2632
I. S. Kim et al. / Tetrahedron 63 (2007) 2622–2633
(s, 1H); 13C NMR (125 MHz, D2O) d 17.46, 29.13, 44.57,
60.47, 60.66, 63.53; HRMS (FAB) Calcd for C6H14NO2
[M+H+]: 132.1024, found: 132.1021.
CHCl3); IR (CH2Cl2) 2924, 2856, 2357, 1733, 1607, 1510,
1455, 1375, 1245, 1175, 1117, 1033 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 0.85–0.91 (br s, 3H), 1.29–1.42 (m,
1H), 1.64–1.67 (br, 1H), 1.80 (br d, 1H, J¼13.0 Hz), 2.05–
2.19 (br, 2H), 2.20 (br d, 1H, J¼10.5 Hz), 2.54–2.57 (br,
1H), 3.00–3.07 (br m, 2H), 3.33–3.36 (br, 1H), 3.85 (s,
3H), 3.94 (d, 1H, J¼12.0 Hz), 4.17 (d, 1H, J¼12.0 Hz),
6.83–7.33 (m, 9H); 13C NMR (125 MHz, CDCl3) d 10.83,
23.81, 31.30, 48.39, 51.80, 55.51, 71.95, 72.73, 81.34,
113.77, 127.46, 127.93, 128.26, 130.09, 138.79; HRMS
(CI) Calcd for C21H28NO2 [M+H+]: 326.2120, found:
326.2120.
4.1.20. (2R,3S)-3-Benzyloxycarbonyl-2-p-methoxyphe-
nylpiperidine (24). To a stirred solution of 9 (0.45 g,
1.04 mmol) in anhydrous MeOH (5.2 mL) was added 10%
Pd/C (0.16 g, 1.56 mmol). The reaction mixture was stirred
for 1 h under H2 balloon at room temperature and concen-
trated in vacuo. The residue was purified by column chroma-
tography (CHCl3/MeOH 15:1) to afford 0.16 g (53%) of 24
as colorless syrup. Rf¼0.27 (CHCl3/MeOH 15:1); [a]D29
ꢀ0.6 (c 1.0, CHCl3); IR (CH2Cl2) 2922, 2855, 2358, 1604,
1
1456, 1375, 1248, 1096, 1031 cmꢀ1; H NMR (500 MHz,
4.1.23. (2R,3S)-1-tert-Butyloxycarbonyl-(3-benzyloxy-2-
p-methoxyphenyl)piperidine (27). To a solution of 24
(0.015 g, 0.050 mmol) in anhydrous CH2Cl2 (0.5 mL) were
added di-tert-butyl dicarbonate (0.017 mL, 0.075 mmol)
and triethylamine (0.014 mL, 0.100 mmol) under N2. The
reaction mixture was stirred for 1 h at room temperature
and quenched with H2O (1 mL). The aqueous layer was
extracted with CH2Cl2 (5 mL) and the organic layer was
washed with H2O and brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by column chroma-
tography (hexane/EtOAc 6:1) to afford 20 mg (100%) of 27
as colorless syrup. Rf¼0.24 (hexane/EtOAc 6:1); [a]D28
ꢀ42.2 (c 0.2, CHCl3); IR (CH2Cl2) 2923, 2856, 2358,
1688, 1607, 1511, 1456, 1414, 1366, 1250, 1172, 1133,
CDCl3) d 1.44 (ddd, 1H, J¼13.0, 11.0, 4.0 Hz), 1.65 (ddt,
1H, J¼13.0, 11.0, 4.0 Hz), 1.78 (ddd, 1H, J¼11.0, 4.5,
2.5 Hz), 2.25 (dt, 1H, J¼11.0, 2.5 Hz), 2.70 (dt, 1H,
J¼11.5, 2.5 Hz), 3.06 (br d, 1H, J¼11.5 Hz), 3.33 (ddd,
1H, J¼11.0, 9.0, 4.5 Hz), 3.47 (d, 1H, J¼9.0 Hz), 3.84 (s,
3H), 4.08 (d, 1H, J¼11.5 Hz), 4.25 (d, 1H, J¼11.5 Hz),
6.89 (dd, 2H, J¼9.0, 2.5 Hz), 6.98 (t, 2H, J¼9.0 Hz), 7.21
(dt, 3H, J¼9.0, 2.5 Hz), 7.37 (dd, 2H, J¼9.0, 2.5 Hz); 13C
NMR (125 MHz, CDCl3) d 25.34, 31.80, 46.97, 55.52,
67.23, 71.73, 80.28, 113.83, 127.50, 127.86, 128.32,
129.40, 134.58, 138.83, 159.31; HRMS (CI) Calcd for
C19H24NO2 [M+H+]: 298.1807, found: 298.1804.
1
4.1.21. (2R,3S)-3-Benzyloxy-2-p-methoxyphenyl-1-methyl-
piperidine (25). To a solution of 24 (0.010 g, 0.034 mmol)
in anhydrous THF (0.3 mL) were added potassium carbon-
ate (14 mg, 0.102 mmol) and iodomethane (0.004 mL,
0.100 mmol) under N2. The reaction mixture was stirred
for 2 h at 50 ꢁC and quenched with H2O (1 mL). The aque-
ous layer was extracted with EtOAc (2 mL) and the organic
layer was washed with H2O and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by col-
umn chromatography (CHCl3/MeOH 30:1) to afford 8.6 mg
(82%) of 25 as colorless syrup. Rf¼0.26 (CHCl3/MeOH
30:1); [a]2D8 ꢀ29.4 (c 0.1, CHCl3); IR (CH2Cl2) 2926,
2856, 2780, 1609, 1510, 1455, 1372, 1295, 1246, 1176,
1033 cmꢀ1; H NMR (500 MHz, CDCl3) d 1.33–1.38 (br
dt, 1H, J¼13.0, 2.0 Hz), 1.46 (s, 9H), 1.58 (t, 1H, J¼13.0,
2.0 Hz), 1.86 (dt, 1H, J¼8.5, 1.5 Hz), 1.98–2.03 (m, 1H),
2.86 (dt, 1H, J¼13.0, 3.0 Hz), 3.81 (s, 3H), 4.08 (dd, 1H,
J¼5.5, 2.5 Hz), 4.12 (br d, 1H, J¼13.0 Hz), 4.62 (d, 1H,
J¼12.0 Hz), 3.76 (d, 1H, J¼12.0 Hz), 5.57–5.59 (br, 1H),
6.88 (dd, 2H, J¼9.0, 2.5 Hz), 7.11 (dd, 2H, J¼9.0, 2.5 Hz),
7.29–7.44 (m, 5H); 13C NMR (125 MHz, CDCl3) d 19.72,
24.62, 28.68, 39.98, 55.49, 55.65, 70.52, 74.23, 79.76,
114.24, 127.70, 127.78, 128.57, 131.14, 138.98, 156.40,
158.55; HRMS (CI) Calcd for C24H32NO4 [M+H+]:
398.2331, found: 398.2331.
1119, 1032 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 1.38
4.1.24. (2R,3S)-1-Acetyl-(3-benzyloxy-2-p-methoxy-
phenyl)piperidine (28). To a solution of 24 (0.015 g,
0.050 mmol) in anhydrous CH2Cl2 (0.5 mL) were added
acetic anhydride (0.007 mL, 0.075 mmol) and triethylamine
(0.014 mL, 0.100 mmol) under N2. The reaction mixture was
stirred for 1 h at room temperature and quenched with H2O
(1 mL). The aqueous layer was extracted with CH2Cl2
(5 mL) and the organic layer was washed with H2O and
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (hexane/
EtOAc 1:1) to afford 17.5 mg (88%) of 28 as colorless
syrup. Rf¼0.25 (hexane/EtOAc 1:1); [a]2D8 ꢀ64.8 (c 0.1,
CHCl3); IR (CH2Cl2) 2921, 2856, 2358, 1737, 1609,
(ddd, 1H, J¼13.0, 12.0, 5.0 Hz), 1.74–1.80 (m, 2H), 2.02
(s, 3H), 2.13 (dt, 1H, J¼11.5, 3.0 Hz), 2.21 (ddd, 1H,
J¼13.0, 10.0, 3.0 Hz), 2.73 (d, 1H, J¼9.0 Hz), 2.97 (br d,
1H, J¼13.0 Hz), 3.37–3.39 (br, 1H), 3.85 (s, 3H), 3.96 (d,
1H, J¼12.0 Hz), 4.20 (d, 1H, J¼12.0 Hz), 6.89–7.31 (m,
9H); 13C NMR (125 MHz, CDCl3) d 23.76, 31.09, 44.09,
55.51, 56.83, 71.96, 75.38, 80.78, 113.81, 127.47, 127.87,
128.27, 129.93, 128.78, 159.13; HRMS (CI) Calcd for
C20H26NO2 [M+H+]: 312.1963, found: 312.1966.
4.1.22. (2R,3S)-3-Benzyloxy-1-ethyl-(2-p-methoxy-
phenyl)piperidine (26). To a solution of 24 (0.020 g,
0.067 mmol) in anhydrous THF (0.7 mL) were added potas-
sium carbonate (37 mg, 0.268 mmol) and iodoethane
(0.016 mL, 0.201 mmol) under N2. The reaction mixture
was stirred for 3 h at 50 ꢁC and quenched with H2O
(1 mL). The aqueous layer was extracted with EtOAc
(2 mL) and the organic layer was washed with H2O and
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (CHCl3/
MeOH 30:1) to afford 14.9 mg (68%) of 26 as colorless
syrup. Rf¼0.28 (CHCl3/MeOH 30:1); [a]2D9 ꢀ15.4 (c 0.1,
1
1456, 1375, 1247, 1122, 1026 cmꢀ1; H NMR (500 MHz,
CDCl3) d 1.41–2.13 (m, 4H), 2.28 (s, 3H), 2.71 (br t, 1H,
J¼12.0 Hz), 3.70 (br d, 1H, J¼12.0 Hz), 3.81 (s, 3H),
4.17 (d, 1H, J¼2.5 Hz), 4.61 (d, 1H, J¼12.0 Hz), 4.72
(d, 1H, J¼12.0 Hz), 5.06–5.08 (br, 1H), 6.88–7.39 (m,
9H); 13C NMR (125 MHz, CDCl3) d 21.62, 25.15, 31.81,
55.53, 60.54, 70.73, 73.41, 74.86, 114.58, 127.50, 127.89,
128.71, 129.50, 129.89, 138.67, 159.24, 170.10; HRMS
(CI) Calcd for C21H26NO3 [M+H+]: 340.1912, found:
340.1915.