From Berbines to Protopines
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14.0 Hz, 1 H each, Ph-CH2), 3.09 (m, 1 H, 5-H), 2.72 (dd, 3J =
145.7 (O-Carom), 134.3, 133.4, 131.1, 128.0, 127.8 (C-Carom), 130.5,
14.0, 7.0 Hz, 1 H, 13Ј-H), 2.70 (m, 1 H, 6-H), 2.60 (m, 1 H, 6Ј-H), 113.1 (H-Carom, Ar-CH2), 124.4, 112.6, 110.4, 109.6 (H-Carom),
2.39 (m, 1 H, 5Ј-H) ppm. 13C NMR (CDCl3): δ = 151.4, 148.0, 100.7 (OCH2O), 60.8 (OMe on C-9), 57.0, 56.5 (C-6, Ar-CH2),
146.3, 146.2 (O-Carom), 139.1, 137.7, 132.1, 131.4, 130.5 (C-Carom), 55.8, 55.1 (2×OMe), 47.7 (C-8), 45.3 (C-13), 30.8 (C-5) ppm. EI-
128.8, 127.9, 126.5 (H-Carom, Ph-CH2), 126.7, 110.2, 110.1, 105.4
MS: m/z (%) = 475 (7) [M]+, 354 (69) [M – 121]+, 164 (54), 121
(H-Carom), 100.7 (OCH2O), 70.3 (C-14), 60.7 (OMe on C-9), 58.3 (100). EI-HR-MS: calcd. for C28H29NO6 475.1995; found 475.2004.
(Ph-CH2) 55.9 (C-6), 55.8 (OMe), 49.6 (C-8), 46.9 (C-13), 33.2 (C-
Preparation of ( )-Canadinium Salt 1c: Methyl iodide was added
5) ppm. EI-MS: m/z (%) = 447 (2) [M]+, 356 (7) [M – 91]+, 339 (9),
to a solution of ( )-canadine (2 g, 5.90 mmol) in acetone (200 mL).
338 (7), 174 (7), 164 (67), 149 (43), 91 (100). EI-HR-MS: calcd. for
After stirring at room temperature, a mixture of cis/trans (1:4) dia-
stereoisomers 1c was obtained. The crude reaction product was fil-
C27H29NO5 447.2046; found 447.2038.
tered and the solid was recrystallized in acetone to yield the trans
diastereoisomer. The filtrate was concentrated under vacuum and
the residue was purified by column chromatography (CHCl3/
MeOH, 10:1) to yield the pure cis diastereoisomer.
( )-N-(p-Methoxybenzyl)-N-nordihydroallocryptopine (6b): Accord-
ing to the procedure used to synthesize 6a, the dihydro derivative
6b (42 mg, 70%) was obtained from 5b (60 mg, 0.127 mmol) as a
white solid. Decomposition at 90–92 °C. IR (KBr): ν = 3400, 1590,
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1500, 1480, 1270, 1250, 1050 cm–1. H NMR (CDCl3): δ = 7.11 (s,
( )-trans-N-Methylcanadinium Iodide (trans-1c): White solid. M.p.
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3
1 H, 1-H), 6.92 (d, J = 8.5 Hz, 1 H, 12-H), 6.79 (d, J = 8.5 Hz,
2 H, Ar-CH2), 6.72 (d, 3J = 8.5 Hz, 1 H, 11-H), 6.65 (d, 3J = 8.5 Hz,
2 H, Ar-CH2), 6.50 (s, 1 H, 4-H), 5.92 (s, 2 H, OCH2O), 5.41 (d,
3J = 6.7 Hz, 1 H, 14-H), 4.09 (d, 3J = 15.3 Hz, 1 H, 8-H), 3.90–
3.80 (m, 2 H, 8Ј-H, 13-H), 3.83, 3.76, 3.73 (3 s, 3 H each, 3×OMe),
237–238 °C (ref.[17] 252–253 °C). IR (KBr): ν = 1612, 1497, 1480,
˜
1287 cm–1. UV (MeOH): λmax (logε) = 208 (4.30), 220 (3.94), 288
(3.44) nm. 1H NMR (CDCl3 + TFA): δ = 7.02, 6.98 (2 d, 3J =
8.3 Hz, 1 H each, 11-H, 12-H), 6.75, 6.70 (2 s, 1 H each, 1-H, 4-
3
H), 6.00 (s, 2 H, OCH2O), 4.81 (dd, J = 12.3, 4.7 Hz, 1 H, 14-H),
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3.55, 3.24 (2 d, J = 14.0 Hz, 1 H each, Ar-CH2), 3.06 (ddd, J =
15.3, 10.4, 3.8 Hz, 1 H, 5-H), 2.8–2.6 (m, 3 H, 13Ј-H, 6-H, 6Ј-H),
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4.88, 4.56 (2 d, J = 15.9 Hz, 1 H each, 8-H, 8Ј-H), 4.2–4.0 (m, 1
3
H, 6-H), 3.88, 3.87 (2 s, 3 H each, 2×OMe), 3.76 (dd, J = 17.6,
2.39 (dt, J = 14.6, 3.4 Hz, 1 H, 5Ј-H) ppm. 13C NMR (CDCl3): δ
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4.7 Hz, 1 H, 13-H), 3.8–3.7(m, 1 H, 6Ј-H), 3.4–3.3 (m, 5-H), 3.14
= 158.2, 151.4, 147.9, 146.3, 146.2 (O-Carom), 139.1, 132.1, 131.6,
130.7, 129.5 (C-Carom), 130.1, 113.3 (H-Carom, Ar-CH2), 126.7,
110.2, 110.0, 105.4 (H-Carom), 100.7 (OCH2O), 70.4 (C-14), 60.7
(OMe on C-9), 57.5 (Ar-CH2), 55.6, 55.1 (2×OMe), 55.5 (C-6),
49.4 (C-8), 46.9 (C-13), 32.3 (C-5) ppm. EI-MS: m/z (%) = 477 (25)
[M]+, 356 (54) [M – 121]+, 339 (14), 338 (25), 192 (17), 164 (49),
149 (28), 121 (100). EI-HR-MS: calcd. for C28H31NO6 477.2151;
found 477.2154.
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(m, 1 H, 5Ј-H), 3.00 (dd, J = 17.6, 12.3 Hz, 1 H, H-13Ј), 2.93 (s,
3 H, NMe) ppm. 13C NMR (CDCl3 + TFA): δ = 151.3, 148.4,
147.9, 145.3 (O-Carom), 123.2, 121.8, 121.1, 119.7 (C-Carom), 124.4,
113.5, 108.5, 105.4 (H-Carom), 101.7 (OCH2O), 66.2 (C-14), 61.9
(C-8), 61.7 (C-6), 61.3 (OMe on C-9), 55.9 (OMe), 39.5 (NMe),
28.8 (C-13), 23.9 (C-5) ppm. EI-MS: m/z (%) = 354 (1) [M]+, 339
(1), 164 (100). C21H24INO4·H2O (499.35): calcd. C 50.51, H 5.25,
N 2.81; found C 50.70, H 5.10, N 2.94.
N-Benzyl-N-norallocryptopine (7a): Pyridinium chlorochromate
(PCC; 20 mg, 0.093 mmol), sodium acetate (16 mg, 0.19 mmol) and
molecular sieves (3 Å; 50 mg) were added to a stirred solution of
the dihydro derivative 6a (20 mg, 0.045 mmol) in dried CH2Cl2
(20 mL) under argon. The mixture was stirred at room temperature
for 2 h. The solution was filtered and washed with H2O (3×5 mL).
The organic phase was dried with MgSO4 and concentrated under
vacuum. The residue was purified by column chromatography
(CHCl3/MeOH, 8:0.1) to yield the protopine 7a (12 mg, 60%) as a
( )-cis-N-Methylcanadinium Iodide (cis-1c): Yellow solid. M.p. 241–
243 °C (ref.[18] 249–251 °C). IR (KBr): ν = 1600, 1500, 1485, 1280,
˜
1230 cm–1. UV (CH3CN): λmax (logε) = 204 (4.20), 230 (3.84), 292
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(3.40) nm. H NMR (CDCl3): δ = 6.89, 6.83 (2 d, J = 8.5 Hz, 1
H each, 11-H, 12-H), 6.74, 6.67 (2 s, 1 H each, 1-H, 4-H), 5.96 (s,
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2 H, OCH2O), 5.33 (dd, J = 9.4, 6.3 Hz, 1 H, 14-H), 5.20 (d, J
= 16.0 Hz, 1 H, 8-H), 4.99 (d, 3J = 16.0 Hz, 1 H, 8Ј-H), 4.1–3.9
(m, 1 H, 6-H), 3.92, 3.83 (2 s, 3 H each, 2×OMe), 3.8–3.6 (m, 1
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H, 5-H), 3.64 (s, 3 H, NMe), 3.45 (dd, J = 18.6, 6.3 Hz, 1 H, 13-
H), 3.39 (ddd, J = 12.5, 12.5, 8.8 Hz, 1 H, 6Ј-H), 3.15 (dd, J =
18.0, 5.0 Hz, 1 H, 5Ј-H), 3.04 (dd, J = 18.6, 9.4 Hz, 1 H, 13Ј-H)
white solid. M.p. 154–155 °C. IR (KBr): ν = 1660, 1580, 1500,
˜
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1250, 1230, 1080 cm–1. 1H NMR (CDCl3): δ = 7.2–7.0 (m, 5 H,
Ph-CH2), 7.00 (s, 1 H, 1-H), 6.92, 6.81 (2 d, 3J = 8.2 Hz, 1 H each,
11-H, 12-H), 6.60 (s, 1 H, 4-H), 5.95 (s, 2 H, OCH2O), 3.90 (br. s,
4 H), 3.86, 3.75 (2 s, 3 H each, 2×OMe), 3.3–2.7 (m, 4 H), 2.5–2.3
(m, 2 H) ppm. 13C NMR (CDCl3): δ = 195.6 (O=C), 151.7, 148.3,
147.8, 146.1 (O-Carom), 136.3, 136.1, 133.2, 133.1, 128.4 (C-Carom),
130.1, 128.0 (H-Carom, Ph-CH2), 126.9, 110.7, 110.6, 108.4 (H-
Carom), 101.2 (OCH2O), 61,1 (OMe on C-9), 61.0, 56.1 (C-6, Ph-
CH2), 55.7 (OMe), 53.8 (C-8), 46.7 (C-13), 31.5 (C-5) ppm. EI-MS:
m/z (%) = 445 (2) [M]+, 354 (21) [M – 91]+, 164 (47), 149 (25), 91
(100). EI-HR-MS: calcd. for C27H27NO5 445.1889; found 445.1911.
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ppm. 13C NMR (CDCl3): δ = 151.4, 148.7, 147.4, 145.7 (O-Carom),
124.4, 121.1, 120.7, 119.6 (C-Carom), 123.5, 113.5, 108.9, 107.0 (H-
Carom), 101.7 (OCH2O), 65.2 (C-14), 61.6 (OMe on C-9), 59.6 (C-
8), 56.0 (OMe), 52.7 (C-6), 50.5 (NMe), 33.4 (C-13), 23.8 (C-5)
ppm.
Reaction of 1c with HNa: A suspension of HNa (60% in mineral
oil, 180 mg, 4.5 mmol), DMSO (0.2 mL), benzene (2 mL) and 1c
(cis/trans = 8:1) (250 mg, 0.52 mmol) was stirred at room tempera-
ture under argon. After 5 h, the crude product was concentrated
under vacuum and the 1H NMR spectrum clearly indicated the
exclusive presence of the Hofmann elimination product 3c.
Attempts to crystallize this product from an MeOH solution
yielded a small amount of the corresponding dibenzazecine 3c as
well as a methanolic solution of the starting material.
N-(p-Methoxybenzyl)-N-norallocryptopine (7b): According to the
above procedure the protopine derivative 7b (16 mg, 65%) was ob-
tained from 6b (25 mg, 0.052 mmol) as a white solid. M.p. 145–
146 °C. IR (KBr): ν = 1680, 1600, 1590, 1510, 1490, 1280, 1260,
˜
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1080 cm–1. H NMR (CDCl3): δ = 7.05 (d, J = 8.6 Hz, 2 H, Ar-
CH2), 7.01 (s, 1 H, 1-H), 6.94, 6.83 (2 d, 3J = 8.2 Hz, 1 H each,
11-H, 12-H), 6.76 (d, J = 8.6 Hz, 2 H, Ar-CH2), 6.61 (s, 1 H, 4-
3,4-Dimethoxy-6-methyl-5,6,7,8-tetrahydro-11H-benzo[c][1,3]benzo-
dioxolo[5,6-g]azecine (3c): White solid. M.p. 126–128 °C (MeOH).
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H), 5.95 (s, 2 H, OCH2O), 4.00 (br. s, 4 H), 3.86 (s, 3 H, OMe),
1H NMR (CDCl3): δ = 7.09, 6.43 (2 d, 3J = 16.5 Hz, 1 H each,
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3.75 (s, 6 H, 2×OMe), 3.3–2.7 (m, 4 H), 2.7–2.4 (m, 2 H) ppm. Holefinic), 6.95, 6.80 (2 d, J = 8.4 Hz, 1 H each, Harom), 6.91, 6.64
13C NMR (CDCl3): δ = 199.0 (O=C), 158.3, 154.0, 146.4, 146.2, (2 s, 1 H each, Harom), 5.92 (s, 2 H, OCH2O), 3.86, 3.79 (2 s, 3 H
Eur. J. Org. Chem. 2006, 964–971
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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