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4.3.3. (1S,3S)-2-Isobutyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-
3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylate 3c
Obtained as a pale yellow solid in 94% yield, mp 91–93 °C.
4.4. Typical procedure for the base-catalyzed epimerization of
(1S,3S)-1,2,3-trisubstituted-tetrahydro-b-carbolines 3a–3e to
prepare (1S,3R)-1,2,3-tri-substituted-tetrahydro-b-carbolines
4a–4e
½
a 2D0
ꢀ
¼ þ131 (c 0.2, CHCl3). 1H NMR 70 °C (DMSO-d6) d 0.93 (d,
J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 1.91–1.99 (m, 1H), 3.03 (dd,
J1 = 15.8 Hz, J2 = 7.1 Hz, 1H), 3.19 (s, 3H), 3.36 (dd, J1 = 15.8 Hz,
J2 = 2.6 Hz, 1H), 3.91–4.00 (m, 2H), 5.26 (dd, J1 = 7.1 Hz, J2 = 2.5 Hz,
1H), 5.95 (s, 2H), 6.38 (s, 1H), 6.64 (dd, J1 = 8.1 Hz, J2 = 1.4 Hz, 1H),
6.74 (d, J = 1.5 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 7.02 (dd, J1 = 7.2 Hz,
J2 = 7.1 Hz, 1H), 7.09 (dd, J1 = 7.9 Hz, J2 = 8.0 Hz, 1H), 7.30 (d,
J = 8.0 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 10.64 (br s, NH on the indole
ring, 1H). 13C NMR 70 °C (DMSO-d6) d 171.28, 155.46, 147.02,
146.59, 136.48, 134.26, 130.99, 125.99, 121.80, 121.27, 118.56,
117.75, 111.17, 108.69, 107.33, 106.16, 100.82, 71.74, 53.48, 51.38,
51.21, 27.51, 21.18, 18.59, 18.58. MS (EI) m/z (relative intensity)
451 (M++1, 6), 450 (M+, 21), 391 (3), 377 (1), 351 (3), 350 (18), 349
(100), 333 (5), 290 (6), 289 (22), 274 (5), 263 (4), 262 (6), 233 (2),
205 (3), 204 (7), 169 (4), 115 (1), 57 (1). IR (KBr film) 3396, 2962,
1743, 1685, 1489, 1414, 1238, 1039, 744 cmꢁ1. HRMS (EI) calcd for
C25H26N2O6: 450.1791; found: 450.1813.
To a solution of compound 3a (3.50 g, 7.22 mmol) in acetonitrile
(20 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (275 mg,
1.81 mmol). The solution was heated to reflux, and stirring was
then continued for 6 h. Removal of acetonitrile by distillation un-
der a vacuum gave a residue, which was dissolved in toluene
(60 mL). The organic phase was washed successively with 1 M
aqueous HCl solution (10 mL), water (10 mL) and brine (10 mL).
After the organic phase was dried over anhydrous MgSO4, the solu-
tion was concentrated in vacuo to give a crude product, which was
purified by chromatography to afford compound 4a (2.50 g,
5.16 mmol) in 71.4% yield and compound 3a (0.83 g, 1.71 mmol)
in 23.7% yield.
Characterization data of (1S,3R)-1,2,3-trisubstituted-tetrahy-
dro-b-carbolines 4a–4e are as follows.
4.4.1. (1S,3R)-2-Benzyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-
3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylate 4a
4.3.4. (1S,3S)-3-Methyl 2-phenyl 1-(benzo[d][1,3]dioxol-5-yl)-
3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylate 3d
Obtained as an off-white solid in 96% yield, mp 111–112 °C.
Off-white solid, mp 100–101 °C. ½a D20
ꢀ
¼ þ41 (c 0.4, CHCl3). 1H
NMR 70 °C (DMSO-d6) d 3.30 (dd, J1 = 15.8 Hz, J2 = 5.5 Hz, 1H), 3.35
(dd, J1 = 15.8 Hz, J2 = 3.7 Hz, 1H), 3.48 (s, 3H), 5.02 (d, J = 12.7 Hz,
1H), 5.08 (d, J = 4.8 Hz, 1H), 5.11 (d, J = 12.8 Hz, 1H), 5.93 (d,
J = 8.2 Hz, 2H), 6.02 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.86 (d, J =
8.1 Hz, 1H), 6.89 (s, 1H), 6.97 (dd, J1 = 7.5 Hz, J2 = 7.3 Hz, 1H), 7.03
(dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1H), 7.10–7.35 (m, 6H), 7.43 (d,
J = 7.8 Hz, 1H), 10.70 (br s, NH on the indole ring, 1H). 13C NMR
70 °C (DMSO-d6) d 171.62, 155.95, 147.10, 146.14, 137.00, 136.34,
136.12, 134.11, 127.98, 127.57, 127.20, 125.79, 121.04, 119.61,
118.64, 117.62, 111.08, 107.75, 106.95, 103.62, 100.71, 66.71,
56.30, 55.26, 51.79, 22.68. MS (EI) m/z (relative intensity) 485
(M++1, 3), 484 (M+, 10), 439 (1), 393 (3), 351 (4), 350 (22), 349
(100), 290 (5), 289 (20), 264 (2), 263 (2), 262 (5), 232 (2), 205 (3),
204 (5), 169 (3), 115 (1), 91 (13), 65 (1). IR (KBr fim) 3400, 2955,
2905, 1741, 1700, 1489, 1444, 1399, 1238, 1092, 1038, 928,
744 cmꢁ1. HRMS (EI) calcd for C28H24N2O6: 484.1634; found:
484.1635.
½
a 2D0
ꢀ
¼ þ116 (c 0.3, CHCl3). 1H NMR 70 °C (DMSO-d6) d 3.17 (dd,
J1 = 15.8 Hz, J2 = 7.0 Hz, 1H), 3.26 (s, 3H), 3.46 (dd, J1 = 15.9 Hz,
J2 = 2.3 Hz, 1H), 5.48 (d, J = 5.6 Hz, 1H), 5.98 (s, 2H), 6.50 (s, 1H),
6.72 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 6.84 (d, J = 7.1 Hz,
1H), 7.04 (dd, J1 = 7.3 Hz, J2 = 7.1 Hz, 1H), 7.11 (dd, J1 = 7.1 Hz,
J2 = 7.2 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H), 7.25 (dd, J1 = 7.4 Hz,
J2 = 7.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.42 (dd, J1 = 7.9 Hz,
J2 = 7.9 Hz, 2H), 7.55 (d, J = 7.8 Hz, 1H), 10.68 (br s, NH on the in-
dole ring, 1H). 13C NMR 70 °C (DMSO-d6) d 170.88, 153.76, 151.00,
146.91, 146.61, 136.36, 133.56, 130.46, 129.07, 125.76, 125.18,
121.96, 121.38, 121.32, 118.54, 117.77, 111.10, 108.57, 107.44,
106.12, 100.79, 53.95, 51.71, 51.42, 20.98. MS (EI) m/z (relative
intensity) 471 (M++1, 11), 470 (M+, 40), 410 (2), 378 (4), 377
(19), 350 (17), 349 (100), 334 (8), 333 (5), 317 (4), 302 (2), 291
(4), 290 (4), 289 (18), 274 (10), 263 (16), 262 (23), 233 (8), 232
(6), 205 (7), 204 (16), 169 (3), 135 (3), 102 (2), 77 (4). IR (KBr
film) 3397, 2894, 1713, 1628, 1489, 1403, 1303, 1238, 1200,
1039, 746 cmꢁ1
found: 470.1479.
. HRMS (EI) calcd for C27H22N2O6: 470.1478;
4.4.2. (1S,3R)-2-Ethyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-
3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylate 4b
Off-white solid, mp 89–90 °C. ½a D20
ꢀ
¼ þ49 (c 0.4, CHCl3). 1H NMR
70 °C (DMSO-d6) d 1.09 (t, J = 7.0 Hz, 3H), 3.27 (dd, J1 = 15.0 Hz,
J2 = 5.5 Hz, 1H), 3.35 (dd, J1 = 15.0 Hz, J2 = 4.1 Hz, 1H), 3.55 (s,
3H), 4.00–4.08 (m, 2H), 5.00 (dd, J1 = 4.8 Hz, J2 = 4.9 Hz, 1H), 5.93
(d, J = 5.3 Hz, 2H), 6.02 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.87 (d,
J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.97 (dd, J1 = 7.5 Hz, J2 = 7.3 Hz, 1H),
7.04 (dd, J1 = 7.4 Hz, J2 = 7.6 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.44
(d, J = 7.8 Hz, 1H), 10.63 (br s, NH on the indole ring, 1H). 13C
NMR 70 °C (DMSO-d6) d 171.59, 156.03, 147.01, 146.06, 136.92,
136.32, 134.08, 125.78, 120.99, 119.72, 118.59, 117.56, 111.03,
107.67, 106.97, 103.83, 100.66, 61.10, 56.14, 54.97, 51.74, 22.61,
13.86. MS (EI) m/z (relative intensity) 423 (M++1, 7), 422 (M+,
28), 377 (2), 350 (18), 349 (100), 333 (5), 313 (5), 301 (4), 290
(5), 289 (21), 274 (8), 264 (5), 263 (5), 262 (9), 239 (4), 205 (4),
204 (10), 169 (7), 144 (2), 109 (3), 95 (4), 84 (4). IR (KBr film)
3402, 2955, 1742, 1699, 1489, 1402, 1238, 1037, 744 cmꢁ1. HRMS
(EI) calcd for C23H22N2O6: 422.1478; found: 422.1491.
4.3.5. (1S,3S)-2-t-Butyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-
3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylate 3e
Obtained as an off-white solid in 92% yield, mp 93–95 °C.
½
a 2D0
ꢀ
¼ þ122 (c 1.2, CHCl3). 1H NMR 70 °C (DMSO-d6) d 1.48 (s,
9H), 3.01 (dd, J1 = 15.4 Hz, J2 = 6.2 Hz, 1H), 3.21 (s, 3H), 3.31 (d,
J = 15.7 Hz, 1H), 5.19 (d, J = 6.2 Hz, 1H), 5.96 (s, 2H), 6.33 (s, 1H),
6.67 (d, J = 7.7 Hz, 1H), 6.78 (s, 1H), 6.80 (d, J = 8.1 Hz, 1H), 7.01
(dd, J1 = 7.2 Hz, J2 = 6.9 Hz, 1H), 7.08 (dd, J1 = 7.8 Hz, J2 = 7.5 Hz,
1H), 7.30 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 10.67 (br s,
NH on the indole ring, 1H). 13C NMR 70 °C (DMSO-d6) d 171.45,
154.27, 146.79, 146.28, 136.20, 134.42, 131.23, 125.79, 121.43,
121.11, 118.42, 117.65, 111.01, 108.29, 107.25, 105.94, 100.66,
80.34, 53.06, 51.13, 51.12, 27.81, 21.11. MS (EI) m/z (relative inten-
sity) 450 (M+, 2), 395 (4), 394 (17), 393 (7), 377 (3), 351 (17), 350
(86), 349 (100), 335 (10), 333 (16), 301 (3), 292 (6), 291 (28), 290
(11), 289 (36), 276 (8), 274 (10), 264 (12), 263 (30), 262 (30), 233
(10), 232 (7), 204 (18), 169 (12), 144 (9), 115 (4), 102 (3), 57 (2), 41
(2). IR (KBr film) 3403, 2978, 1741, 1692, 1488, 1398, 1303, 1238,
1165, 1039, 1007, 744 cmꢁ1. HRMS (EI) calcd for C25H26N2O6:
450.1791; found: 450.1796.
4.4.3. (1S,3R)-2-Isobutyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-
3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylate 4c
White solid, mp 110–111 °C. ½a D20
ꢀ
¼ þ55 (c 0.2, CHCl3). 1H NMR
70 °C (DMSO-d6) d 0.79 (d, J = 6.6 Hz, 6H), 1.73–1.81 (m, 1H), 3.29