Total Synthesis of New 8-(Arylmethyl)berbines
temperature. The organic phase was washed with 10 % aqueous
K2CO3 until basic pH, dried with MgSO4 and the solvent removed
under vacuum. The residue was purified by column chromatog-
raphy (SiO2, CHCl3/MeOH, 9.6:0.4) to yield compound 5 as a yel-
lowish solid (600 mg, 61%); m.p. 158–160 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.12 (s, 1 H, CHO), 7.41–7.35 (m, 5 H, Ph-H), 7.31
(d, J = 8.6 Hz, 2 H, 2Ј-H, 6Ј-H), 7.17 (s, 1 H, α-H), 6.92 (d, J =
8.6 Hz, 2 H, 3Ј-H, 5Ј-H), 6.75, 6.58 (2ϫs, 1 H each, 5-H, 8-H),
5.03 (s, 2 H, CH2Ph), 3.96 (t, J = 5.9 Hz, 2 H, 3-H), 3.93, 3.86
1257 cm–1. EI-MS: m/z (%) = 402 (28) [M + H]+, 401 (69) [M]+,
400 (62) [M – H]+, 311 (38), 310 (100), 210 (13), 190 (34), 176 (19),
91 (72). HRMS: calcd. for C26H27NO3 401.1991; found 401.1988.
Preparation of Berbinium Salts 8-cis and 8-trans: A solution of 1-
(bromomethyl)-4-(trityloxy)benzene (prepared from p-trityloxytol-
uene[17] and NBS) (624 mg, 1.45 mmol) in dry CH2Cl2 (10 mL),
was added to a mixture of berbine 7 (530 mg, 1.32 mmol) and
K2CO3 (200 mg, 1.45 mmol) in dry CH2Cl2 (15 mL) under argon.
The reaction mixture was stirred at room temperature for 20 h, then
the K2CO3 was filtered off and the solvent was concentrated under
(2ϫs, 3 H each, 2ϫOMe), 2.86 (t, J = 5.9 Hz, 2 H, 4-H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 162.8 (CHO), 157.7 (C-4Ј), 149.5,
147.9 (C-6, C-7), 136.7 (Ph-Cq), 132.4 (C-1Ј), 130.0 (C-2Ј, C-6Ј),
128.5, 127.9, 127.4 (Ph-CH), 127.7, 127.3 (C-4a, C-8a), 123.5 (C-
1), 115.2 (C-3Ј, C-5Ј), 113.3, 111.5 (C-5, C-8), 105.4 (C-α), 69.9
(CH2Ph), 56.0, 55.8 (2 ϫ OMe), 38.4 (C-3), 28.7 (C-4) ppm. IR
1
vacuum. The crude H NMR spectrum indicated a mixture of ste-
reoisomers 8 in a cis/trans ratio of 1.5:1, which was purified by
column chromatography (SiO2, CHCl3/MeOH, 9.6:0.4) to obtain
the pure diastereoisomers 8-cis (603 mg, 55%) and 8-trans (329 mg,
30%).
(neat): ν = 3063, 2954, 2723, 1670, 1601, 1577, 1541, 1461, 1453,
˜
1259 cm–1. EI-MS: m/z (%) = 416 (20) [M + H]+, 415 (54) [M]+,
414 (12), 386 (22), 325 (35), 324 (100), 296 (62), 280 (20), 91 (38).
HRMS: calcd. for C26H25NO4 415.1784; found 415.1788.
(؎)-cis-10-Benzyloxy-2,3-dimethoxy-N-[(p-trityloxy)benzyl]ber-
binium Bromide (8-cis): Yellow solid; m.p. 130–132 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.37 (d, J = 7.0 Hz, 6 H, C(Ph-H)3), 7.24–
7.16 (m, 16 H, 2ЈЈ-H, 6ЈЈ-H, C(Ph-H)3, Ph-H), 6.93 (d, J = 8.0 Hz,
1 H, 12-H), 6.84 (dd, J = 8.0, 1.6 Hz, 1 H, 11-H), 6.78 (d, J =
1.6 Hz, 1 H, 9-H), 6.70 (d, J = 8.6 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 6.71,
6.58 (2ϫs, 1 H each, 1-H, 4-H), 5.22 (d, J = 12.9 Hz, 1 H, α-H),
5.07 (d, J = 15.6 Hz, 1 H, 8-H), 4.99 (d, J = 5.4 Hz, 2 H, CH2Ph),
4.89 (d, J = 15.6 Hz, 1 H, 8Ј-H), 4.75 (d, J = 12.9 Hz, 1 H, αЈ-H),
4.74 (dd, J = 10.2, 6.7 Hz, 1 H, 14-H), 4.24 (dd, J = 11.3, 9.7 Hz,
1 H, 6-H), 3.85 (s, 6 H, 2ϫOMe), 3.56 (ddd, J = 11.3, 9.7, 4.8 Hz,
1 H, 6Ј-H), 3.44–3.26 (m, 2 H, 5-H, 5Ј-H), 3.14 (dd, J = 18.3,
6.7 Hz, 1 H, 13-H), 2.96 (dd, J = 18.3, 10.2 Hz, 1 H, 13Ј-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 158.4, 158.1 (C-10, C-4ЈЈ), 149.7,
148.7 (C-2, C-3), 143.4 (3ϫCq CPh3), 136.2 (Cq CH2Ph), 133.6 (C-
2ЈЈ, C-6ЈЈ), 128.9 (C-12), 128.6, 128.5, 128.0, 127.7, 127.4, 127.3
(CH CPh3, CH2Ph), 128.4, 126.9, 124.0, 119.9, 118.9 (C-1ЈЈ, C-4a,
C-8a, C-12a, C-14a), 121.4 (C-3ЈЈ, C-5ЈЈ), 116.8 (C-11), 112.2 (C-
9), 111.7, 109.1 (C-1, C-4), 91.1 (CPh3), 70.0 (CH2Ph), 61.7 (C-14),
61.6 (C-α), 58.3 (C-8), 56.3, 56.0 (2ϫOMe), 48.8 (C-6), 34.6 (C-
10-Benzyloxy-2,3-dimethoxyberberinium Iodide (6): A solution of
enamide 5 (739 mg, 1.78 mmol) in a mixture of dioxane/tert-butyl
alcohol (2:1, 400 mL) and HI (1.5 mL, 57%), was stirred at room
temperature under helium and irradiated with a mercury lamp
(125 W). After 48 h irradiation, a yellow precipitate was formed,
which was filtered and washed with several portions of diethyl ether
1
to obtain compound 6 (718 mg, 77%); m.p. 275–277 °C. H NMR
(200 MHz, DMSO): δ = 9.74 (s, 1 H, 8-H), 9.03 (s, 1 H, 13-H),
8.20 (d, J = 9.0 Hz, 1 H, 12-H), 7.92 (dd, J = 9.0, 1.9 Hz, 1 H, 11-
H), 7.83 (d, J = 1.9 Hz, 1 H, 9-H), 7.71 (s, 1 H, 1-H), 7.55 (d, J =
6.8 Hz, 2 H, Ph-H), 7.48–7.38 (m, 3 H, Ph-H), 7.11 (s, 1 H, 4-H),
5.38 (s, 2 H, CH2Ph), 4.86 (t, J = 5.9 Hz, 2 H, 6-H), 3.94, 3.87
(2ϫs, 3 H each, 2ϫOMe), 3.23 (t, J = 5.9 Hz, 2 H, 5-H) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 158.7 (C-10), 151.4, 148.5 (C-2, C-
3), 147.7 (Ph-Cq), 138.2 (C-8), 135.7 (C-14), 134.3, 130.0, 128.9,
128.4 (C-12a, C-14a, C-8a, C-1a), 128.5, 128.2, 127.8 (Ph-CH),
127.0 (C-13), 120.0, 118.7 (C-12, C-9), 111.1, 108.6, 107.5 (C-11,
C-1, C-4), 70.0 (CH2Ph), 56.1, 55.8 (2ϫOMe), 55.4 (C-6), 25.9 (C-
13), 23.1 (C-5) ppm. IR (neat): ν = 3028, 2934, 1612, 1509, 1446,
˜
1266 cm–1. FAB-MS: m/z (%) = 751 (1) [M + H]+, 750 (2) [M]+,
508 (100), 403 (20), 402 (71), 401 (15), 400 (37), 310 (18), 243 (42),
192 (18). HRMS: calcd. for C52H48NO4 750.3583; found 750.3585.
5) ppm. IR (neat): ν = 3053, 2969, 1603, 1570, 1512, 1455, 1267
˜
cm–1. EI-MS: m/z (%) = 398 (61) [M]+, 396 (42), 322 (42), 308
(100), 307 (42), 306 (88), 91 (99). HRMS: calcd. for C26H24NO3
398.1756; found 398.1758.
(؎)-trans-10-Benzyloxy-2,3-dimethoxy-N-[(p-trityloxy)benzyl]ber-
binium Bromide (8-trans): Yellow solid; m.p. 170–172 °C. 1H NMR
10-Benzyloxy-2,3-dimethoxyberbine (7): To a solution of salt 6
(137 mg, 0.26 mmol) in MeOH, NaBH4 (60 mg, 1.6 mmol) was (400 MHz, CDCl3): δ = 7.40 (d, J = 7.5 Hz, 6 H, C(Ph-H)3), 7.37–
added over a period of 15 min and the mixture was stirred for 4 h.
The solvent was evaporated under vacuum and the obtained resi-
due was dissolved in CHCl3 (30 mL) and washed with water. The
organic layer was dried with anhydrous MgSO4 and the solvent
was concentrated under vacuum to yield berbine 7 (96 mg, 91%)
as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J =
7.4 Hz, 2 H, Ph-H), 7.39 (t, J = 7.4 Hz, 2 H, Ph-H), 7.33 (t, J =
7.4 Hz, 1 H, Ph-H), 7.09 (d, J = 8.3 Hz, 1 H, 12-H), 6.83 (d, J =
7.20 (m, 16 H, 2ЈЈ-H, 6ЈЈ-H, C(Ph-H)3, Ph-H), 7.14 (d, J = 8.6 Hz,
1 H, 12-H), 6.98 (dd, J = 8.6, 2.1 Hz, 1 H, 11-H), 6.70–6.66 (m, 4
H, 1-H, 4-H, 3ЈЈ-H, 5ЈЈ-H), 6.49 (d, J = 2.1 Hz, 1 H, 9-H), 6.06
(dd, J = 11.8, 5.6 Hz, 1 H, 14-H), 5.71 (d, J = 15.3 Hz, 1 H, 8-H),
5.07 (d, J = 11.8 Hz, 1 H, α-H), 5.02 (s, 2 H, CH2Ph), 4.93–4.84
(m, 1 H, 6-H), 3.96–3.93 (m, 1 H, 13-H), 3.89, 3.87 (2ϫs, 3 H
each, 2ϫOMe), 3.80 (d, J = 15.3 Hz, 1 H, 8Ј-H), 3.36–3.19 (m, 4
H, αЈ-H, 6Ј-H, 5-H, 5Ј-H), 3.14 (dd, J = 16.9, 11.8 Hz, 1 H, 13Ј-
8.3 Hz, 1 H, 11-H), 6.75 (s, 1 H, 1-H), 6.71 (s, 1 H, 9-H), 6.63 (s, H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.7, 158.3 (C-10, C-
1 H, 4-H), 5.05 (s, 2 H, CH2Ph), 3.98 (d, J = 15.0 Hz, 1 H, 8-H), 4ЈЈ), 149.6, 148.8 (C-2, C-3), 143.3 (3 ϫ Cq CPh3), 136.3 (Cq
3.90, 3.88 (2ϫs, 3 H each, 2ϫOMe), 3.75 (d, J = 15.0 Hz, 1 H,
8Ј-H), 3.59 (dd, J = 10.9, 3.1 Hz, 1 H, 14-H), 3.28 (dd, J = 15.5,
CH2Ph), 132.1 (C-2ЈЈ, C-6ЈЈ), 130.4 (C-12), 128.7, 128.5, 127.9,
127.5, 127.3, 127.2 (CH CPh3, CH2Ph), 129.5, 128.1, 127.7, 117.7,
3.1 Hz, 1 H, 13-H), 3.18–3.11 (m, 2 H, 5-H, 6-H), 2.84 (dd, J = 116.7 (C-1ЈЈ, C-4a, C-8a, C-12a, C-14a), 121.6 (C-3ЈЈ, C-5ЈЈ), 115.3
15.5, 10.9 Hz, 1 H, 13Ј-H), 2.68–2.57 (m, 2 H, 5Ј-H, 6Ј-H) ppm.
(C-11), 112.3 (C-9), 111.1, 108.4 (C-1, C-4), 91.4 (CPh3), 70.2
(CH2Ph), 66.2 (C-14), 60.5 (C-8), 56.3, 56.0 (2ϫOMe), 54.8 (C-6),
13C NMR (100 MHz, CDCl3): δ = 156.7 (C-10), 147.2 (C-2, C-3),
137.0 (Ph-Cq), 135.3 (C-12a), 129.6 (C-4a), 129.5 (C-12), 128.3, 50.8 (C-α), 29.0 (C-13), 23.7 (C-5) ppm. IR (neat): ν = 3058, 2919,
˜
127.7, 127.2 (Ph-CH), 126.7 (C-14a), 126.5 (C-8a), 113.3 (C-11),
111.7 (C-9), 111.1 (C-4), 108.3 (C-1), 69.8 (CH2Ph), 59.5 (C-14),
2850, 1647, 1607, 1508, 1448, 1263 cm–1. FAB-MS: m/z (%) = 751
(2) [M + H]+, 750 (3) [M]+, 402 (13), 401 (10), 400 (16), 310 (10),
58.6 (C-8), 55.8, 55.6 (2ϫOMe), 51.2 (C-6), 35.9 (C-13), 28.9 (C- 243 (100), 192 (10), 191 (10). HRMS: calcd. for C52H48NO4
5) ppm. IR (neat): ν = 3030, 2928, 1644, 1609, 1506, 1462, 1446, 750.3583; found 750.3571.
˜
Eur. J. Org. Chem. 2010, 638–645
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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