The first example of the stereoselective synthesis of 7 β-carbamoyl-4,5 α-epoxymorphinan via a novel and reactive γ-lactone

Article abstract of DOI:10.1248/cpb.52.747

7 β-Carbamoyl-4,5 α-epoxymorphinans 5 were stereoselectively synthesized from the 7 α-carboxylate intermediate 3 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and amines under reflux conditions in mesitylene via a novel and reactive γ-lacton

Full text of DOI:10.1248/cpb.52.747

June 2004
Chem. Pharm. Bull. 52(6) 747—750 (2004)
747
b
a
The First Example of the Stereoselective Synthesis of 7 -Carbamoyl-4,5 -
g
epoxymorphinan via a Novel and Reactive -Lactone
Hideaki FUJII, Noriyuki HIRANO, Hiromi UCHIRO,1) Kuniaki KAWAMURA,* and Hiroshi NAGASE
2)
Pharmaceutical Research Laboratories, Toray Industries, Inc.; 1111 Tebiro, Kamakura, Kanagawa 248–8555, Japan.
Received February 27, 2004; accepted April 7, 2004; published online April 8, 2004
7b-Carbamoyl-4,5a-epoxymorphinans 5 were stereoselectively synthesized from the 7a-carboxylate inter-
mediate 3 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and amines under reflux conditions in
mesitylene via a novel and reactive g-lactone 7. These were the first examples of the stereoselective syntheses of
7b-substituted 4,5a-epoxymorphinans. The mechanism of the reaction process was elucidated as follows: 1)
epimerization of 7a-carboxylate 3, 2) intramolecular lactonization of 7b-carboxylate 6, and 3) aminolysis of the
resultant g-lactone 7. The aminolysis of the isolated reactive g-lactone 7 with allylamine and the alcoholysis with
MeOH in the presence of NaBH4 proceeded at room temperature. The g-lactone 7 can be a useful intermediate
for the preparation of 7b-substituted 4,5a-epoxymorphinans that would be potent selective d opioid receptor lig-
ands. The stereoselective syntheses of the 7a-carbamoyl-4,5a-epoxymorphinans 9 from 7a-carboxylate 3 via 7a-
carboxylic acid were also successful.
Key words 7b-substituted 4,5a-epoxymorphinan; intramolecular lactonization; g-lactone; aminolysis
During the course of our research directed toward the de- with the boat form of the C-ring. Moreover, the chemical
velopment of selective opioid receptor ligands, we focused shift of the 7a-proton of 5b was observed at 1.98—2.06 ppm
on the 7b-carbamoyl-4,5a-epoxymorphinans. To the best of which was at a higher field than that of the a-methyne proton
our knowledge, though several synthetic methods of 7a- of the normal carboxamide compound.9) The higher chemical
monosubstituted or 7,7-disubstituted 4,5a-epoxymorphinans shift caused by the shielding effect of the benzene ring sup-
are known,3—7) there were no reports on the stereoselective ported the stereostructure of 5b as 6a-hydroxy-7b-carbox-
syntheses of the 7b-substituted derivatives. Portoghese et al. amide.10)
reported that thermodynamically less favored 7b-substituted
The mechanism for the conversion of the 7a-carboxylate 3
4,5a-epoxymorphinan detected only by TLC or liquid chro- into the 7b-carboxamide 4 was speculated as follows (Chart
matography/mass spectrometry (LC/MS) could not be iso- 2). In general, the direct aminolysis of esters required a reac-
lated.4) Herein, we report the first stereoselective synthesis of tion temperature higher than 200 °C or high pressure.11,12)
7b-carbamoyl-4,5a-epoxymorphinan from 4,5a-epoxymor- Therefore, the direct aminolysis of the 7a-carboxylate 3ꢀ
phinan-7a-carboxylate and its reasonable mechanism, and could not occur. On the other hand, a harsh basic condition
also report the stereoselective synthesis of 7a-carbamoyl- could deprotonate from the 7 position of the 7a-carboxylate
4,5a-epoxymorphinan from the same substrate.
3ꢀ to reach an equilibrium between the 7a-carboxylate 3ꢀ and
the 7b-carboxylate 6. The resulting 7b-carboxylate 6 (chair)
should be converted to the g-lactone 7, because the 7b-sub-
Results and Discussion
Chemistry Naltrexone 3-O-benzyl ether (1) was con- stituent would be closed to the 14-hydroxyl group in the
verted to ethyl 7a-carboxylate 3 via compound 2 by heating chair form of the C-ring. Examples of the intramolecular re-
in the presence of sodium hydride in diethyl carbonate as a action between the 7b- and the 14-substituents have been re-
solvent followed by reduction using NaBH4 (Chart 1). The ported.7,13,14) The right shift of the equilibrium would allow
NMR spectra showed ethyl 7-carboxylate 2 existed in only the intramolecular formation of the g-lactone 7 eliminating
the enol form.7) Compound 3 was refluxed in mesitylene in the alcohol (R4OH) under the reaction conditions. The novel,
the presence of DBU and amines to give the 7-carboxamides strained, and reactive g-lactone 7 could easily react with the
4. The desired compounds 5 were obtained by the debenzyla-
tion8) of the corresponding 7-carboxamides 4.
The stereochemistry of compounds 3 and 5 was confirmed
by NMR spectral analyses. For compound 3, a positive nu-
clear Overhauser effect (NOE) between the 5b-proton and
the 7-proton was observed, but not between the 6-proton and
8a-proton. On the other hand, positive NOEs both between
the 5b-proton and the 7-proton and between the 6-proton and
the 8a-proton were observed on the 6-epimer of compound
3, which was obtained by the reduction of compound 2 as a
by-product. These observations suggested that compound 3
would possess the 6a-hydroxyl and the 7a-ethoxycarbonyl
Reagents and conditions: a) NaH, CO(OEt)2, 100 °C, b) NaBH4, MeOH/MeCN, rt.,
c) N-methylphenethylamine for 4a, allylamine for 4b, DBU, mesitylene, reflux, d) H2,
Pd/C, AcOH, MeOH, rt. for conversion of 4a, e) conc. HCl, AcOH, 80 °C for conver-
sion of 4b
groups. On compound 5b, a positive NOE between the 6-
proton and the 8b-proton was observed, and the J6,7 coupling
constant was 12.0 Hz. These observations suggested that 5b
would possess the 6a-hydroxyl and the 7b-carbamoyl groups
Chart 1
∗ To whom correspondence should be addressed. e-mail: kuniaki_kawamura@nts.toray.co.jp
© 2004 Pharmaceutical Society of Japan

748
Vol. 52, No. 6
Reagents and conditions: a) LiOH aq, THF aq, 40 °C, b) N-methylphenethylamine
for 8a, allylamine for 8b, (PrPO2)3, N-ethylmorpholine, DMF, rt., c) H2, Pd/C, AcOH,
MeOH, rt. for conversion of 8a, d) conc. HCl, AcOH, 80 °C for conversion of 8b
Chart 3
Conclusion
The 7b-carbamoyl-4,5a-epoxymorphinans 5 were stereos-
electively synthesized from 7a-carboxylate 3 via the novel
and reactive g-lactone 7. These were the first examples of the
stereoselective syntheses of the 7b-substituted morphinans.
The mechanism for the reaction process was elucidated. The
aminolysis of the isolated reactive g-lactone 7 with allyl-
amine and the alcoholysis with MeOH in the presence of
NaBH4 proceeded at room temperature. The g-lactone 7
could be a useful intermediate for the preparation of the 7b-
substituted 4,5a-epoxymorphinans that would be potent se-
lective d opioid receptor ligands. The stereoselective synthe-
ses of the 7a-carbamoyl-4,5a-epoxymorphinams 9 from the
same substrate, 7a-carboxylate 3, via the 7a-carboxylic acid
were also successful.
Chart 2. The Speculated Mechanism for the Conversion from 7a-Car-
boxylate 3ꢀ to 7b-Carbamoyl-4,5a-epoxymorphinan 4ꢀ
CPM: cyclopropylmethyl.
amine to produce the 7b-carboxamide 4ꢀ. Since the a-proton
of the amides is generally less acidic than that of esters, the
7b-carboxamide 4ꢀ could be obtained without epimerization
at the 7 position under the given reaction conditions. This
proposed mechanism was confirmed to be reasonable by the
following experiments and results. First, the reaction of 3ꢀ
(R3ꢁMe, R4ꢁEt) with DBU in the absence of a primary or
secondary amine gave the g-lactone 7 (R3ꢁMe) in 71%
yield. Second, the aminolysis of the isolated g-lactone 7
(R3ꢁH) with allylamine proceeded at room temperature to
give the corresponding carboxamides 5b in 71% yield. More-
over, the reaction of the g-lactone 7 (R3ꢁBn) with MeOH in
the presence of NaBH4 for 1 h in accordance with Chadha’s
Experimental
Genaral Nuclear magnetic resonance spectra were recorded on a Varian
GEMINI 300 (300 MHz), JEOL JNM-AL 400 (400 MHz), Varian UNITY
plus 500 (500 MHz), Varian INOVA 600 (600 MHz) spectrometers, and the
chemical shifts are recorded as d values (ppm) relative to tetramethylsilane
reaction conditions15) gave the methyl 7b-carboxylate 6 (TMS). Infrared (IR) spectra were obtained using a JASCO FT/IR-5000 as
(R3ꢁBn, R4ꢁMe) in 54% yield with a trace amount of the
KBr pellets or neat. Mass spectra were obtained on a JEOL JMS-D300,
JEOL JMS-DX303, VG ZAB-HF, or micromass LCT (HP1100) (A-MS-4)
instruments by applying an electric ionization (EI) method, a fast atom bom-
bardment (FAB) ionization method, or an electrospray ionization (ESI)
method. Elemental analyses were determined with a Heraeus CHN-
ORAPID for carbon, hydrogen, and nitrogen, Yokogawa IC-7000 for sulfur.
Elemental analyses were within 0.4% of the theoretical values. The progress
of the reaction was determined on Merck silica Gel Art.5715 or Fuji Silycia
NH Silica Gel. All the column chromatographies were carried out using
reduced product, the triol derivative. On compound 6
(R3ꢁBn, R4ꢁMe), the NOE between the 6-proton and the
8b-proton was observed, and the J6,7 coupling constant was
11.5 Hz. Moreover, the chemical shift of the 7-proton of 6
(R3ꢁBn, R4ꢁMe) was observed at 2.03—2.13 ppm which
was at a higher field than that of the a-methyne proton of the
normal ester compound.9) These observations suggested that
Merck Silica Gel Art.9385, Merck Silica Gel Art.7734, Fuji Silycia Silica
Gel DM-2010, or Fuji Silycia Silica Gel DM-2035. All the experiments
were carried out under an argon atmosphere.
6 (R3ꢁBn, R4ꢁMe) would possess the 6a-hydroxyl and the
7b-methoxycarbonyl groups with the boat form of the C-
Ethyl 3-O-Benzyl-17-(cyclopropylmethyl)-4,5a-epoxy-6a,14b-dihy-
ring. These observations strongly supported the occurrence
droxymorphinan-7a-carboxylate (3) Sodium hydride (60% in oil, 1.67 g,
of the reactive g-lactone 7 as an intermediate.
The 7a-carbamoyl-4,5a-epoxymorphinans 9 were also
41.8 mmol) was 3 times washed with pentane (10 ml) and suspended in di-
ethyl carbonate (20 ml). To the stirred suspension was added dropwise a so-
synthesized as the 7-position epimers of compounds 5 (Chart
3). The 7a-carboxylic acid, which was derived by the hydrol-
ysis of ethyl 7a-carboxylate 3, was condensed with amines
using propyl phosphoric acid anhydride16) to give the 7a-car-
boxamides 8. Compounds 8 were converted to the desired
lution of 3-O-benzyl naltrexone (1) (5.65 g, 13.1 mmol) in diethyl carbonate
(30 ml). Effervescence was observed. After refluxing for 1 h, the reaction
mixture was cooled to room temperature. To the solution was added water at
0 °C, then 1 M hydrochloric acid was added until the solution was acidic. The
resulting solution was basified with aqueous ammonia, and extracted with
chloroform. The organic layer was dried over magnesium sulfate and evapo-
compounds 9 by the same debenzylation conditions. The rated in vacuo. The residue was chromatographed on silica gel to give 3.25 g
(49%) of 2. To a stirred solution of 2 (1.0 g, 1.99 mmol) in methanol (10 ml)
and acetonitrile (20 ml) was added sodium borohydride (154 mg, 4.07 mmol)
at room temperature, and the mixture was stirred for 1 h. The resulting solu-
tion was poured into a saturated sodium bicarbonate solution, and then ex-
stereochemistry of the 7a-carboxamide 9b was confirmed by
observation of a positive NOE between the 5b-proton and the
7b-proton.
Bioassay The opioid activities of the synthesized com-
pounds were preliminarily evaluated using the mouse vas
deference in which the d opioid receptors are predominantly
expressed. Of all the synthesized compounds, the 7b-carbox-
amide 5b showed d opioid receptor antagonistic activities.17)
The detail pharmacological properties of the 7a- and the 7b-
carboxamides are now under investigation.
tracted with ethyl acetate. The combined organic layer was washed with
brine and dried over magnesium sulfate. After removing the solvent in
vacuo, the residue was chromatographed on silica gel to give 756 mg (75%)
of 3 and 21 mg (2%) of the 6-epimer of 3. 3: IR (KBr) cmꢂ1: 3390, 2940,
1736, 1501, 1451, 1251, 1184, 1048, 1000. NMR (CDCl3, 500 MHz) d:
0.08—0.18 (2H, m), 0.47—0.58 (2H, m), 0.79—0.88 (1H, m), 1.21 (3H, t,
Jꢁ7.2 Hz), 1.45 (1H, br d, Jꢁ11.6 Hz), 1.72 (1H, dd, Jꢁ3.1, 13.3 Hz), 1.85
(1H, t, Jꢁ12.7 Hz), 2.12 (1H, dd, Jꢁ1.3, 3.0 Hz), 2.12—2.20 (1H, m), 2.22

June 2004
749
etate. The extract was washed with brine, dried over magnesium sulfate, and
evaporated in vacuo. The residue was chromatographed on silica gel to give
69 mg (63%) of 5b: NMR (CDCl3, 600 MHz) d: 0.08—0.16 (2H, m), 0.49—
0.57 (2H, m), 0.80—0.88 (1H, m), 1.61—1.70 (1H, m), 1.63 (1H, dd,
Jꢁ5.0, 15.0 Hz), 1.88 (1H, dd, Jꢁ8.3, 15.0 Hz), 1.98—2.06 (1H, m), 2.22—
2.34 (3H, m), 2.38 (1H, dd, Jꢁ6.3, 12.7 Hz), 2.53 (1H, dd, Jꢁ6.7, 18.6 Hz),
2.63—2.70 (1H, m), 3.04 (1H, d, Jꢁ18.6 Hz), 3.12 (1H, d, Jꢁ6.7 Hz),
3.58—3.64 (1H, m), 3.74—3.81 (1H, m), 4.44 (1H, dd, Jꢁ4.3, 12.0 Hz),
4.74 (1H, d, Jꢁ4.3 Hz), 4.99 (1H, dd, Jꢁ1.3, 10.2 Hz), 5.05 (1H, dd, Jꢁ1.3,
17.2 Hz), 5.62—5.70 (1H, m), 6.50 (1H, d, Jꢁ8.1 Hz), 6.71 (1H, d,
Jꢁ8.1 Hz), 6.98 (1H, br s). To a stirred solution of 5b in methanol was
added dropwise methane sulfonic acid at 0 °C until the solution became
acidic. Ethyl acetate was then added to the solution. The precipitated salt
was filtered to give 5b·CH3SO3H: IR (KBr) cmꢂ1: 3394, 1640, 1509, 1320,
1201, 1058. NMR (DMSO-d6, 300 MHz) d: 0.31—0.74 (4H, m), 0.91—1.08
(1H, m), 1.48—1.73 (2H, m), 1.86—2.03 (2H, m), 2.30 (3H, s), 2.34—2.50
(1H, m), 2.60—3.10 (4H, m), 3.21—3.70 (3H, m), 3.86 (1H, br d,
Jꢁ6.6 Hz), 4.31 (1H, dd, Jꢁ4.3, 11.1 Hz), 4.56 (1H, d, Jꢁ4.4 Hz), 4.94—
5.02 (1H, m), 5.05—5.14 (1H, m), 5.71 (1H, tdd, Jꢁ5.0, 10.2, 17.2 Hz),
6.22 (1H, br s), 6.54 (1H, d, Jꢁ8.1 Hz), 6.70 (1H, d, Jꢁ8.1 Hz), 7.94 (1H,
br t, Jꢁ7.6 Hz), 8.75 (1H, br s), 9.24 (1H, br s). HR-MS (ESI) m/z Calcd for
C24H30N2O5: 427.2233. Found: 427.2267.
3-O-Benzyl-17-(cyclopropylmethyl)-4,5a-epoxy-6a-hydroxymorphi-
nan-7b,14b-carbolactone (7: R3ꢁBn) To a stirred solution of 3 (300 mg,
0.59 mmol) in mesitylene (10 ml) was added DBU (0.62 ml, 4.1 mmol), and
the mixture was refluxed for 3 h. After cooling to room temperature, the re-
action mixture was poured into 1 M hydrochloric acid. The aqueous layer
was basified with saturated sodium bicarbonate solution, then extracted with
ethyl acetate. The extract was washed with brine, dried over magnesium sul-
fate, and evaporated in vacuo. The residue was chromatographed on silica
gel to give 150 mg (55%) of 7 (R3ꢁBn): IR (KBr) cmꢂ1: 3448, 2921, 1774,
1499, 1452, 1191, 1067, 1046, 953. NMR (CDCl3, 300 MHz) d: 0.08—0.17
(2H, m), 0.48—0.59 (2H, m), 0.85—0.96 (1H, m), 1.53—1.61 (1H, m), 1.85
(1H, dd, Jꢁ5.1, 12.2 Hz), 1.99 (1H, d, Jꢁ12.5 Hz), 2.27—2.41 (3H, m),
2.48—2.61 (3H, m), 2.72—2.82 (1H, m), 2.94 (1H, t, Jꢁ4.6 Hz), 3.23 (1H,
d, Jꢁ18.3 Hz), 3.66 (1H, d, Jꢁ5.6 Hz), 4.40 (1H, dd, Jꢁ4.3, 6.5 Hz), 4.63
(1H, d, Jꢁ6.8 Hz), 5.13 (1H, d, Jꢁ12.0 Hz), 5.21 (1H, d, Jꢁ12.0 Hz), 6.66
(1H, d, Jꢁ8.3 Hz), 6.82 (1H, d, Jꢁ8.3 Hz), 7.30—7.45 (5H, m). HR-MS
(EI) m/z Calcd for C28H29NO5: 459.2046. Found: 459.2065.
17-Cyclopropylmethyl-4,5a-epoxy-6a-hydroxy-3-O-methylmorphi-
nan-7b,14b-carbolactone (7: R3ꢁMe) The title compound was synthe-
sized from 3ꢀ (R3ꢁMe, R4ꢁEt) by the same procedure described above:
IR (KBr) cmꢂ1: 3475, 2938, 1775, 1504, 1452, 1332, 1282, 1264, 1190,
1139. NMR (CDCl3, 300 MHz) d: 0.09—0.19 (2H, m), 0.48—0.60 (2H, m),
0.86—0.97 (1H, m), 1.55—1.62 (1H, m), 1.86 (1H, dd, Jꢁ5.3, 12.2 Hz),
1.99 (1H, d, Jꢁ12.0 Hz), 2.32—2.42 (3H, m), 2.52—2.61 (2H, m), 2.75—
2.82 (2H, m), 2.96 (1H, t, Jꢁ4.6 Hz), 3.24 (1H, d, Jꢁ18.6 Hz), 3.67 (1H, d,
Jꢁ5.4 Hz), 3.88 (3H, s), 4.45 (1H, dd, Jꢁ3.9, 6.6 Hz), 4.66 (1H, d,
Jꢁ7.1 Hz), 6.69 (1H, d, Jꢁ8.2 Hz), 6.76 (1H, d, Jꢁ8.2 Hz). HR-MS (EI) m/z
Calcd for C22H25NO5: 383.1733. Found: 383.1742.
17-Cyclopropylmethyl-4,5a-epoxy-3,6a-dihydroxymorphinan-7b,14b-
carbolactone (7: R3ꢁH) To a stirred solution of 7 (R3ꢁMe) (742 mg,
2.01 mmol) in dry dichloromethane (20 ml) was added dropwise a 1.0 M so-
lution of boron tribromide in dry dichloromethane (29.0 ml, 29.0 mmol) at
0 °C. After stirring at room temperature for 5 h, the reaction mixture was
cooled to 0 °C. To the solution was added cooled saturated sodium bicarbon-
ate solution, then stirred vigorously at 0 °C. The resulting mixture was sepa-
rated and extracted with dichloromethane. The combined organic layers
were dried over magnesium sulfate and evaporated in vacuo. The residue
was chromatographed on silica gel to give 484 mg (68%) of 7 (R3ꢁH):
IR (KBr) cmꢂ1: 3409, 2927, 1775, 1639, 1617, 1503, 1461, 1331, 1234,
1190, 1142, 1064, 1034, 959. NMR (CDCl3, 300 MHz) d: 0.07—0.20 (2H,
m), 0.46—0.62 (2H, m), 0.84—0.98 (1H, m), 1.54 (1H, d, Jꢁ9.3 Hz), 1.85
(1H, dd, Jꢁ4.9, 12.4 HZ), 2.00 (1H, d, Jꢁ12.1 Hz), 2.33—2.44 (3H, m),
2.50—2.63 (2H, m), 2.73—2.84 (1H, m), 2.90—2.96 (1H, m), 3.23 (1H, d,
Jꢁ18.4 Hz), 3.68 (1H, d, Jꢁ5.5 Hz), 4.42 (1H, dd, Jꢁ4.0, 6.5 Hz), 4.58—
4.64 (1H, m), 6.60 (1H, d, Jꢁ8.2 Hz), 6.73 (1H, d, Jꢁ8.2 Hz). HR-MS (ESI)
m/z Calcd for C21H23NO5: 370.1654. Found: 370.1684.
(1H, dt, Jꢁ4.5, 12.1 Hz), 2.36 (1H, dd, Jꢁ6.4, 12.5 Hz), 2.39 (1H, dd,
Jꢁ6.5, 12.5 Hz), 2.61—2.69 (2H, m), 3.03 (1H, d, Jꢁ18.3 Hz), 3.12 (1H, d,
Jꢁ5.6 Hz), 3.13—3.18 (1H, m), 4.08 (1H, dq, Jꢁ7.2, 10.8 Hz), 4.13 (1H,
dq, Jꢁ7.2, 10.8 Hz), 4.52—4.57 (1H, m), 4.67 (1H, d, Jꢁ6.0 Hz), 5.11 (1H,
d, Jꢁ11.9 Hz), 5.18 (1H, d, Jꢁ12.1 Hz), 5.20 (1H, br s), 6.56 (1H, d,
Jꢁ8.2 Hz), 6.73 (1H, d, Jꢁ8.2 Hz), 7.26—7.32 (1H, m), 7.32—7.38 (2H,
m), 7.40—7.44 (2H, m). HR-MS (EI) m/z Calcd for C30H35NO6: 505.2464.
Found: 505.2448.
6-Epimer of 3: IR (neat) cmꢂ1: 3406, 2932, 2832, 1729, 1499, 1448, 1379,
1278, 1263, 1183, 1046, 913, 729. NMR (CDCl3, 500 MHz) d: 0.07—0.16
(2H, m), 0.48—0.58 (2H, m), 0.78—0.88 (1H, m), 1.24 (3H, t, Jꢁ7.2 Hz),
1.44—1.50 (1H, m), 1.49 (1H, t, Jꢁ12.9 Hz), 1.84 (1H, dd, Jꢁ2.7, 13.0 Hz),
2.09 (1H, dt, Jꢁ3.5, 12.1 Hz), 2.22 (1H, dt, Jꢁ5.1, 12.6 Hz), 2.36 (2H, d,
Jꢁ6.6 Hz), 2.56 (1H, dd, Jꢁ5.8, 18.5 Hz), 2.62 (1H, dd, Jꢁ4.5, 11.8 Hz),
3.01 (1H, d, Jꢁ18.5 Hz), 3.04—3.13 (2H, m), 3.65 (1H, dd, Jꢁ6.4,
11.3 Hz), 4.13 (2H, q, Jꢁ7.2 Hz), 4.51 (1H, d, Jꢁ6.4 Hz), 5.17 (1H, d,
Jꢁ12.1 Hz), 5.23 (1H, d, Jꢁ12.1 Hz), 6.56 (1H, d, Jꢁ8.2 Hz), 6.76 (1H, d,
Jꢁ8.2 Hz), 7.26—7.31 (1H, m), 7.33—7.38 (2H, m), 7.40—7.46 (2H, m).
MS (EI) m/z 505.
Ethyl 17-(Cyclopropylmethyl)-4,5a-epoxy-6a,14b-dihydroxy-3-O-
methylmorphinan-7a-carboxylate (3ꢀ: R3ꢁMe, R4ꢁEt) The title com-
pound was synthesized by the same procedure described above.
IR (KBr) cmꢂ1: 3402, 2942, 2834, 1736, 1638, 1614, 1504, 1443, 1280,
1259, 1184, 1052, 1001. NMR (CDCl3, 300 MHz) d: 0.07—0.20 (2H, m),
0.48—0.59 (2H, m), 0.77—0.92 (1H, m), 1.21 (3H, t, Jꢁ7.1 Hz), 1.42—
1.50 (1H, m), 1.73 (1H, dd, Jꢁ3.3, 13.4 Hz), 1.86 (1H, dd, Jꢁ12.1,
13.2 Hz), 2.11—2.29 (2H, m), 2.32 (1H, dd, Jꢁ1.2, 3.2 Hz), 2.36 (1H, dd,
Jꢁ6.6, 12.9 Hz), 2.39 (1H, dd, Jꢁ6.6, 12.9 Hz), 2.58—2.72 (2H, m), 3.05
(1H, d, Jꢁ18.4 Hz), 3.11—3.21 (1H, m), 3.14 (1H, d, Jꢁ3.3 Hz), 3.85 (3H,
s), 4.08 (1H, dq, Jꢁ7.1, 10.7 Hz), 4.13 (1H, dq, Jꢁ7.1, 10.7 Hz), 4.55—4.61
(1H, m), 4.69 (1H, d, Jꢁ6.0 Hz), 5.21 (1H, br s), 6.61 (1H, d, Jꢁ8.2 Hz),
6.70 (1H, d, Jꢁ8.2 Hz). HR-MS (EI) m/z Calcd for C24H31NO6: 429.2151.
Found: 429.2130.
17-(Cyclopropylmethyl)-4,5a-epoxy-3,6a,14b-trihydroxymorphinan-
7b -(N-methyl-N-phenethyl)carboxamide · Methane Sulfonate
(5a·CH3SO3H) To a stirred solution of 3 (201 mg, 0.4 mmol) in mesity-
lene (5 ml) were added DBU (0.5 ml, 3.3 mmol) and N-methylphenethyl-
amine (1.2 ml, 8.2 mmol), and the mixture was then refluxed for 8.5 h. After
cooling to room temperature, the reaction mixture was poured into 1 M hy-
drochloric acid. The aqueous layer was basified with saturated sodium bicar-
bonate solution, then extracted with ethyl acetate. The extract was washed
with brine, dried over magnesium sulfate, and evaporated in vacuo. The
residue was chromatographed on silica gel to give 128 mg (54%) of 4a. A
solution of 4a (128 mg, 0.22 mmol) in methanol (5 ml) with acetic acid
(24 ml, 0.52 mmol) was stirred for 14 h with 10% palladium charcoal (50%
wet, 20 mg) under a hydrogen atmosphere (1 atm) at room temperature. The
catalyst was removed by filtration, and the filtrate was concentrated in vacuo
to half the volume. The resulting solution was poured into a saturated
sodium bicarbonate solution, and extracted with ethyl acetate. The extract
was washed with brine, dried over magnesium sulfate, and evaporated in
vacuo. The residue was chromatographed on silica gel to give 82 mg (76%)
of 5a. To a stirred solution of 5a in methanol was added dropwise methane
sulfonic acid at 0 °C until the solution became acidic. Ethyl acetate was then
added to the solution. The precipitated salt was filtered to give
5a·CH3SO3H: IR (KBr) cmꢂ1: 3388, 1620, 1504, 1208, 1118, 1058. NMR
(DMSO-d6, 300 MHz) d: 0.32—0.51 (2H, m), 0.52—0.73 (2H, m), 0.91—
1.06 (1H, m), 1.14 (0.7H, dd, Jꢁ9.3, 14.8 Hz), 1.48 (0.3H, dd, Jꢁ9.5,
15.5 Hz), 1.58—1.72 (1H, m), 1.82 (0.7H, dd, Jꢁ8.4, 15.2 Hz), 1.96 (0.3H,
dd, Jꢁ9.2, 15.0 Hz), 2.26—2.57 (3H, m), 2.30 (3.3H, s), 2.57—2.81 (2H,
m), 2.62 (0.9H, s), 2.76 (2.1H, s), 2.83—3.12 (4H, m), 3.22—3.54 (3H, m),
3.78 (0.7H, d, Jꢁ6.6 Hz), 3.86 (0.3H, d, Jꢁ6.6 Hz), 4.23—4.35 (1H, m),
4.58 (0.7H, d, Jꢁ4.1 Hz), 4.60 (0.3H, d, Jꢁ4.4 Hz), 6.22 (0.7H, br s), 6.29
(0.3H, br s), 6.56 (0.3H, d, Jꢁ8.2 Hz), 6.62 (0.7H, d, Jꢁ8.2 Hz), 6.71 (0.3H,
d, Jꢁ8.0 Hz), 6.80 (0.7H, d, Jꢁ8.0 Hz), 6.88—6.96 (1.3H, m), 7.14—7.32
(3.7H, m), 8.74 (1H, br s), 9.21 (0.3H, br s), 9.29 (0.7H, br s). MS (FAB) m/z
505 (MꢃHꢃ). Anal. Calcd for C30H36N2O5·1.1MeSO3H·0.5H2O: C, 60.31;
H, 6.74; N, 4.52; S, 5.70. Found: C, 60.07; H, 6.77; N, 4.66; S, 5.57.
17-(Cyclopropylmethyl)-4,5a-epoxy-3,6a,14b-trihydroxymorphinan-
7b-(N-allyl)carboxamide·Methane Sulfonate (5b·CH3SO3H) A stirred
solution of 4b (131 mg, 0.25 mmol), which was synthesized from 3 (313 mg,
0.62 mmol) in 40% yield by the procedure described above, in concentrated
hydrochloric acid (2 ml) and acetic acid (4 ml) was heated at 80 °C for
30 min. After cooling to room temperature, the reaction mixture was poured
into cooled concentrated aqueous ammonia, then extracted with ethyl ac-
17-(Cyclopropylmethyl)-4,5a-epoxy-3,6a,14b-trihydroxymorphinan-
7a -(N-methyl-N-phenethyl)carboxamide · Methane Sulfonate
(9a·CH3SO3H) To a stirred solution of 3 (170 mg, 0.4 mmol) in THF
(4.5 ml) and distilled water (1.5 ml) was added 1 M lithium hydroxide solu-
tion (0.5 ml), then the mixture was heated at 40 °C for 5.5 h. After cooling to
room temperature, the reaction mixture was concentrated in vacuo and the

750
Vol. 52, No. 6
Alcoholysis of g-Lactone 7 To a solution of 7 (R3ꢁBn) (50 mg,
0.11 mmol) in methanol (5 ml) was added sodium borohydride (9 mg,
0.24 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 h.
The reaction mixture was poured into saturated sodium bicarbonate solution,
then extracted with chloroform/ethanol (3/1). The combined organic layer
was dried over magnesium sulfate and evaporated in vacuo. The residue was
chromatographed on silica gel to give 29 mg (54%) of 6 (R3ꢁBn, R4ꢁMe)
residual water was removed by evaporation with benzene. To a solution of
the residue in DMF were added N-ethylmorpholine (0.36 ml, 2.8 mmol), N-
methylphenethylamine (0.1 ml, 0.69 mmol), and a 50% solution of propyl
phosphoric acid anhydride in DMF (0.3 ml, 0.51 mmol), then the mixture
was stirred for 15 h at room temperature. The reaction mixture was poured
into saturated sodium bicarbonate solution, then extracted with ethyl acetate.
The extract was washed with brine, dried over magnesium sulfate, and evap-
orated in vacuo. The residue was chromatographed on silica gel to give
144 mg (72%) of 8a. A solution of 8a (144 mg, 0.24 mmol) in methanol
(5 ml) with acetic acid (50 ml, 0.87 mmol) was stirred for 4.5 h with 10%
palladium charcoal (50% wet, 36 mg) under a hydrogen atmosphere (1 atm)
at room temperature. The catalyst was removed by filtration, and the filtrate
was concentrated in vacuo to half the volume. The resulting solution was
poured into saturated sodium bicarbonate solution, then extracted with ethyl
acetate. The extract was washed with brine, dried over magnesium sulfate,
and evaporated in vacuo. The residue was chromatographed on silica gel to
give 97 mg (79%) of 9a. To a stirred solution of 9a in methanol was added
dropwise methane sulfonic acid at 0 °C until the solution became acidic.
Ethyl acetate was then added to the solution. The precipitated salt was fil-
tered to give 9a·CH3SO3H: IR (KBr) cmꢂ1: 3390, 1616, 1502, 1459, 1329,
1211, 1194, 1059, 1042. NMR (DMSO-d6, 300 MHz) d: 0.35—0.75 (4H,
m), 0.96—1.13 (1H, m), 1.30—1.50 (2H, m), 1.72—1.87 (1H, m), 2.30
(3.3H, s), 2.32—2.56 (2H, m), 2.64—2.75 (1H, m), 2.76—3.12 (5H, m),
2.83 (1.5H, s), 3.00 (1.5H, s), 3.17—3.75 (4H, m), 3.77—3.85 (1H, m), 3.86
(0.5H, d, Jꢁ6.0 Hz), 4.23 (0.5H, d, Jꢁ6.6 Hz), 4.48 (0.5H, d, Jꢁ5.5 Hz),
4.68 (0.5H, d, Jꢁ5.5 Hz), 6.11 (1H, br s), 6.48—6.64 (2H, m), 7.15—7.41
(5H, m), 8.77 (1H, br s), 8.96 (1H, br s). MS (free base, EI) m/z 504 (Mꢃ).
Anal. Calcd for C30H36N2O5·1.1MeSO3H·0.8H2O: C, 59.79; H, 6.78; N,
4.48; S, 5.67. Found: C, 59.67; H, 6.84; N, 4.49; S, 5.78.
with a trace amount of triol derivative. 6 (R3ꢁBn, R4ꢁMe): IR (KBr) cmꢂ1
:
3392, 2922, 1741, 1504, 1454, 1282, 1173, 1047. NMR (CDCl3, 400 MHz)
d: 0.08—0.16 (2H, m), 0.49—0.58 (2H, m), 0.77—0.89 (1H, m), 1.57—
1.63 (1H, m), 1.71 (1H, dd, Jꢁ9.4, 14.8 Hz), 1.89 (1H, dd, Jꢁ8.8, 14.6 Hz),
2.03—2.13 (1H, m), 2.20—2.33 (3H, m), 2.38 (1H, dd, Jꢁ6.5, 12.6 Hz),
2.40 (1H, d, Jꢁ10.0 Hz), 2.57 (1H, dd, Jꢁ6.6, 18.3 Hz), 2.60—2.67 (1H,
m), 3.04 (1H, d, Jꢁ18.3 Hz), 3.12 (1H, d, Jꢁ6.6 Hz), 3.68 (3H, s), 4.41 (1H,
ddd, Jꢁ4.4, 10.0, 11.5 Hz), 4.70 (1H, d, Jꢁ4.2 Hz), 4.99 (1H, br s), 5.14
(1H, d, Jꢁ12.2 Hz), 5.23 (1H, d, Jꢁ12.2 Hz), 6.56 (1H, d, Jꢁ8.2 Hz), 6.78
(1H, d, Jꢁ8.2 Hz), 7.25—7.46 (5H, m). HR-MS (EI) m/z Calcd for
C29H33NO6: 491.2308. Found: 491.2278.
References and Notes
1) Present address: Faculty of Pharmaceutical Sciences, Tokyo University
of Science, 2641 Yamazaki, Noda, Chiba 278–8510, Japan.
2) Present address: School of Pharmaceutical Sciences, Kitasato Univer-
sity, 5–9–1 Shirokane, Minato-ku, Tokyo 108–8641, Japan.
3) Casy A. F., Parfitt R. T., “Opioid Analgesics Chemistry and Recep-
tors,” Chap. 2, Plenum Press, New York, 1986, pp. 9—104 and refer-
ences therein.
4) Gao P., Portoghese P. S., J. Med. Chem., 60, 2276—2278 (1995).
5) Ohkawa S., DiGiacomo B., Larson D. L., Takemori A. E., Portoghese
P. S., J. Med. Chem., 40, 1720—1725 (1997).
17-(Cyclopropylmethyl)-4,5a-epoxy-3,6a,14b-trihydroxymorphinan-
7a-(N-allyl)carboxamide·Methane Sulfonate (9b·CH3SO3H) A stirred
solution of 8b (171 mg, 0.32 mmol), which was synthesized from 3 (319 mg,
0.63 mmol) in 53% yield by the procedure described above, in concentrated
hydrochloric acid (2 ml) and acetic acid (4 ml) was heated at 80 °C for
30 min. After cooling to room temperature, the reaction mixture was poured
into cooled concentrated aqueous ammonia, then extracted with ethyl ac-
etate. The extract was washed with brine, dried over magnesium sulfate, and
evaporated in vacuo. The residue was chromatographed on silica gel to give
87 mg (63%) of 9b: NMR (free base, CDCl3, 600 MHz) d: 0.09—0.18 (2H,
m), 0.49—0.59 (2H, m), 0.80—0.89 (1H, m), 1.41—1.48 (1H, m), 1.56 (1H,
dd, Jꢁ2.3, 12.5 Hz), 1.97 (1H, t, Jꢁ15.4 Hz), 2.15—2.25 (2H, m), 2.34—
2.42 (2H, m), 2.60—2.68 (1H, m), 2.61 (1H, dd, Jꢁ5.3, 18.5 Hz), 3.03 (1H,
d, Jꢁ18.5 Hz), 3.03—3.08 (1H, m), 3.11 (1H, d, Jꢁ5.3 Hz), 3.79—3.84
(2H, m), 4.51 (1H, dd, Jꢁ1.9, 5.9 Hz), 4.61 (1H, d, Jꢁ5.9 Hz), 5.09 (1H, dd,
Jꢁ1.3, 10.3 Hz), 5.14 (1H, dd, Jꢁ1.3, 17.2 Hz), 5.73—5.81 (1H, m), 6.09
(1H, br s), 6.36 (1H, br s), 6.53 (1H, d, Jꢁ8.1 Hz), 6.67 (1H, d, Jꢁ8.1 Hz).
To a stirred solution of 9b in methanol was added dropwise methane sul-
fonic acid at 0 °C until the solution became acidic. Ethyl acetate was then
added to the solution. The precipitated salt was filtered to give
9b·CH3SO3H: IR (KBr) cmꢂ1: 3370, 1638, 1547, 1506, 1463, 1427, 1329,
1196, 1050. NMR (DMSO-d6, 300 MHz) d: 0.35—0.74 (4H, m), 0.96—1.12
(1H, m), 1.37 (1H, br d, Jꢁ10.4 Hz), 1.62 (1H, br d, Jꢁ11.5 Hz), 1.78 (1H, t,
Jꢁ12.8 Hz), 2.31—2.55 (2H, m), 2.33 (3.9H, s), 2.74—2.89 (2H, m),
2.95—3.08 (2H, m), 3.25—3.41 (2H, m), 3.59—3.71 (2H, m), 3.77—3.85
(1H, m), 4.31 (1H, dd, Jꢁ2.5, 5.5 Hz), 4.59 (1H, d, Jꢁ5.8 Hz), 4.96—5.03
(1H, m), 5.07—5.16 (1H, m), 5.74 (1H, tdd, Jꢁ4.9, 10.3, 17.2 Hz), 6.06
(1H, br s), 6.52 (1H, d, Jꢁ8.2 Hz), 6.61 (1H, d, Jꢁ8.2 Hz), 7.74 (1H, br t,
Jꢁ5.9 Hz), 8.77 (1H, br s). MS (free base, EI) m/z 426 (Mꢃ). Anal. Calcd for
C24H30N2O5·1.3MeSO3H·0.5H2O: C, 54.22; H, 6.51; N, 5.00; S, 7.44.
Found: C, 54.45; H, 6.50; N, 4.95; S, 7.47.
6) Gao P., Larson D. L., Portoghese P. S., J. Org. Chem., 41, 3091—3098
(1998).
7) Nagase H., Portoghese P. S., J. Org. Chem., 55, 365—367 (1990).
8) Bhatt M. V., Kulkarni S. U., Synthesis, 1983, 249—282 (1983).
9) Silverstein R. M., Webster F. X., “Spectrometric Identification of Or-
ganic Compounds,” 6th ed., John Wiley & Sons Inc., New York, 1997,
pp. 144—216.
10) The boat form of the C-ring would spatially locate the 7a-proton of 5b
above the benzene ring.
11) Benz G., “Comprehensive Organic Synthesis,” Vol. 6, ed. by Trost B.
M., Fleming I., Pergamon Press, Oxford, 1991, pp. 381—417.
12) Bailey P. D., Collier I. D., Morgan K. M., “Comprehensive Organic
Functional Group Transformation,” Vol. 5, ed. by Katritzky A. R.,
Meth-Cohn O., Rees C. W., Pergamon Press, Oxford, 1995, pp. 257—
306.
13) Kotic M. P., J. Org. Chem., 48, 1819—1822 (1983).
14) Yu H., Wang L., Flippen-Anderson J. L., Tian X., Coop A., Rice K. C.,
Heterocycles, 51, 2343—2347 (1999).
15) Padhi S. K., Chadha A., Synlett, 2003, 639—642 (2003).
16) Wissmann H., Kleiner H.-J., Angew. Chem. Int. Ed. Engl., 19, 133—
134 (1980).
17) The antagonist activity is expressed as IC50 ratio and pA2. The IC50
ratio is calculated from the equation:
IC50 ratioꢁ(IC50 value of the agonist in the presence of the antagonist)/(IC50
value of the agonist in the absence of the antagonist)
The pA2 is calculated from the equation:
pA2ꢁꢂlogꢀ[antagonist]/(IC50 ratioꢂ1)ꢁ
Aminolysis of g-Lactone 7 To a solution of 7 (R3ꢁH) (32 mg,
0.09 mmol) in dichloromethane (2 ml) was added allylamine (26 ml,
0.35 mmol), and the mixture was stirred at room temperature for 17 h. The
reaction mixture was poured into saturated sodium bicarbonate solution,
then extracted with chloroform. The combined organic layer was dried over
magnesium sulfate and evaporated in vacuo. The residue was chro-
matographed on silica gel to give 26 mg (71%) of 5b.
The assay was performed using morphine as the m opioid receptor agonist,
DPDPE as the d opioid receptor agonist, and U-50,488H as the k opioid re-
ceptor agonist. The IC50 ratio and pA2 of 7b-carboxiamide 5b against
DPDPE was 5.2 and 8.1, respectively. The IC50 ratio against morphine or U-
50,488H was not able to be determined because 5b showed no antagonistic
activities against the m or k opioid receptors.