H NMR (CDCl3, 500 MHz): d=7.50–7.44
(m, 2H), 7.32–7.26 (m, 3H), 6.52–6.46 (m, 2H), 6.41 (d, J=8.4 Hz,
2H), 6.27 (dd, J=13.0, 2.5 Hz, 1H), 6.01 (dd, J=2.5, 1.3 Hz, 1H),
5.85 (ddt, J=17.2, 10.8, 4.0 Hz, 1H), 5.19 (s, 1H), 5.13–5.03 (m, 2H),
4.54 (s, 1H), 4.37–4.30 (m, 1H), 4.06–4.00 (m, 1H), 3.90 (s, 3H), 3.78
(s, 3H), 3.68 (s, 3H), 3.27 (s, 3H), 2.99 (s, 3H), 2.91 ppm (s, 3H);
13C NMR (CDCl3, 126 MHz): d=168.0, 163.0, 161.0, 160.1, 160.0,
159.7, 159.6, 158.3, 157.5, 149.4, 139.5, 134.5, 131.3, 131.2, 128.4,
127.6, 127.1, 114.5, 111.7, 108.5, 106.5, 106.4, 94.5, 94.1, 93.9, 89.8,
89.3, 65.1, 58.4, 56.9, 55.4, 55.2, 55.0, 37.8, 34.4 ppm; IR n˜max (film):
3446, 1680, 1624, 1585, 1295, 1217, 1101, 1068 cmꢀ1; ESI-MS: m/z
calculated for C33H36FNNaO7 [M+Na+]: 600.2374, found 600.2361.
1
(c=0.93, CHCl3, 98.5:1.5 e.r.); m.p.: 181.9–183.08C; H NMR (CDCl3,
500 MHz): d=7.16 (d, J=8.9 Hz, 2H), 7.08–7.01 (m, 3H), 7.00–6.96
(m, 2H), 6.58 (d, J=8.9 Hz, 2H), 6.23 (d, J=2.0 Hz, 1H), 6.07 (d, J=
2.0 Hz, 1H), 4.36 (s, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.67
(s, 3H), 3.08 (s, 3H), 2.84 ppm (s, 3H); 13C NMR (CDCl3, 126 MHz):
d=167.0, 163.3, 160.6, 158.5, 157.7, 156.2, 137.4, 129.3, 128.6,
127.6, 127.0, 126.7, 112.3, 107.4, 101.2, 92.5, 89.0, 89.0, 60.2, 59.4,
55.6, 55.5, 55.0, 37.8, 34.5, 29.8 ppm; IR n˜max (film): 3455, 2940,
2840, 1733, 1620, 1498, 1398, 1299, 838, 818 cmꢀ1; ESI-MS: m/z cal-
culated for C30H31NNaO7 [M+Na+]: 540.1998, found 540.1969.
(2R,3S,3aR,8bR)-8b-Hydroxy-6,8-dimethoxy-3a-(4-methoxyphen-
yl)-N,N-dimethyl-1-oxo-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclo-
penta[b]benzofuran-2-carboxamide 41:
A solution of MgI2
(67 mg, 0.24 mmol, 5.0 equiv) in 2.0 mL toluene and 2.0 mL diethyl
ether was heated to 908C with vigorous stirring. After 15 min a so-
lution of 40 (25 mg, 0.048 mmol, 1.0 equiv) in 1.0 mL toluene and
1.0 mL diethyl ether was added to the MgI2 solution at 908C. The
reaction mixture was vigorously stirred for 15 min before being
quenched by the addition of 15 mL saturated aq. Na2S2O3. The or-
ganic layer was separated, diluted with 25 mL diethyl ether and
washed with 15 mL saturated aq. NaCl. Aftering drying (Na2SO4)
the organic layer was concentrated under reduced pressure and
the residue was purified on silica gel (30–40% EtOAc in hexanes)
to give 41 (22 mg, 92%) as a white solid. ½aꢂ2D0 = +628 (c=1.10,
1
CHCl3, 98.5/1.5 e.r.); m.p.: 144.2–146.08C; H NMR (CDCl3, 500 MHz):
d=7.11–7.05 (m, 3H), 6.99 (d, J=8.8 Hz, 2H), 6.86–6.81 (m, 2H),
6.71 (d, J=8.8 Hz, 2H), 6.33 (d, J=2.0 Hz, 1H), 6.08 (d, J=2.0 Hz,
1H), 4.50 (d, J=13.1 Hz, 1H), 4.33 (d, J=13.1 Hz, 1H), 3.84 (s, 3H),
3.80 (s, 3H), 3.73 (s, 3H), 3.25 (s, 3H), 2.90 ppm (s, 3H); 13C NMR
(CDCl3, 126 MHz): d=205.7, 165.3, 164.8, 161.0, 158.8, 158.5, 136.1,
127.99, 127.96, 127.9, 126.9, 126.0, 113.2, 110.6, 106.0, 99.2, 93.0,
89.8, 88.5, 55.7, 55.1, 53.8, 52.0, 37.7, 36.2 ppm; IR n˜max (film): 3417,
1747, 1651, 1616, 1600, 1516, 1500, 1149, 894 cmꢀ1; ESI-MS: m/z
(3R,4R,5R)-3-(2-Fluoro-4,6-dimethoxyphenyl)-3,4-dihydroxy-2-
methoxy-4-(4-methoxyphenyl)-N,N-dimethyl-5-phenylcyclopent-
&
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Chem. Eur. J. 2016, 22, 1 – 9
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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