Asymmetric Synthesis of Tetrahydropalmatine
(3S)-3-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-
tetrahydroisoquinoline [(S)-22]. (S)-22 was prepared in the
same manner as described for the synthesis of (R)-22 using
dihydroisoquinolinone (S,R)-20 (0.300 g, 0.66 mmol) and BH3‚
THF (13.1 mL, 13.14 mmol, 1 M in THF). After purification
by column chromatography (Et2O/MeOH ) 20/1), 0.182 g (83%)
of (S)-22 was obtained as a champagne-beige solid: ee ) 99%
(Chiralpak AD; n-heptane/i-PrOH ) 65/35; Rt ) 11.47 min; λ
3.61 (d, J ) 16.5 Hz, 1H), 3.71-3.78 (m, 2H), 3.83 (s, 3H),
3.85 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 4.17 (d, J ) 16.5 Hz,
1H), 6.79-6.88 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3) δ
35.6, 48.8, 54.7 (CH2), 55.7, 55.8, 55.8 (CH3), 58.3 (CH2), 60.1
(CH3), 63.1, 110.9, 110.8, 110.9, 120.0, 123.2 (CH), 127.3, 127.9,
134.1, 145.1, 148.1, 148.9, 150.1 (C) ppm; MS (EI) m/z (%) 373
(M+, 10), 343 (23), 342 (100), 314 (11), 313 (49), 282 (13), 175
(12), 164 (16), 151 (12), 149 (16); IR (in CHCl3) ν 3563, 3536,
3379, 3314, 3012, 2936, 2836, 1596, 1497, 1461, 1423, 1373,
1263, 1233, 1145, 1087, 1030, 986, 877, 756, 667 cm-1; HRMS
m/z calcd for C21H27NO5 (M+): 373.1889. Found: 373.1890.
) 214 nm); [R]27 -84.8 (c 0.70, CHCl3).
D
(3S)-2-(2-Phenylsulfinylethyl)-3-(3,4-dimethoxyphenyl)-
7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline [(S)-23]. In
a 10-mL flask under argon, a solution of tetrahydroisoquinoline
(S)-22 (0.109 g, 0.33 mmol) and phenyl vinyl sulfoxide (66 µL,
0.50 mmol) in abs. MeOH (2 mL) was heated at reflux for 22
h. The solvent was evaporated under reduced pressure, and
the residue was purified by column chromatography (pure
Et2O then Et2O/MeOH ) 20/1) to give 0.150 g (94%) of (S)-23
as a yellow syrup: dr ) 64/36 (spherical silica; n-heptane/i-
PrOH ) 9/1; Rt ) 21.82 min; Rt ) 27.90 min; λ ) 254 nm); 1H
NMR (400 MHz, CDCl3, mixture of diastereomers) δ 2.46-
2.54 (m, 1H), 2.73-3.18 (m, 11H), 3.55 (d, J ) 16.1 Hz, 1H),
3.58-3.75 (m, 3H), 3.78 (s, 3H), 3.83 (s, 6H), 3.85 (s, 9H), 3.88
(s, 3H), 3.89 (s, 3H), 4.06 (d, J ) 16.2 Hz, 1H), 4.18 (d, J )
16.1 Hz, 1H), 6.75-6.84 (m, 9H), 6.91 (s, 1H), 7.43-7.49 (m,
8H), 7.51-7.55 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3,
mixture of diastereomers) δ 36.1, 36.7, 47.1, 49.4, 49.5, 54.8,
55.3 (CH2), 55.7, 55.8, 55.8, 60.1, 60.2 (CH3), 63.0, 63.6, 110.4,
110.5, 110.6, 111.0, 119.9, 120.0, 123.1, 123.7 (CH), 127.2,
127.3, 127.7, 127.9 (C), 128.9, 128.9, 130.6 (CH), 133.8, 134.1,
143.5, 144.0, 145.0, 148.1, 148.2, 148.8, 149.0, 150.0 (C) ppm;
MS (EI) m/z (%) 466 (10), 465 (31), 464 (M+ - OH, 100), 355
(10), 354 (12), 313 (17), 164 (27), 149 (11), 137 (25); IR (in
CHCl3) ν 3013, 2962, 2935, 1513, 1497, 1461, 1263, 1219, 1143,
1083, 1032, 758, 667 cm-1; HRMS m/z calcd for C27H30NO4S
(M+ - OH): 464.1896. Found: 464.1896.
(3S)-2-(2-Chloroethyl)-3-(3,4-dimethoxyphenyl)-7,8-
dimethoxy-1,2,3,4-tetrahydroisoquinoline [(S)-26]. In a
25-mL Schlenk flask under argon, a solution of the alcohol (S)-
25 (0.135 g, 0.36 mmol) in abs. CH2Cl2 (12 mL) was cooled to
0 °C. Et3N (55 µL, 0.40 mmol), methanesulfonyl chloride (31
µL, 0.40 mmol), and LiCl (0.061 g, 1.45 mmol) were succes-
sively added, and the temperature was increased to room
temperature. After 5 h the reaction was diluted with CH2Cl2,
and the organic phase was washed twice with sat. aqueous
NaHCO3 and twice with H2O. After drying over MgSO4,
filtration, and concentration under reduced pressure, the
residue was purified by column chromatography (n-pentane/
Et2O ) 1/1) to yield 0.097 g (70%) of (S)-26 as a colorless solid;
1
mp 113-115 °C; H NMR (300 MHz, CDCl3) δ 2.51-2.62 (m,
1H), 2.88-3.11 (m, 3H), 3.53-3.68 (m, 4H), 3.85 (s, 3H), 3.85
(s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 4.26 (d, J ) 16.1 Hz, 1H),
6.85-6.88 (m, 4H), 6.97 (d, J ) 1.2 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ 36.6, 41.8, 50.2, 55.5 (CH2), 55.9, 55.9, 60.2
(CH3), 63.8, 110.5, 110.8, 111.1, 120.1, 123.3 (CH), 127.5, 128.0,
134.9, 145.2, 148.4, 149.2, 150.3 (C) ppm; MS (EI) m/z (%) 393
(M+, 22), 392 (18), 391 (M+, 61), 390 (11), 343 (13), 342 (68),
328 (19), 313 (46), 312 (24), 165 (13), 164 (100), 149 (36); IR
(KBr) ν 2999, 2931, 2831, 2362, 1596, 1512, 1458, 1373, 1325,
1263, 1234, 1153, 1081, 1030, 980, 878, 807, 761, 741 cm-1
;
HRMS m/z calcd for C21H26ClNO4 (M+): 391.1550. Found:
(13aS)-2,3,9,10-Tetramethoxy-5-phenylsulfanyl-
5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine [(S)-
24]. In a 25-mL flask under argon, a solution of sulfoxide (S)-
23 (0.124 g, 0.26 mmol), TFAA (0.11 mL, 0.77 mmol), and TFA
(0.12 mL, 1.55 mmol) in abs. toluene (12 mL) was heated at
reflux for 15 h. The volatiles were removed under reduced
pressure, and a part of the resulting crude mixture was
purified by preparative TLC (Et2O/MeOH ) 20/1) for analysis
whereas the rest was passed through silica (Et2O/MeOH ) 20/
1). The combined products were then used for the next step
391.1551.
(3R)-2-(2,2-Diethoxyethyl)-3-(3,4-dimethoxyphenyl)-
7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline [(R)-27]. In
a 10-mL flask, bromoacetaldehyde diethyl acetal (72 µL, 0.48
mmol) was added to a suspension of tetrahydroisoquinoline
(R)-22 (0.132 g, 0.40 mmol), K2CO3 (0.061 g, 0.44 mmol), and
KI (0.080 g, 0.48 mmol) in anhydrous DMF (5 mL). The
reaction mixture was heated at 110 °C for 24 h and diluted
with H2O. The organic phase was kept, and the aqueous phase
was extracted 4 times with Et2O. The combined organic phases
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The resulting crude mixture was purified
by column chromatography (n-pentane/Et2O ) 1/3) to yield
0.135 g (75%) of (R)-27 as a yellow syrup: ee ) 99% (Chiralpak
AD; n-heptane/i-PrOH ) 9/1; Rt ) 15.54 min; λ ) 230.1 nm);
[R]24D +46.8 (c 1.10, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.15
(t, J ) 7.2 Hz, 3H), 1.19 (t, J ) 7.2 Hz, 3H), 2.39 (dd, J ) 5.2
Hz, J ) 13.4 Hz, 1H), 2.76 (dd, J ) 5.2 Hz, J ) 13.4 Hz, 1H),
2.95 (dd, J ) 4.7 Hz, J ) 16.3 Hz, 1H), 3.05 (dd, J ) 9.2 Hz,
J ) 16.3 Hz, 1H), 3.38-3.72 (m, 6H), 3.84 (s, 3H), 3.85 (s, 6H),
3.87 (s, 3H), 4.38 (d, J ) 16.6 Hz, 1H), 4.64 (t, J ) 5.2 Hz,
1H), 6.74 (m, 3H), 6.86 (dd, J ) 1.7 Hz, J ) 8.4 Hz, 1H), 6.96
(d, J ) 1.7 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 15.3
(CH3), 36.2, 50.8 (CH2), 55.8, 55.9 (CH3), 56.3 (CH2), 60.2 (CH3),
61.5, 62.2 (CH2), 63.6, 102.4, 110.8, 120.3, 123.3 (CH), 127.7,
128.9, 135.3, 145.3, 148.2, 149.0, 150.3 (C) ppm; MS (EI) m/z
(%) 445 (M+, 6), 400 (12), 399 (11), 343 (32), 342 (100), 329
(13), 314 (20), 313 (50); IR (in CHCl3) ν 2973, 2933, 2903, 2835,
1594, 1497, 1460, 1423, 1373, 1265, 1236, 1138, 1085, 1058,
1030, 988, 803, 757 cm-1; Anal. Calcd for C25H35NO6: C, 67.39;
H, 7.92; N, 3.14. Found: C, 67.22; H, 7.90; N, 2.94.
1
without any further purification. H NMR (400 MHz, CDCl3,
mixture of diastereomers) δ 2.71-3.00 (m, 4H), 3.18-3.40 (m,
4H), 3.42-3.71 (m, 4H), 3.78 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H),
3.86 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s,
3H), 4.15 (d, J ) 15.9 Hz, 1H), 4.21 (d, J ) 15.9 Hz, 1H), 4.36
(s, 1H), 4.72 (dd, J ) 5.2 Hz, J ) 9.9 Hz, 1H), 6.64 (s, 1H),
6.73 (s, 1H), 6.75-6.90 (m, 4H), 7.24-7.35 (m, 8H), 7.42-7.52
(m, 4H) ppm; 13C NMR (100 MHz, CDCl3, mixture of diaster-
eomers) δ 35.8, 36.1 (CH2), 45.9, 47.7 (CH), 53.0, 53.3 (CH2),
55.8, 55.8, 56.0 (CH3), 57.7 (CH2), 58.9, 59.1 (CH), 60.8 (CH3),
108.0, 108.2, 110.7, 110.8, 110.9, 111.7, 123.6 (CH), 126.2 (C),
127.0 (CH), 128.0 (C), 128.7, 128.9 (CH), 130.8 (C), 131.6 (CH),
132.3, 134.5, 144.9, 147.4, 148.0, 150.1 (C) ppm.
2-[(3S)-3-(3,4-Dimethoxyphenyl)-7,8-dimethoxy-3,4-di-
hydro-1H-isoquinolin-2-yl]-ethanol [(S)-25]. In a flask
under argon, a suspension of tetrahydroisoquinoline (S)-22
(0.097 g, 0.30 mmol), anhydrous MeCN (3 mL), 2-iodoethanol
(25 µL, 0.32 mmol), and NaHCO3 (0.027 g, 0.32 mmol) was
heated to reflux overnight (24 h). After cooling to room
temperature, the reaction mixture was filtered with CH2Cl2,
and the volatiles were evaporated under reduced pressure. The
resulting crude mixture was purified by column chromatog-
raphy (Et2O/MeOH ) 80/1 to 20/1) providing 0.089 g (80%) of
(3S)-2-(2,2-Diethoxyethyl)-3-(3,4-dimethoxyphenyl)-
7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline [(S)-27]. (S)-
27 was prepared in the same manner as described for the
synthesis of (R)-27 using bromoacetaldehyde diethyl acetal (71
µL, 0.47 mmol), tetrahydroisoquinoline (S)-22 (0.129 g, 0.39
1
(S)-25 as a pale yellow foam; [R]25 -36.9 (c 0.45, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 2.38 (dt, J ) 4.7 Hz, J ) 12.9 Hz,
1H), 2.59 (br, 1H), 2.80 (ddd, J ) 4.7 Hz, J ) 12.9 Hz, 1H),
2.99-3.12 (m, 2H), 3.55 (dt, J ) 4.7 Hz, J ) 11.0 Hz, 1H),
J. Org. Chem, Vol. 70, No. 23, 2005 9493