Total Synthesis of (ꢀ)-Morphine
MeCN (23 mL) was added Et3N (1.89 mL, 13.6 mmol) at room tempera-
ture and the solution was stirred for 1 h at 858C. Then the solvent was re-
moved in vacuo, and the residue was purified by column chromatography
on silica gel (20% ethyl acetate in n-hexane) to afford 21 (2.60 g, 96%)
as a yellow oil. ½aꢁ2D4 =ꢀ15.88 (c=1.00, CHCl3); IR (film): n˜ =2930, 1717,
N-[2-[(3aR,9RS,9bS)-3a,8,9,9a-tetrahydro-9-(methanesulfonyloxy)-5-
methoxy-3-oxo-9b-phenanthro[4,5-bcd]furanyl]ethyl]-N-methyl-2,4-
AHCTUNGERTGdNNUN initrobenzenesulfonamide (29) To a stirred solution of 28 (659 mg,
G
ACHTUNGTRENNUNG
1.11 mmol) in toluene (22 mL) was added 50% aqueous TFA (6 mL) at
room temperature. After stirring at 508C for 2 h, the solvent was re-
moved in vacuo. The residue was dissolved in CH2Cl2, and to the result-
ing solution were added N,N-diisopropylethylamine (290 mL, 1.67 mmol)
and mesyl chloride (103 mL, 1.33 mmol) at 08C. After stirring at 08C for
10 min, aqueous ammonium chloride was added, and the solution was ex-
tracted with CH2Cl2. The combined organic solution was washed with
brine, dried over sodium sulfate, and filtered. The filtrate was concentrat-
ed in vacuo and the residue was purified by column chromatography on
1507, 1251, 1119 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.33 (m, 5H),
;
6.71 (s, 2H), 5.97 (d, J=10.1 Hz 1H), 5.69 (ddd, J=10.1, 4.0, 4.0 Hz,
1H), 5.05 (s, 2H), 4.76 (br, 1H), 4.56 (t, J=5.4 Hz, 1H), 4.49 (d, J=
7.1 Hz, 1H), 3.96 (dd, J=12.2 Hz, 7.1 Hz, 1H), 3.82 (s, 3H), 3.36 (s, 3H),
3.31 (s, 3H), 3.19–3.24 (m, 1H), 2.88–2.91 (m, 1H), 2.89 (d, J=5.4 Hz,
2H), 2.56 (ddd, J=16.4, 4.0, 4.0 Hz, 1H), 2.09 (dd, J=16.4, 7.1 Hz, 1H),
1.98 (t, J=7.6 Hz, 2H), 0.89 (s, 9H), 0.13 (s, 3H), 0.02 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=156.1, 146.2, 143.7, 136.6, 132.1, 129.6,
128.5, 128.0, 125.3, 124.5, 122.9, 111.7, 105.2, 89.1, 68.1, 66.5, 55.8, 53.9,
53.1, 51.3, 39.5, 37.4, 35.1, 30.5, 25.8, 18.1, ꢀ4.8, ꢀ5.3 ppm; HRMS (ESI)
calcd for C33H47NO7SiNa [M+Na]+: 620.3020, found 620.3036.
silica gel (50% ethyl acetate in n-hexane) to afford 29 (492 mg, 71%) as
24
a yellow oil. Analytical data of the major isomer of mesylate 29: ½aꢁD
=
ꢀ25.38 (c=1.00, CHCl3); IR (film): n˜ =1681, 1550, 1510, 1352, 1281,
1166 cmꢀ1 1H NMR (400 MHz, CDCl3): d=8.48 (d, J=2.0 Hz, 1H), 8.46
;
(dd, J=8.5 Hz, 2.0 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 6.91 (dd, J=
10.5 Hz, 4.0 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H),
6.20 (d, J=10.5 Hz, 1H), 4.86 (s, 1H), 4.71 (dd, J=10.3 Hz, 6.2 Hz, 1H),
3.88 (s, 3H), 3.50 (m, 1H), 3.22 (dd, J=6.2 Hz, 4.0 Hz, 1H), 3.16 (s, 3H),
3.16 (1H), 3.10 (m, 1H), 2.94 (s, 3H), 2.91 (m, 1H), 2.23 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=193.0, 149.7, 148.1, 146.4, 144.8, 143.8,
137.3, 132.7, 129.2, 127.8, 126.2, 121.6, 121.2, 119.8, 114.9, 86.7, 81.4, 56.7,
46.2, 46.1, 43.9, 38.6, 38.9, 35.3, 32.2 ppm; HRMS (ESI) calcd for
C25H25N3O12S2Na [M+Na]+: 646.0778, found 646.0756.
N-[2-[(5aR,9aS)-6,7-dihydro-1-(2,2-dimethoxyethyl)-4-methoxy-6-oxo-9a-
ACHTUNGTRENNUNG(5aH)-dibenzofuranyl]ethyl]-N-methyl-2,4-dinitrobenzenesulfonamide
(28) To a stirred solution of 21 (2.60 g, 4.35 mmol) in THF (22 mL) was
added LiAlH4 (496 mg, 13.0 mmol) at room temperature and the solution
was stirred for 1 h at 708C. After dilution with diethyl ether, the reaction
mixture was quenched with excess amount of aqueous NaOH. The result-
ing white precipitate was removed by filtration. To the filtrate was added
2,4-dinitrobenzenesulfonyl chloride (1.16 g, 4.35 mmol), and the solution
was stirred for 10 min at room temperature. The mixture was extracted
with ethyl acetate, washed with water, dried over sodium sulfate, and fil-
tered. Concentration of the filtrate gave a crude sulfonamide, which was
used for the next step without further purification.
(ꢀ)-Codeine (34) To a stirred solution of 29 (440 mg, 0.71 mmol) in
CH2Cl2 (7 mL) was added N,N-diisopropylethylamine (369 mL,
2.12 mmol) and mercaptoacetic acid (69 mL, 0.99 mmol) at 08C. After
stirring at 08C for 30 min, aqueous sodium carbonate was added. After
stirring for 30 min at room temperature, the solution was extracted with
CH2Cl2. The combined organic solution was washed with brine, dried
over sodium sulfate, and filtered. Concentration of the filtrate gave a
10:1 mixture of neopinone (32) and codeinone (33).
To a stirred solution of the crude sulfonamide in methanol (22 mL) was
added camphorsulfonic acid (101 mg, 0.44 mmol) at room temperature.
After stirring at room temperature for 6 h, aqueous sodium bicarbonate
was added, and the solution was extracted with CH2Cl2. The combined
organic solution was washed with brine, dried over sodium sulfate, and
filtered. The filtrate was concentrated in vacuo and the residue was puri-
fied by column chromatography on silica gel (50% ethyl acetate in n-
hexane) to afford alcohol S1 (1.75 g, 68% for 2 steps) as a yellow oil.
½aꢁ2D4 =ꢀ3.188 (c=1.00, CHCl3); IR (film): n˜ =3490, 2937, 1554, 1505,
To a stirred solution of neopinone (32) and codeinone (33) in CHCl3
(7 mL) was added 4m HCl in dioxane (2 mL) at room temperature. After
stirring at room temperature for 10 h, aqueous NaOH was added. After
stirring for 30 min at room temperature, the solution was extracted with
10% EtOH in CH2Cl2. The combined organic solution was washed with
brine, dried over sodium sulfate, and filtered. Concentration of the fil-
trate gave codeinone (33) as a single product.
1
1353, 1275, 1119 cmꢀ1; H NMR (400 MHz, CDCl3): d=8.46 (s, 1H), 8.45
(d, J=8.5 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.75
(d, J=8.4 Hz, 1H), 6.02 (dd, J=10.0, 1.6 Hz, 1H), 5.83 (ddd, J=10.0, 5.9,
2.3 Hz, 1H), 4.53 (t, J=4.5 Hz, 1H), 4.37 (d, J=8.5 Hz, 1H), 4.37 (s,
3H), 4.37 (1H), 3.37 (s, 3H), 3.35 (m, 1H), 3.31 (s, 3H), 2.97 (m, 1H),
2.91 (s, 3H), 2.86 (d, J=4.5 Hz, 1H), 2.38–2.45 (m, 1H), 2.04–2.16 (m,
2H), 1.93–2.00 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=149.6,
148.0, 145.3, 143.8, 137.8, 132.5, 131.6, 128.5, 126.0, 125.7, 125.4, 123.7,
119.7, 111.7, 105.1, 90.1, 67.6, 55.8, 54.2, 53.2, 51.5, 46.3, 37.4, 35.3, 34.9,
29.3 ppm; HRMS (ESI) calcd for C26H31N3O11SNa [M+Na]+ : 616.1577,
found 616.1604.
Codeinone (33) was dissolved in methanol (7 mL). To this solution was
added NaBH4 (27 mg, 0.71 mmol) in portions at room temperature. After
stirring at room temperature for 10 min, water was added, and the solu-
tion was thoroughly extracted with 10% EtOH in CH2Cl2. The combined
organic solution was washed with brine, dried over sodium sulfate, and
filtered. The filtrate was concentrated in vacuo and the residue was puri-
fied by column chromatography on silica gel (10% EtOH in CH2Cl2) to
afford codeine (34) (148 mg, 70% from 29) as an amorphous solid.
½aꢁ2D4 =ꢀ1368 (c=0.10, EtOH, lit. ½aꢁ2D4 =ꢀ1378); IR (film): n˜ =3356, 2929,
To a stirred solution of alcohol S1 (800 mg, 1.35 mmol) in CH2Cl2 (9 mL)
was added Dess–Martin periodinane (800 mg, 1.89 mmol) at room tem-
perature. After stirring at 408C for 30 min, aqueous sodium thiosulfate
was added, and the solution was extracted with CH2Cl2. The combined
organic solution was washed with brine, dried over sodium sulfate, and
filtered. The filtrate was concentrated in vacuo, and the residue was puri-
fied by column chromatography on silica gel (30% ethyl acetate in n-
hexane) to afford 28 (702 mg, 88%) as an amorphous solid. ½aꢁ2D4 =ꢀ24.28
(c=1.00, CHCl3); IR (film): n˜ =2937, 1736, 1553, 1507, 1353, 1281,
1
1504, 1453, 1277, 1052 cmꢀ1; H NMR (400 MHz, CDCl3): d=6.67 (d, J=
8.4 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 5.71 (d, J=9.8 Hz, 1H), 5.30 (ddd,
J=9.8, 2.6, 2.6 Hz, 1H), 4.90 (d, J=6.0 Hz, 1H), 4.50 (dd, J=6.0, 2.6 Hz,
1H), 3.84 (s, 3H), 3.36 (dd, J=6.0, 3.2 Hz, 1H), 3.05 (d, J=18.6 Hz, 1H),
2.68 (dd, J=2.5, 2.5 Hz, 1H), 2.60 (dd, J=12.4, 4.2 Hz, 1H), 2.45 (s, 3H),
2.39 (dd, J=12.4, 3.6 Hz, 1H), 2.31 (dd, J=18.6, 6.4 Hz, 1H), 2.08 (ddd,
J=12.5, 5.0, 5.0 Hz, 1H), 1.88 ppm (dd, J=12.5, 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=146.2, 142.2, 133.4, 131.0, 128.2, 127.1, 119.6,
112.8, 91.3, 66.4, 58.9, 56.3, 46.5, 43.1, 42.9, 40.7, 35.8, 20.4 ppm; HRMS
(ESI) calcd for C18H21NO3Na [M+Na]+: 322.1410, found 322.1424.
1
1165 cmꢀ1; H NMR (400 MHz, CDCl3): d=8.50 (dd, J=8.5, 2.0 Hz, 1H),
8.45 (d, J=2.0 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H),
6.76 (d, J=8.5 Hz, 1H), 6.04 (dd, J=10.1, 2.1 Hz, 1H), 5.88 (ddd, J=
10.1, 3.9, 3.9 Hz, 1H), 4.83 (s, 1H), 4.50 (t, J=4.8 Hz, 1H), 3.88 (s, 3H),
3.37 (s, 3H), 3.34 (m, 1H), 3.32 (s, 3H), 3.08–3.12 (m, 3H), 2.95 (s, 3H),
2.85 (dd, J=3.9, 3.9 Hz, 2H), 2.21–2.27 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=203.7, 149.7, 148.0, 146.6, 143.6, 137.6, 132.6,
129.7, 128.8, 126.1, 125.0, 124.5, 124.3, 119.8, 112.6, 105.4, 87.6, 57.4, 56.1,
54.4, 53.5, 46.3, 37.3, 36.6, 35.4, 35.0 ppm; HRMS (ESI) calcd for
C26H29N3O11SNa [M+Na]+: 614.1421, found 614.1440.
(ꢀ)-Morphine (1) To
a stirred solution of codeine (34, 10 mg,
0.033 mmol) in CH2Cl2 (0.3 mL) 1m boron tribromide (167 mL,
0.167 mmol) was added at room temperature. After stirring at room tem-
perature for 10 min, 28% aqueous ammonia was added and the solution
was extracted with 10% ethanol in CH2Cl2. The combined organic solu-
tion was washed with brine, dried over sodium sulfate and filtered. The
filtrate was concentrated in vacuo and the residue was purified with prep-
arative thin layer chromatography (10% EtOH in CH2Cl2) to afford 1
24
(6.0 mg, 63%) as white crystals. ½aꢁ2D4 =ꢀ1328 (c=0.10, EtOH, lit. ½aꢁD
=
Chem. Asian J. 2010, 5, 2192 – 2198
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2197