954
Vol. 51, No. 8
1
mixture was extracted with CHCl3. The organic layer was extracted with
10% aq. HCl, and the acidic aqueous layer was basified using 20% aqueous
NaOH. The aqueous mixture was extracted with CHCl3. The organic layer
was dried over MgSO4, and evaporated off to give 7 (17 mg, 61%). In order
to compare the [a]D value with that of the reported one, compound 7
(15 mg) was dissolved in EtOH (0.5 ml) and reacted with concentrated HCl
(1 drop) at 80 °C. The solvent was evaporated off to leave a hydrochloride
salt of 7, which was recrystallized from MeOH/Et2O (mp 224—226 °C,
lit.11); mp 228—229 °C). Colorless oil. 1H-NMR (CDCl3) d: 1.85—1.96
(2H, m), 2.60—2.79 (4H, m), 2.91—2.99 (1H, m), 3.12—3.19 (1H, m),
3.82 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 3.95
(1H, d, Jϭ14.8 Hz), 4.14 (1H, dd, Jϭ9.0, 5.0 Hz), 4.54 (1H, d, Jϭ14.8 Hz).
FAB-MS: 400 (MϩH)ϩ. Hydrochloride salt [a]D25ϭϪ111.3° (cϭ0.13,
MeOH). These data are identical with the reported ones (lit. [a]D25ϭϪ112.5°
(MeOH)).13)
ethyl]isoquinoline. The NMR data of the product are as follows: H-NMR
(CDCl3) d:1.43 (3H, d, Jϭ7.0 Hz), 2.01—2.10 (2H, m), 2.66—2.88 (2H, m),
3.39—3.46 (1H, m), 3.80 (3H, s), 3.84 (6H, s), 3.87 (3H, s), 3.88 (3H, s),
4.25—4.32 (2H, m), 5.20 (1H, dd, Jϭ10.3, 5.0 Hz), 5.69 (1H, d, Jϭ9.9 Hz),
6.20 (2H, d, Jϭ8.6 Hz), 6.55 (2H, s), 6.56 (1H, s), 6.60 (1H, s), 7.45 (2H, d,
Jϭ8.6 Hz). 13C-NMR (CDCl3) d: 20.3, 28.1, 39.3, 45.8, 49.3, 50.2, 55.9,
56.0, 56.2, 60.8, 69.4, 102.5, 102.6, 109.9, 111.1, 114.3, 124.3, 128.1, 129.1,
138.1, 138.8, 140.0, 147.8, 148.0, 153.2, 172.5.
2-[N-(4-Aminobenzenesulfonyl)-(R)-alanyl]-1,2,3,4-tetrahydro-6,7-
dimethoxy-1-(S)-(3,4,5-trimethoxyphenethyl)isoquinoline (4) To the
AcOH/TFA (20 ml/2 ml) solution of compound 3 (310 mg, 0.49 mmol) was
added a 50% aqueous suspension of 10% Pd/C (1.05 g), and the mixture was
allowed to stand for 20 h at room temperature under H2 atmosphere. Then,
the mixture was filtrated with Celite, and the solvent was evaporated off. To
the residue thus formed was added ethyl acetate, and the organic layer was
washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated
off. The crude product thus obtained was recrystallized from AcOEt–hexane
to give compound 4 (210 mg, 71%) as a colorless powder. [a]D20ϭϩ6.3°
(cϭ0.45, CHCl3). mp 108—110 °C. The product was obtained as a mixture
of several conformational isomers. The NMR spectra of the major isomer
2-Methyl-1,2,3,4-Tetrahydro-6,7-dimethoxy-1-(S)-(3,4,5-trimethoxy-
phenethyl)isoquinoline (8) To the CH3CN solution of the compound 6
(23 mg, 0.059 mmol) were added 37% aqueous HCHO (22 ml, 0.29 mmol)
and NaBH3CN (6 mg, 0.095 mmol), and the mixture was allowed to react for
2.5 h at room temperature. Then, 4 ml of 10% aqueous NaOH was added,
and the mixture was extracted with AcOEt (6 mlϫ3). The organic layer was
extracted with 10% aqueous HCl, and the acidic aqueous layer thus obtained
was basified with 20% aqueous NaOH. The basic aqueous layer was ex-
tracted with AcOEt. The AcOEt layer was washed with brine, dried over
MgSO4, and evaporated off to give the product 8 (19 mg, 80%) as a colorless
oil. In order to compare the [a]D value with that of the reported one, com-
pound 8 was further purified using preparative TLC (silica 5717, Merck)
1
are shown; H-NMR (CDCl3) d: 1.37 (3H, d, Jϭ6.8 Hz), 1.89—2.01 (2H,
m), 2.46 (1H, ddd, Jϭ15.6, 10.0, 5.6 Hz), 2.57—2.66 (3H, m), 3.46 (1H,
ddd, Jϭ13.6, 8.8, 5.6 Hz), 3.62 (1H, dt, Jϭ13.2, 4.0 Hz), 3.79 (3H, s), 3.81
(6H, s), 3.84 (3H, s), 3.86 (3H, s), 4.19 (1H, dq, Jϭ8.8, 7.2 Hz), 5.26 (1H,
dd, Jϭ8.8, 4.8 Hz), 5.80 (1H, d, Jϭ9.2 Hz), 6.27 (2H, d, Jϭ8.8 Hz), 6.37
(2H, s), 6.47 (1H, s), 6.56 (1H, s), 7.45 (2H, d, Jϭ8.4 Hz). 13C-NMR
(CDCl3) d: 20.5, 22.9, 28.2, 32.8, 37.7, 39.1, 49.2, 52.4, 56.1, 56.2, 60.9,
105.2, 105.4, 110.30, 111.32, 111.7, 114.3, 124.6, 129.0, 129.1, 136.3,
137.1, 147.5, 147.8, 153.2, 170.9. Anal. Calcd for C31H39N3O8S: C, 60.64;
H, 6.42; N, 6.85. Found: C, 60.45; H, 6.70; N, 6.47.
1
(CHCl3/MeOHϭ10). [a]D25ϭϩ6.1° (cϭ0.92, MeOH). H-NMR (CDCl3) d:
2.02—2.10 (2H, m), 2.49 (3H, s), 2.49—2.55 (1H, m), 2.62—2.83 (4H, m),
3.13—3.21 (1H, m), 3.45 (1H, t, Jϭ5.5 Hz), 3.82 (3H, s), 3.83 (3H, s), 3.84
(6H, s), 3.86 (3H, s), 6.40 (2H, s), 6.55 (1H, s), 6.58 (1H, s). 13C-NMR
(CDCl3) d: 25.33, 32.07, 36.92, 42.71, 47.97, 52.95, 55.82, 56.03, 56.07,
60.86, 62.70, 105.32, 110.14, 111.31, 126.71, 129.62, 135.95, 138.70,
147.31, 153.08. These data are identical with the reported ones (lit. [a]D25ϭ
ϩ4.8° (MeOH)).13)
1,2,3,4-Tetrahydro-6,7-dimethoxy-2-{N-[4-(trifluoroacetylamino)ben-
zenesulfonyl]-(R)-alanyl}-1-(S)-(3,4,5-trimethoxyphenethyl)-isoquinoline
(5) To the CH2Cl2 solution of compound 4 (44 mg, 0.072 mmol) was
added trifluoroacetic anhydride (27 ml, 0.30 mmol) and pyridine (18 ml,
0.22 mmol), and the mixture was allowed to react for 5 h at room tempera-
ture. The solvent was evaporated off to leave a residue, which was dissolved
in AcOEt. The organic layer thus formed was washed with 5% aqueous HCl
and H2O, dried over MgSO4, and evaporated off. The crude product thus ob-
tained was recrystallized from Et2O–hexane to give 5 (47 mg, 91%) as a col-
orless powder. [a]D20 ϩ21.35° (cϭ1.05, CHCl3). mp 111—113 °C. The prod-
uct was obtained as a mixture of several conformational isomers, thus the
NMR spectra of the major isomer are shown; 1H-NMR (CDCl3) d: 1.42 (3H,
d, Jϭ7.0 Hz), 1.92—2.18 (2H, m), 2.44 (1H, ddd, Jϭ16.5, 11.0, 5.8 Hz),
2.53—2.67 (3H, m), 3.44—3.51 (1H, m), 3.62—3.69 (1H, m), 3.80 (3H, s),
3.82 (6H, s), 3.83 (3H, s), 3.84 (3H, s), 4.26 (1H, dq, Jϭ8.9, 7.0 Hz), 5.27
(1H, dd, Jϭ9.8, 5.2 Hz), 6.14 (1H, d, Jϭ8.8 Hz), 6.35 (2H, s), 6.40 (1H, s),
6.50 (1H, s), 7.40 (2H, d, Jϭ8.5 Hz), 7.72 (2H, d, Jϭ8.9 Hz), 8.12 (1H, br).
13C-NMR (CDCl3) d: 20.6, 22.7, 28.2, 32.8, 37.5, 39.0, 49.3, 52.3, 56.0,
56.1, 60.9, 105.1, 110.0, 111.4, 115.4 (q, JC-Fϭ288.6 Hz), 119.9, 124.0,
128.4, 128.5, 136.2, 136.7, 137.0, 138.9, 147.7, 148.0, 153.2, 170.1 (q,
1-(R)-Allyl-5,8-dibromo-1,2-dihydro-2-[N-phthaloyl-(S)-alanyl]iso-
quinoline (11) The reaction was carried out according to the reported
method,1) except that tetrabutylammonium iodide was used as an additive.
The addition of the quaternary salt increased the reaction yield of 11 up to
95% from 75%.1)
5,8-Dibromo-1,2-dihydro-1-(R)-(3-hydroxypropyl)-2-[N-phthaloyl-(S)-
alanyl]isoquinoline (12) To the THF solution (30 ml) of the compound 11
(2.0 g, 3.8 mmol) was added 1 M BH3–THF solution (3.8 ml, 3.8 mmol)
under Ar atmosphere at room temperature, and the mixture was allowed to
react for 2 h. Water was added to quench the remaining BH3–THF. Then,
30% aqueous H2O2 (0.8 ml) and 3 N aqueous NaOH (0.8 ml) were added to
the mixture, and the reaction continued for another 1 h. Thereafter, water
was added, and the mixture was extracted with ether. The organic layer was
washed with water and brine, dried over MgSO4, and evaporated off. A
residue thus obtained was chromatographed on a silica gel (CH2Cl2/AcOEtϭ
5) to give the crude product. It was recrystallized from AcOEt/Hexane
to give 12 as a colorless powder (1.46 g, 70%). [a]D25ϭϪ572.3° (cϭ1.04,
MeOH). mp 173.2—174.6 °C. 1H-NMR (CDCl3) d: 1.60—1.66 (3H, m),
1.70 (3H, d, Jϭ6.9 Hz), 1.80 (1H, m), 3.69 (2H, t, Jϭ5.5 Hz), 5.18
(1H, q, Jϭ6.8 Hz), 6.07 (2H, d, Jϭ7.7 Hz), 6.52 (1H, d, Jϭ7.9 Hz), 7.20
(1H, d, Jϭ8.8 Hz), 7.22 (1H, d, Jϭ8.8 Hz), 7.70—7.78 (4H, m). 13C-NMR
(CDCl3) d: 15.8, 28.5, 28.8, 47.1, 53.9, 62.4, 110.4, 119.3, 120.3, 123.4,
125.5, 130.7, 131.1, 132.2, 134.2, 135.5, 166.8, 167.7. Anal. Calcd for
C23H20Br2N2O4: C, 50.39; H, 3.68; N, 5.11. Found C, 50.11; H, 3.45; N,
4.99.
1,2,3,4-Tetrahydro-1-(R)-(3-hydroxypropyl)-2-[N-phthaloyl-(S)-alanyl]-
isoquinoline (14) To the MeOH solution (80 ml) of the compound 12
(1.37 g, 2.5 mmol) was added 10% Pd/C (880.0 mg, 0.8 mmol) under H2 at-
mosphere at room temperature, and the mixture was allowed to react for 6 h
at room temperature. Thereafter, AcOEt was added, and the mixture was fil-
tered with Celite. The filtrate was evaporated off to leave a residue, which
was chromatographed on silica gel (CH2Cl2/MeOHϭ20) to give the product
14 as a colorless, amorphous product (610 mg, 62%). [a]D25ϭϪ71.7°
(cϭ1.03, MeOH). The product was obtained as a mixture of two isomers
(1 : 0.4). The NMR spectra of the major isomer are shown; 1H-NMR
(CDCl3) d: 1.59—1.67 (1H, m), 1.80 (3H, d, Jϭ7.3 Hz), 1.82—2.02 (2H,
m), 2.81 (1H, t, Jϭ7.3 Hz), 3.58—3.76 (4H, m), 5.26 (1H, q, Jϭ7.3 Hz),
5.56 (1H, dd, Jϭ8.5, 4.9 Hz), 7.02 (1H, d, Jϭ8.1 Hz), 7.11—7.22 (3H, m),
7.70—7.72 (2H, m), 7.81—7.83 (2H, m). 13C-NMR (CDCl3) d: 15.6, 28.8,
J
C-Fϭ50.7 Hz), 170.46. Anal. Calcd for C33H38F3N3O9S: C, 55.85; H, 5.40;
N, 5.92. Found: C, 56.27; H, 5.65; N, 5.52.
1,2,3,4-Tetrahydro-6,7-dimethoxy-1-(S)-(3,4,5-trimethoxyphenethyl)-
isoquinoline (6) To the CH2Cl2 solution (2 ml) of compound 5 (151 mg,
0.21 mmol) was added lithium aluminum hydride LiAlH4 (121 mg,
3.18 mmol) at 0 °C, and the mixture was allowed to stand for 2 h. Then, the
additional LiAlH4 (42 mg, 1.11 mmol) was applied to the mixture, and the
reaction continued for another 3 h. Water was introduced to quench the re-
ducing agent, and the mixture was warmed to room temperature. The mix-
ture was extracted with AcOEt, and the organic layer thus obtained was
washed with brine, dried over MgSO4, and evaporated off. The residue was
chromatographed on silica gel (CHCl3/MeOHϭ10) to give the product 6
(52 mg, 64%) as a colorless oil. Although the yield was moderate, no side
products were detected in the reaction. [a]D25ϭϪ14.1° (cϭ0.34, CHCl3); 1H-
NMR (CDCl3) d: 1.83 (1H, br), 2.03—2.19 (2H, m), 2.66—2.85 (4H, m),
3.04 (1H, ddd, Jϭ12.8, 7.6, 5.2 Hz), 3.28 (1H, dt, Jϭ12.8, 5.2 Hz), 3.82
(3H, s), 3.83 (3H, s), 3.84 (6H, s), 3.85 (3H, s), 4.02 (1H, dd, Jϭ8.4,
3.6 Hz), 6.47 (2H, s), 6.576 (1H, s), 6.582 (1H, s). These data are identical
with the reported ones.13)
(S)-2,3,9,10,11-Pentamethoxyhomoprotoberberine (7) The compound
6 (27 mg, 0.07 mmol) was mixed with 48% aq. HBr (43 mg) in water
(2.5 ml), then 1.7 ml of 37% aqueous HCHO was added to the mixture. The
reaction was carried out under reflux for 3 h. After cooling to room tempera-
ture, 20% aqueous NaOH was added to make the mixture basic, and the