M. Scheunemann et al. / Bioorg. Med. Chem. 12 (2004) 1459–1465
1463
and characterized13,14b according to the described
procedures.
NMR (CDCl3): d 26.07, 27.62 (2C, not resolved), 33.90,
34.24, 42.97, 45.22, 53.24, 64.53, 68.52, 69.82, 73.30,
126.13, 126.80, 127.28, 127.35, 128.32, 128.38, 138.98,
146.24. MS (ESI) m/z 366.3 (M+1). Anal. calcd for
C24H31NO2: C, 78.86; H, 8.55; N, 3.83. Found: C,
78.61; H, 8.63; N, 4.05.
4.1.1. (1SR,3SR,6RS) 3-Benzyloxy-7-oxa-bicyclo[4.1.0]-
heptane (8a). Following an already reported proce-
dure;19 to a solution of 7 (1.69 g, 14.8 mmol) in DMF
(12mL) NaH (0.72g of 60% suspension in mineral oil,
18 mmol) was added at 0 ꢂC and stirred for 30 min.
Benzylbromide (2.2 mL, 17.8 mmol) was added at 0 ꢂC
via a syringe. The reaction mixture was allowed to
warm to 22 ꢂC and stirring was continued for 18 h. H2O
(20 mL) was added and the resulting mixture was
extracted with MTBE (3ꢃ15 mL). The combined
extracts were washed (satd NaCl, 10 mL) and dried
(MgSO4). After filtration and concentration, the oily
residue was purified via column chromatography (sili-
cagel: 16 g, column: 150ꢃ20 mm, solvent: hexane–
MTBE, 5:1) to yield 2.19 g (73%) of a yellowish oil. Rf
0.31 (hexane/MTBE, 5:1). 1H NMR (CDCl3): d 1.46
(ddd, J=24.0, 12.0, 4.4 Hz, 1H, 4-Ha), 1.70 (m, 1H, 4-
Hb), 1.77 (m, 1H, 5-Ha), 1.85 (dd, J=15.0, 10.1 Hz, 1H,
2-Ha), 2.22 (m, 1H, 5-Hb), 2.34 (m, 1H, 2-Hb), 3.09 (m,
2H, oxirane: 1-H and 6-H), 3.32 (m, 1H, 3-H), 4.51 (AB,
2H, PhCH2O), 7.25–7.33 (m, 5H, ArH). 13C NMR
(CDCl3): d 23.79 (2C, not resolved), 30.83, 50.92, 51.85,
69.83, 73.06, 127.50 (3C, not resolved), 128.36, 138.64.
4.1.4. (1RS,2RS,4SR) 4-(4-Fluoro-benzyloxy)-2-(4-phenyl-
piperidin-1-yl)-cyclohexanol (10b). It was obtained from
8b (0.444 g, 2mmol) and 9 (0.3 g, 2mmol) in the same
way as described above for compound 10a and recrys-
tallized from MeOH (10 mL) to yield 0.452g (59%),
white crystals. Mp 128–130 ꢂC. 1H NMR (CDCl3): d
1.27–1.41 (m, 2H, 5-H2), 1.63–1.76 (m, 2H, 30-Ha, 50-
Ha), 1.78–1.88 (2m, 3H, 6-Ha, 30-Hb, 50-Hb), 1.95–2.02
(m, 2H, 6-Hb, 3-Hb), 2.08–2.12 (m, 1H, 3-Ha), 2.17–2.22
(m, 1H, 20-Ha), 2.48 (tt-like, J=12.1, 3.7 Hz, 1H, 40-H),
2.65–2.79 (2m, 3H, 60-H2, 2-H), 2.92–2.95 (m, 1H, 20-
Hb), 3.46 (m, 1H, 1-H), 3.83 (m, 1H, 4-H), 4.04 (bs, 1H,
OH), 4.46 (AB, 2H, J=11.8 Hz), 7.00–7.33 (3m, 9H,
ArH). 13C NMR (CDCl3): d 26.09, 27.54, 27.60, 33.90,
34.24, 42.96, 45.23, 53.27, 64.54, 68.47, 69.14, 73.37,
115.14 (d, J=21.3 Hz, 2C, 3-C), 126.15, 126.79, 128.39,
128.93 (d, J=8.4 Hz, 2C, 2-C), 134.8 (not resolved, 1C,
1-C), 146.21, 162.18 (d, J=238 Hz, 1C, 4-C). MS (ESI)
m/z 384.3 (M+1). Anal. calcd for C24H30FNO2: C,
75.16; H, 7.88; N, 3.65. Found: C, 74.87; H, 7.97; N,
3.92.
4.1.2. (1SR,3SR,6RS) 3-(4-Fluoro-benzyloxy)-7-oxa-bi-
cyclo[4.1.0]heptane (8b). It was obtained from 2 (2.1 g,
18.4 mmol), NaH (0.88 g, 60%, 22.1 mmol) and 4-
fluorobenzylbromide (2.72 mL, 22.1 mmol) in the same
way as described above for benzylether 8a and purified
via column chromatography (silicagel: 16 g, column:
150ꢃ20 mm, solvent: hexane-MTBE, 5:1) to yield 61%
of a yellowish oil. Rf 0.25 (hexane/MTBE, 5:1). 1H
NMR (CDCl3): d 1.46 (ddd, J=24.4, 12.4, 4.4 Hz, 1H,
4-Ha), 1.69 (m, 1H, 4-Hb), 1.77 (m, 1H, 5-Ha), 1.85 (dd,
J=14.8, 10.0 Hz, 1H, 2-Ha), 2.21 (m, 1H, 5-Hb), 2.34
(m, 1H, 2-Hb), 3.10 (m, 2H, oxirane: 1-H and 6-H), 3.31
(dddd, J=11.6, 10.0, 6.4, 3.2Hz, 1H, 3-H), 4.51 (AB,
2H, PhCH2O), 7.25–7.33 (m, 5H, ArH). 13C NMR
(CDCl3): d 23.72 (2C, not resolved), 30.78, 50.83, 51.79,
69.14, 73.15, 115.17 (d, J=21.4 Hz, 2C, 3-C), 129.16 (d,
J=8.4 Hz, 2C, 2-C), 134.36 (d, J=3.0 Hz, 1C, 1-C),
162.21 (d, J=245.7 Hz, 1C, 4-C).
4.1.5. (1RS,2RS,5RS) 5-Benzyloxy-2-(4-phenyl-piperidin-
1-yl)-cyclohexanol (11a). To a solution of LiClO4 (0.37
g, 3.5 mmol) and 8a (0.41 g, 2mmol) in MeCN (3 mL)
was added 9 (0.37 g, 2.5 mmol) and stirred for 16 h at
22 ꢂC. The suspension of a white solid obtained was
stirred with CHCl3 (20 mL) and H2O (15 mL) for 5 min.
The organic phase was separated, concentrated, and the
solid residue was recrystallized from MeOH–EtOH (8
mL/12mL) to yield 0.653 g (89%) white crystals. Mp
174–175.5 ꢂC. 1H NMR (CDCl3): d 1.13–1.26 (m, 1H, 3-
HA), 1.28–1.42 (m, 2H, 4-HA, 6-HA), 1.60–1.72(m, 1H,
30-HA), 1.74–1.92(m, 4H, 3-H B, 30-HB, 50-H2), 2.13–2.33
(m, 3H, 60-HA, 4-HB, 6-HB), 2.49 (tt-like, J=12, 4 Hz,
1H, 40-H), 2.59 (m, 1H, 2-H), 2.70–2.90 (m, 3H, 60-HB,
20-H2), 3.33–3.45 (m, 2H, 5-H, 1-H), 3.94 (bs, 1H, OH),
4.57 (AB, 2H, PhCH2O), 7.17–7.36 (m, 10, ArH). 13C
NMR (CDCl3): d 18.58, 31.43, 33.88, 34.29, 38.75,
42.91, 45.37, 53.67, 66.26, 69.92, 70.19, 74.79, 126.17,
126.78, 127.53, 127.57, 128.39, 128.41, 138.66, 146.13. MS
(ESI) m/z 366.3 (M+1). Anal. calcd for C24H31NO2: C,
78.86; H, 8.55; N, 3.83. Found: C, 78.55; H, 8.69; N,
4.01.
4.1.3. (1RS,2RS,4SR) 4-Benzyloxy-2-(4-phenyl-piperidin-
1-yl)-cyclohexanol (10a). A mixture of 8a (4 g, 19.6
mmol) and 9 (2.96 g, 19.8 mmol) in EtOH (abs., 14 mL)
was stirred at 55–60 ꢂC for 3 days. After concentration
the red residue was dissolved in CHCl3 (30 mL), washed
with H2O (20 mL), dried (Na2CO3) and subsequently
treated with silica gel (2g) until the colour disappeared.
After filtration and evaporation, the solid residue was
recrystallized from MeOH–EtOH (10 mL/25 mL) to
4.1.6. (1RS,2RS,5RS) 5-(4-Fluoro-benzyloxy)-2-(4-phenyl-
piperidin-1-yl)-cyclohexanol (11b). It was obtained from
8b (0.679 g, 3.05 mmol), LiClO4 (0.57 g, 5.34 mmol) and
9 (0.46 g, 3.05 mmol) in the same way as described
above for compound 11a and recrystallized from EtOH
(30 mL) to yield 1.005 g (86%), white crystals. Mp
178.5–180 ꢂC. 1H NMR (CDCl3): d 1.14–1.25 (m, 1H, 3-
HA), 1.28–1.41 (m, 2H, 4-HA, 6-HA), 1.60–1.71 (m, 1H,
30-HA), 1.74–1.92(m, 4H, 3-H B, 30-HB, 50-H2), 2.12–2.32
(m, 3H, 60-HA, 4-HB, 6-HB), 2.49 (tt-like, J=12, 4 Hz,
1H, 40-H), 2.57 (m, 1H, 2-H), 2.70–2.90 (m, 3H, 60-HB,
yield 5.2g (73%) white crystals. Mp 132.5–136 ꢂC. H
1
NMR (CDCl3): d 1.26–1.41 (m, 2H, 5-H2), 1.62–1.87
(3m, 5H, 30-H2, 50-H2, 6-HA), 1.93-2.04 (m, 2H, 6-HB, 3-
HB), 2.08–2.14 (m, 1H, 3-HA), 2.15–2.22 (m, 1H, 20-
HA), 2.48 (tt-like, J=12.0, 3.8 Hz, 1H, 40-H), 2.64–2.79
(2m, 3H, 60-H2, 2-H), 2.91–2.95 (m, 1H, 20-HB), 3.46 (m,
1H, 1-H), 3.84 (m, 1H, 4-H), 4.06 (bs, 1H, OH), 4.46
(AB, 2H, J=12.2 Hz), 7.17–7.35 (m, 10H, ArH). 13C