The Journal of Organic Chemistry
ARTICLE
(6%) of N-cyclopropylmethyl nororipavine 10 as a pale-yellow, crys-
talline solid; Rf 0.25 (20% MeOH/EtOAc); mp 165ꢀ166 °C (DCM),
[7r-Acetyl-17-(cyclopropylmethyl)-6,14-endo(ethano)tetra-
hydronororipavine]. 1-[(5r,7r)-17-(Cyclopropylmethyl)-4,5-epoxy-
3-hydroxy-6-methoxy-6,14-ethanomorphinan-7-yl]ethanone (12). The
DielsꢀAlder adduct 11 (1.64 g; 4.01 mmol), tartaric acid (642 mg; 4.01
mmol), and Pd/C (450 mg; 10 wt %) were suspended in deionized water
(15 mL). The flask was then evacuated/refilled with H2 gas (four cycles)
and subjected to hydrogenation (1 atm.). The reaction mixture was then
stirred at 80 °C for 16 h under 1 atm of hydrogen. TLC (ethyl acetate)
analysis showed only traces of starting material (Rf = 0.5) and a majority of
12 (Rf = 0.4). The TLC sample was prepared by extraction of few drops of
reaction mixture between ethyl acetate (0.5 mL) and a satd solution of
NaHCO3 (0.5 mL). The hot reaction mixture was then filtered through a
0.7 cm pad of Celite which was then washed with hot deionized water
(70 °C, 2 ꢁ 2 mL). After the filtrate was cooled to room temperature, the
pH was adjusted to 6.60ꢀ6.70 (40% KOH; 930 μL) with vigorous stirring.
The resulting white precipitate was then filtered off and dried overnight
under vacuum at 50 °C to yield a porous white solid (1.52 g). 1H NMR
showed that this material contains ∼3% of starting 11 and ∼3% of corres-
ponding β-diastereomer. Chromatography (10 mL silica, hexane/ethyl
acetate 1:1) of 150 mg of this material afforded 135 mg of pure 12. It was
determined that the crude material contained ∼10% water and inorganic
impurities. The yield of 12 was estimated to be 1.37 g (83%).
12: mp 170ꢀ172 °C (EtOH), 166ꢀ168 °C (crude evaporated from
ethyl acetate); Rf = 0.4 (ethyl acetate); [R]20D ꢀ109.93° (c = 1, CHCl3);
IR (KBr, cmꢀ1) ν 3463, 3075, 2956, 2924, 2874, 2853, 2813, 2777, 1709,
1647, 1610, 1502, 1458, 1384, 1356, 1331, 1283, 1160, 1095, 1030, 958,
820, 702; 1H NMR (CDCl3, 300 MHz) δ 6.70 (d, J = 8.1 Hz, 1H), 6.53
(d, J = 8.1 Hz, 1H), 4.51 (d, J = 1.8 Hz, 1H), 3.43 (s, 3H), 3.10ꢀ3.04 (m,
2H), 2.97 (d, J = 18.3 Hz, 1H), 2.76 (ddd, J = 13.5, 11.4, 3.9 Hz, 1H),
2.65 (dd, J = 12.0, 5.1 Hz, 1H), 2.37ꢀ2.23 (m, 7H), 2.05 (ddd, J = 12.6,
12.6, 5.7 Hz, 1H), 1.74 (dd, J = 13.2, 6.3 Hz, 1H), 1.69ꢀ1.40 (m, 3H),
1.30 (ddd, J = 12.3, 12.3, 8.7 Hz, 1H), 0.83ꢀ0.64 (m, 2H), 0.54ꢀ0.40
(m, 2H), 0.15ꢀ0.05 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 210.9,
145.3, 137.4, 132.4, 128.2, 119.7, 116.5, 94.8, 77.8, 59.8, 58.4, 52.1, 49.5,
46.7, 43.8, 35.5, 35.2, 33.6, 30.5, 28.6, 22.8, 17.6, 9.4, 4.1, 3.4; MS (þEI)
m/z (%) 409 (6), 368 (5), 155 (2), 149 (4), 129 (5), 123 (4), 113 (7),
112 (9), 111 (6); HRMS (þEI) calcd for C25H31N1O4: 409.2253.
Found 409.2261; Anal. Calcd for C25H31N1O4: C, 73.32; H, 7.63.
Found C,73.22; H, 7.59.
[7r-Acetyl-17-(cyclopropylmethyl)-3-[(ethoxycarbonyl)oxy]-
6,14-endo(ethano)tetrahydronororipavine]. (1-[(5r,7r)-17-
(Cyclopropylmethyl)-4,5-epoxy-3-[(ethoxycarbonyl)oxy]-18,19-dihydro-
6-methoxy-6,14-ethenomorphinan-7-yl]ethanone (13). To a suspension
of 12 (0.5 g, ∼1.21 mmol; ∼90% purity;) in warm toluene (10 mL, 40 °C)
were added ethyl chloroformate (171 mg; 1.58 mmol) and triethylamine
(271 μL, 1.94 mmol). Upon addition of triethylamine, most of 12 was
dissolved and the reaction mixture turned a slight-yellow color followed by
red. TLC (ethyl acetate/hexane 1:1) analysis after 10 min showed disap-
pearance of starting material, a major spot corresponding to 13 (Rf =
0.3ꢀ0.4) and two spots of minor impurities (Rf = 0.4, 0.45). After being
stirred for an additional 30 min at room temperature, the reaction mixture
was filtered through a short pad of Celite, and triethylammonium hydro-
chloride and other inorganic material from the previous step were
removed. The filter cake was then washed with toluene (2 ꢁ 2.5 mL)
andthefiltrateconcentratedinvacuo.1H NMR of crude showedessentially
pure 13 and traces of toluene. The crude product (520 mg) was then
dissolvedin EtOH (2.5 mL) at 55°C and crystallized overnight in a freezer,
giving 320 mg (∼61%) of white crystals with slight yellow tinge. When
chromatography (30 mL silica, hexane/ethyl acetate 4:1) was used for
purification, the yield of 13 was 498 mg (95%).
mp 166ꢀ167 °C (methanol); [R]20 ꢀ168.60 (c = 1, CHCl3); IR
D
(KBr) ν 3445, 2908, 1630, 1458, 1234, 1046, 1016, 926, 868 cmꢀ1; 1H
NMR (600 MHz, CDCl3) δ 6.65 (d, J = 8.4 Hz, 1 H), 6.55 (d, J = 8.4
Hz, 1 H), 5.59 (d, J = 6.6 Hz, 1 H), 5.29 (s, 1 H), 5.07 (d, J = 6.6 Hz,
1 H), 4.02 (d, J = 6.6 Hz, 1 H), 3.61 (s, 3 H), 3.29 (d, J = 18.0 Hz, 1 H),
3.00 (dd, J = 12.6, 4.2 Hz, 1 H), 2.90 (m, 1 H), 2.76 (dd, J = 18.0, 7.2
Hz, 1 H), 2.55 (m, 2 H), 2.24 (m, 1 H), 1.71 (d, J = 11.4 Hz, 1 H), 0.97
(m, 1 H), 0.56 (d, J = 8.4 Hz, 2 H), 0.19 (d, J = 8.4 Hz, 2H); 13C NMR
(150 MHz, CDCl3) δ 152.2, 143.1, 138.8, 133.2, 132.6, 126.7, 119.7,
116.5, 112.1, 96.4, 89.4, 58.57, 58.55, 54.9, 46.9, 43.8, 36.2, 31.2, 9.2, 3.9
(2 ꢁ CH2); MS (þEI) m/z (%): 43 (100), 58(19), 84 (56), 227 (8),
282 (12), 337 (41); HRMS calcd for C21H23NO3 337.1678, found
337.1681.
[7r-Acetyl-17-(cyclopropylmethyl)-6,14-endo(etheno)tetra-
hydronororipavine]. 1-[(5r,7r)-17-(Cyclopropylmethyl)-4,5-epoxy-
3-hydroxy-6-methoxy-6,14-ethenomorphinan-7-yl]ethanone (11). Cy-
clopropylmethyl nororipavine 10 (157 mg; 0.53 mmol) was dissolved in
toluene (2.4 mL), and methylvinyl ketone (0.8 mL) was added. The
reaction mixture was stirred with a magnetic stirbar and heated to 80 °C.
After 12 h, TLC (ethyl acetate) analysis indicated no starting material (Rf =
0.05) but the presence of 11 (Rf = 0.5) and the adduct 18 (Rf = 0.4). The
reaction mixture was then concentrated in vacuo, and the resulting light
brown solid was crystallized from hot EtOH (0.4 mL), yielding 11 (182mg,
85%) as a white solid.
11: mp 211ꢀ214 °C(EtOH);Rf =0.5(ethylacetate);[R]20D ꢀ236.47°
(c = 1, CHCl3); IR (KBr, cmꢀ1) ν 3587, 3072, 3051, 3027, 3000, 2970,
2935, 2920, 2891, 2839, 2814, 2788, 1702, 1637, 1607, 1500, 1467, 1427,
1381, 1352, 1317, 1242, 1217, 1163, 1124, 1096, 1084, 1028, 932, 822, 786,
735; 1H NMR (CDCl3, 600 MHz) δ 6.62 (d, J = 7.8 Hz, 1H), 6.49 (d, J =
7.8 Hz, 1H), 5.87 (d, J = 9.0 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.62 (s, 1 H),
3.60ꢀ3.57 (m, 4H), 3.11 (d, J = 18.6 Hz, 1H), 3.03 (dd, J = 12.6, 10.2 Hz,
1H), 2.95 (dd, J = 9.0, 9.0 Hz, 1H), 2.73 (dd, J = 12.0, 4.8 Hz, 1H),
2.45ꢀ2.38 (m, 3H), 2.35 (dd, J= 12.6, 6.6 Hz, 1H), 2.16 (s, 3H), 1.98 (ddd,
J = 13.2, 13.2, 5.4 Hz, 1H), 1.86 (dd, J = 12.6, 2.4 Hz, 1H), 1.36 (dd, J = 12.6,
6.6 Hz, 1H), 0.85ꢀ0.83 (m, 1H), 0.56ꢀ0.49 (m, 2H), 0.17ꢀ0.12 (m, 2H);
13C NMR (CDCl3, 150 MHz) δ 209.3, 146.6, 137.4, 136.4, 134.1, 127.8,
125.7, 119.9, 116.3, 95.2, 81.3, 59.8, 57.1, 53.2, 50.7, 48.5, 44.0, 43.3, 33.5,
30.3, 30.0, 23.3, 9.5, 4.1, 3.5; MS (FABþ) m/z (%) 408 (18), 407 (13), 243
(22), 242 (100), 184 (11), 142 (19); HRMS (FABþ) calcd for C25H29-
N1O4: 407.2096. Found 407.2096.
[7r-Acetyl-17-(cyclopropylmethyl)-6,14-endo(etheno)tetra-
hydronororipavine]. 1-[(5r,7r)-17-(Cyclopropylmethyl)-4,5-epoxy-
3-(3-oxobutyl)-6-methoxy-6,14-ethenomorphinan-7-yl]ethanone (18).
This material was isolated by chromatography of combined filtrates left
after the crystallization of 11. First chromatography: hexane/ethyl acetate
4:1. Second chromatography: toluene/ethyl acetate 3:1.
18: Colorless oil. Rf = 0.5 (ethyl acetate); [R]20D ꢀ183.61° (c = 1,
CHCl3); IR (KBr, cmꢀ1) ν 3484, 3421, 3406, 3075, 2997, 2924, 2835,
2813, 2777, 1712, 1629, 1600, 1497, 1444, 1384, 1357, 1250, 1205, 1170,
1103, 1054, 937, 796; 1H NMR (CDCl3, 300 MHz) δ 6.64(d, J = 8.1 Hz,
1H), 6.51 (d, J = 8.1 Hz, 1H), 5.90 (d, J = 9.0 Hz, 1H), 5.60 (d, J = 9.0 Hz,
1H), 4.57 (s, 1 H), 4.40ꢀ4.20 (m, 2H), 3.61 (s, 3H), 3.58 (dd, J = 11.7,
6.3 Hz, 1H), 3.11 (d, J = 18.3 Hz, 1H), 3.08ꢀ2.90 (m, 2H), 2.87 (t, J =
6.6 Hz, 1H), 2.72 (dd, J = 11.7, 4.5 Hz, 1H), 2.48ꢀ2.28 (m, 4H), 2.22 (s,
3H), 2.16 (s, 3H), 1.98 (ddd, J = 12.0, 12.0, 5.1 Hz, 1H), 1.85 (dd, J =
12.9, 2.7 Hz, 1H), 1.37 (dd, J = 12.0, 5.7 Hz, 1H), 0.91ꢀ0.77 (m, 1H),
0.57ꢀ0.47 (m, 2H), 0.19ꢀ0.09 (m, 2H); 13C NMR (CDCl3, 75 MHz)
δ 209.3, 206.8, 148.6, 140.4, 136.4, 134.6, 129.2, 125.6, 119.6, 116.3,
95.6, 81.4, 65.2, 59.8, 56.9, 53.6, 50.8, 48.1, 43.9, 43.4, 43.2, 33.6, 30.60,
30.55, 29.9, 23.3, 9.5, 4.1, 3.4; MS (FABþ) m/z (%) 478 (100), 408 (26),
407 (16), 326 (14), 246 (28); HRMS from 408 fragment (FABþ) calcd
for C25H30N1O4: 408.2174. Found 408.2142.
13: mp 105ꢀ107 °C (MeOH); Rf = 0.3ꢀ0.4 (ethyl acetate/hexane
1:1); [R]20D ꢀ148.51° (c = 1, CHCl3); IR (KBr, cmꢀ1) ν 3077, 2965,
2930, 2837, 2812, 2778, 2745, 2255, 1764, 1711, 1614, 1492, 1451, 1384,
1369, 1356, 1259, 1243, 1200, 1163, 1130, 1095, 1063, 1024, 993, 958,
4632
dx.doi.org/10.1021/jo200567n |J. Org. Chem. 2011, 76, 4628–4634