The Journal of Organic Chemistry
Article
short flash column chromatography (DCM/MeOH = 100:1 to 80:1).
A yellow solid, mp = 171.4−173.8 °C (lit.16 170 °C). 1H NMR (600
MHz, chloroform-d): δ 7.18 (s, 1H), 6.75 (s, 2H), 6.60 (s, 1H), 5.99
(s, 1H), 4.33 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.84 (s,
3H), 3.15 (t, J = 6.0 Hz, 2H), 2.90 (t, J = 6.0 Hz, 2H). 13C{1H} NMR
(150 MHz, chloroform-d): δ 150.5, 149.1, 147.9, 144.7, 141.8, 128.8,
127.5, 123.3, 122.2, 118.8, 111.6, 110.7, 106.8, 95.9, 60.9, 56.2, 56.1,
56.0, 49.6, 49.3, 29.5. IR (neat): 2998, 2953.2, 1602.6, 1506.4, 1450.2,
1362.9, 1271.5, 1184.7, 1107.4, 1019.4, 862.4, 809.9, 649.9, 585.2,
406.1 cm−1. HRMS (ESI) m/z: calcd for C21H24NO4 [M + H]+,
354.1700; found, 354.1608.
(−)-Rotundine (2). (−)-Rotundine (2) was prepared from 5b in
95% yield, 101 mg, according to the general procedure C after flash
column chromatography (DCM/MeOH = 50:1). A pale yellow solid,
mp = 135.8−137.8 °C (lit.18 141−142 °C). H NMR (400 MHz,
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chloroform-d): δ 6.88 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H),
6.73 (s, 1H), 6.62 (s, 1H), 4.25 (d, J = 15.6 Hz, 1H), 3.89 (s, 3H),
3.87 (s, 3H), 3.86−3.84 (m, 6H), 3.56 (d, J = 15.2 Hz, 2H), 3.27 (dd,
J = 15.6, 3.6 Hz, 1H), 3.23−3.10 (m, 2H), 2.89−2.79 (m, 1H), 2.74−
2.60 (m, 2H). 13C{1H} NMR (100 MHz, chloroform-d): δ 150.2,
147.5, 147.4, 145.1, 129.7, 128.7, 127.7, 126.7, 123.8, 111.4, 111.0,
108.6, 60.1, 59.3, 56.1, 55.9, 55.8, 54.0, 51.5, 36.3, 29.1. IR (neat):
2926.9, 2836.9, 2736.3, 1609.1, 1510.7, 1491.8, 1453.2, 1255, 1227.9,
1139.6, 1078.6, 1027.9, 858.3, 783.3, 509, 426 cm−1. HRMS (ESI) m/
z: calcd for C21H26NO4 [M + H]+, 356.1856; found, 356.1860. [α]2D0
−263.2 (c 0.9, CHCl3) [lit.18 [α]D20 −269.0 (c 0.8, CHCl3)]. The
product was analyzed by HPLC to determine the enantiomeric excess:
97% ee (CHIRALPAK ADH, hexane/i-PrOH = 80/20, flow rate: 1.0
mL/min, T = 30 °C, 210 nm), tR(major) = 11.2 min, tR(minor) = 6.2
min.
(−)-Sinactine (3). (−)-Sinactine (3) was prepared from 5c in 90%
yield, 95 mg, according to the general procedure C after flash column
chromatography (DCM/MeOH = 50:1). A pale orange solid, mp =
162.4−165.5 °C (lit.19 175 °C). 1H NMR (400 MHz, chloroform-d):
δ 6.73 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.62
(s, 1H), 5.96 (s, 1H), 5.93 (s, 1H), 4.11 (d, J = 15.2 Hz, 1H), 3.89 (s,
3H), 3.87 (s, 3H), 3.63−3.52 (m, 2H), 3.28 (dd, J = 16.0, 3.2 Hz,
1H), 3.20−3.10 (m, 2H), 2.87−2.77 (m, 1H), 2.73−2.60 (m, 2H).
13C{1H} NMR (100 MHz, chloroform-d): δ 147.5, 147.4, 145.0,
143.3, 129.5, 128.6, 126.7, 121.0, 116.9, 111.3, 108.5, 106.7, 101.0,
59.4, 56.1, 55.8, 53.0, 51.3, 36.3, 29.1. IR (neat): 2890.1, 2833.9,
1511.1, 1455.5, 1357.3, 1253, 1137.4, 1035, 1019.3, 911.2, 797.3,
756.1, 591.6, 477.2 cm−1. HRMS (ESI) m/z: calcd for C20H21NO4
[M + H]+, 340.1543; found, 340.1548. [α]D20 −279.1 (c 0.6, CHCl3)
[lit.19 [α]D20 −312 (c 0.37, CHCl3)]. The product was analyzed by
HPLC to determine the enantiomeric excess: 92% ee (CHIRALPAK
ADH, hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, T = 30 °C,
210 nm), tR(major) = 27.6 min, tR(minor) = 13.0 min.
Dihydroepiberberine (5c). Dihydroepiberberine 5c was prepared
from 6c in 62% yield, 52 mg, according to the general procedure B
after short flash column chromatography (DCM/MeOH = 100:1 to
80:1). A dark yellow solid,8g mp = 162.8−164.7 °C. H NMR (400
1
MHz, chloroform-d): δ 7.17 (s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.60 (s,
1H), 6.52 (d, J = 8.0 Hz, 1H), 6.02 (s, 1H), 5.93 (s, 2H), 4.25 (s,
2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.14 (t, J = 5.6 Hz, 2H), 2.90 (t, J =
5.6 Hz, 2H). 13C{1H} NMR (100 MHz, chloroform-d): δ 149.1,
147.9, 145.4, 142.8, 141.5, 129.6, 127.5, 123.3, 116.0, 110.7, 110.0,
107.5, 106.7, 101.0, 96.6, 56.2, 56.0, 49.3, 49.0, 29.5. IR (neat):
2925.9, 2831.7, 1509.9, 1455.3, 1373.8, 1216.3, 1157, 1062.3, 1016.8,
852.9, 810, 775.4, 481.6 cm−1. HRMS (ESI) m/z: calcd for
C20H20NO4 [M + H]+, 338.1387; found, 338.1302.
Dihydropseudopalmatine (5d). Dihydropseudopalmatine 5d was
prepared from 6d in 70% yield, 62 mg, according to the general
procedure B after short flash column chromatography (DCM/MeOH
= 100:1 to 80:1). A yellow solid,8g mp = 182.3−184.5 °C. H NMR
1
(400 MHz, chloroform-d): δ 7.19 (s, 1H), 6.63 (s, 1H), 6.62 (s, 1H),
6.60 (s, 1H), 6.02 (s, 1H), 4.19 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H),
3.87 (s, 3H), 3.86 (s, 3H), 3.13 (t, J = 6.0 Hz, 2H), 2.90 (t, J = 6.0 Hz,
2H). 13C{1H} NMR (100 MHz, chloroform-d): δ 149.1, 148.7, 147.9,
146.8, 142.1, 127.8, 127.4, 123.2, 120.1, 110.7, 109.3, 107.1, 106.7,
96.3, 56.4, 56.1, 56.1, 56.0, 55.1, 49.4, 29.5. IR (neat): 2997.4, 2929.1,
2833.9, 1610.1, 1512.4, 1461.8, 1346.9, 1256.8, 1141.5, 1100.1,
1022.3, 855.6, 730.1, 562.8 cm−1. HRMS (ESI) m/z: calcd for
C21H24NO4 [M + H]+, 354.1700; found, 354.1620.
General Procedure C of Ir-Catalyzed Enantioselective
Hydrogenation: for the Synthesis of Tetrahydroprotoberber-
ine Alkaloids 1−4. A mixture of [Ir(COD)Cl]2 (1.0 mg, 1.5 μmol,
0.5 mol %) and (S,S)-f-BINAPHANE (5 mg, 6.0 μmol, 2.0 mol %)
was dissolved in a degassed mixed-solvent DCM/AcOH (v/v = 9:1, 3
mL) in an argon atmosphere, and the resulting solution was allowed
to stir at room temperature for 30 min. Then, the dihydroproto-
berberine alkaloids 5 (0.3 mmol, 1.0 equiv) and KBr (3.5 mg, 0.03
mmol, 10 mol %) were added. The mixture was transferred to an
autoclave, which was purged (3 × 10 atm) and charged with H2 (80
atm); then, the reaction was stirred at 25 °C for 72 h. The hydrogen
gas was released slowly, and the solution was quenched with sat.
Na2CO3 aq. The resulting mixture was extracted with DCM (3 × 5
mL). The combined organic phase was dried with Na2SO4 and
evaporated in vacuum. The resulting residue was purified by silica gel
chromatography to give the tetrahydroprotoberberine alkaloids 1−4.
(−)-Canadine (1). (−)-Canadine (1) was prepared from 5a in 93%
yield, 94 mg, according to the general procedure C after flash column
chromatography (DCM/MeOH = 50:1). A pale yellow solid, mp =
132.8−134.8 °C (lit.17 134 °C). 1H NMR (400 MHz, chloroform-d):
δ 6.86 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.59
(s, 1H), 5.91 (s, 2H), 4.24 (d, J = 16.0 Hz, 1H), 3.85 (s, 6H), 3.60−
3.48 (m, 2H), 3.29−3.04 (m, 3H), 2.91−2.75 (m, 1H), 2.73−2.54
(m, 2H). 13C{1H} NMR (100 MHz, chloroform-d): δ 150.4, 146.2,
146.0, 145.2, 130.9, 128.7, 127.9, 127.8, 124.0, 111.1, 108.5, 105.6,
100.8, 60.3, 59.7, 56.0, 54.0, 51.5, 36.5, 29.7. IR (neat): 2901.3,
2832.2, 2744.8, 1483.7, 1387.7, 1274.9, 1219, 1082, 1035.2, 936.4,
858.4, 732.7, 506.1, 438 cm−1. HRMS (ESI) m/z: calcd for
C20H22NO4 [M + H]+, 340.1543; found, 340.1543. [α]2D0 −290.8 (c
1.0, CHCl3) [lit.17 [α]D20 −291 (c 0.93, CHCl3)]. The product was
analyzed by HPLC to determine the enantiomeric excess: 99.9% ee
(CHIRALPAK ADH, hexane/i-PrOH = 80/20, flow rate: 1.0 mL/
min, T = 30 °C, 210 nm), tR(major) = 10.1 min, tR(minor) = 6.4 min.
(−)-Xylopinine (4). (−)-Xylopinine (4) was prepared from 5d in
91% yield, 97 mg, according to the general procedure C after flash
column chromatography (DCM/MeOH = 50:1). A pale yellow solid,
mp = 176.9−178.7 °C (lit.8e 177−178 °C). H NMR (400 MHz,
1
chloroform-d): δ 6.74 (s, 1H), 6.66 (s, 1H), 6.62 (s, 1H), 6.58 (s,
1H), 3.95 (d, J = 14.6 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.86 (s,
3H), 3.85 (s, 3H), 3.68 (d, J = 14.4 Hz, 1H), 3.62−3.56 (m, 1H),
3.25 (dd, J = 16.0, 3.2 Hz, 1H), 3.15 (d, J = 7.2 Hz, 2H), 2.89−2.79
(m, 1H), 2.71−2.57 (m, 2H). 13C{1H} NMR (100 MHz, chloroform-
d): δ 147.7, 147.6, 147.5, 147.5, 129.9, 126.8, 126.4, 126.4, 111.5,
111.5, 109.1, 108.6, 59.7, 58.4, 56.1, 56.1, 56.0, 55.9, 51.5, 36.5, 29.1.
IR (neat): 2928.3, 2833.7, 1610, 1514.3, 1461.9, 1354.9, 1257.8,
1142.7, 1101.1, 1022.7, 856, 729.9 cm−1. HRMS (ESI) m/z: calcd for
C21H26NO4 [M + H]+, 356.1856; found, 356.1852. [α]2D0 −262.3 (c
0.6, CHCl3) [lit.8e [α]D20 −282.4 (c 0.7, CHCl3)]. The product was
analyzed by HPLC to determine the enantiomeric excess: 91% ee
(CHIRALPAK ADH, hexane/i-PrOH = 80/20, flow rate: 1.0 mL/
min, T = 30 °C, 210 nm), tR(major) = 53.5 min, tR(minor) = 14.7
min.
Synthesis of (−)-Canadine (1) on a Gram Scale with 0.1 mol
% Ir Catalyst. A mixture of [Ir(COD)Cl]2 (2.0 mg, 3.0 μmol, 0.1
mol %) and (S,S)-f-BINAPHANE (9.6 mg, 12.0 μmol, 0.4 mol %)
was dissolved in a degassed mixed-solvent DCM/AcOH (v/v = 9:1,
30 mL) in an argon atmosphere, and the resulting solution was
allowed to be stirred at room temperature for 30 min. Then,
dihydroberberine 5a (1.0 g, 3.0 mmol, 1.0 equiv) and KBr (35 mg, 0.3
mmol, 10 mol %) were added. The mixture was transferred to an
autoclave, which was purged (3 × 10 atm) and charged with H2 (80
atm); then, the reaction mixture was stirred at 25 °C for 72 h. The
hydrogen gas was released slowly, and the solution was quenched with
sat. Na2CO3 aq. The resulting mixture was extracted with DCM (3 ×
50 mL). The combined organic phase was dried with Na2SO4 and
evaporated in vacuum. The resulting residue was purified by silica gel
8151
J. Org. Chem. 2021, 86, 8143−8153