Total synthesis of (±)-morphine

Article abstract of DOI:10.3987/COM-08-S(F)103

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

Full text of DOI:10.3987/COM-08-S(F)103

HETEROCYCLES, Vol. 77, No. 2, 2009
1219
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 1219 - 1234. © The Japan Institute of Heterocyclic Chemistry
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,a,b Satoshi Yokoshima,a Toshiyuki Kan,a,c and Tohru
Fukuyama*a
aGraduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, 113-0033, Japan, E-mail: fukuyama@mol.f.u-tokyo.ac.jp
bPresent Address: Medicinal Chemistry Research Laboratories, Pharmaceutical
Research Center, Kyowa Hakko Kogyo Co., Ltd. 1188 Shimotogari,
Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan
cPresent Address: School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka-shi, 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
Celebration of the 75th Birthday of Dr. Keiichiro Fukumoto, Emeritus Professor of Tohoku University.

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HETEROCYCLES, Vol. 77, No. 2, 2009
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
HO
MeO
MeO
A
CHO
NHR
B
E
O
O
O
H
H
NMe
NR
D
C
HO
O
O
1
2
3
MeO
OTBS
MeO
HO
CHO
NHR
OMe
OMe
+
O
I
O
I
5
6
OH
4
Scheme 1. Retrosynthetic Analysis
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.
MeO
MeO
MeO
HO
ref. 1i
AcOH
OMe
OMe
MOMO
MOMO
CHO
and ref. 5
THF-H2O
rt, 89%
CHO
I
8
I
9
7
MeO
MeO
HO
OMe
OMe
MeOCH2PPh3Cl
HCl
MOMO
OMe
NaHMDS, THF
0 °C to rt, 95%
MeOH
40 °C
96%
I
10
I
5
Scheme 2. Conversion of Isovanillin
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

HETEROCYCLES, Vol. 77, No. 2, 2009
1221
for a scaled up reaction, provided desired 11 in 91% yield in a completely regio- and stereoselective
manner.
Table 1. Tsuji-Trost Reaction with Phenol 5 and Epoxide 6
MeO
MeO
OMe
OMe
OMe
OMe
OTBS
OTBS
MeO
HO
Pd2(dba)3
P(2-furyl)3
OMe
OMe
(a)
(b)
+
+
O
O
I
I
OTBS
O
solvent, rt
(a)
(b)
I
5
6
OH
11 (desired)
HO
12 (undesired)
entry
yield (11 : 12) (%)
solvent
1
2
3
4
toluene
THF
64 : 30
71 : 18
DMF
91 : trace
91 : trace
MeCN
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).
MeO
MeO
OMe
OMe
OTBS
OMe
OMe
MeO
OMe
OMe
OTBS
OH
p-nitrobenzoic acid
O
O
DEAD, PPh3
CSA
I
I
O
OH
I
toluene-THF
0 °C to rt, 90%
MeOH
rt, 94%
O
O
O
Ar
O
Ar
11
13
14
MeO
OMe
OMe
MeO
HO CN
OMe
OMe
DEAD, PPh3
O
K2CO3
I
CN
O
I
toluene
0 °C to rt
MeOH, rt
93% (2 steps)
CN
O
O
Ar
15
16
Scheme 3. Functionalities of the C Ring

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HETEROCYCLES, Vol. 77, No. 2, 2009
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.
MeO
OMe
MeO
MeO
OMe
OMe
OMe
OMe
OMe
LiBH4
Et2O-MeOH
TBSCl
imidazole
O
I
CN
O
O
O
I
I
CN
OH
CN
OTBS
0 °C to rt
95% (2 steps)
DMF, rt
96%
O
Ar
15
17
18
DIBAL
MeO
MeO
OMe
Pd2(dba)3
P(o-tolyl)3
Et3N
CH2Cl2, –78 °C;
NaBH4, MeOH
–78 °C to rt;
OMe
OMe
OMe
NHR
O
O
I
MeCN, reflux;
TBAF, rt
a) ClCO2Me, K2CO3
b) NsCl, K2CO3
NHR
O
OTBS
19a (R = CO2Me) (94%)
19b (R = Ns) (96%)
20a (87%)
20b (96%)
Scheme 4. Construction of the E Ring
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.

HETEROCYCLES, Vol. 77, No. 2, 2009
1223
MeO
MeO
MeO
OMe
OMe
HCl
O
O
O
OMe
H
MeOH
reflux
94%
NCO2Me
NCO2Me
NHCO2Me
O
20a
O
22
O
21a
MeO
MeO
MeO
OMe
OMe
HCl
O
O
O
H
NHNs
NNs
MeOH
reflux
91%
NHNs
O
O
O
20b
23
21b
Scheme 5. Construction of the B and D Rings
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.
MeO
MeO
MeO
1) TMSCl
LHMDS
aq H2O2
NaOH
THF, 0 °C
O
H
O
O
H
H
NCO2Me
MeCN
0 °C to rt
91%
NCO2Me
NCO2Me
2) Pd(OAc)2
MeCN
O
O
O
rt, 92%
O
(2 steps)
21a
24
25
MeO
H2NNH2·H2O
AcOH
O
H
NCO2Me
MeOH
reflux
HO
26
Scheme 6. Attempted Wharton Reaction

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HETEROCYCLES, Vol. 77, No. 2, 2009
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
MeO
MeO
MeO
1) TCDI, DMAP
ClCH2CH2Cl
60 °C
NaBH4
O
O
H
H
O
H
NCO2Me
NCO2Me
MeOH-CH2Cl2
0 °C, 91%
NCO2Me
2) Et3B
n-Bu3SnH
THF, rt, 48%
(2 steps)
O
OH
HO
O
O
25
27
26
MeO
O
MeO
HO
Dess-Martin
periodinane
BBr3
(ref. 11)
LiAlH4
THF
O
O
H
H
H
CH2Cl2, rt
96%
CH2Cl2
rt, 74%
NCO2Me
NMe
NMe
reflux
81%
O
HO
HO
28
29
1
Scheme 7. Total Synthesis of Morphine
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,
13
q = quartet, m = multiplet, and br = broad. Chemical shifts for C 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

HETEROCYCLES, Vol. 77, No. 2, 2009
1225
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
1
a white solid. mp 93.0-94.0 °C; IR (film, cm-1) 1682, 1575, 1479, 1274, 1249, 1021, 904, 773; H 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 =
13
12.8 Hz), 5.16 (2H, s), 3.83 (3H, s), 3.72 (3H, s), 3.68 (3H, s); C NMR (100 MHz, CDCl3) δ: 150.1,
1
149.4, 145.8, 133.6, 120.9, 112.8, 109.6, 98.9, 98.6, 58.5, 56.5, 56.2. Z: H 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
13
(2H, s), 3.84 (3H, s), 3.75 (3H, s), 3.68 (3H, s); C NMR (100 MHz, CDCl3) δ: 150.0, 147.8, 145.4,

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HETEROCYCLES, Vol. 77, No. 2, 2009
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
1
90.0-91.3 °C; IR (film, cm-1) 3374, 2937, 2835, 1599, 1483, 1281, 1119, 1034, 804; H 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
1
yellow oil. IR (film, cm-1) 3421, 2933, 2856, 2360, 1587, 1473, 1265, 1119, 1072, 1030, 839; H 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),
13
0.92 (9H, s), 0.069 (3H, s), 0.065 (3H, s); C 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,

HETEROCYCLES, Vol. 77, No. 2, 2009
1227
1
1529, 1473, 1344, 1269, 1119; H 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),
13
3.10-3.07 (2H, m), 2.60-2.52 (1H, m), 2.18-2.10 (1H, m), 1.97-1.79 (2H, m); C 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),

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HETEROCYCLES, Vol. 77, No. 2, 2009
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),
13
2.62-2.55 (1H, m), 2.13-2.05 (1H, m), 1.95-1.88 (2H, m); C 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,
1
2936, 2835, 2250, 1589, 1476, 1268, 1119, 1066, 1027; H 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),
13
0.89 (9H, s), 0.10 (3H, s), 0.09 (3H, s); C 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.

HETEROCYCLES, Vol. 77, No. 2, 2009
1229
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,
1
1026, 835, 775; H 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),
13
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); C
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

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HETEROCYCLES, Vol. 77, No. 2, 2009
(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
1
(film, cm-1) 2949, 1709, 1504, 1448, 1405, 1313, 1263, 1130, 920, 730; H 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,
13
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); C 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,

HETEROCYCLES, Vol. 77, No. 2, 2009
1231
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,
1
cm-1) 3440, 2933, 1680, 1506, 1452, 1408, 1327, 1275, 1128, 1057, 918, 800, 733; H 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),
13
1.80-1.61 (2H, m); C 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

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HETEROCYCLES, Vol. 77, No. 2, 2009
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)
1
3417, 2952, 1680, 1606, 1504, 1450, 1327, 1275, 1028, 796, 731; H 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,
1
1504, 1446, 1406, 1321, 1273, 1234, 731; H 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),
13
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); C
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.

HETEROCYCLES, Vol. 77, No. 2, 2009
1233
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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