Clive et al.
combined organic extracts were washed with water and brine, dried
(Na2SO4), and evaporated. Flash chromatography of the residue
over silica gel, using 1:4 EtOAc-hexane, gave 33d (249 mg, 81%)
3380, 2961, 1691, 1493 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.95-
1.05 (m, 4 H), 1.25-1.39 (m, 1 H), 2.25-2.35 (br m, 1 H), 2.52
(dd, J ) 16.5, 11.4 Hz, 1 H), 2.84 (dd, J ) 16.5, 5.0 Hz, 1 H),
4.74 (s, 1 H), 5.71 (d, J ) 5.0 Hz, 1 H), 6.65 (d, J ) 3.0 Hz, 1 H),
6.69 (dd, J ) 9.0, 3.0 Hz, 1 H), 6.92 (br d, J ) 7.2 Hz, 2 H),
7.10-7.14 (m, 2 H), 7.17 (tt, J ) 7.5, 1.1 Hz, 1 H), 7.24-7.28 (m,
3 H), 7.31 (tt, J ) 7.9, 2.0 Hz, 2 H), 7.95 (br m, 1 H); 13C NMR
(CDCl3, 100 MHz) δ 11.7 (q), 25.1 (t), 29.9 (t), 39.5 (d), 61.8 (d),
113.9 (d), 115.1 (d), 121.7 (d), 125.4 (d), 127.3 (d), 127.8 (d), 128.2
(d), 129.2 (d), 130.1 (s), 130.6 (s), 139.2 (s), 151.1 (s), 151.7 (s),
153.4 (s), (apparently, two aromatic signals overlap); exact mass
m/z calcd for C24H23NO3 373.16779, found 373.16811.
1
as an oil: FTIR (CH2Cl2 cast) 2964, 1720, 1674, 1493 cm-1; H
NMR (acetone-d6, 500 MHz) δ 1.00 (t, J ) 7.4 Hz, 3 H), 1.39-
1.43 (m, 1 H), 1.82-1.89 (m, 1 H), 2.39-2.43 (m, 1 H), 2.95-
3.02 (m, 1 H), 3.35 (br s, 3 H), 3.52 (dd, J ) 10.6, 2.9 Hz, 1 H),
5.10-5.40 (br s, 1 H), 6.22 (dd, J ) 10.0, 1.5 Hz, 1 H), 6.20-
6.28 (br s, 1 H), 6.58-6.62 (br s, 1 H), 6.99 (br s, 2 H), 7.18 (tt,
J ) 7.5, 1.0 Hz, 1 H), 7.29-7.44 (m, 6 H), 7.68 (d, J ) 6.9 Hz,
2 H); 13C NMR (C6D6, 100 MHz) δ 11.1 (q), 16.6 (t), 24.7 (t),
40.2 (d), 51.1 (q), 61.9 (d), 84.4 (s), 121.7 (d), 125.6 (d), 128.4
(d), 128.9 (d), 129.5 (d), 129.9 (d), 130.5 (d), 140.5 (s), 144.6 (d),
150.9 (s), 152.4 (s), 184.3 (s); exact mass (electrospray) m/z calcd
for C25H26INNaO4 [M + Na] 554.07988 found 554.07956.
(2S,3R,4aR,8aR)-3-Ethyl-8a-methoxy-6-oxo-2-phenyl-3,4,4a,5,6,-
8a-hexahydro-2H-quinoline-1-carboxylic Acid Phenyl Ester
(trans-33e) and (2S,3R,4aR,8aS)-3-Ethyl-8a-methoxy-6-oxo-2-
phenyl-3,4,4a,5,6,8a-hexahydro-2H-quinoline-1-carboxylic Acid
Phenyl Ester (cis-33e). A solution of Bu3SnH (0.04 mL, 0.14
mmol) and AIBN (4 mg, 0.02 mmol) in PhH (2 mL) was added
over 4 h (syringe pump) to a stirred and heated (85 °C) solution of
33d (64 mg, 0.12 mmol) in PhH (6 mL) (N2 atmosphere). After
the addition, heating was continued for 4 h. Evaporation of the
solvent and flash chromatography of residue over silica gel, using
1:10 to 1:4 EtOAc-hexane, gave trans-33e (23.3 mg, 48%) and
cis-33e (11.8 mg, 24%) as oils. trans-33e: FTIR (CH2Cl2 cast)
2961, 2933, 1718, 1683, 1495 cm-1; 1H NMR (C6D6, 400 MHz) δ
0.60 (t, J ) 7.4 Hz, 3 H), 0.77 (sextet, J ) 7.4 Hz, 1 H), 0.94
(sextet, J ) 7.4 Hz, 1 H), 1.00 (ddd, J ) 13.8, 4.4, 3.3 Hz, 1 H),
1.78 (ddddd, J ) 13.8, 7.4, 7.4, 6.9, 4.4 Hz, 1 H), 2.00-2.11 (m,
2 H), 2.40 (dddd, J ) 12.6, 4.9, 3.3, 3.3 Hz, 1 H), 2.55 (dd, J )
16.4, 12.6 Hz, 1 H), 5.45 (d, J ) 6.9 Hz, 1 H), 2.82 (s, 3 H), 5.91
(dd, J ) 10.4, 1.1 Hz, 1 H), 6.86-6.91 (m, 1 H), 6.93-6.97 (m,
2 H), 6.99-7.04 (m, 2 H), 7.09-7.14 (m, 3 H), 7.42 (d, J ) 10.4
Hz, 1 H), 7.63-7.67 (m, 2 H); 13C NMR (C6D6, 125 MHz) δ 11.7
(q), 26.4 (t), 27.3 (t), 35.0 (d), 40.2 (t), 41.2 (d), 50.3 (q), 61.1 (d),
86.4 (s), 122.2 (d), 125.4 (d), 125.7 (d), 128.1 (d), 128.3 (d), 129.5
(d), 131.4 (d), 139.0 (s), 147.3 (d), 151.7 (s), 155.6 (s), 197.8 (s);
exact mass (electrospray) m/z calcd for C25H28NO4 [M + H]
406.20128, found 406.20115.
cis-33e: FTIR (CH2Cl2 cast) 2932, 1725, 1687, 1494 cm-1; 1H
NMR (C6D6, 300 MHz) δ 0.30 (br m, 1 H), 0.59 (t, J ) 7.5 Hz, 3
H), 0.88 (br m, 1 H), 1.09-1.30 (br m, 2 H), 1.76 (br m, 1 H),
2.15-2.30 (m, 2 H), 2.72 (dd, J ) 16.0, 5.8 Hz, 1 H), 3.17 (s, 3
H), 5.98 (d, J ) 6.7 Hz, 1 H), 6.03 (d, J ) 10.4 Hz, 1 H), 6.63-
6.69 (m, 2 H), 6.78-6.86 (m, 2 H), 6.90-7.00 (m, 3 H), 7.00-
7.12 (m, 3 H), 7.37 (d, J ) 10.4 Hz, 1 H); 13C NMR (C6D6, 125
MHz) δ 11.8 (q), 25.9 (t), 27.3 (t), 40.2 (d), 41.5 (d), 41.7 (t), 50.7
(d), 65.2 (q), 88.1 (s), 122.1 (d), 125.5 (d), 127.4 (d), 128.3 (d),
128.4 (d), 129.0 (d), 129.3 (d), 141.4 (s), 145.6 (d), 151.6 (s), 154.2
(s), 196.3 (s); exact mass (electrospray) m/z calcd for C25H28NO4
[M + H] 406.20128, found 406.20137. NOEs were observed
between the OCH3 group and both the CH(Ph) and ring-fusion
hydrogen, thus establishing the stereochemistry shown for cis-33e.
Corresponding NOEs were not observed for trans-33e.
cis-3-[(4-Methoxymethoxy)phenyl]amino]cyclohexanol (cis-
35) and trans-3-[(4-Methoxymethoxy)phenyl]amino]cyclohexanol
(trans-35). CuI (35.8 mg, 0.19 mmol), L-proline (43.3 mg, 0.38
mmol), K2CO3 (520.0 mg, 3.76 mmol), and 3-aminocyclohexanol
(cis/trans mixture, 325 mg, 2.82 mmol) were added in that order
to a solution of iodide 15 (499 mg, 1.88 mmol) in DMSO (8 mL).
The mixture was stirred for 12 h at 85 °C (Ar atmosphere), cooled
to room temperature, diluted with water, and extracted with EtOAc.
The combined organic extracts were washed with water and brine,
dried (Na2SO4), and evaporated. Flash chromatography of the
residue over silica gel, using 1:1 EtOAc-hexane, gave cis-35 (303
mg, 64%) and trans-35 (57 mg, 12%) as oils. trans-35: FTIR (CH2-
1
Cl2 cast) 3383, 2932, 1511 cm-1; H NMR (CDCl3, 400 MHz) δ
1.18-1.31 (m, 1 H), 1.46-1.63 (m, 4 H), 1.74-1.81 (br m, 1 H),
1.94-2.00 (br m, 2 H), 2.55 (br s, 2 H), 3.47 (s, 3 H), 3.66 (dddd,
J ) 8.6, 8.6, 3.7, 3.7 Hz, 1 H), 4.10 (br m, 1 H), 5.06 (s, 2 H),
6.53-6.58 (m, 2 H), 6.86-6.91 (m, 2 H); 13C NMR (CDCl3, 100
MHz) δ 19.4 (t), 32.2 (t), 33.2 (t), 39.9 (t), 48.1 (d), 55.8 (d), 66.9
(q), 95.6 (t), 114.5 (d), 118.0 (d), 142.5 (s), 149.2 (s); exact mass
m/z calcd for C14H21NO3 251.15215, found 251.15243. We observed
no NOE between CH(OH) and CH(N); consequently the amino
and hydroxy groups are trans.
Major isomer (cis-35): FTIR (CH2Cl2 cast) 3365, 2932, 1511
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.00-1.44 (m, 4 H), 1.79-
1.87 (m, 1 H), 1.89-2.02 (m, 2 H), 2.28 (br d, J ) 12.2 Hz, 1 H),
2.56 (br s, 2 H), 3.26 (dddd, J ) 10.0, 10.0, 3.7, 3.7 Hz, 1 H), 3.47
(s, 3 H), 3.74 (dddd, J ) 8.5, 8.5, 4.0, 4.0 Hz, 1 H), 5.08 (s, 2 H),
6.53-6.58 (m, 2 H), 6.87-6.91 (m, 2 H); 13C NMR (CDCl3, 100
MHz) δ 32.2 (t), 34.8 (t), 41.9 (t), 51.2 (d), 55.8 (d), 69.2 (q), 95.6
(t), 114.7 (d), 118.0 (d), 142.4 (s), 149.5 (s), 21.0 (t); exact mass
m/z calcd for C14H21NO3 251.15215, found 251.15191. A TROESY
spectrum showed an NOE between CHN and CHOH, suggesting
that this isomer has the amino and hydroxy groups cis.
cis-(3-Hydroxycyclohexyl)[(4-methoxymethoxy)phenyl]car-
bamic Acid Phenyl Ester (35a). i-Pr2NEt (0.24 mL, 1.40 mmol)
and PhOCOCl (0.18 mL, 1.40 mmol) were added in that order to
a stirred solution of cis-35 (major isomer) (294 mg, 1.18 mmol) in
CH2Cl2 (6 mL). Stirring was continued for 5 h, water was then
added, and the mixture was extracted with CHCl3. The combined
organic extracts were washed with brine, dried (Na2SO4), and
evaporated. Flash chromatography of the residue over silica gel,
using 3:7 EtOAc-hexane, gave 35a (397 mg, 91%) as an oil: FTIR
(CH2Cl2 cast) 3430, 2934, 1716, 1510 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.00 (qd, J ) 12.4, 3.5 Hz, 1 H), 1.12-1.32 (m, 2 H),
1.37 (dt, J ) 13.4, 3.2 Hz, 1 H), 1.80 (dq, J ) 13.4, 3.3 Hz, 1 H),
1.92 (br m, 2 H), 2.26 (br d, J ) 11.7 Hz, 1 H), 3.51 (s, 3 H), 3.72
(dddd, J ) 10.5, 10.5. 4.1, 4.1 Hz, 1 H), 4.28 (tt, J ) 12.2, 3.5 Hz,
1 H), 5.19 (s, 2 H), 6.98-7.09 (m, 4 H), 7.09-7.18 (m, 3 H), 7.30
(t, J ) 7.4 Hz, 2 H) (OH signal not observed); 13C NMR (CDCl3,
100 MHz) δ 21.9 (t), 30.3 (t), 34.4 (t), 40.7 (t), 56.1 (d), 54.9 (d),
69.5 (q), 94.4 (t), 116.3 (d), 121.6 (d), 125.2 (d), 129.1 (d), 130.8
(d), 131.5 (s), 151.4 (s), 154.2 (s), 156.7 (s); exact mass m/z calcd
for C21H25NO5 371.17328, found 371.17418.
(2S,3R)-3-Ethyl-6-hydroxy-2-phenyl-3,4-dihydro-2H-quino-
line-1-carboxylic acid Phenyl Ester (33f). Concentrated hydro-
chloric acid (one drop) was added to a stirred solution of trans-
33e (20.0 mg, 0.049 mmol) in CHCl3 (3 mL). Stirring was continued
for 3 min, and the solvent was then evaporated. Flash chromatog-
raphy of the residue over silica gel, using 1:4 EtOAc-hexane, gave
33f (15.6 mg, 85%) as a solid: mp 170-171 °C.
cis-33e was subjected to the same conditions. Concentrated
hydrochloric acid (one drop) was added to a stirred solution of cis-
33e (11.0 mg, 0.027 mmol) in CHCl3 (3 mL). Stirring was continued
for 3 min, and the solvent was then evaporated. Flash chromatog-
raphy of the residue over silica gel, using 1:4 EtOAc-hexane, gave
33f (8.3 mg, 82%) as a solid: mp 170-171 °C; FTIR (CHCl3 cast)
(trans-3-Iodocyclohexyl)[(4-methoxymethoxy)phenyl]carbam-
ic Acid Phenyl Ester (35b). Imidazole (106 mg, 1.56 mmol), Ph3P
(410 mg, 1.56 mmol), and I2 (396 mg, 1.56 mmol) were added in
that order to a stirred solution of 35a (290 mg, 0.78 mmol) in THF
2342 J. Org. Chem., Vol. 73, No. 6, 2008