3540
B. Czakó et al. / Bioorg. Med. Chem. 18 (2010) 3535–3542
210.14 (C20), 146.31 (C4), 142.93 (C3), 137.28–116.59 (6C, 4 aro-
matics, C18, C19), 96.01 (C5), 90.06 (C6), 70.11 (C9), 59.49 (C6-O–
CH2), 56.34 (OCH3), 53.38 (C7), 49.60 (C14), 47.42 (C16), 45.90
(C13), 44.25 (NCH3), 35.26 (C15), 32.09 (C20-CH3), 29.31 (C8),
22.98 (C10), 16.25 (C6-O–CH2–CH3), 13.02 (C6-OCH2–CH2–CH3).
[11H, m, H7b, H8a, H8b, H15a, H15b, C20-(CH3)2], 1.14 (3H, t, C6-
O–CH2–CH3, J 7.3); dC (90.6 MHz CDCl3) 147.76 (C4), 142.29 (C3),
135.61–113.45 (6C, 4 aromatics, C18, C19), 101.23 (C5), 89.02
(C6), 75.93 (C20), 69.67 (C9), 58.43 (C6-O–CH2), 56.56 (OCH3),
52.42 (C14), 49.10 (C7), 48.11–47.66 (2C, C13, C16), 44.65
(NCH3), 34.18 (C15), 29.67 (C8), 28.34 [2C, C20-(CH3)2], 22.45
(C10), 14.70 (C6-O–CH2–CH3).
4.2.4. 7a-Acetyl-6-(cyclopropylmethoxy)-6-demethoxy-6,7,8,14-
tetrahydro-6b,14b-endoethenothebaine (8d)
Off-white prisms; mp: 121–123 °C; yield: 1920 mg (57%); ½a D25
ꢂ
4.3.3. 7a-(1-Hydroxy-1-methyl-ethyl)-6-propoxy-6-demethoxy-
ꢁ224 (c 0.68, methanol);
m
max(KBr disc) 1723 (CO) cmꢁ1; calcd
6,7,8,14-tetrahydro-6b,14b-endoethenothebaine (9c)
for C26H31NO4: C, 73.91; H, 7.39; N, 3.31; found: C, 73.68; H,
7.52; N, 3.19; MS m/z (%) 421 (M+, 100); dH (200 MHz CDCl3)
6.59–6.50 (2H, 2d, H1, H2, J8–9 8.0), 5.75 (1H, d, H18, J18–19 8.7),
5.59 (1H, d, H19, J18–19 8.8), 4.48 (1H, s, H5), 3.83 (3H, s, OCH3),
3.43 (2H, d, C6-OCH2, J 10.1) 3.23–2.19 (9H, m, H7b, H9, H10a,
H10b, H16a, H16b, NCH3), 2.01 (3H, s, C20-CH3), 1.91–1.61 (4H,
m, H8a, H8b, H15a, H15b), 0.51–0.11 (5H, m, C6-OCH2–CH–CH2–
CH2); dC (90.6 MHz CDCl3) 208.66 (C20), 147.28 (C4), 142.47 (C3),
133.81–112.23 (6C, 4 aromatics, C18, C19), 96.12 (C5), 89.76
(C6), 78.45 (C6-O–CH2), 68.11 (C9), 56.34 (OCH3), 54.17 (C7),
49.79 (C14), 48.11 (C16), 46.45 (C13), 44.25 (NCH3), 33.26 (C15),
31.30 (C20-CH3), 28.25 (C8), 22.50 (C10), 13.59 (C6-OCH2–CH@),
4.29 (2C, C6-OCH2–CH–CH2–CH2).
White prisms; mp: 135–137 °C; yield: 776 mg (73%); ½a D25
ꢁ187
ꢂ
(c 0.5, chloroform); mmax(KBr disc) 3400 (OH); calcd for C26H35NO4:
C, 73.38; H, 8.29; N, 3.29; found: C, 73.14; H, 8.23; N, 3.45; MS m/z
(%) 425 (M+, 100); dH (200 MHz CDCl3) 6.49–6.41 (2H, 2d, H1, H2, J
8.0), 5.61 (1H, d, H18, J18–19 8.4), 5.48 (1H, d, H19, J18–19 8.5),
1–2
4.66 (1H, s, H5), 3.85–3.78 (5H, m, OCH3, C6-OCH2) 3.23–2.22
(8H, m, H9, H10a, H10b, H16a, H16b, NCH3), 1.99–1.29 [13H, m,
H7b, H8a, H8b, H15a, H15b, C6-OCH2CH–CH2, C20-(CH3)2], 1.14
(3H, t, C6-O–CH2CH–CH3, J 8.3); dC (90.6 MHz CDCl3) 147.26 (C4),
142.92 (C3), 136.15–115.48 (6C, 4 aromatics, C18, C19), 101.59
(C5), 89.51 (C6), 74.36 (C20), 71.43 (C6-O–CH2), 69.51 (C9),
56.13 (OCH3), 52.11 (C14), 49.39 (C7), 48.10–47.63 (2C, C13,
C16), 44.22 (NCH3), 33.68 (C15), 29.40 (C8), 28.31 [2C, C20-
(CH3)2], 22.53 (C10), 21.25 (C6-O–CH2CH–CH3), 10.98 (C6-OCH2–
CH2–CH3).
4.2.5. 7a-Acetyl-6-phenyl-6-demethoxy-6,7,8,14-tetrahydro-
6b,14b-endoethenothebaine (8e)
Light brown solid; mp: 111–113 °C; yield: 2289 mg (67%); ½a D25
ꢂ
m
max(KBr disc) 1730 (CO) cmꢁ1; calcd for
4.3.4. 7a-(1-Hydroxy-1-methyl-ethyl)-6-(cyclopropylmethoxy)-
6-demethoxy-6,7,8,14-tetrahydro-6b,14b-endoethenothebaine
ꢁ201 (c 0.1, methanol);
C28H29NO3: C, 78.66; H, 6.84; N, 3.28; found: C, 78.38; H, 6.91; N,
3.20; MS m/z (%) 427 (M+, 100); dH (360 MHz CDCl3) 7.37–7.23
(5H, m, C6-Ph), 6.65–6.52 (2H, 2d, H1, H2, J8–9 8.1), 5.92 (1H, d,
H18, J18–19 8.6), 5.69 (1H, d, H19, J18–19 8.6), 4.58 (1H, s, H5), 3.80
(3H, s, OCH3) 3.19–2.32 (9H, m, H7b, H9, H10a, H10b, H16a, H16b,
NCH3), 2.09 (3H, s, C20-CH3), 1.88–1.51 (4H, m, H8a, H8b, H15a,
H15b); dC (90.6 MHz CDCl3) 209.54 (C20), 147.71 (C4), 142.51
(C3), 136.65–113.48 (12C, 10 aromatics, C18, C19), 87.01 (C5),
68.91 (C9), 56.25 (OCH3), 51.16 (C7), 49.38 (C14), 48.42 (C16),
46.30 (C13), 44.55 (NCH3), 41.06 (C6), 33.62 (C15), 31.31 (C20-
CH3), 30.09 (C8), 22.06 (C10).
(9d)
Off-white needles; mp: 151–152 °C; yield: 821 mg (75%); ½a D25
ꢂ
ꢁ204 (c 0.6, chloroform);
mmax(KBr disc) 3400 (OH); calcd for
C27H35NO4: C, 73.93; H, 8.04; N, 3.19; found: C, 73.69; H, 8.23; N,
3.09; MS m/z (%) 438 (M+, 100); dH (200 MHz CDCl3) 6.57–6.52
(2H, 2d, H1, H2, J1–2 8.3), 5.74 (1H, d, H18, J18–19 8.9), 5.56 (1H, d,
H19, J18–19 9.0), 4.59 (1H, s, H5), 3.83 (3H, s, OCH3), 3.43 (2H, d,
C6-OCH2, J 10.7), 3.31–2.18 (9H, m, H7b, H9, H10a, H10b, H16a,
H16b, NCH3), 2.02–1.41 [10H, m, H8a, H8b, H15a, H15b, C20-
(CH3)2], 0.51–0.11 (5H, m, C6-OCH2–CH–CH2–CH2); dC (90.6 MHz
CDCl3) 148.01 (C4), 143.16 (C3), 135.55-113.25 (6C, 4 aromatics,
C18, C19), 101.59 (C5), 89.76 (C6), 78.45 (C6-O–CH2), 74.67
(C20), 68.11 (C9), 56.34 (OCH3), 52.79 (C14), 49.67 (C7), 48.11
(C16), 46.45 (C13), 44.25 (NCH3), 33.26 (C15), 29.25 (C8), 28.30
[(2C, C20-(CH3)2], 22.56 (C10), 11.72 (C6-OCH2–CH@), 3.19 (2C,
C6-OCH2–CH–CH2–CH2).
4.3. General procedure for Grignard–Barbier reaction
Thevinones 8a–e (2.5 mmol) in anhyd THF (5 mL) was added
slowly to a solution of alkylmagnesium halide prepared from the
methyl bromide (282 mg, 3 mmol) and magnesium (73 mg,
3 mmol) in diethyl ether (10 mL). Directly after the addition, TLC
showed complete conversion. The excess of Grignard reagent was
decomposed with a saturated solution of ammonium chloride
(10 mL) and the layers were separated. The aqueous layer was ex-
tracted with diethyl ether (2 ꢃ 15 mL), the combined organic layers
were washed with a saturated NaCl solution and dried (Na2SO4).
Evaporating of the solvent in vacuo yielded the crude product.
4.3.5. 7a-(1-Hydroxy-1-methyl-ethyl)-6-phenyl-6-demethoxy-
6,7,8,14-tetrahydro-6b,14b-endoethenothebaine (9e)
White prisms; mp: 114–116 °C; yield: 753 mg (68%); ½a D25
ꢁ167
ꢂ
(c 0.4, chloroform); mmax(KBr disc) 3440 (OH); calcd for C29H33NO3:
C, 78.52; H, 7.50; N, 3.16; found: C, 78.34; H, 7.67; N, 3.01; MS m/z
(%) 443 (M+, 100); dH (360 MHz CDCl3) 7.37–7.23 (5H, m, C6-Ph),
6.65–6.54 (2H, 2d, H1, H2, J1–2 8.2), 5.97 (1H, d, H18, J18–19 8.8),
5.61 (1H, d, H19, J18–19 8.7), 4.59 (1H, s, H5), 3.81 (3H, s, OCH3)
3.11–2.20 (8H, m, H9, H10a, H10b, H16a, H16b, NCH3), 2.04–1.20
[11H, m, H7b, H8a, H8b, H15a, H15b, C20-(CH3)2];dC (90.6 MHzCDCl3)
147.21 (C4), 142.33 (C3), 136.09–113.39 (12C, 10 aromatics, C18,
C19), 88.25 (C5), 70.84 (C20), 69.51 (C9), 56.44 (OCH3), 52.11
(C14), 49.89 (C7), 48.65–48.21 (2C, C13, C16), 44.65 (NCH3), 39.51
(C6), 33.60 (C15), 28.31 [2C, C20-(CH3)2], 22.89–22.23 (2C, C8, C10).
4.3.1. 7a-(1-Hydroxy-1-methyl-ethyl)-6,7,8,14-tetrahydro-6b,
14b-endoethenothebaine (9a)
Physical and spectral data are in agreement with previously
published results.1,21
4.3.2. 7a-(1-Hydroxy-1-methyl-ethyl)-6-ethoxy-6-demethoxy-
6,7,8,14-tetrahydro-6b,14b-endoethenothebaine (9b)
White prisms; mp: 118–120 °C; yield: 606 mg (59%); ½a D25
ꢁ118
ꢂ
(c 0.4, methanol); mmax(KBr disc) 3420 (OH); calcd for C25H33NO4:
4.4. General procedure for the 3-O-demethylation of thevinols
9a–e
C, 72.96; H, 8.08; N, 3.40; found: C, 72.67; H, 8.31; N, 3.19; MS
m/z (%) 411 (M+, 100); dH (200 MHz CDCl3) 6.41–6.34 (2H, 2d,
H1, H2, J1–2 8.1), 5.63 (1H, d, H18, J18–19 8.5), 5.58 (1H, d, H19, J
The methyl ethers 9a–e (1 mmol) and potassium hydroxide
8.5), 4.36 (1H, s, H5), 3.83–3.72 (5H, m, OCH3, C6-OCH2)
18–19
(350 mg, 6.2 mmol) were dissolved in a mixture of glycol (3 mL)
3.03–2.26 (8H, m, H9, H10a, H10b, H16a, H16b, NCH3), 1.91–1.24