Synthesis of a novel 4,6′-epoxymorphinan derivative and a highly strained novel conjugated ketone

Article abstract of DOI:10.1016/j.tetlet.2007.07.194

A modification of the 4,5-epoxymorphinan skeleton of naltrexone was carried out to improve the potency and the selectivity of the ligand for an opioid receptor subtype. As one of the modified structures, we newly designed and synthesized a novel 7-membere

Full text of DOI:10.1016/j.tetlet.2007.07.194

Tetrahedron Letters 48 (2007) 7413–7417
Synthesis of a novel 4,60-epoxymorphinan derivative
and a highly strained novel conjugated ketone
Toru Nemoto, Hideaki Fujii, Noriko Sato and Hiroshi Nagase*
School of Pharmacy, Kitasato University 5-9-1, Shirokane, Minatoku, Tokyo 108-8641, Japan
Received 23 July 2007; accepted 30 July 2007
Available online 2 August 2007
Abstract—A modification of the 4,5-epoxymorphinan skeleton of naltrexone was carried out to improve the potency and the selec-
tivity of the ligand for an opioid receptor subtype. As one of the modified structures, we newly designed and synthesized a novel 7-
membered ring ether derivative, which had an inserted OCH2 group between the 4- and 6-positions of the morphinan skeleton. The
derivative with a 7-membered ring ether, 4,60-epoxymorphinan, has a more fixed chair form than the 4,5-epoxymorphinan. In addi-
tion, we found a new cleavage reaction of the 4,5-epoxy ring in naltrexone, and also obtained a highly strained novel conjugated
ketone.
Ó 2007 Elsevier Ltd. All rights reserved.
Three types of opioid receptors (l, d, j) are now well
established not only by pharmacological studies but also
by molecular biological characterizations.1 Although
many highly selective and potent ligands for opioid
receptor types are presently available,2–6 the only selec-
tive ligands that target opioid receptor subtypes are
TAN-677,8 (d1), BNTX9 (d1) and NTB10 (d2). Ligands
that are specifically directed against the subtypes of opi-
oid receptors (l1, l2, d1, d2 and j1, j2, j3) are highly
desirable for the investigation of the pharmacological
effects attributed to these receptor subtypes. We have
been interested in the design of j and d receptor subtype
(d1, d2 and j1, j2, j3) selective compounds and have
attempted to design and synthesize them using naltrex-
one 1 with the 4,5-epoxymorphinan skeleton.
site, which are an ionic interaction, a p–p interaction
and a hydrogen bond.12,13 We noted that the conforma-
tion of the C-ring of naltrexone is flexible and rather half
chair form, and attempted to change the flexible chair
form into a fixed form in order to obtain ligands selec-
tive for the l opioid receptor subtype.
Herein, we report the conversion of the 4,5-epoxy mor-
phinan structure of naltrexone into 4,60-epoxymorph-
inan skeleton 2 (NS13) (7-membered ring ether),
whose C-ring has a fixed chair form (Fig. 1).
In planning the retrosynthetic pathway, we utilized a
new epoxy ring cleavage reaction (Scheme 1), which
was found by chance in the course of a trial of C-6 side
chain extension. Although a similar 4,5-epoxy ring
cleavage reaction has been reported,14 we independently
found the new cleavage reaction using the Wittig reac-
tion. In spite of extensive investigation, the double bond
of key intermediate 5 could not be selectively reduced
However, we had limited success in obtaining subtype
selective ligands synthesized from 4,5-epoxymorphinan
derivatives. Therefore, we focused on modifying the
4,5-epoxymorphinan skeleton itself. The 4,5-epoxy-
morphinan structure of naltrexone is believed to influ-
ence the intrinsic activity of the opioid receptor and the
substituents may help distinguish among the opioid
receptor types.11 The 4,5-epoxymorphinan structure
has been considered to contribute to three points of
association between the drug molecule and the receptor
OH
17
OH
14
8
16 N9
7
N
C
6
15
13
6 O
5O
10
12
6'
4O
OH
2 (NS13)
11
4
1
3
OH
2
naltrexone 1
Keywords: Opioid; Naltrexone; 4,60-Epoxymorphinan; Analgesics.
Figure 1. Structures of naltrexone 1 and the novel 4,60-epoxymorph-
inan 2.
*
Corresponding author. Tel.: +81 3 5791 6372; fax: +81 3 3442
5707; e-mail: nagaseh@pharm.kitasato-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.194

7414
T. Nemoto et al. / Tetrahedron Letters 48 (2007) 7413–7417
OH
OH
OH
OH
OH
N
N
N
N
N
a)
6
OCH3
b)
c)
5
O
O
O
a)
O
C
H
O
OH
O
O
O
4
OCH3
OCH3
OCH3
OCH3
OH
4
3
naltrexone 1
3
OH
OH
OH
OH
N
OH
N
N
N
N
b)
OCH3
c)
CHO
OR
CH2OH
CHO d)
OH
OH
OH
O
OCH3
OCH3
R=H: 6a
R=Ac: 6b
OCH3
OCH3
OH
7a
5
2
d)
N
OH
Scheme 1. Reagents and conditions: (a) CH3I, K2CO3, DMF, rt, 90%;
(b) Ph3P+ CꢀHOMe, Wittig reaction; (c) HCl, rt, 68% (two steps) (d)
PtO2, H2, CH3OH, 15%.
OH
N
f)
e)
CH2OR1
OR2
CH2OMs
OH
OCH3
OCH3
R1=H, R2=H: 7a
R1=H, R2=Ac: 7b
R1=Ac, R2=H: 7c
because of steric hindrance around the double bond.
The reaction afforded diol 7a as the main product in
low yields concomitantly with some unidentified
products.
8
Scheme 3. Reagents and conditions: (a) Zn, HCl, CH3COOH, reflux,
90%; (b) Ph3P+CꢀHOMe, Wittig reaction; (c) HCl, rt, separation from
b isomer (19%), 60% (two steps); (d) (CH3CO)2O, Py; (e) NaBH4,
CH3OH, 0 °C to rt, 80%; (f) CH3SO2Cl, Py, 0 °C, quant.
Therefore, we undertook another retrosynthetic analysis
of the objective 7-membered ring ether compound 2
(Scheme 2). In this alternative approach, the 7-mem-
bered ring ether 2 would be obtained via compound 8,
which could be derived from compound 4 by the Wittig
reaction followed by hydrolysis, reduction and mesylation.
The intramolecular cyclization of mesylate 8 to the
objective 7-membered ring ether 9a was performed
under various conditions (Table 1). Using DBU as a
base (entry 3) gave the best result. Contrary to our
expectation, not only 9a, but also the highly strained
novel conjugated ketone 10, was obtained under some
conditions. Ketone 10 was obtained with loss of its
aromaticity. To the best of our knowledge, this reac-
tion is the first example of an intramolecular reaction
leading to preparation of a compound like 10 with a
highly strained structure, although such intermole-
cular reactions in low yields have been previously
reported.17–20
The phenolic hydroxyl group of naltrexone 1 was meth-
ylated with CH3I, and the epoxy ring of the resulting nal-
trexone methyl ether 3 was reductively cleaved with zinc
in acetic acid and hydrochloric acid to give compound
4.15 Ketone 4 was converted to aldehyde 6a (6a:6b =
3:1) by the Wittig reaction16 with methoxymethyltriphen-
ylphosphonium chloride and sodium hydride in DMSO
followed by hydrolysis. To obtain mono mesylate 8, we
first tried a series of reactions as follows: compound 6a
was acetylated with acetic anhydride in pyridine followed
by reduction of aldehyde 6b with NaBH4 in CH3OH.
However the reduction afforded a mixture of two ace-
tates, 7b and 7c, which would be obtained by intramole-
cular transacetylation. The results gave us an insight into
the selective functionalization of the primary hydroxyl
group over the phenolic hydroxyl. Then we tried the
selective mesylation of diol 7a, which was obtained by
the reduction of aldehyde 6a. As we expected, the mesyl-
ation of diol 7a with methanesulfonyl chloride in pyri-
dine exclusively gave the desired mono mesylate 8
(Scheme 3).
With the desired 4,60-epoxymorphinan in hand, we tried
21
demethylation of compound 9a with BBr3 or 1-
C3H7SK,22 but obtained only highly polar compounds.
We postulated that the opening of a 7-membered ring
ether in 2 might lead to highly polar, air sensitive cathe-
chol (Scheme 4).
Therefore, 9b, obtained by the same procedure shown in
Scheme 3 using BnBr instead of CH3I, was converted to
compound 2 by catalytic hydrogenation with Pd
(Scheme 5).
The structure of 9a was determined by NMR and
OH
1
OH
HRMS.23 In H NMR, peaks of methylene protons of
7
N
N
C-60 were observed at 3.42 ppm, 4.47 ppm, and a peak
of a methyne proton of C-6 was observed at 2.52 ppm.
In addition, NOE was observed between H-7eq
(1.32 ppm) and H-60 (3.42 ppm), and NOE was also
observed between H-60 (4.47 ppm) and H-6 (2.52 ppm).
In HRMS (FAB), a molecular ion peak was observed
at 356.2216 [M+H]+, indicating the molecular formula
of 9a as C22H30NO3 [M+H]+ (Fig. 2).
6
O6'
5
CH2OMs
OH
4
1
OCH3
3
OH
2
8
2
OH
OH
N
N
O
O
O
OH
OCH3
OH
naltrexone 1
4
The structure of 2 was also determined by NMR and
Scheme 2.
HRMS. In HMBC (heteronuclear multiple-bond corre-

T. Nemoto et al. / Tetrahedron Letters 48 (2007) 7413–7417
Table 1. Reaction conditions of the preparation for 9a and 10
7415
OH
OH
N
N
+
8
O
O
OCH3
OCH3
9a
10
Entry
Condition
9a (yield)
10 (yield)
1
2
3
4
5
6
7
8
(a) DMF/K2CO3, rt, 19 h
(b) DMF/KCN, 50 °C, 40 h
(c) DBU,a rt, 5 h
60%
53%
62%
51%
26%
21%
b
—
b
(d) DBU, 50 °C, 5 h
—
b
b
(e) DMF, 100 °C, 40 h
(f) DMF/NaN3, 50 °C, 16 h
(g) DMF/NaI, 50 °C, 15 h
(h) DMF/NaI, 100 °C, 50 h
—
—
b
b
—
—
—
b
b
—
c
c
—
—
a 1,8-Diazabicyclo[5.4.0]undec-7-ene.
b Not obtained.
c Mixtures (not isolated).
OH
OH
OH
H
(a)-(c)
N
N
-Nu
7
1.32 ppm
N
7-membered
ring ether
cleavage
H
O
O
6
H
2.52 ppm 1.6 %
OR
OH
H
9
2
3.42 ppm
6'
4
6.1%
R = CH3: 9a
R = Bn : 9b
O
H
4.47 ppm
Scheme 4. Reagents and conditions: (a) BBr3, CH2Cl2, 0 °C, overnight
(b) BBr3, CH2Cl2, 0 °C to rt, 0.5 h; (c) 1-C3H7SH, t-BuOK, DMF,
150 °C, 7 h.
OCH3
9a
NOE(%)
OH
OH
OH
OH
N
N
f)
N
N
CHO
OH
O
O
6
c)
d)
b)
OH
a)
O
1
H3.42 ppm
OBn
OBn
N
6'
O
OBn
4
146.9
ppm
13
12
H
11
OH
4.45 ppm
OH
N
e)
CH2OMs
OH
CH2OH
OH
OH
2
OBn
OBn
15
14
HMBC
g)
h)
Figure 2. Structures of the novel 4,60-epoxymorphinans 9a and 2.
9b
2
Scheme 5. Reagents and conditions: (a) BnBr, K2CO3, DMF, rt, 96%;
(b) Zn, HCl, CH3COOH, reflux, 55%; (c) Ph3P+CꢀHOMe, Wittig
reaction; (d) HCl, rt, separation from b isomer, 17% (two steps); (e)
NaBH4, MeOH, 0 °C to rt, 63%; (f) CH3SO2Cl, Py, 0 °C, quant; (g)
K2CO3, DMF, rt, 72%; (h) Pd–C, H2, MeOH, rt, 80%.
was observed at 2.37 ppm and methylene protons of
C-60 at 1.53 ppm, 2.63 ppm. Protons of C-1 and C-2
were observed at 5.80 ppm, 5.86 ppm, (not aromatic
region) respectively, while proton peaks of C-1 and
C-2 of naltrexone (4,5-epoxymorphinan) were observed
at 6.58 ppm, 6.71 ppm (aromatic region). Long range
couplings were observed between H-7eq (1.49 ppm)
and H-5eq (2.62 ppm) (J = 1.5 Hz), and H-60ax
(1.53 ppm) and H-5ax (1.78 ppm) (J = 1.0 Hz). In 13C
NMR, a peak of a ketone of C-4 was observed at
200.3 ppm, and that of C-12 was observed at 63.5 ppm
(Fig. 3). In HMBC measurement, a correlation was
observed between a ketone of C-4 and H-60 (1.53 ppm,
2.63 ppm). In addition, NOE was also observed as
lation) measurement,
a correlation was observed
between C-4 (146.9 ppm) and H-60 (3.42 ppm,
4.45 ppm). In addition, HRMS supported the molecular
formula of 2 (Fig. 2). Taken together, these results sup-
ported the 7- membered ring ether structures shown in
Figure 2.
The structure of 10 was also determined by NMR, IR
1
and HRMS.24 In H NMR, a methyne proton of C-6

7416
T. Nemoto et al. / Tetrahedron Letters 48 (2007) 7413–7417
1.8%
469; (b) Wang, J. B.; Johnson, P. S.; Persico, A. M.;
OH
H
Hawkins, A. L.; Griffins, C. A.; Uhl, G. R. FEBS Lett.
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1437.
H
1.78 ppm
1.49 ppm
1.8%
H
5
N
7
H
8
6
H
2.37 ppm
2.62 ppm
H
3.2%
2.1%
2. Portoghese, P. S. J. Med. Chem. 1991, 34, 1757–1762.
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H
H
H
H
2.2%
1.53 ppm
6'
12
10
63.5 ppm
4
O
200.3 ppm
H
2.63 ppm
1
5.80Hppm
2
OCH3
5.H86 ppm
10
NOE(%)
Figure 3. The structure of a highly strained novel conjugated ketone
10.
shown in Figure 3. The absorption bands derived
from the unsaturated ketone at 1674, 1639 cmꢀ1 were
observed in IR. HRMS also supported the molecular
formula of 10.
Compound 2 showed strong antagonistic activity for
DAMGO (l agonist) more than naltrexone, whose
activity may be derived from different l subtype from
naltrexone. Furthermore, 17-methyl-4,60-epoxymorph-
inan derivative showed strong agonistic activity for l
receptor. We are also examining the subtype selectivity
of these compounds. These pharmacological data will
be reported in detail as full paper near future.
10. Takemori, A. E.; Sultana, M.; Nagase, H.; Portoghese, P.
S. Life Sci. 1992, 50, 1491–1495.
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hedron 2003, 59, 4275–4280.
In conclusion, we have designed and synthesized a novel
7-membered ring ether derivative 2 in order to obtain
more potent ligands selective for opioid receptor sub-
types. Conversion of the 4,5-epoxy ring to the 4,60-epoxy
ring resulted in a more rigid morphinan skeleton. A new
analgesic could be obtained by synthesizing various
derivatives with this skeleton.
18. Manini, P.; Panzella, L.; Napolitano, A.; d’lschia, M.
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Our strategy of 4,5-epoxy ring cleavage, whose example
was reported, proceeded under very mild conditions to
give novel unsaturated aldehyde 5. Moreover, a highly
strained conjugated ketone 10 with a rigid 5-membered
ring was surprisingly obtained in the course of the cycli-
zation of mesylate 8.
22. Kawamura, K.; Kawai, K.; Miyamoto, T.; Ooshima, K.;
Nagase, H. Heterocycles 1998, 48, 267–283.
These reactions may give crucial clues to the design and
synthesis of new ligands with novel skeletons.
23. Analytical and spectral data for compound 9a. Mp 192–
194 °C; IR (KBr) cmꢀ1
:
3388; 1H NMR (CDCl3,
400 MHz): d 0.08–0.18 (2H, m), 0.46–0.58 (2H, m), 0.87
(1H, m), 1.18 (1H, ddd, J = 1.0, 4.0, 13.5 Hz), 1.32 (1H,
ddt, J = 5.0, 14.0, 1.5 Hz), 1.36 (1H, ddd, J = 1.5, 5.5,
13.5 Hz), 1.65 (1H, dt, J = 5.0, 13.5 Hz), 1.83 (1H, ddd,
J = 5.0, 12.0, 13.5 Hz), 2.14 (1H, dd, J = 5.0, 13.5 Hz),
2.19 (1H, ddt, J = 13.5, 14.0, 5.5 Hz), 2.39 (1H, dt,
J = 12.0, 4.0 Hz), 2.35–2.58 (5H, m), 2.58 (1H, ddd,
J = 1.0, 5.0, 12.0 Hz), 2.94 (1H, m), 3.13 (1H, d, J =
18.0 Hz), 3.42 (1H, dd, J = 6.5, 12.5 Hz), 3.81 (3H, s),
4.47 (1H, dd, J = 11.0, 12.5 Hz), 6.69 (1H, d, J =
8.0 Hz), 6.71 (1H, d, J = 8.0 Hz). MS (FAB) m/z = 356
[M+H]+. HRMS (FAB) Calcd for C22H30NO3[M+H]+:
356.2226; found, 356.2216. Anal. Calcd for C22H29NO3:
C, 74.33; H, 8.22; N, 3.94. Found: C, 74.01; H; 8.14, N;
4.00.
Acknowledgement
We acknowledge the Institute of Instrumental Analysis
of Kitasato University, School of Pharmacy for its
facilities.
References and notes
1. (a) Knapp, R. J.; Malatynska, E.; Fang, L.; Li, X.; Babin,
E.; Nguyen, M.; Santoro, G.; Varga, E. V.; Hruby, V. J.;
Roeske, W. R.; Yamamura, H. I. Life Sci. 1994, 54, 463–

T. Nemoto et al. / Tetrahedron Letters 48 (2007) 7413–7417
7417
24. Analytical and spectral data for compound 10. Mp 147–
150 °C; IR (neat) cmꢀ1: 3397, 1674, 1639; 1H NMR
(CDCl3, 400 MHz): d 0.03–0.14 (2H, m), 0.44–0.55 (2H,
m), 0.80 (1H, m), 1.49 (1H, m), 1.53 (1H, dt, J = 14.5,
1.0 Hz), 1.56 (1H, ddd, J = 4.0, 6.0, 13.5 Hz), 1.78 (1H,
dd, J = 1.0, 11.5 Hz), 1.85 (1H, ddt, J = 6.0, 13.5, 2.0 Hz),
1.93–2.00 (2H, m), 2.06 (1H, ddt, J = 7.0, 13.5, 2.0 Hz),
2.20 (1H, dt, J = 12.0, 4.0 Hz), 2.27 (1H, ddd, J = 1.0, 6.0
13.0 Hz), 2.31 (1H, ddd, J = 1.0, 6.0, 13.0 Hz), 2.37 (1H,
m), 2.60 (1H, ddd, J = 1.5, 5.5, 12.0 Hz), 2.62 (1H, ddd,
J = 2.0, 6.0, 11.5 Hz), 2.63 (1H, dd, J = 8.0, 14.5 Hz), 2.72
(1H, dt, J = 19.0, 1.0 Hz), 2.82 (1H, dd, J = 1.0, 5.5 Hz),
2.88 (1H, ddd, J = 3.0, 5.5, 19.0 Hz), 3.66 (3H, s), 5.80
(1H, ddd, J = 1.0, 3.0, 6.5 Hz), 5.86 (1H, d, J = 6.5 Hz).
MS (FAB) m/z = 356 [M+H]+. HRMS (FAB) Calcd for
C22H30NO3[M+H]+: 356.2226; found, 356.2212. Anal.
Calcd for C22H29NO3Æ1/3H2O: C, 72.77; H, 8.11; N, 3.98.
Found: C, 72.91; H; 7.92; N, 3.99.