HETEROCYCLES

Paper | Special issue | Vol. 77, No. 2, 2009, pp. 1219-1234
Received, 7th August, 2008, Accepted, 24th September, 2008, Published online, 25th September, 2008.
DOI: 10.3987/COM-08-S(F)103

■ Total Synthesis of (±)-Morphine

Kenji Uchida, Satoshi Yokoshima, Toshiyuki Kan, and Tohru Fukuyama*

Laboratory of Synthetic Organic & Medicinal Chemistry, Schol of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan

Abstract

The morphinan skeleton was effectively synthesized by an intramolecular Mannich-type reaction. Further transformation led to the total synthesis of morphine.

INTRODUCTION
Morphine (1) is a fascinating compound, which has been used as an efficient analgesic and is indispensable in treating pain associated with cancer. Although morphine is strictly controlled by authorities due to its addictive nature, its structure is quite attractive from a synthetic point of view. Its complicated pentacyclic skeleton, which includes a quaternary carbon center, has stimulated extensive synthetic efforts. Hence, a number of synthetic studies as well as the total syntheses of morphine have been reported.1 Among them, the Pd-mediated total synthesis reported recently by Trost and co-workers seems quite versatile.1f,g,2 However, in our efforts to develop a novel, non-addictive morphine-type drug, we have investigated the efficient total synthesis of (±)-morphine which involves the unique construction of the morphinan skeleton.

RESULTS AND DISCUSSION
Scheme 1 shows our retrosynthetic analysis. Morphine could be derived from ketone intermediate 2, which in turn could be prepared from ketoaldehyde 3 by either a successive aldol-Michael protocol or a Mannich-type reaction (vide infra). Ketoaldehyde 3 could be obtained via an intramolecular Heck reaction1f,g,2 of 4, which could be prepared from phenol 5 and epoxide 63 using Tsuji-Trost coupling.4

Our synthesis commenced with the conversion of isovanillin (7) into iodide 8 according to a known procedure (Scheme 2).1i,5 Acidic hydrolysis of the acetal and subsequent Wittig olefination gave the enol ether 10, which upon treatment with methanolic HCl furnished phenol 5.

Tsuji-Trost reaction4 was used to condense A ring 5 and C ring 6. As shown in Table 1, this Pd-mediated coupling reaction of phenol 5 and epoxide 6 had an interesting solvent effect. A higher selectivity for desired ether 11, which resulted from the reaction at (a) of 6, was obtained upon employing a polar solvent, such as acetonitrile or N,N-dimethylformamide (entries 3 and 4) instead of toluene or tetrahydrofuran (entries 1 and 2). Hence, Tsuji-Trost reaction of 5 and 6 in acetonitrile, which is suitable for a scaled up reaction, provided desired 11 in 91% yield in a completely regio- and stereoselective manner.

We then focused on the functionalities of the C ring (Scheme 3). After inversion of the hydroxyl group of 11 under Mitsunobu conditions,6 the t-butyldimethylsilyl (TBS) group was removed to give alcohol 14. The alcohol was then converted to nitrile 15 using a Mitsunobu reaction.7 Attempts to cleave the p-nitrobenzoate of 15 under basic conditions provided unsaturated nitrile 16 as a single isomer (E or Z was not determined).

Treatment with lithium borohydride affected the cleavage of the p-nitrobenzoate (Scheme 4). The resulting alcohol was protected as TBS ether 18. To suppress the reductive cleavage of the aromatic iodide, the nitrile was initially reduced with diisobutylaluminum hydride (DIBAL) at –78 °C, and methanol and sodium borohydride were subsequently added to give the desired amine, which was isolated as corresponding methyl carbonate 19a and 2-nitrobenzenesulfonamide (Ns amide) 19b. The crucial intramolecular Heck reaction of 19 proceeded smoothly in refluxing acetonitrile to give a silyl enol ether, which upon treatment with tetrabutylammonium fluoride (TBAF) furnished ketone 20.

With requisite ketone 20 in hand, we then focused on constructing the B and D rings as shown in Scheme 5. To our surprise, acidic hydrolysis conditions for dimethylacetal of 20 provided double cyclization product 21. Upon treatment of 20 in refluxing methanolic HCl, the desired tandem cyclization reaction proceeded smoothly to give desired 21 in excellent yield as the sole product. Even if different amide 20a and 20b was employed, the reaction gave the desired product 21a or 21b, respectively. However, the reaction intermediates were completely different. In the reaction of 20a, which was protected with a methoxycarbonyl group, eight-membered hemiaminal 22 could also be isolated by terminating the reaction after a short time. On the other hand, similar treatment with 20b produced enone 23. These results suggest that in the case of 20a, the reaction proceeds via an intramolecular Mannich-type reaction, while the reaction of 20b proceeds via an aldol condensation-Michael reaction.

The next task in the synthesis of 1 was to change the oxidation state at the C ring. After conversion to the sillyl enol ether from ketone 21a, a Pd-mediated Ito-Saegusa reaction8 provided the enone 24 (Scheme 6). Upon treatment of 24 with H2O2 under basic conditions, the β-selective epoxidation reaction proceeded smoothly to furnish epoxyketone 25 as a single isomer. Although we initially tested the Wharton reaction9 of 25 to obtain allylic alcohol 26, the reaction of 25 and hydrazine in acidic conditions did not proceed, even upon refluxing. Thus, we then investigated a radical fragmentation of epoxyalcohol 27 derived from 25.

Reduction of ketone 25 gave the epoxyalcohol 27 as the sole isomer (Scheme 7). 27 was converted to the thiocarbamate, and subsequent exposure to radical conditions10 using 2,2’-azobis(isobutyronitrile) (AIBN) and tributyltin hydride only led to the decomposition of the thiocarbamate under reflux conditions. However, switching from AIBN to triethylborane induced the epoxide opening at room temperature, and provided allylic alcohol 26. The resulting alcohol was inverted by a two-step oxidation-reduction sequence where the methyl carbamate was reduced with lithium aluminum hydride to afford codeine (29).1h Finally, the methyl ether was cleaved according to a literature procedure to furnish morphine (1).11

In summary, we successfully synthesized morphine using an intramolecular Mannich-type reaction to construct the B and D rings. The substrate for this critical reaction was efficiently prepared by taking advantage of two types of palladium-catalyzed reactions. Further studies on a more efficient and enantioselective total synthesis of morphine are currently underway, and our results will be reported in due course.

EXPERIMENTAL
General. Nuclear magnetic resonance (1H NMR and 13C NMR) spectra were determined on a JEOL-LA400 instrument. Chemical shifts for 1H NMR are reported in parts per million (ppm) downfield from tetramethylsilane (δ) in deuterochloroform as the internal standard, while coupling constants are in hertz (Hz). The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. Chemical shifts for 13C NMR are reported in ppm relative to the centerline of a triplet at 77.0 ppm for deuterochloroform (CDCl3). Melting points (mp) were determined on a Yanaco Micro Melting Point Apparatus. Infrared spectra (IR), which are reported in wavenumbers (cm–1), were recorded on a JASCO FT/IR-410 Fourier Transform Infrared Spectrometer. Mass spectra (MS) were obtained on a JEOL JMS-GCmate MS-DIP20 with polyethylene glycol as the matrix. Analytical thin layer chromatography (TLC) was performed on Merck precoated analytical plates, 0.25 mm thick, silica gel 60 F254. Preparative TLC separations were made on Merck precoated analytical plates, 0.50 mm thick, silica gel 60 F254. Compounds were eluted from the adsorbent with 10% MeOH in CHCl3. Flash column chromatography separations were performed on KANTO CHEMICAL Silica Gel 60 (40-100 mesh). All non-aqueous reactions were carried out in oven-dried glass apparatuses under a slight positive pressure of argon. All solvents were dried over molecular sieves 3A or 4A before use. All other reagents were commercially available, and used without further purification, unless otherwise specified.
2-Iodo-4-methoxy-3-(methoxymethoxy)benzaldehyde (9).
Water (100 mL) and acetic acid (200 mL) were added at 0 °C to a stirred solution of 8 (51.0 g, 139 mmol) in THF (250 mL). Then the reaction mixture was warmed to rt. After stirring for 3 h, the solvent was evaporated under reduced pressure. The crude product was rinsed with hexane to give 9 (39.5 g, 89%) as a white solid. mp 93.0-94.0 °C; IR (film, cm-1) 1682, 1575, 1479, 1274, 1249, 1021, 904, 773; 1H NMR (400 MHz, CDCl3) δ: 10.04 (1H, s), 7.73 (1H, d, J = 8.7 Hz), 6.98 (1H, d, J = 8.7 Hz), 5.20 (2H, s), 3.94 (3H, s), 3.70 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 195.8, 157.8, 146.4, 129.7, 128.0, 112.5, 101.2, 99.5, 59.2, 56.9. Anal. Calcd for C10H11IO4: C, 37.29; H, 3.44; N, 0. Found: C, 37.08; H, 3.58; N, 0.
2-Iodo-4-methoxy-3-(methoxymethoxy)-1-(2-methoxyvinyl)benzene (10).
0.99 M Sodium bis(trimethylsilyl)amide in THF (108 mL, 107 mmol) was added over 50 min at 0 °C to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (36.7 g, 107 mmol) in THF (350 mL). After stirring at 0 °C for 10 min, a solution of 9 (32.8 g, 102 mmol) in THF (135 mL) was added to the reaction mixture over 1 h at 0 °C. After stirring at 0 °C for 10 min, the reaction mixture was warmed to rt, and was subsequently stirred for 4 h. The reaction was quenched with saturated aqueous NH4Cl (50 mL), and the solvent was evaporated under reduced pressure. The residue was diluted with Et2O, and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc/hexane = 25/75) to give 10 (34.0 g, 95%) as a white solid. The product was a mixture of E and Z (70:30) isomers. Anal. Calcd for C12H15IO4: C, 41.10; H, 4.39; N, 0. Found: C, 41.16; H, 4.32; N, 0. E: 1H NMR (400 MHz, CDCl3) δ: 7.04 (1H, d, J = 8.2 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.77 (1H, d, J = 12.8 Hz), 5.99 (1H, d, J = 12.8 Hz), 5.16 (2H, s), 3.83 (3H, s), 3.72 (3H, s), 3.68 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 150.1, 149.4, 145.8, 133.6, 120.9, 112.8, 109.6, 98.9, 98.6, 58.5, 56.5, 56.2. Z: 1H NMR (400 MHz, CDCl3) δ: 7.73 (1H, d, J = 8.2 Hz), 6.87 (1H, d, J = 8.2 Hz), 6.16 (1H, d, J = 7.3 Hz), 5.50 (1H, d, J = 7.3 Hz), 5.14 (2H, s), 3.84 (3H, s), 3.75 (3H, s), 3.68 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 150.0, 147.8, 145.4,
132.1, 125.3, 112.3, 109.2, 98.8, 98.6, 60.6, 58.4, 56.1.
2-Iodo-6-methoxy-3-(2,2-dimetoxyethyl)phenol (5).
Acetyl chloride (4.3 mL, 60.0 mmol) was added at rt to a stirred solution of 10 (42.0 g, 120 mmol) in MeOH (500 mL). After stirring at 40 °C for 1 h, pulverized K2CO3 (8.30 g, 60.0 mmol) was added, and the solvent was evaporated under reduced pressure. The residue was diluted with Et2O, and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was rinsed with hexane to give 5 (39.0 g, 96%) as white crystals. mp 90.0-91.3 °C; IR (film, cm-1) 3374, 2937, 2835, 1599, 1483, 1281, 1119, 1034, 804; 1H NMR (400 MHz, CDCl3) δ: 6.85 (1H, d, J = 8.4 Hz), 6.78 (1H, d, J = 8.4 Hz), 6.19 (1H, s), 4.58 (1H, t, J = 5.5 Hz), 3.89 (3H, s), 3.36 (6H, s), 3.04 (2H, d, J = 5.5 Hz); 13C NMR (100 MHz, CDCl3) δ: 145.4, 144.4, 132.5, 122.1, 110.2, 104.3, 88.7, 56.3, 54.0 (2C), 43.4. Anal. Calcd for C11H15IO4: C, 39.07; H, 4.41; N, 0. Found: C, 39.07; H, 4.47; N, 0.
3-(tert-Butyldimethylsilyloxymethyl)-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-
cyclohexenol (12).
Tris(dibenzylideneacetone)dipalladium(0) (948 mg, 1.04 mmol) and tri-2-furylphosphine (961 mg, 4.14 mmol) were added at rt to a stirred solution of 5 (35.0 g, 104 mmol) and 6 (28.6 g, 119 mmol) in MeCN (280 mL). After stirring for 20 min, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/hexane = 20/80) to give 12 (52.8 g, 91%) as a yellow oil. IR (film, cm-1) 3421, 2933, 2856, 2360, 1587, 1473, 1265, 1119, 1072, 1030, 839; 1H NMR (400 MHz, CDCl3) δ: 6.99 (1H, d, J = 8.2 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.03 (1H, s), 4.88 (1H, s), 4.57 (1H, t, J = 5.5 Hz), 4.48 (1H, d, J = 14.7 Hz), 4.33 (1H, d, J = 14.7 Hz), 4.25 (1H, br), 3.82 (3H, s), 3.36 (3H, s), 3.35 (3H, s), 3.06 (2H, d, J = 5.5 Hz), 2.16-2.01 (2H, m), 1.91-1.88 (1H, m), 1.57-1.53 (1H, m), 0.92 (9H, s), 0.069 (3H, s), 0.065 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 150.2, 146.5, 139.6, 132.8, 127.1, 125.7, 112.0, 104.1, 100.9, 74.9, 66.8, 63.6, 55.5, 54.0, 53.8, 44.1, 28.8, 26.0, 25.9 (3C), 18.3, -5.4 (2C); HRMS (FAB) Calcd for C24H39IO6Si: 578.1561 (M+). Found: 578.1571.
3-(tert-Butyldimethylsilyloxymethyl)-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-
cyclohexen-1-yl 4-nitrobenzoate (13).
2.2 M Diethyl azodicarboxylate in toluene (24.0 mL, 52.8 mmol) was added dropwise over 80 min at 0 °C to a stirred solution of 11 (25.5 g, 44.0 mmol), p-nitrobenzoic acid (8.46 g, 50.6 mmol), and triphenylphosphine (15.0 g, 57.2 mmol) in toluene (200 mL) and THF (40 mL). The reaction mixture was warmed to rt. After stirring for 20 min, the solvent was evaporated under reduced pressure. The residue was diluted with Et2O (50 mL) and hexane (50 mL), and then filtered to remove triphenylphosphine oxide. The filtrate was evaporated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexane = 17/83) to give 13 (28.7 g, 90%) as a yellow foam. IR (film, cm-1) 2933, 2857, 2360, 1720, 1529, 1473, 1344, 1269, 1119; 1H NMR (400 MHz, CDCl3) δ: 8.28 (2H, d, J = 9.2 Hz), 8.19 (2H, d, J = 9.2 Hz), 7.01 (1H, d, J = 8.2 Hz), 6.85 (1H, d, J = 8.2 Hz), 6.11 (1H, s), 5.70 (1H, s), 5.06 (1H, s), 4.58 (1H, t, J = 5.5 Hz), 4.53 (1H, d, J = 14.7 Hz), 4.36 (1H, d, J = 14.7 Hz), 3.85 (3H, s), 3.36 (3H, s), 3.35 (3H, s), 3.07 (2H, d, J = 5.5 Hz), 2.64-2.55 (1H, m), 2.05-2.00 (1H, m), 1.91-1.84 (2H, m), 0.91 (9H, s), 0.07 (3H, s), 0.06 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 164.2, 150.4, 150.3, 146.0, 143.5, 136.1, 133.0, 130.7 (2C), 125.9, 123.4 (2C), 121.3, 112.1, 104.2, 100.9, 74.4, 69.4, 63.8, 55.6, 54.0, 53.8, 44.1, 25.9 (3C), 25.3, 24.9, 18.4, -5.3, -5.4; HRMS (FAB) Calcd for C31H42INO9Si: 727.1674 (M+). Found: 727.1690.
4-[3-(2,2-Dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-3-hydroxymethyl-2-cyclohexen-1-yl 4-nitro-
benzoate (14).
10-Camphorsulfonic acid (16.1 mg, 0.0695 mmol) was added at rt to a stirred solution of 13 (1.01 g, 1.39 mmol) in MeOH (10 mL). After stirring for 80 min, the reaction mixture was diluted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 40/60) to give 14 (802 mg, 94%) as a yellow foam. IR (film, cm-1) 3454, 2939, 2835, 2360, 1720, 1527, 1475, 1344, 1271, 1119, 1024; 1H NMR (400 MHz, CDCl3) δ: 8.28 (2H, d, J = 9.2 Hz), 8.19 (2H, d, J = 9.2 Hz), 7.06 (1H, d, J = 8.2 Hz), 6.89 (1H, d, J = 8.2 Hz), 6.07 (1H, s), 5.69 (1H, s), 5.16-5.14 (1H, m), 4.58 (1H, t, J = 5.5 Hz), 4.49 (1H, d, J = 13.6 Hz), 4.33 (1H, d, J = 13.6 Hz), 3.89 (3H, s), 3.37 (3H, s), 3.36 (3H, s), 3.10-3.07 (2H, m), 2.60-2.52 (1H, m), 2.18-2.10 (1H, m), 1.97-1.79 (2H, m); 13C NMR (100 MHz, CDCl3) δ: 163.8, 150.0, 149.8, 145.3 143.0, 135.5, 132.8, 130.4 (2C), 126.0, 123.3, 123.1 (2C), 111.8, 103.8, 100.9, 75.1, 69.2, 63.8, 55.5, 53.7, 53.5, 43.7, 25.3, 25.0. Anal. Calcd for C25H28INO9: C, 48.95; H, 4.60; N, 2.28. Found: C, 48.88; H, 4.65; N, 2.15.
3-Cyanomethyl-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-cyclohexen-1-yl 4-nitro-
benzoate (15).
2.2 M Diethyl azodicarboxylate in toluene (18.6 mL, 40.9 mmol) was added dropwise over 1 h at 0 °C to a stirred solution of 14 (20.9 g, 34.1 mmol), acetone cyanohydrin (6.92 mL, 68.2 mmol), and triphenylphosphine (11.6 g, 44.2 mmol) in toluene (200 mL). Then the reaction mixture was warmed to rt. After stirring for 40 min, the solvent was evaporated under reduced pressure. The residue was diluted with EtOAc (20 mL) and hexane (30 mL), and then filtered to remove triphenylphosphine oxide. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (CH2Cl2 only, EtOAc/hexane = 25/75 – 33/67, CH2Cl2 only) to give 15 (22.0 g), which contained impurities. The product was not further purified at this stage. IR (film, cm-1) 2941, 2833, 2252, 1722, 1527, 1475, 1346, 1271, 1119, 1026, 918, 721; 1H NMR (400 MHz, CDCl3) δ: 8.28 (2H, d, J = 9.2 Hz), 8.20 (2H, d, J = 9.2 Hz), 7.06 (1H, d, J = 8.2 Hz), 6.89 (1H, d, J = 8.2 Hz), 6.25 (1H, d, J = 2.7 Hz), 5.70 (1H, s), 5.04 (1H, s), 4.58 (1H, t, J = 5.5 Hz), 3.90 (3H, s), 3,63-3.52 (2H, m), 3.37 (3H, s), 3.36 (3H, s), 3.12-3.03 (2H, m), 2.62-2.55 (1H, m), 2.13-2.05 (1H, m), 1.95-1.88 (2H, m); 13C NMR (100 MHz, CDCl3) δ: 164.0, 150.5, 150.1, 145.3 135.0, 134.3, 133.1, 130.7 (2C), 127.5, 126.5 123.5 (2C), 117.4, 112.0, 104.1, 100.8, 75.1, 68.7, 55.6, 54.0, 53.7, 44.0, 25.1, 24.9, 22.4; HRMS (FAB) Calcd for C26H27INO8: 622.0812 (M+). Found: 622.0811.
3-Cyanomethyl-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-cyclohexenol (17).
2.0 M Lithium borohydride in THF (20.5 mL, 40.9 mmol) was added dropwise over 20 min at 0 °C to a stirred solution of crude 15 (22.0 g) in Et2O (200 mL) and MeOH (10.0 mL). The reaction mixture was warmed to rt and stirred for 40 min. Saturated aqueous NH4Cl was added to the solution, and the mixture was extracted with Et2O. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 40/60 – 60/40) to give 17 (15.3 g, 95% in 2 steps) as a colorless oil. IR (film, cm-1) 3449, 2936, 2835, 2250, 1589, 1476, 1268, 1119, 1066, 1027; 1H NMR (400 MHz, CDCl3) δ: 7.03 (1H, d, J = 8.2 Hz), 6.86 (1H, d, J = 8.2 Hz), 6.14 (1H, s), 4.94 (1H, s), 4.57 (1H, t, J = 5.5 Hz), 4.39 (1H, s), 3.87 (3H, s), 3.52 (2H, s), 3.36 (3H, s), 3.35 (3H, s), 3.07-3.04 (2H, m), 2.38-2.28 (1H, m), 1.95-1.84 (2H, m), 1.63-1.55 (1H, m); 13C NMR (100 MHz, CDCl3) δ: 150.2, 145.5, 132.9, 132.0, 131.2, 126.3, 117.8, 111.9, 104.1, 100.0, 76.2, 65.0, 55.6, 54.1, 53.8, 44.0, 28.9, 25.4, 22.0; HRMS (FAB) Calcd for C19H24INO5: 473.0699 (M+). Found: 473.0698.
tert-Butyldimethyl[3-cyanomethyl-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-
cyclohexenoxy]silane (18).
t-Butyldimethylchlorosilane (4.89 g, 32.5 mmol) was added at rt to a stirred solution of 17 (12.8 g, 27.0 mmol) and imidazole (2.21 g, 32.5 mmol) in DMF (67.5 mL), and then the reaction mixture was stirred for 1 h. Water was then added to the solution, and the mixture was extracted with Et2O. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was rinsed with hexane and filtered to collect 18 (13.5 g) as white crystals. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (Et2O/hexane = 20/80 – 25/75) to give 18 (1.70 g) as white crystals. Finally, 15.2 g of 18 was obtained in 96% yield. mp 106.5-107.5 °C; IR (film, cm-1) 2952, 2894, 2856, 2250, 1589, 1475, 1265, 1120, 1072, 1022, 837, 804; 1H NMR (400 MHz, CDCl3) δ: 7.01 (1H, d, J = 8.2 Hz), 6.85 (1H, d, J = 8.2 Hz), 6.00 (1H, s), 4.94 (1H, s), 4.56 (1H, t, J = 5.5 Hz), 4.36 (1H, s), 3.85 (3H, s), 3.54 (1H, d, J = 19.2 Hz), 3.45 (1H, d, J = 19.2 Hz), 3.35 (3H, s), 3.34 (3H, s), 3.08-3.02 (2H, m), 2.21-2.16 (1H, m), 1.92-1.89 (2H, m), 1.57-1.49 (1H, m), 0.89 (9H, s), 0.10 (3H, s), 0.09 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 150.2, 145.6, 132.9 (2C), 130.0 126.2, 117.8, 111.9, 104.2, 101.0, 76.8, 65.9, 55.6, 54.0, 53.8, 44.0, 29.8, 25.9, 25.8 (3C), 21.8, 18.1, -4.6, -4.7. Anal. Calcd for C25H38INO5Si: C, 51.10; H, 6.52; N, 2.38. Found: C, 51.03; H, 6.39; N, 2.36.
tert-Butyldimethyl[3-[2-methoxycarbonylaminoethyl]-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]-phenoxy-2-cyclohexenoxy]silane (19a).
0.99 M Diisobutylaluminium hydride in toluene (3.67 mL, 3.63 mmol) was added dropwise over 10 min at -78 °C to a stirred solution of 18 (1.64 g, 2.79 mmol) in CH2Cl2 (30.0 mL), and then the reaction mixture was stirred for 2 h. Sodium borohydride (317 mg, 8.37 mmol) and MeOH (10.0 mL) were added to the solution. The reaction mixture was warmed to rt, and was subsequently stirred for 40 min. Pulverized K2CO3 (463 mg, 3.35 mmol) and methyl chloroformate (259 µL, 3.35 mmol) were added, and the reaction mixture was stirred for 30 min. 30% Aqueous potassium sodium (+)-tartrate (30.0 mL) was added to the mixture. The reaction mixture was stirred for 1 h, and then extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 25/75) to give 19a (1.71 g, 94%) as a white foam. IR (film, cm-1) 3352, 2950, 2856, 1724, 1475, 1255, 1120, 1072, 1026, 835, 775; 1H NMR (400 MHz, CDCl3) δ: 6.94 (1H, d, J = 8.2 Hz), 6.79 (1H, d, J = 8.2 Hz), 5.57 (1H, s), 5.08 (1H, s), 5.02 (1H, s), 4.51 (1H, t, J = 5.5 Hz), 4.26 (1H, s), 3.78 (3H, s), 3.59 (2H, s), 3.43-3.37 (2H, m), 3.31 (3H, s), 3.29 (3H, s), 3.06-2.96 (2H, m), 2.62-2.52 (2H, m), 2.40-2.32 (1H, m), 2.13-2.05 (1H, m), 1.80-1.72 (2H, m), 1.47-1.40 (1H, m), 0.85 (9H, s), 0.05 (3H, s), 0.04 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 156.9, 150.2, 145.4, 136.7, 132.7, 131.5, 125.6, 111.9, 104.1, 101.1, 77.3, 66.1, 55.5, 53.9, 53.6, 51.7, 44.0, 39.6, 33.6, 29.8, 25.7 (3C), 25.4, 18.0, -4.8 (2C); HRMS (FAB) Calcd for C27H44INO7Si: 649.1932 (M+). Found: 649.1935.
1-(2,2-Dimethoxyethyl)-4-methoxy-9a-(2-methoxycarbonylaminoethyl)-5a,6,7,9-tetrahydrodibenzo-
furan-8-one (20a).
Tris(dibenzylideneacetone)dipalladium(0) (116 mg, 0.127 mmol) was added at rt to a stirred solution of 19a (1.65 g, 2.54 mmol), tri-o-tolylphosphine (155 mg, 0.508 mmol), and triethylamine (704 µL, 5.08 mmol) in MeCN (17.0 mL). Then the reaction mixture was refluxed for 1 h, cooled to rt and 1.0 M tetrabutylammonium fluoride in THF (3.05 mL, 3.05 mmol) was added. After stirring for 90 min, saturated aqueous NH4Cl was added to the mixture, which was subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 25/75 – 100/0) to give 20a (897 mg, 87%) as a pale yellow foam. IR (film, cm-1) 3327, 2941, 2837, 1716, 1541, 1506, 1435, 1344, 1281, 1169, 1120, 1068, 733; 1H NMR (400 MHz, CDCl3) δ: 6.77-6.70 (2H, m), 4.96 (1H, s), 4.62-4.52 (2H, m), 3.85 (3H, s), 3.62 (3H, s), 3.39 (3H, s), 3.34 (3H, s), 3.30-3.20 (1H, m), 2.92 (1H, d, J = 15.6 Hz), 2.90-2.80 (3H, m), 2.65 (1H, d, J = 15.6 Hz), 2.40-2.14 (5H, m), 1.93-1.83 (1H, m); 13C NMR (100 MHz, CDCl3) δ: 210.0, 156.8, 147.8, 142.6, 127.9, 125.8, 122.8, 111.9, 105.5, 84.7, 55.7, 54.5, 53.6, 51.9, 49.4, 48.2, 40.1, 37.0, 34.4, 33.1, 26.4; HRMS (FAB) Calcd for C21H29NO7: 407.1944
(M+). Found: 407.1952.
4,5-Epoxy-3-methoxy-17-methoxycarbonylmorphinan-8-one (21a).
Acetyl chloride (969 µL, 13.6 mmol) was added at rt to a stirred solution of 20a (555 mg, 1.36 mmol) in MeOH (10.0 mL), and then the reaction mixture was refluxed for 12 h. It was cooled to rt, and acetyl chloride (969 µL, 13.6 mmol) was added. Then the reaction mixture was refluxed for another 12 h, and cooled to rt, diluted with toluene, and evaporated under reduced pressure to remove MeOH. The organic layer was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 50/50) to give 21a (440 mg, 94%) as a white foam. mp 126-128 °C; IR (film, cm-1) 2949, 1709, 1504, 1448, 1405, 1313, 1263, 1130, 920, 730; 1H NMR (400 MHz, CDCl3) δ: 6.75 (1H, d, J = 8.2 Hz), 6.58 (1H, d, J = 8.2 Hz), 5.42-5.34 (minor amide rotamer) (0.40 1H, br), 5.29-5.21 (major amide rotamer) (0.60 1H, br), 4.90 (1H, s), 4.11 (major amide rotamer) (0.60 1H, d, J = 13.8 Hz), 3.96 (minor amide rotamer) (0.40 1H, d, J = 13.8 Hz), 3.87 (3H, s), 3.74 (3H, s), 3.20-2.70 (2H, m), 2.72 (1H, s), 2.64 (1H, d, J = 18.3 Hz), 2.35-2.04 (3H, m), 1.95-1.75 (3H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 207.6, 155.4, 146.5, 141.6, 128.0, 126.4, 119.8, 114.1, 88.1, 56.2, 52.6, 50.8, 47.7, 42.8, 37.0, 35.8, 33.4, 29.0, 26.7 (minor amide rotamer) δ: 207.0, 155.3, 146.5, 141.6, 128.0, 126.6, 119.8, 114.1, 88.1, 56.2, 52.6, 50.6, 47.6, 42.9, 37.1, 36.1, 33.4, 28.9, 26.7; HRMS (FAB) Calcd for C19H21NO5: 343.1420 (M+). Found: 343.1430.
4,5-Epoxy-3-methoxy-17-methoxycarbonylmorphinan-6-en-8-one (24).
1.00 M Lithium bis(trimethylsilyl)amide in THF (12.4 mL, 12.4 mmol) was added over 5 min at 0 °C to a stirred solution of 21a (3.03 g, 8.82 mmol) and chlorotrimethylsilane (1.34 mL, 10.6 mmol) in THF (50.0 mL). After stirring for 40 min, saturated aqueous NH4Cl was added to the mixture, which was subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was dissolved in MeCN (50.0 mL), and palladium acetate (2.97 g, 13.2 mmol) was added to the solution at rt. After stirring for 2 h, saturated aqueous NaHCO3 was added to the mixture, which was subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 40/60 – 60/40) to give 24 (2.78 g, 92% in 2 steps) as a white foam. mp 122-124 °C; IR (film, cm-1) 2951, 1697, 1504, 1446, 1277, 910, 764; 1H NMR (400 MHz, CDCl3) δ: 6.76 (1H, d, J = 8.2 Hz), 6.65-6.56 (2H, m), 6.00 (1H, d, J = 10.1 Hz), 5.42-5.19 (2H, m), 4.15-4.10 (major amide rotamer) (0.60 1H, m), 4.05-3.97 (minor amide rotamer) (0.40 1H, m), 3.86 (3H, s), 3.76 (major amide rotamer) (0.60 3H, s), 3.73 (minor amide rotamer) (0.40 3H, s), 3.15-3.00 (1H, m), 2.90-2.80 (1H, m), 2.67 (1H, d, J = 18.3 Hz), 1.96-1.80 (2H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 194.6, 155.3, 142.8, 142.5, 140.2, 131.3, 127.8, 125.8, 120.0, 114.2, 84.8, 56.1, 52.5, 48.7, 46.8, 42.8, 37.3, 33.2, 28.7 (minor amide rotamer) δ: 194.3, 155.4, 142.8, 142.5, 139.8, 131.4, 127.8, 126.0, 120.0, 114.2, 84.8, 56.1, 52.5, 48.7, 46.7, 42.9,
37.4, 33.5, 28.5; HRMS (FAB) Calcd for C19H19NO5: 342.1341 (M++H). Found: 342.1338.
4,5-Epoxy-6,7-epoxy-3-methoxy-17-methoxycarbonylmorphinan-8-one (25).
30% Aqueous H2O2 (897 µL, 8.79 mmol) and 5% aqueous sodium hydroxide (3.52 mL, 4.39 mmol) were added at 0 °C to a stirred solution of 24 (600 mg, 1.76 mmol) in MeCN (12.0 mL). After stirring for 15 min, saturated aqueous NH4Cl was added to the mixture, which was subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was rinsed with EtOAc/hexane (15/85) to give 25 (572 mg, 91%) as white crystals. mp 189-192 °C; IR (film, cm-1) 2951, 1699, 1506, 1448, 1315, 1279, 1132, 1053, 798, 733; 1H NMR (400 MHz, CDCl3) δ: 6.78 (1H, d, J = 8.2 Hz), 6.65 (1H, d, J = 8.2 Hz), 5.17-4.96 (2H, m), 4.07 (major amide rotamer) (0.55 1H, d, J = 13.7 Hz), 3.93 (minor amide rotamer) (0.45 1H, d, J = 13.7 Hz), 3.88 (3H, s), 3.74 (major amide rotamer) (0.55 3H, s), 3.71 (minor amide rotamer) (0.45 3H, s), 3.61 (1H, s), 3.31-3.19 (1H, m), 3.18-3.11 (2H, m), 2.85-2.70 (1H, m), 2.63 (1H, d, J = 18.3 Hz), 2.05-1.94 (1H, m), 1.84-1.73 (1H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 202.3, 155.0, 144.1, 142.3, 126.5, 125.5, 120.3, 114.3, 83.8, 58.1, 56.0, 54.8, 52.6, 47.2, 46.5, 45.8, 36.9, 35.0, 29.1 (minor amide rotamer) δ: 202.0, 155.2, 144.1, 142.3, 126.7, 125.5, 120.3, 114.3, 83.8, 58.1, 56.0, 54.8, 52.5, 47.2, 46.3, 45.7, 37.0, 35.3, 28.9; HRMS (FAB) Calcd for C19H20NO6: 358.1290 (M++H). Found: 358.1280.
4,5-Epoxy-6,7-epoxy-3-methoxy-17-methoxycarbonylmorphinan-8-ol (27).
Sodium borohydride (60.6 mg, 1.60 mmol) was added at 0 °C to a stirred solution of 25 (572 mg, 1.60 mmol) in MeOH (5.0 mL) and CH2Cl2 (5.0 mL). After stirring for 20 min, saturated aqueous NH4Cl was added to the mixture, which was subsequently extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was rinsed with Et2O/hexane (50/50) to give 27 (521 mg, 91%) as white crystals. mp 182-185 °C; IR (film, cm-1) 3440, 2933, 1680, 1506, 1452, 1408, 1327, 1275, 1128, 1057, 918, 800, 733; 1H NMR (400 MHz, CDCl3) δ: 6.80 (1H, d, J = 8.2 Hz), 6.69 (1H, d, J = 8.2 Hz), 5.00-4.81 (2H, m), 4.31-4.23 (1H, m), 4.08-3.88 (4H, m), 3.75 (minor amide rotamer) (0.40 3H, s), 3.71 (major amide rotamer) (0.60 3H, s), 3.39-3.28 (2H, m), 3.22-3.18 (1H, m), 2.98-2.81 (1H, m), 2.70 (1H, d, J = 18.3 Hz), 2.17 (1H, s), 1.80-1.61 (2H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 155.3, 144.6, 142.3, 128.2, 127.5, 119.4, 113.5, 84.9, 64.9, 56.0, 54.6, 52.5, 50.9, 49.9, 38.7, 38.1, 37.6, 37.4, 31.7 (minor amide rotamer) δ: 154.9, 144.6, 142.4, 128.0, 127.5, 119.5, 113.7, 84.9, 65.4, 56.1, 54.5, 52.6, 50.9, 50.1, 38.7, 38.2, 37.3, 37.2, 31.9; HRMS (FAB) Calcd for C19H21NO6: 360.1447 (M++H). Found: 360.1457.
4,5-Epoxy-3-methoxy-17-methoxycarbonylmorphinan-7-en-6-ol (26).
N,N-Dimethylaminopyridine (16.3 mg, 0.134 mmol) and 1,1’-thiocarbonyldiimidazole (44.1 mg, 0.223
mmol) were added at rt to a stirred solution of 27 (40.0 mg, 0.111 mmol) in 1,2-dichloroethane (1.0 mL). The reaction mixture was heated for 15 h at 60 °C, cooled to rt, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (CH2Cl2 only, twice) to give thioimidazolide (48.3 mg), which contained impurities. The product was dissolved in THF (1.0 mL), and to the cloudy solution were added tributylthin hydride (89.8 µL, 0.334 mmol) and 1.02 M triethylborane in hexane (109 µL, 0.111 mmol) at rt. The mixture turned clear, and was stirred for 3 h. Half saturated aqueous potassium fluoride was added to the mixture, stirred for 2 h, and subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc/hexane = 50/50 – 60/40) to give 26 (18.3 mg, 48% in 2 steps) as a white foam. IR (film, cm-1) 3417, 2952, 1680, 1606, 1504, 1450, 1327, 1275, 1028, 796, 731; 1H NMR (400 MHz, CDCl3) δ: 6.70 (1H, d, J = 8.0 Hz), 6.57 (1H, d, J = 8.0 Hz), 6.05-6.00 (1H, m), 5.68-5.60 (1H, m), 4.85-4.75 (2H, m), 4.27 (1H, s), 4.12 (minor amide rotamer) (0.40 1H, dd, J = 13.7 Hz, 4.6 Hz), 3.97 (major amide rotamer) (0.60 1H, dd, J = 13.7 Hz, 4.6 Hz), 3.85 (3H, s), 3.76 (minor amide rotamer) (0.40 3H, s), 3.73 (major amide rotamer) (0.60 3H, s), 3.01-2.80 (3H, m), 2.75 (1H, d, J = 18.3 Hz), 2.03-1.84 (2H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 155.9, 145.7, 142.3, 131.8, 131.7, 129.3, 125.8, 119.2, 113.2, 94.0, 67.7, 56.2, 52.7, 50.3, 44.2, 38.9, 38.0, 35.3, 28.9 (minor amide rotamer) δ: 155.6, 145.7, 142.3, 131.8, 131.6, 129.3, 125.6, 119.2, 113.2, 94.1, 67.7, 56.2, 52.8, 50.6, 44.2, 39.1, 38.0, 35.1, 29.2; HRMS (FAB) Calcd for C19H21NO5: 343.1420 (M+). Found: 343.1421.
4,5-Epoxy-3-methoxy-17-methoxycarbonylmorphinan-7-en-6-one (28).
Dess-Martin periodinane (72.3 mg, 0.170 mmol) was added at rt to a stirred solution of 26 (45.0 mg, 0.131 mmol) in CH2Cl2 (1.5 mL). After stirring for 30 min, saturated aqueous NaHCO3 was added to the mixture, which was subsequently extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by PTLC (EtOAc/hexane = 67/33) to give 28 (42.8 mg, 96%) as a white foam. IR (film, cm-1) 2952, 1684, 1504, 1446, 1406, 1321, 1273, 1234, 731; 1H NMR (400 MHz, CDCl3) δ: 6.72 (1H, d, J = 8.2 Hz), 6.68-6.61 (2H, m), 6.14 (1H, dd, J = 10.1 Hz, 2.8 Hz), 5.07-5.01 (major amide rotamer) (0.60 1H, br), 4.91-4.85 (minor amide rotamer) (0.40 1H, br), 4.70 (1H, s), 4.18-4.11 (minor amide rotamer) (0.40 1H, m), 4.04-3.97 (major amide rotamer) (0.60 1H, m), 3.87 (3H, s), 3.78 (minor amide rotamer) (0.40 3H, s), 3.74 (major amide rotamer) (0.60 3H, s), 3.07-3.04 (1H, m), 2.96-2.80 (3H, m), 2.03-1.87 (2H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 194.0, 155.9, 147.1, 144.9, 142.8, 133.2, 127.8, 124.6, 120.5, 115.1, 87.7, 56.7, 52.9, 50.4, 43.5, 40.3, 38.1, 33.5, 29.1 (minor amide rotamer) δ: 194.0, 155.4, 146.8, 144.9, 142.8, 133.3, 127.8, 124.4, 120.5, 115.1, 87.7, 56.7, 53.0, 50.7, 43.4, 40.4, 38.1, 33.3, 29.4; HRMS (FAB) Calcd for C19H19NO5: 341.1263 (M+). Found: 341.1274.
Codeine (29).
Lithium aluminum hydride (17.2 mg, 0.454 mmol) was added at rt to a stirred solution of 28 (31.0 mg,
0.0908 mmol) in THF (2.0 mL). The reaction mixture was refluxed for 40 min, and subsequently cooled to 0 °C. Then MeOH (0.2 mL) and sodium sulfate decahydrate (250 mg) were added. The mixture was diluted with CH2Cl2, stirred for 3 h, filtered, and evaporated under reduced pressure. The crude product was purified by PTLC (CHCl3/MeOH = 90/10) to give codeine (29) (22.0 mg, 81%) as white crystals. mp 144-146 °C (recrystallized with MeOH/H2O); IR (film, cm-1) 3386, 2931, 2839, 1633, 1602, 1502, 1450, 1279, 1255, 1120, 1055, 787, 731; 1H NMR (400 MHz, CDCl3) δ: 6.67 (1H, d, J = 8.2 Hz), 6.57 (1H, d, J = 8.2 Hz), 5.71 (1H, ddd, J = 9.8 Hz, 1.4 Hz, 1.4 Hz), 5.30 (1H, ddd, J = 9.8 Hz, 2.5 Hz, 2.5 Hz), 4.90 (1H, dd, J = 6.6 Hz, 1.2 Hz), 4.21-4.15 (1H, m), 3.85 (3H, s), 3.38-3.32 (1H, m), 3.05 (1H, d, J = 18.7 Hz), 2.70-2.65 (1H, m), 2.59 (1H, dd, J = 12.4 Hz, 4.0 Hz), 2.44 (3H, s), 2.40 (1H, dd, J = 12.4 Hz, 3.6 Hz), 2.30 (1H, dd, J = 18.7 Hz, 6.4 Hz), 2.06 (1H, dt, J = 12.4 Hz, 5.0 Hz), 1.88 (1H, d, J = 10.8 Hz); 13C NMR (100 MHz, CDCl3) δ: 146.2, 142.1, 133.4, 130.9, 128.2, 127.0, 119.5, 112.7, 91.3, 66.3, 58.8, 56.2, 46.4, 43.0, 42.9, 40.7, 35.7, 20.3; HRMS (FAB) Calcd for C18H21NO3: 299.1521 (M+). Found: 299.1532.
Morphine (1).
1.0 M Boron tribromide in CH2Cl2 (481 µL, 0.481 mmol) was added at rt to a stirred solution of 29 (24.0 mg, 0.0802 mmol) in CH2Cl2 (2.0 mL). After stirring for 30 min, 10% aqueous ammonia was added to the mixture at 0 °C, which was subsequently extracted with CH2Cl2/EtOH (90/10). The organic layer was dried over anhydrous MgSO4, filtered, and evaporated under a reduced pressure. The crude product was crystallized from MeOH/CHCl3/Et2O to give morphine (1) (17.0 mg, 74%) as white crystals. mp 202-206 °C (decomp.); IR (film, cm-1) 3357, 2929, 2850, 1635, 1614, 1504, 1458, 1250, 1120, 787, 731; 1H NMR (400 MHz, CDCl3) δ: 6.63 (1H, d, J = 8.2 Hz), 6.59 (1H, d, J = 8.2 Hz), 5.64 (1H, d, J = 9.8 Hz), 5.27-5.23 (1H, m), 4.86 (1H, d, J = 6.4 Hz), 4.20-4.17 (1H, m), 3.43-3.40 (1H, m), 3.02 (1H, d, J = 18.7 Hz), 2.75-2.69 (1H, m), 2.67 (1H, dd, J = 12.0 Hz, 4.4 Hz), 2.49-2.42 (1H, m), 2.46 (3H, s), 2.33 (1H, dd, J = 18.7 Hz, 6.4 Hz), 2.11 (1H, dt, J = 12.6 Hz, 4.8 Hz ), 1.87 (1H, d, J = 11.4 Hz); 13C NMR (100 MHz, CDCl3) δ: 145.9, 138.7, 133.0, 130.5, 128.1, 125.6, 119.9, 117.5, 91.2, 66.5, 58.9, 46.4, 42.9, 42.8, 40.2, 35.1, 20.6; HRMS (FAB) Calcd for C17H19NO3: 285.1365 (M+). Found: 285.1367.
ACKNOWLEDGEMENTS
This work was supported in part by Grants-in-Aid (15109001 and 16073205) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
2-Iodo-4-methoxy-3-(methoxymethoxy)-1-(2-methoxyvinyl)benzene (10).
0.99 M Sodium bis(trimethylsilyl)amide in THF (108 mL, 107 mmol) was added over 50 min at 0 °C to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (36.7 g, 107 mmol) in THF (350 mL). After stirring at 0 °C for 10 min, a solution of 9 (32.8 g, 102 mmol) in THF (135 mL) was added to the reaction mixture over 1 h at 0 °C. After stirring at 0 °C for 10 min, the reaction mixture was warmed to rt, and was subsequently stirred for 4 h. The reaction was quenched with saturated aqueous NH4Cl (50 mL), and the solvent was evaporated under reduced pressure. The residue was diluted with Et2O, and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc/hexane = 25/75) to give 10 (34.0 g, 95%) as a white solid. The product was a mixture of E and Z (70:30) isomers. Anal. Calcd for C12H15IO4: C, 41.10; H, 4.39; N, 0. Found: C, 41.16; H, 4.32; N, 0. E: 1H NMR (400 MHz, CDCl3) δ: 7.04 (1H, d, J = 8.2 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.77 (1H, d, J = 12.8 Hz), 5.99 (1H, d, J = 12.8 Hz), 5.16 (2H, s), 3.83 (3H, s), 3.72 (3H, s), 3.68 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 150.1, 149.4, 145.8, 133.6, 120.9, 112.8, 109.6, 98.9, 98.6, 58.5, 56.5, 56.2. Z: 1H NMR (400 MHz, CDCl3) δ: 7.73 (1H, d, J = 8.2 Hz), 6.87 (1H, d, J = 8.2 Hz), 6.16 (1H, d, J = 7.3 Hz), 5.50 (1H, d, J = 7.3 Hz), 5.14 (2H, s), 3.84 (3H, s), 3.75 (3H, s), 3.68 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 150.0, 147.8, 145.4,
132.1, 125.3, 112.3, 109.2, 98.8, 98.6, 60.6, 58.4, 56.1.
2-Iodo-6-methoxy-3-(2,2-dimetoxyethyl)phenol (5).
Acetyl chloride (4.3 mL, 60.0 mmol) was added at rt to a stirred solution of 10 (42.0 g, 120 mmol) in MeOH (500 mL). After stirring at 40 °C for 1 h, pulverized K2CO3 (8.30 g, 60.0 mmol) was added, and the solvent was evaporated under reduced pressure. The residue was diluted with Et2O, and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was rinsed with hexane to give 5 (39.0 g, 96%) as white crystals. mp 90.0-91.3 °C; IR (film, cm-1) 3374, 2937, 2835, 1599, 1483, 1281, 1119, 1034, 804; 1H NMR (400 MHz, CDCl3) δ: 6.85 (1H, d, J = 8.4 Hz), 6.78 (1H, d, J = 8.4 Hz), 6.19 (1H, s), 4.58 (1H, t, J = 5.5 Hz), 3.89 (3H, s), 3.36 (6H, s), 3.04 (2H, d, J = 5.5 Hz); 13C NMR (100 MHz, CDCl3) δ: 145.4, 144.4, 132.5, 122.1, 110.2, 104.3, 88.7, 56.3, 54.0 (2C), 43.4. Anal. Calcd for C11H15IO4: C, 39.07; H, 4.41; N, 0. Found: C, 39.07; H, 4.47; N, 0.
3-(tert-Butyldimethylsilyloxymethyl)-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-
cyclohexenol (12).
Tris(dibenzylideneacetone)dipalladium(0) (948 mg, 1.04 mmol) and tri-2-furylphosphine (961 mg, 4.14 mmol) were added at rt to a stirred solution of 5 (35.0 g, 104 mmol) and 6 (28.6 g, 119 mmol) in MeCN (280 mL). After stirring for 20 min, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/hexane = 20/80) to give 12 (52.8 g, 91%) as a yellow oil. IR (film, cm-1) 3421, 2933, 2856, 2360, 1587, 1473, 1265, 1119, 1072, 1030, 839; 1H NMR (400 MHz, CDCl3) δ: 6.99 (1H, d, J = 8.2 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.03 (1H, s), 4.88 (1H, s), 4.57 (1H, t, J = 5.5 Hz), 4.48 (1H, d, J = 14.7 Hz), 4.33 (1H, d, J = 14.7 Hz), 4.25 (1H, br), 3.82 (3H, s), 3.36 (3H, s), 3.35 (3H, s), 3.06 (2H, d, J = 5.5 Hz), 2.16-2.01 (2H, m), 1.91-1.88 (1H, m), 1.57-1.53 (1H, m), 0.92 (9H, s), 0.069 (3H, s), 0.065 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 150.2, 146.5, 139.6, 132.8, 127.1, 125.7, 112.0, 104.1, 100.9, 74.9, 66.8, 63.6, 55.5, 54.0, 53.8, 44.1, 28.8, 26.0, 25.9 (3C), 18.3, -5.4 (2C); HRMS (FAB) Calcd for C24H39IO6Si: 578.1561 (M+). Found: 578.1571.
3-(tert-Butyldimethylsilyloxymethyl)-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-
cyclohexen-1-yl 4-nitrobenzoate (13).
2.2 M Diethyl azodicarboxylate in toluene (24.0 mL, 52.8 mmol) was added dropwise over 80 min at 0 °C to a stirred solution of 11 (25.5 g, 44.0 mmol), p-nitrobenzoic acid (8.46 g, 50.6 mmol), and triphenylphosphine (15.0 g, 57.2 mmol) in toluene (200 mL) and THF (40 mL). The reaction mixture was warmed to rt. After stirring for 20 min, the solvent was evaporated under reduced pressure. The residue was diluted with Et2O (50 mL) and hexane (50 mL), and then filtered to remove triphenylphosphine oxide. The filtrate was evaporated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexane = 17/83) to give 13 (28.7 g, 90%) as a yellow foam. IR (film, cm-1) 2933, 2857, 2360, 1720, 1529, 1473, 1344, 1269, 1119; 1H NMR (400 MHz, CDCl3) δ: 8.28 (2H, d, J = 9.2 Hz), 8.19 (2H, d, J = 9.2 Hz), 7.01 (1H, d, J = 8.2 Hz), 6.85 (1H, d, J = 8.2 Hz), 6.11 (1H, s), 5.70 (1H, s), 5.06 (1H, s), 4.58 (1H, t, J = 5.5 Hz), 4.53 (1H, d, J = 14.7 Hz), 4.36 (1H, d, J = 14.7 Hz), 3.85 (3H, s), 3.36 (3H, s), 3.35 (3H, s), 3.07 (2H, d, J = 5.5 Hz), 2.64-2.55 (1H, m), 2.05-2.00 (1H, m), 1.91-1.84 (2H, m), 0.91 (9H, s), 0.07 (3H, s), 0.06 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 164.2, 150.4, 150.3, 146.0, 143.5, 136.1, 133.0, 130.7 (2C), 125.9, 123.4 (2C), 121.3, 112.1, 104.2, 100.9, 74.4, 69.4, 63.8, 55.6, 54.0, 53.8, 44.1, 25.9 (3C), 25.3, 24.9, 18.4, -5.3, -5.4; HRMS (FAB) Calcd for C31H42INO9Si: 727.1674 (M+). Found: 727.1690.
4-[3-(2,2-Dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-3-hydroxymethyl-2-cyclohexen-1-yl 4-nitro-
benzoate (14).
10-Camphorsulfonic acid (16.1 mg, 0.0695 mmol) was added at rt to a stirred solution of 13 (1.01 g, 1.39 mmol) in MeOH (10 mL). After stirring for 80 min, the reaction mixture was diluted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 40/60) to give 14 (802 mg, 94%) as a yellow foam. IR (film, cm-1) 3454, 2939, 2835, 2360, 1720, 1527, 1475, 1344, 1271, 1119, 1024; 1H NMR (400 MHz, CDCl3) δ: 8.28 (2H, d, J = 9.2 Hz), 8.19 (2H, d, J = 9.2 Hz), 7.06 (1H, d, J = 8.2 Hz), 6.89 (1H, d, J = 8.2 Hz), 6.07 (1H, s), 5.69 (1H, s), 5.16-5.14 (1H, m), 4.58 (1H, t, J = 5.5 Hz), 4.49 (1H, d, J = 13.6 Hz), 4.33 (1H, d, J = 13.6 Hz), 3.89 (3H, s), 3.37 (3H, s), 3.36 (3H, s), 3.10-3.07 (2H, m), 2.60-2.52 (1H, m), 2.18-2.10 (1H, m), 1.97-1.79 (2H, m); 13C NMR (100 MHz, CDCl3) δ: 163.8, 150.0, 149.8, 145.3 143.0, 135.5, 132.8, 130.4 (2C), 126.0, 123.3, 123.1 (2C), 111.8, 103.8, 100.9, 75.1, 69.2, 63.8, 55.5, 53.7, 53.5, 43.7, 25.3, 25.0. Anal. Calcd for C25H28INO9: C, 48.95; H, 4.60; N, 2.28. Found: C, 48.88; H, 4.65; N, 2.15.
3-Cyanomethyl-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-cyclohexen-1-yl 4-nitro-
benzoate (15).
2.2 M Diethyl azodicarboxylate in toluene (18.6 mL, 40.9 mmol) was added dropwise over 1 h at 0 °C to a stirred solution of 14 (20.9 g, 34.1 mmol), acetone cyanohydrin (6.92 mL, 68.2 mmol), and triphenylphosphine (11.6 g, 44.2 mmol) in toluene (200 mL). Then the reaction mixture was warmed to rt. After stirring for 40 min, the solvent was evaporated under reduced pressure. The residue was diluted with EtOAc (20 mL) and hexane (30 mL), and then filtered to remove triphenylphosphine oxide. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (CH2Cl2 only, EtOAc/hexane = 25/75 – 33/67, CH2Cl2 only) to give 15 (22.0 g), which contained impurities. The product was not further purified at this stage. IR (film, cm-1) 2941, 2833, 2252, 1722, 1527, 1475, 1346, 1271, 1119, 1026, 918, 721; 1H NMR (400 MHz, CDCl3) δ: 8.28 (2H, d, J = 9.2 Hz), 8.20 (2H, d, J = 9.2 Hz), 7.06 (1H, d, J = 8.2 Hz), 6.89 (1H, d, J = 8.2 Hz), 6.25 (1H, d, J = 2.7 Hz), 5.70 (1H, s), 5.04 (1H, s), 4.58 (1H, t, J = 5.5 Hz), 3.90 (3H, s), 3,63-3.52 (2H, m), 3.37 (3H, s), 3.36 (3H, s), 3.12-3.03 (2H, m), 2.62-2.55 (1H, m), 2.13-2.05 (1H, m), 1.95-1.88 (2H, m); 13C NMR (100 MHz, CDCl3) δ: 164.0, 150.5, 150.1, 145.3 135.0, 134.3, 133.1, 130.7 (2C), 127.5, 126.5 123.5 (2C), 117.4, 112.0, 104.1, 100.8, 75.1, 68.7, 55.6, 54.0, 53.7, 44.0, 25.1, 24.9, 22.4; HRMS (FAB) Calcd for C26H27INO8: 622.0812 (M+). Found: 622.0811.
3-Cyanomethyl-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-cyclohexenol (17).
2.0 M Lithium borohydride in THF (20.5 mL, 40.9 mmol) was added dropwise over 20 min at 0 °C to a stirred solution of crude 15 (22.0 g) in Et2O (200 mL) and MeOH (10.0 mL). The reaction mixture was warmed to rt and stirred for 40 min. Saturated aqueous NH4Cl was added to the solution, and the mixture was extracted with Et2O. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 40/60 – 60/40) to give 17 (15.3 g, 95% in 2 steps) as a colorless oil. IR (film, cm-1) 3449, 2936, 2835, 2250, 1589, 1476, 1268, 1119, 1066, 1027; 1H NMR (400 MHz, CDCl3) δ: 7.03 (1H, d, J = 8.2 Hz), 6.86 (1H, d, J = 8.2 Hz), 6.14 (1H, s), 4.94 (1H, s), 4.57 (1H, t, J = 5.5 Hz), 4.39 (1H, s), 3.87 (3H, s), 3.52 (2H, s), 3.36 (3H, s), 3.35 (3H, s), 3.07-3.04 (2H, m), 2.38-2.28 (1H, m), 1.95-1.84 (2H, m), 1.63-1.55 (1H, m); 13C NMR (100 MHz, CDCl3) δ: 150.2, 145.5, 132.9, 132.0, 131.2, 126.3, 117.8, 111.9, 104.1, 100.0, 76.2, 65.0, 55.6, 54.1, 53.8, 44.0, 28.9, 25.4, 22.0; HRMS (FAB) Calcd for C19H24INO5: 473.0699 (M+). Found: 473.0698.
tert-Butyldimethyl[3-cyanomethyl-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]phenoxy-2-
cyclohexenoxy]silane (18).
t-Butyldimethylchlorosilane (4.89 g, 32.5 mmol) was added at rt to a stirred solution of 17 (12.8 g, 27.0 mmol) and imidazole (2.21 g, 32.5 mmol) in DMF (67.5 mL), and then the reaction mixture was stirred for 1 h. Water was then added to the solution, and the mixture was extracted with Et2O. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was rinsed with hexane and filtered to collect 18 (13.5 g) as white crystals. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (Et2O/hexane = 20/80 – 25/75) to give 18 (1.70 g) as white crystals. Finally, 15.2 g of 18 was obtained in 96% yield. mp 106.5-107.5 °C; IR (film, cm-1) 2952, 2894, 2856, 2250, 1589, 1475, 1265, 1120, 1072, 1022, 837, 804; 1H NMR (400 MHz, CDCl3) δ: 7.01 (1H, d, J = 8.2 Hz), 6.85 (1H, d, J = 8.2 Hz), 6.00 (1H, s), 4.94 (1H, s), 4.56 (1H, t, J = 5.5 Hz), 4.36 (1H, s), 3.85 (3H, s), 3.54 (1H, d, J = 19.2 Hz), 3.45 (1H, d, J = 19.2 Hz), 3.35 (3H, s), 3.34 (3H, s), 3.08-3.02 (2H, m), 2.21-2.16 (1H, m), 1.92-1.89 (2H, m), 1.57-1.49 (1H, m), 0.89 (9H, s), 0.10 (3H, s), 0.09 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 150.2, 145.6, 132.9 (2C), 130.0 126.2, 117.8, 111.9, 104.2, 101.0, 76.8, 65.9, 55.6, 54.0, 53.8, 44.0, 29.8, 25.9, 25.8 (3C), 21.8, 18.1, -4.6, -4.7. Anal. Calcd for C25H38INO5Si: C, 51.10; H, 6.52; N, 2.38. Found: C, 51.03; H, 6.39; N, 2.36.
tert-Butyldimethyl[3-[2-methoxycarbonylaminoethyl]-4-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxy]-phenoxy-2-cyclohexenoxy]silane (19a).
0.99 M Diisobutylaluminium hydride in toluene (3.67 mL, 3.63 mmol) was added dropwise over 10 min at -78 °C to a stirred solution of 18 (1.64 g, 2.79 mmol) in CH2Cl2 (30.0 mL), and then the reaction mixture was stirred for 2 h. Sodium borohydride (317 mg, 8.37 mmol) and MeOH (10.0 mL) were added to the solution. The reaction mixture was warmed to rt, and was subsequently stirred for 40 min. Pulverized K2CO3 (463 mg, 3.35 mmol) and methyl chloroformate (259 µL, 3.35 mmol) were added, and the reaction mixture was stirred for 30 min. 30% Aqueous potassium sodium (+)-tartrate (30.0 mL) was added to the mixture. The reaction mixture was stirred for 1 h, and then extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 25/75) to give 19a (1.71 g, 94%) as a white foam. IR (film, cm-1) 3352, 2950, 2856, 1724, 1475, 1255, 1120, 1072, 1026, 835, 775; 1H NMR (400 MHz, CDCl3) δ: 6.94 (1H, d, J = 8.2 Hz), 6.79 (1H, d, J = 8.2 Hz), 5.57 (1H, s), 5.08 (1H, s), 5.02 (1H, s), 4.51 (1H, t, J = 5.5 Hz), 4.26 (1H, s), 3.78 (3H, s), 3.59 (2H, s), 3.43-3.37 (2H, m), 3.31 (3H, s), 3.29 (3H, s), 3.06-2.96 (2H, m), 2.62-2.52 (2H, m), 2.40-2.32 (1H, m), 2.13-2.05 (1H, m), 1.80-1.72 (2H, m), 1.47-1.40 (1H, m), 0.85 (9H, s), 0.05 (3H, s), 0.04 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 156.9, 150.2, 145.4, 136.7, 132.7, 131.5, 125.6, 111.9, 104.1, 101.1, 77.3, 66.1, 55.5, 53.9, 53.6, 51.7, 44.0, 39.6, 33.6, 29.8, 25.7 (3C), 25.4, 18.0, -4.8 (2C); HRMS (FAB) Calcd for C27H44INO7Si: 649.1932 (M+). Found: 649.1935.
1-(2,2-Dimethoxyethyl)-4-methoxy-9a-(2-methoxycarbonylaminoethyl)-5a,6,7,9-tetrahydrodibenzo-
furan-8-one (20a).
Tris(dibenzylideneacetone)dipalladium(0) (116 mg, 0.127 mmol) was added at rt to a stirred solution of 19a (1.65 g, 2.54 mmol), tri-o-tolylphosphine (155 mg, 0.508 mmol), and triethylamine (704 µL, 5.08 mmol) in MeCN (17.0 mL). Then the reaction mixture was refluxed for 1 h, cooled to rt and 1.0 M tetrabutylammonium fluoride in THF (3.05 mL, 3.05 mmol) was added. After stirring for 90 min, saturated aqueous NH4Cl was added to the mixture, which was subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 25/75 – 100/0) to give 20a (897 mg, 87%) as a pale yellow foam. IR (film, cm-1) 3327, 2941, 2837, 1716, 1541, 1506, 1435, 1344, 1281, 1169, 1120, 1068, 733; 1H NMR (400 MHz, CDCl3) δ: 6.77-6.70 (2H, m), 4.96 (1H, s), 4.62-4.52 (2H, m), 3.85 (3H, s), 3.62 (3H, s), 3.39 (3H, s), 3.34 (3H, s), 3.30-3.20 (1H, m), 2.92 (1H, d, J = 15.6 Hz), 2.90-2.80 (3H, m), 2.65 (1H, d, J = 15.6 Hz), 2.40-2.14 (5H, m), 1.93-1.83 (1H, m); 13C NMR (100 MHz, CDCl3) δ: 210.0, 156.8, 147.8, 142.6, 127.9, 125.8, 122.8, 111.9, 105.5, 84.7, 55.7, 54.5, 53.6, 51.9, 49.4, 48.2, 40.1, 37.0, 34.4, 33.1, 26.4; HRMS (FAB) Calcd for C21H29NO7: 407.1944
(M+). Found: 407.1952.
4,5-Epoxy-3-methoxy-17-methoxycarbonylmorphinan-8-one (21a).
Acetyl chloride (969 µL, 13.6 mmol) was added at rt to a stirred solution of 20a (555 mg, 1.36 mmol) in MeOH (10.0 mL), and then the reaction mixture was refluxed for 12 h. It was cooled to rt, and acetyl chloride (969 µL, 13.6 mmol) was added. Then the reaction mixture was refluxed for another 12 h, and cooled to rt, diluted with toluene, and evaporated under reduced pressure to remove MeOH. The organic layer was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 50/50) to give 21a (440 mg, 94%) as a white foam. mp 126-128 °C; IR (film, cm-1) 2949, 1709, 1504, 1448, 1405, 1313, 1263, 1130, 920, 730; 1H NMR (400 MHz, CDCl3) δ: 6.75 (1H, d, J = 8.2 Hz), 6.58 (1H, d, J = 8.2 Hz), 5.42-5.34 (minor amide rotamer) (0.40 1H, br), 5.29-5.21 (major amide rotamer) (0.60 1H, br), 4.90 (1H, s), 4.11 (major amide rotamer) (0.60 1H, d, J = 13.8 Hz), 3.96 (minor amide rotamer) (0.40 1H, d, J = 13.8 Hz), 3.87 (3H, s), 3.74 (3H, s), 3.20-2.70 (2H, m), 2.72 (1H, s), 2.64 (1H, d, J = 18.3 Hz), 2.35-2.04 (3H, m), 1.95-1.75 (3H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 207.6, 155.4, 146.5, 141.6, 128.0, 126.4, 119.8, 114.1, 88.1, 56.2, 52.6, 50.8, 47.7, 42.8, 37.0, 35.8, 33.4, 29.0, 26.7 (minor amide rotamer) δ: 207.0, 155.3, 146.5, 141.6, 128.0, 126.6, 119.8, 114.1, 88.1, 56.2, 52.6, 50.6, 47.6, 42.9, 37.1, 36.1, 33.4, 28.9, 26.7; HRMS (FAB) Calcd for C19H21NO5: 343.1420 (M+). Found: 343.1430.
4,5-Epoxy-3-methoxy-17-methoxycarbonylmorphinan-6-en-8-one (24).
1.00 M Lithium bis(trimethylsilyl)amide in THF (12.4 mL, 12.4 mmol) was added over 5 min at 0 °C to a stirred solution of 21a (3.03 g, 8.82 mmol) and chlorotrimethylsilane (1.34 mL, 10.6 mmol) in THF (50.0 mL). After stirring for 40 min, saturated aqueous NH4Cl was added to the mixture, which was subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was dissolved in MeCN (50.0 mL), and palladium acetate (2.97 g, 13.2 mmol) was added to the solution at rt. After stirring for 2 h, saturated aqueous NaHCO3 was added to the mixture, which was subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane = 40/60 – 60/40) to give 24 (2.78 g, 92% in 2 steps) as a white foam. mp 122-124 °C; IR (film, cm-1) 2951, 1697, 1504, 1446, 1277, 910, 764; 1H NMR (400 MHz, CDCl3) δ: 6.76 (1H, d, J = 8.2 Hz), 6.65-6.56 (2H, m), 6.00 (1H, d, J = 10.1 Hz), 5.42-5.19 (2H, m), 4.15-4.10 (major amide rotamer) (0.60 1H, m), 4.05-3.97 (minor amide rotamer) (0.40 1H, m), 3.86 (3H, s), 3.76 (major amide rotamer) (0.60 3H, s), 3.73 (minor amide rotamer) (0.40 3H, s), 3.15-3.00 (1H, m), 2.90-2.80 (1H, m), 2.67 (1H, d, J = 18.3 Hz), 1.96-1.80 (2H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 194.6, 155.3, 142.8, 142.5, 140.2, 131.3, 127.8, 125.8, 120.0, 114.2, 84.8, 56.1, 52.5, 48.7, 46.8, 42.8, 37.3, 33.2, 28.7 (minor amide rotamer) δ: 194.3, 155.4, 142.8, 142.5, 139.8, 131.4, 127.8, 126.0, 120.0, 114.2, 84.8, 56.1, 52.5, 48.7, 46.7, 42.9,
37.4, 33.5, 28.5; HRMS (FAB) Calcd for C19H19NO5: 342.1341 (M++H). Found: 342.1338.
4,5-Epoxy-6,7-epoxy-3-methoxy-17-methoxycarbonylmorphinan-8-one (25).
30% Aqueous H2O2 (897 µL, 8.79 mmol) and 5% aqueous sodium hydroxide (3.52 mL, 4.39 mmol) were added at 0 °C to a stirred solution of 24 (600 mg, 1.76 mmol) in MeCN (12.0 mL). After stirring for 15 min, saturated aqueous NH4Cl was added to the mixture, which was subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was rinsed with EtOAc/hexane (15/85) to give 25 (572 mg, 91%) as white crystals. mp 189-192 °C; IR (film, cm-1) 2951, 1699, 1506, 1448, 1315, 1279, 1132, 1053, 798, 733; 1H NMR (400 MHz, CDCl3) δ: 6.78 (1H, d, J = 8.2 Hz), 6.65 (1H, d, J = 8.2 Hz), 5.17-4.96 (2H, m), 4.07 (major amide rotamer) (0.55 1H, d, J = 13.7 Hz), 3.93 (minor amide rotamer) (0.45 1H, d, J = 13.7 Hz), 3.88 (3H, s), 3.74 (major amide rotamer) (0.55 3H, s), 3.71 (minor amide rotamer) (0.45 3H, s), 3.61 (1H, s), 3.31-3.19 (1H, m), 3.18-3.11 (2H, m), 2.85-2.70 (1H, m), 2.63 (1H, d, J = 18.3 Hz), 2.05-1.94 (1H, m), 1.84-1.73 (1H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 202.3, 155.0, 144.1, 142.3, 126.5, 125.5, 120.3, 114.3, 83.8, 58.1, 56.0, 54.8, 52.6, 47.2, 46.5, 45.8, 36.9, 35.0, 29.1 (minor amide rotamer) δ: 202.0, 155.2, 144.1, 142.3, 126.7, 125.5, 120.3, 114.3, 83.8, 58.1, 56.0, 54.8, 52.5, 47.2, 46.3, 45.7, 37.0, 35.3, 28.9; HRMS (FAB) Calcd for C19H20NO6: 358.1290 (M++H). Found: 358.1280.
4,5-Epoxy-6,7-epoxy-3-methoxy-17-methoxycarbonylmorphinan-8-ol (27).
Sodium borohydride (60.6 mg, 1.60 mmol) was added at 0 °C to a stirred solution of 25 (572 mg, 1.60 mmol) in MeOH (5.0 mL) and CH2Cl2 (5.0 mL). After stirring for 20 min, saturated aqueous NH4Cl was added to the mixture, which was subsequently extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was rinsed with Et2O/hexane (50/50) to give 27 (521 mg, 91%) as white crystals. mp 182-185 °C; IR (film, cm-1) 3440, 2933, 1680, 1506, 1452, 1408, 1327, 1275, 1128, 1057, 918, 800, 733; 1H NMR (400 MHz, CDCl3) δ: 6.80 (1H, d, J = 8.2 Hz), 6.69 (1H, d, J = 8.2 Hz), 5.00-4.81 (2H, m), 4.31-4.23 (1H, m), 4.08-3.88 (4H, m), 3.75 (minor amide rotamer) (0.40 3H, s), 3.71 (major amide rotamer) (0.60 3H, s), 3.39-3.28 (2H, m), 3.22-3.18 (1H, m), 2.98-2.81 (1H, m), 2.70 (1H, d, J = 18.3 Hz), 2.17 (1H, s), 1.80-1.61 (2H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 155.3, 144.6, 142.3, 128.2, 127.5, 119.4, 113.5, 84.9, 64.9, 56.0, 54.6, 52.5, 50.9, 49.9, 38.7, 38.1, 37.6, 37.4, 31.7 (minor amide rotamer) δ: 154.9, 144.6, 142.4, 128.0, 127.5, 119.5, 113.7, 84.9, 65.4, 56.1, 54.5, 52.6, 50.9, 50.1, 38.7, 38.2, 37.3, 37.2, 31.9; HRMS (FAB) Calcd for C19H21NO6: 360.1447 (M++H). Found: 360.1457.
4,5-Epoxy-3-methoxy-17-methoxycarbonylmorphinan-7-en-6-ol (26).
N,N-Dimethylaminopyridine (16.3 mg, 0.134 mmol) and 1,1’-thiocarbonyldiimidazole (44.1 mg, 0.223
mmol) were added at rt to a stirred solution of 27 (40.0 mg, 0.111 mmol) in 1,2-dichloroethane (1.0 mL). The reaction mixture was heated for 15 h at 60 °C, cooled to rt, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (CH2Cl2 only, twice) to give thioimidazolide (48.3 mg), which contained impurities. The product was dissolved in THF (1.0 mL), and to the cloudy solution were added tributylthin hydride (89.8 µL, 0.334 mmol) and 1.02 M triethylborane in hexane (109 µL, 0.111 mmol) at rt. The mixture turned clear, and was stirred for 3 h. Half saturated aqueous potassium fluoride was added to the mixture, stirred for 2 h, and subsequently extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc/hexane = 50/50 – 60/40) to give 26 (18.3 mg, 48% in 2 steps) as a white foam. IR (film, cm-1) 3417, 2952, 1680, 1606, 1504, 1450, 1327, 1275, 1028, 796, 731; 1H NMR (400 MHz, CDCl3) δ: 6.70 (1H, d, J = 8.0 Hz), 6.57 (1H, d, J = 8.0 Hz), 6.05-6.00 (1H, m), 5.68-5.60 (1H, m), 4.85-4.75 (2H, m), 4.27 (1H, s), 4.12 (minor amide rotamer) (0.40 1H, dd, J = 13.7 Hz, 4.6 Hz), 3.97 (major amide rotamer) (0.60 1H, dd, J = 13.7 Hz, 4.6 Hz), 3.85 (3H, s), 3.76 (minor amide rotamer) (0.40 3H, s), 3.73 (major amide rotamer) (0.60 3H, s), 3.01-2.80 (3H, m), 2.75 (1H, d, J = 18.3 Hz), 2.03-1.84 (2H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 155.9, 145.7, 142.3, 131.8, 131.7, 129.3, 125.8, 119.2, 113.2, 94.0, 67.7, 56.2, 52.7, 50.3, 44.2, 38.9, 38.0, 35.3, 28.9 (minor amide rotamer) δ: 155.6, 145.7, 142.3, 131.8, 131.6, 129.3, 125.6, 119.2, 113.2, 94.1, 67.7, 56.2, 52.8, 50.6, 44.2, 39.1, 38.0, 35.1, 29.2; HRMS (FAB) Calcd for C19H21NO5: 343.1420 (M+). Found: 343.1421.
4,5-Epoxy-3-methoxy-17-methoxycarbonylmorphinan-7-en-6-one (28).
Dess-Martin periodinane (72.3 mg, 0.170 mmol) was added at rt to a stirred solution of 26 (45.0 mg, 0.131 mmol) in CH2Cl2 (1.5 mL). After stirring for 30 min, saturated aqueous NaHCO3 was added to the mixture, which was subsequently extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by PTLC (EtOAc/hexane = 67/33) to give 28 (42.8 mg, 96%) as a white foam. IR (film, cm-1) 2952, 1684, 1504, 1446, 1406, 1321, 1273, 1234, 731; 1H NMR (400 MHz, CDCl3) δ: 6.72 (1H, d, J = 8.2 Hz), 6.68-6.61 (2H, m), 6.14 (1H, dd, J = 10.1 Hz, 2.8 Hz), 5.07-5.01 (major amide rotamer) (0.60 1H, br), 4.91-4.85 (minor amide rotamer) (0.40 1H, br), 4.70 (1H, s), 4.18-4.11 (minor amide rotamer) (0.40 1H, m), 4.04-3.97 (major amide rotamer) (0.60 1H, m), 3.87 (3H, s), 3.78 (minor amide rotamer) (0.40 3H, s), 3.74 (major amide rotamer) (0.60 3H, s), 3.07-3.04 (1H, m), 2.96-2.80 (3H, m), 2.03-1.87 (2H, m); 13C NMR (100 MHz, CDCl3) (major amide rotamer) δ: 194.0, 155.9, 147.1, 144.9, 142.8, 133.2, 127.8, 124.6, 120.5, 115.1, 87.7, 56.7, 52.9, 50.4, 43.5, 40.3, 38.1, 33.5, 29.1 (minor amide rotamer) δ: 194.0, 155.4, 146.8, 144.9, 142.8, 133.3, 127.8, 124.4, 120.5, 115.1, 87.7, 56.7, 53.0, 50.7, 43.4, 40.4, 38.1, 33.3, 29.4; HRMS (FAB) Calcd for C19H19NO5: 341.1263 (M+). Found: 341.1274.
Codeine (29).
Lithium aluminum hydride (17.2 mg, 0.454 mmol) was added at rt to a stirred solution of 28 (31.0 mg,
0.0908 mmol) in THF (2.0 mL). The reaction mixture was refluxed for 40 min, and subsequently cooled to 0 °C. Then MeOH (0.2 mL) and sodium sulfate decahydrate (250 mg) were added. The mixture was diluted with CH2Cl2, stirred for 3 h, filtered, and evaporated under reduced pressure. The crude product was purified by PTLC (CHCl3/MeOH = 90/10) to give codeine (29) (22.0 mg, 81%) as white crystals. mp 144-146 °C (recrystallized with MeOH/H2O); IR (film, cm-1) 3386, 2931, 2839, 1633, 1602, 1502, 1450, 1279, 1255, 1120, 1055, 787, 731; 1H NMR (400 MHz, CDCl3) δ: 6.67 (1H, d, J = 8.2 Hz), 6.57 (1H, d, J = 8.2 Hz), 5.71 (1H, ddd, J = 9.8 Hz, 1.4 Hz, 1.4 Hz), 5.30 (1H, ddd, J = 9.8 Hz, 2.5 Hz, 2.5 Hz), 4.90 (1H, dd, J = 6.6 Hz, 1.2 Hz), 4.21-4.15 (1H, m), 3.85 (3H, s), 3.38-3.32 (1H, m), 3.05 (1H, d, J = 18.7 Hz), 2.70-2.65 (1H, m), 2.59 (1H, dd, J = 12.4 Hz, 4.0 Hz), 2.44 (3H, s), 2.40 (1H, dd, J = 12.4 Hz, 3.6 Hz), 2.30 (1H, dd, J = 18.7 Hz, 6.4 Hz), 2.06 (1H, dt, J = 12.4 Hz, 5.0 Hz), 1.88 (1H, d, J = 10.8 Hz); 13C NMR (100 MHz, CDCl3) δ: 146.2, 142.1, 133.4, 130.9, 128.2, 127.0, 119.5, 112.7, 91.3, 66.3, 58.8, 56.2, 46.4, 43.0, 42.9, 40.7, 35.7, 20.3; HRMS (FAB) Calcd for C18H21NO3: 299.1521 (M+). Found: 299.1532.
Morphine (1).
1.0 M Boron tribromide in CH2Cl2 (481 µL, 0.481 mmol) was added at rt to a stirred solution of 29 (24.0 mg, 0.0802 mmol) in CH2Cl2 (2.0 mL). After stirring for 30 min, 10% aqueous ammonia was added to the mixture at 0 °C, which was subsequently extracted with CH2Cl2/EtOH (90/10). The organic layer was dried over anhydrous MgSO4, filtered, and evaporated under a reduced pressure. The crude product was crystallized from MeOH/CHCl3/Et2O to give morphine (1) (17.0 mg, 74%) as white crystals. mp 202-206 °C (decomp.); IR (film, cm-1) 3357, 2929, 2850, 1635, 1614, 1504, 1458, 1250, 1120, 787, 731; 1H NMR (400 MHz, CDCl3) δ: 6.63 (1H, d, J = 8.2 Hz), 6.59 (1H, d, J = 8.2 Hz), 5.64 (1H, d, J = 9.8 Hz), 5.27-5.23 (1H, m), 4.86 (1H, d, J = 6.4 Hz), 4.20-4.17 (1H, m), 3.43-3.40 (1H, m), 3.02 (1H, d, J = 18.7 Hz), 2.75-2.69 (1H, m), 2.67 (1H, dd, J = 12.0 Hz, 4.4 Hz), 2.49-2.42 (1H, m), 2.46 (3H, s), 2.33 (1H, dd, J = 18.7 Hz, 6.4 Hz), 2.11 (1H, dt, J = 12.6 Hz, 4.8 Hz ), 1.87 (1H, d, J = 11.4 Hz); 13C NMR (100 MHz, CDCl3) δ: 145.9, 138.7, 133.0, 130.5, 128.1, 125.6, 119.9, 117.5, 91.2, 66.5, 58.9, 46.4, 42.9, 42.8, 40.2, 35.1, 20.6; HRMS (FAB) Calcd for C17H19NO3: 285.1365 (M+). Found: 285.1367.
ACKNOWLEDGEMENTS
This work was supported in part by Grants-in-Aid (15109001 and 16073205) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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