Rearrangement of 4,5α-epoxymorphinan derivatives with carbamoylepoxy rings provide novel oxazatricyclodecane structures

Article abstract of DOI:10.1016/j.tet.2011.04.097

We describe the rearrangement of a carbamoylepoxy 4,5α-epoxymorphinan derivative that provided a novel 4,5α-epoxymorphinan derivative with an oxazatricyclodecane structure via an oxabicyclo[2.2.2]octane intermediate. We proposed the mechanism of the rearrangement reaction based on results observed in different deprotonation conditions. Epimerization occurred during rearrangement under reversible, but not irreversible, deprotonation conditions. The rearrangement product had a novel fundamental structure with moderate affinities for opioid receptors (K_i (μ)=47.7 nM, K_i (δ)=174.6 nM, and K_i (κ)=248.1 nM). Thus, the rearrangement products might have high potency as opioid ligands.

Full text of DOI:10.1016/j.tet.2011.04.097

Tetrahedron 67 (2011) 6682e6688
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rearrangement of 4,5
a-epoxymorphinan derivatives with carbamoylepoxy rings
provide novel oxazatricyclodecane structures
*
Kohei Hayashida, Hideaki Fujii, Shigeto Hirayama, Toru Nemoto, Hiroshi Nagase
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the rearrangement of a carbamoylepoxy 4,5
a
-epoxymorphinan derivative that provided
Received 28 March 2011
Received in revised form 27 April 2011
Accepted 27 April 2011
a novel 4,5a-epoxymorphinan derivative with an oxazatricyclodecane structure via an oxabicyclo[2.2.2]
octane intermediate. We proposed the mechanism of the rearrangement reaction based on results ob-
served in different deprotonation conditions. Epimerization occurred during rearrangement under re-
versible, but not irreversible, deprotonation conditions. The rearrangement product had a novel
Available online 5 May 2011
fundamental structure with moderate affinities for opioid receptors (Ki (
and Ki (
m
)¼47.7 nM, Ki ( )¼174.6 nM,
d
Keywords:
Rearrangement
4,5a-Epoxymorphinan
k
)¼248.1 nM). Thus, the rearrangement products might have high potency as opioid ligands.
Ó 2011 Elsevier Ltd. All rights reserved.
Oxazatricyclodecane structure
1,2-Shift
1. Introduction
found a rearrangement that provided novel morphinan derivatives
1 with an oxazatricyclodecane structure. To the best of our
Due to its strong analgesic effect, morphine has been used for
the alleviation of postoperative and cancer pain. However, it also
causes severe side effects, including addiction, constipation, and
respiratory depression. A landmark investigation1 demonstrated
knowledge, although previous studies had described 4,5
ymorphinan derivatives with a bicyclic structure like etorphine,
buprenorphine,9 and KNT-63, no reports described 4,5
-epox-
ymorphinan derivatives with a tricyclic structure, like 1. Herein, we
report a novel rearrangement that provided 1, and we discuss the
mechanism of the rearrangement.
a-epox-
a
that the side effects of morphine would be derived only from the
opioid receptor, but not from the and opioid receptors. That
study encouraged many medicinal chemists to focus on the prop-
erties of the and opioid receptors in an effort to develop an ideal
m
d
k
O
O
d
k
( )
S
R
analgesic without morphine-like side effects. Recently, a novel
k
O
O
N
N
H
H
selective agonist, nalfurafine hydrochloride (TRK-820)2 was
N
N
launched in Japan as an antipruritic for patients undergoing
H
O
O
hemodialysis.2c,d Many classical
k selective agonists, like U-
H
O
O
O
50,488H3 and its derivatives (arylacetamide derivatives), were
synthesized and developed; however, none of those derivatives
were approved as either analgesics or antipruritics due to serious
side effects, including psychotomimetic and aversive reactions.4 On
the other hand, nalfurafine did not exhibit either aversive or ad-
dictive effects.5 We previously investigated the basis for the dif-
ferent pharmacological effects of nalfurafine and arylacetamide
derivatives in conformational analyses.6 Based on the analyses and
our detailed structureeactivity relationship investigation7 of nal-
furafine derivatives, we designed and synthesized some com-
H
63
Me
O
-
1
KNT
Fig. 1. Structures of KNT-63 and novel morphinan derivatives
1 with an oxaza-
tricyclodecane structure.
2. Results and discussion
pounds7,8 that were
k
agonists, including KNT-638a (Fig. 1). In the
2.1. Rearrangement of (R)-carbamoylepoxy 4,5a-epoxymorph-
course of investigating the synthesis of KNT-63 derivatives, we
inan derivatives provide novel oxazatricyclodecane structures
The key reaction in the synthesis of the KNT-63 derivatives
was the intramolecular cyclization of the (R)-carbamoylepoxy
* Corresponding author. Tel.: þ81 3 5791 6372; fax: þ81 3 3442 5707; e-mail
address: nagaseh@pharm.kitasato-u.ac.jp (H. Nagase).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.097

K. Hayashida et al. / Tetrahedron 67 (2011) 6682e6688
6683
4,5
a
-epoxymorphinan derivatives 3, which were obtained by
treatment of compound 3a in the presence of NaH and 15-crown-5
at THF refluxing temperature for 1 h, the starting material 3a dis-
appeared and compound 4a and trace amount of the rearrange-
ment product 1a appeared by a TLC analysis. After refluxing for 6 h,
compounds 4a and 1a were obtained in 24% and 40% yield, re-
spectively. These results indicated that the reaction temperature
was an important factor in facilitating the rearrangement. However,
the reaction at 100 ꢀC with DMF as the solvent furnished a complex
treating (R)-ethoxycarbonylepoxy 4,5
a
-epoxymophinan 2 with
lithium amides, prepared in situ by n-BuLi and amines, to afford the
oxabicyclo[2.2.2]octane derivatives 4 (Scheme 1).10 When R is
a benzyl group, the yield of 4a was 69% under THF reflux conditions
in the presence of NaH (Scheme 2). To improve the yield, we
attempted to elevate the reaction temperature by changing the
solvent from THF (bp 66 ꢀC) to cyclopentyl methyl ether (CPME, bp
Scheme 1. Reagents and conditions: (i) n-BuLi, RNH2, THF, ꢁ78 ꢀC; (ii) NaH, THF, reflux.
106 ꢀC). Surprisingly, the reaction under the CPME reflux conditions
did not give the objective compound 4a, but a novel oxaza-
tricyclodecane structure 1a in 81% yield (Scheme 2). The structure
of compound 1a11 was confirmed in NOESY experiments and X-ray
crystallographic analysis12 (Figs. 2 and 3). To the best of our
knowledge, this is the first report of the synthesis of the oxaza-
tricyclodecane derivatives 1. Therefore, we were interested in the
rearrangement reaction and began to investigate it in detail.
R
Fig. 3. ORTEP plot of compound 1a.
Scheme 2. Reagents and conditions: (i) NaH, THF, reflux, 69%; (ii) NaH, CPME, reflux,
81%.
mixture. The replacement of NaH and CPME with t-BuOK and
t-BuOH (bp 83 ꢀC), respectively, gave a fruitful result; the rear-
rangement product 1a was obtained in 93% yield. It is noteworthy
that no 5a (Fig. 4) was produced in any of these experiments, in
spite of the strong basic reaction conditions.
2.2. Rearrangement of (S)-carbamoylepoxy 4,5a-epoxymorp-
hinan derivatives
With two optimal reaction conditions (condition A: NaH, CPME
reflux; conditionB: t-BuOK, t-BuOH, reflux)for the rearrangementin
hand, we examined the reaction of (S)-carbamoylepoxy 4,5a-
epoxymorphinan 6a, the epimer of compound 3a. Astonishingly,
each of the two reaction conditions provided different products.
Under reaction conditions A, compound 5a was obtained in 91%
yield, whereas the reaction of 6a afforded compound 1a in 89% yield
under reaction conditions B. The latter was the same product that
Fig. 2. Observed NOESY and HMBC spectra of compound 1a.
First, we treated compound 3a under various reaction condi-
tions. The reaction at 60 ꢀC (bath temperature) with CPME as
a solvent in the presence of NaH provided only compound 4a in 84%
yield and compound 3a was recovered in 11% yield. In the
was obtained from (R)-carbamoylepoxy 4,5a-epoxymorphinan 3a

6684
K. Hayashida et al. / Tetrahedron 67 (2011) 6682e6688
reaction conditions. On the other hand, the reaction conditions B
(reversible deprotonation conditions) would permit the deproto-
nation of the a-proton of the amide group to enable an epimeriza-
tion. Eventually, the cyclization (7a0/1a0) could prompt
a convergent production of the rearrangement product 1a, regard-
less of the configuration of the amide group in carbamoylepoxy
4,5a-epoxymorphinan 3a or 6a. According to this proposed mech-
anism, 4a0 was an important intermediate. Indeed, under the rear-
rangement reaction conditions, the oxabicyclo[2.2.2]octane
derivative 4a gave the rearrangement product 1a in 57% yield
(Scheme 5); this supported the proposed reaction mechanism.
Fig. 4. Structure of compound 5a.
(Scheme 3). These results suggested that an epimerization occurred
under reaction conditions B, but not under reaction conditions A.
Scheme 5. Reagents and conditions: (i) NaH, CPME, reflux, 57%.
Scheme 3. Reagents and conditions: (i) NaH, CPME, reflux (conditions A), 91%; (ii) t-
BuOK, t-BuOH, reflux (conditions B), 89%.
2.4. Rearrangement of an oxabicyclo[2.2.2]octane-N-phenyl-
carboxamide derivative
We next attempted to apply the rearrangement to N-phenyl-
2.3. Proposed reaction mechanism of the rearrangement
amides. Because N-phenylcarbamoylepoxy 4,5
3b (R¼Ph) could not be prepared from (R)-ethoxycarbonylepoxy
4,5 -epoxymorphinan 2, due to the low nucleophilicity of lithium
a-epoxymorphinan
On the basis of the above results, we proposed a reaction
mechanism of the rearrangement (Scheme 4). In the case of reaction
conditions A, NaH would irreversibly deprotonate two acidic pro-
a
N-phenylamide,8a we used oxabicyclo[2.2.2]octane-N-phenyl-
carboxamide derivative 4b as the starting material. Treatment of 4b
under the rearrangement reaction conditions A provided the rear-
rangement product 5b and an equilibrium mixture of 1b and 7b
(Scheme 6). Although an epimerization was not observed in the
reaction of N-benzylamide 3a under reaction conditions A, an
epimerization was observed in the case of N-phenylamide 4b. The
electron-withdrawing property of the phenyl group may increase
tons (NH and OH) in (R)-carbamoylepoxy 4,5
to provide 3a0. The resulting alkoxide in 3a0 would attack the
-carbon of the amide group to afford the intermediate 4a0. When
a-epoxymorphinan 3a
a
the reaction temperature was not too high (e.g., a THF refluxing
temperature), the reaction would stop at this stage to give the oxa-
bicyclo[2.2.2]octane derivative 4a. A higher reaction temperature
(e.g., a CPME or t-BuOH refluxing temperature) would promote the
following rearrangement. The alkoxide in 4a0 would facilitate a 1,2-
shift of the C6eC7 bond and, concomitantly, cleave the epoxy bridge
to provide the intermediate 7a0. The amide and ketone moieties in
7a0 were located sufficiently close to each other that the subsequent
cyclization could proceed smoothly to afford the rearrangement
product 1a. The formation of dianion species may prevent further
the acidity of the a-proton of the amide group and also decrease the
nucleophilicity of the amide nitrogen. Due to the low nucleophi-
licity of the amide nitrogen, part of the epimer 7b could cyclize to
achieve equilibrium between 1b and 7b. Moreover, when either
alkoxide anion or amide anion in 7b may be transiently protonated,
the more acidic a-proton may be simultaneously deprotonated to
promote an epimerization. Ultimately, three compounds 1b, 7b,
and 5b would be provided.
deprotonation of the
epimerization would not be observed, despite the strong basic
a-proton of the amide group. Therefore, the
Scheme 4. Proposed reaction mechanism for the rearrangement (condition A).

K. Hayashida et al. / Tetrahedron 67 (2011) 6682e6688
6685
Scheme 6. Reagents and conditions: (i) NaH, CPME, reflux. The ratio of 1b:7b was around 3:1.
2.5. Rearrangement of the bicyclo[2.2.2]octanecarboxamide
derivative
which lacked an electron-withdrawing group. We expected to ob-
tain important information on the mechanistic details of the rear-
rangement (via a 1,2-shift or not) by testing the rearrangement
with a compound that lacked an electron-withdrawing group, like
compound 13. Compound 13 was prepared from (R)-ethox-
Bicyclo[2.2.2]octanecarboxamide 10 has a well-known structure
in the opioid field with a typical endoethanotetrahydrooripavine
skeleton, which resembles oxabicyclo[2.2.2]octanecarboxamides 4.
Therefore, we examined the behavior of 10 under rearrangement
reaction conditions. Compound 10 was prepared by O-methylation
of compound 813 and subsequent catalytic hydrogenation. As
expected, the treatment of 10 with NaH under CPME reflux con-
ditions (condition A) gave the corresponding rearrangement
product 11 in 77% yield (Scheme 7).
ycarbonylepoxy 4,5a-epoxymophinan 2 by reduction with NaBH4
and subsequent intramolecular cyclization. The treatment of com-
pound 13 with NaH under CPME reflux conditions (condition A)
provided an equilibrium mixture of 14 and 15; subsequent acety-
lation of the mixture afforded diacetate 16 in 85% yield (Scheme 8).
The preparation of diacetate 16 strongly suggested that the rear-
rangement of 13 would proceed via a 1,2-shift.
Scheme 7. Reagents and conditions: (i) MeI, K2CO3, DMF, rt, 92%; (ii) H2 (0.5 MPa), Pd/C, MeOH, 50 ꢀC, 90%; (iii) NaH, CPME, reflux, 77%.
Scheme 8. Reagents and conditions: (i) NaBH4, MeOH, rt, 94%; (ii) NaH, DMF, rt, 79%; (iii) NaH, CPME, reflux; (iv) Ac2O, 60 ꢀC, 85% from 13.
2.6. Rearrangement of the oxabicyclo[2.2.2]octanylmethanol
derivative
3. Conclusion
We found that a rearrangement of carbamoylepoxy 4,5a-epox-
After the rearrangements of compounds with electron-
withdrawing carboxamide groups, we next investigated the rear-
rangement of oxabicyclo[2.2.2]octanylmethanol derivative 13,
ymorphinan derivatives 3 provide novel oxazatricyclodecane ones
1 via oxabicyclo[2.2.2]octane intermediates 4. We observed the
same rearrangement in a reaction of a 4,5a-epoxymorphinan

6686
K. Hayashida et al. / Tetrahedron 67 (2011) 6682e6688
derivative with the bicyclo[2.2.2]octane structure 10. We proposed
the reaction mechanism of the rearrangement based on the dif-
ferent results produced by different deprotonation conditions
(irreversible or reversible). An epimerization occurred during the
rearrangement under reversible, but not under irreversible,
deprotonation conditions. The rearrangement product 1a had
a novel fundamental structure that showed moderate affinities for
poured into saturated NH4Cl solution and extracted with AcOEt. The
combined organic layers were washed with saturated NaHCO3 so-
lution and brine, and dried over anhydrous Na2SO4 followed by re-
moving the solvent under reduced pressure. The resulting residue
was purified by silica gel column chromatography (CHCl3/
MeOH¼100/0 to 100/2) to give the title compound 4a (277 mg, 69%)
as an amorphous material. IR (neat, cmꢁ1): 3408, 1650. 1H NMR
the opioid receptors (Ki (
m
)¼47.7 nM, Ki (
d
)¼174.6 nM, and Ki (
k
)¼
(300 MHz, CDCl3) d 0.05e0.18 (m, 2H), 0.42e0.64 (m, 2H), 0.79e1.06
248.1 nM); this indicated that the rearrangement products would
be expected to have potency as opioid ligands. We are currently
investigating the rearrangement product derivatives as potential
opioid ligands.
(m, 2H),1.31e1.53 (m, 2H),1.66e1.91 (m, 2H), 2.12 (dd, J¼8.1,12.6 Hz,
1H), 2.18e2.35 (m, 2H), 2.41 (dt, J¼3.6, 12.6 Hz, 1H), 2.66e2.82 (m,
2H), 3.20 (d, J¼18.3 Hz, 1H), 3.54 (d, J¼6.6 Hz, 1H), 3.89 (s, 3H), 4.28
(d, J¼2.4 Hz, 1H), 4.46 (dd, J¼5.7, 14.7 Hz, 1H), 4.54 (d, J¼1.5 Hz, 1H),
4.59(dd, J¼6.6,14.7 Hz,1H), 5.49 (br s,1H), 6.53(d, J¼8.1 Hz,1H), 6.72
(d, J¼8.1 Hz, 1H), 7.23e7.38 (m, 5H), 7.51e7.73 (m, 1H). 13C NMR
4. Experimental section
4.1. General
(75 MHz, CDCl3) d 2.9, 4.9, 8.5, 21.0, 24.8, 28.0, 34.1, 35.2, 39.8, 43.6,
46.9, 57.0, 59.6, 70.8, 74.1, 74.9, 93.6, 117.9, 120.3, 126.5, 126.6, 128.6,
128.6,131.7,138.2,138.3,146.0,172.1. HRMS (FAB): [MþH]þ calcd for
C30H35N2O5: 503.2540. Found: 503.2557.
Melting points were measured on a Yanaco MT-5 melting point
apparatus. Infrared (IR) spectra were measured on a JASCO FT/
IRe460Plus. Nuclear magnetic resonance (NMR) spectra were
recorded on a Varian Mercurye300 (300 MHz) or Varian UNITY-
400 (400 MHz) spectrometer. Chemical shifts were reported as
4.4. (1S,3aS,5aS,6R,11bR,11cR)-3-Benzyl-14-(cyclopropylmethyl)-
3a,11-dihydroxy-10-methoxy-1,3,3a,4,5,6,7,11c-octahydro-2H-
6,11b-(iminoethano)-1,5a-epoxynaphtho[1,2-e]indol-2-one (1a)
d
values (ppm) related to tetramethylsilane (TMS). Mass spectra
(MS) were measured on a JMSe700 MStation or JMS-T100LP in-
strument by applying a fast atom bombardment (FAB) or electron
spray ionization (ESI) method. The progress of the reaction was
determined on Merck Silica Gel Art. 5715. Column chromatogra-
phies were carried out using Kanto Silica Gel 60N or Fuji Silysia
DM2035 (The surface of the silica gel was modified by amino
group). Preparative TLCs were performed using Merck Silica Gel
Art. 5744 or Fuji Silysia NH TLC plate.
Condition A: Under an Ar atmosphere, NaH (60% in oil, 700 mg,
17.5 mmol) was washed with anhydrous hexane and suspended in
CPME (30 mL). To the suspension was added a solution of 3a (4.32 g,
8.6 mmol) in CPME (20 mL) and refluxed for 3 h with stirring. The
reaction mixture was poured into saturated NaHCO3 aqueous so-
lution and extracted with AcOEt. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4 followed by
removing the solvent under reduced pressure. The resulting resi-
due was crystallized from MeOH solution to give the title com-
pound 1a (3.51 g, 81%) as a white crystal.
Condition B: Under an Ar atmosphere, to a solution of 3a
(101 mg, 0.20 mmol) in t-BuOH (2 mL) was added t-BuOK (224 mg,
2.0 mmol) and refluxed for 1 h with stirring. The reaction mixture
was poured into 2 M HCl and basified with saturated NaHCO3
aqueous solution, and then extracted with CHCl3. The combined
organic layers were washed with brine and dried over anhydrous
Na2SO4 followed by removing the solvent under reduced pressure.
The resulting residue was purified by silica gel column chroma-
tography (ammonia saturated CHCl3) to give the title compound 1a
(93.2 mg, 93%).
Preparation from compound 4a: Under an Ar atmosphere, to
a suspension of NaH (60% in oil, 1.90 g, 47.5 mmol) in CPME (15 mL)
was added a solution of 4a (1.90 g, 3.8 mmol) in CPME (15 mL) and
refluxed for 15 h with stirring. The reaction mixture was poured
into saturated NaHCO3 aqueous solution and extracted with AcOEt.
The combined organic layers were washed with brine and dried
over anhydrous Na2SO4 followed by removing the solvent under
reduced pressure. The resulting residue was crystallized from
AcOEt solution to give the title compound 1a (1.08 g, 57%).
Preparation from compound 6a: Under an Ar atmosphere, to
a solution of 6a (100.5 mg, 0.2 mmol) in t-BuOH (2 mL) was added
t-BuOK (224 mg, 2.0 mmol) and refluxed for 1 h with stirring. The
reaction mixture was poured into 2 M HCl and basified with satu-
rated NaHCO3 aqueous solution, and then extracted with CHCl3. The
combined organic layers were washed with brine and dried over
anhydrous Na2SO4 followed by removing the solvent under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (ammonia saturated CHCl3) to give the title com-
pound 1a (89.4 mg, 89%). IR (KBr, cmꢁ1): 3338, 2933, 1689, 720. 1H
4.2. (30R,5R,6S,9R,13S,14S)-N-Benzyl-17-(cyclopropylmethyl)-
4,5-epoxy-14-hydroxy-3-methoxyspiro[morphinane-6,20-
oxirane]-30-caroxyamide (3a)
Under an Ar atmosphere, to a solution of BnNH2 (4.4 mL,
40 mmol) in THF (100 mL) solution was added 1.65 M n-BuLi in
hexane solution (24.2 mL, 40 mmol) dropwise at ꢁ78 ꢀC and stirred
for 15 min. To the reaction mixture was added a solution of com-
pound 2 (4.42 g, 10 mmol) in THF (50 mL) dropwise at the same
temperature and stirred for 1 h. The reaction mixture was poured
into saturated NaHCO3 aqueous solution and extracted with AcOEt.
The combined organic layers werewashed with brine and dried over
anhydrous Na2SO4 followed by removing the solvent under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (ammonia saturated CHCl3) to give the title com-
pound 3a (4.97 g, 99%) as a white amorphous material. IR (neat,
cmꢁ1): 3407, 1666. 1H NMR (300 MHz, CDCl3)
d 0.05e0.22 (m, 2H),
0.43e0.62 (m, 2H), 0.83e0.95 (m, 1H), 1.26e1.36 (m, 1H), 1.41e1.66
(m, 3H), 2.12 (dt, J¼3.6, 12.0 Hz, 1H), 2.20e2.43 (m, 4H), 2.53e2.71
(m, 2H), 3.04 (d, J¼18.6 Hz, 1H), 3.10 (d, J¼5.4 Hz, 1H), 3.68 (s, 1H),
3.85 (s, 3H), 4.31e4.46 (m, 2H), 4.75 (s,1H), 5.15 (br s,1H), 6.37e6.53
(m, 1H), 6.61 (d, J¼8.4 Hz, 1H), 6.72 (d, J¼8.4 Hz, 1H), 7.12e7.34 (m,
5H). 13C NMR (75 MHz, CDCl3)
d 3.7, 3.9, 9.4, 21.4, 22.6, 28.6, 30.9,
43.0, 44.0, 47.9, 56.8, 57.7, 59.1, 62.3, 63.2, 70.1, 85.5, 114.8, 118.8,
125.2,127.7,127.9,128.7,130.3,137.3,142.0,145.7,166.8. HRMS (FAB):
[MþH]þ calcd for C30H35N2O5: 503.2540. Found: 503.2558.
4.3. (5R,6S,7S,9R,13S,14S)-N-Benzyl-17-(cyclopropylmethyl)-
4,5-epoxy-6,14-ethano-6-hydroxy-3-methoxy-8-
oxamorphinan-7-carboxyamide (4a)
NMR (300 MHz, CDCl3):
d 0.02e0.14 (m, 2H), 0.40e0.58 (m, 2H),
Under an Ar atmosphere, to the solution of compound 3a
(400 mg, 0.8 mmol) in THF (20 mL) was added NaH (50% in oil,
400 mg, 8.3 mmol) and refluxed for 3 h. The reaction mixture was
0.87e1.00 (m, 2H), 1.32e1.42 (m, 3H), 1.63 (dd, J¼7.8, 14.4 Hz, 1H),
1.91 (dt, J¼4.8, 12.6 Hz, 1H), 2.10 (dt, J¼3.0, 12.3 Hz, 1H), 2.25 (dd,
J¼7.5, 12.6 Hz, 1H), 2.63 (dt, J¼3.6, 11.4 Hz, 2H), 2.86 (dd, J¼6.3,

K. Hayashida et al. / Tetrahedron 67 (2011) 6682e6688
6687
18.6 Hz, 1H), 3.09 (d, J¼18.6 Hz, 1H), 3.30 (d, J¼5.7 Hz, 1H), 3.68 (d,
J¼6.0 Hz,1H), 3.84 (s, 3H), 4.40 (d, J¼14.7 Hz,1H), 4.51 (d, J¼14.7 Hz,
1H), 4.72 (d, J¼6.0 Hz, 1H), 6.68 (d, J¼8.7 Hz, 1H), 6.70 (d, J¼8.4 Hz,
1H), 7.13e7.30 (m, 3H), 7.41 (d, J¼6.9 Hz, 2H). (Two protons were not
124.2,124.7,128.9,129.5,137.6,142.3,145.0,169.3, 207.3. HRMS (ESI):
calcd for C29H33N2O5 [MþH]þ: 489.2390. Found: 489.2372.
4.7. (5R,6R,7S,9R,13S,14R)-N-Benzyl-17-(cyclopropylmethyl)-
4,5-epoxy-6-hydroxy-3-methoxy-6,14-ethenomorpinan-7-
carboxamide (9)
observed.) 13C NMR (75 MHz, CDCl3):
d 3.0, 4.5, 9.0, 27.3, 30.6, 31.2,
31.9, 42.0, 43.1, 43.5, 54.6, 55.5, 55.9, 59.9, 79.2, 82.2, 91.4,109.1,119.5,
126.4,127.1,128.2,128.4,130.0,138.6,140.5,144.7,170.4. HRMS (ESI):
calcd for C30H35N2O5 [MþH]þ: 503.2546. Found: 503.2530.
Under an Ar atmosphere, to a solution of 8 (402 mg, 0.83 mmol) in
DMF (10 mL) were added K2CO3 (276 mg, 2.0 mmol) and MeI (61.9
1.0 mmol) and stirred at rt for 24 h under light shielding conditions.
To the reaction mixture was added MeI (20.6 L, 0.33 mmol) and
mL,
4.5. (4R,4aR,10R,10aS,12S)-N-Benzyl-13-(cyclopropylmethyl)-
5-hydroxy-6-methoxy-3-oxo-1,2,3,4,9,10-hexahydro-10,4a-
(iminoethano)-10a,4-(epoxymethano)phenanthren-12-
carboxyamide (5a)
m
stirred for 6 h. The reaction mixture was poured into distillated water
and extracted with AcOEt. The combined organic layers werewashed
with distillated water and brine, and then dried over anhydrous
Na2SO4 followed by removing the solvent under reduced pressure.
The resulting residue was purified by silica gel column chromatog-
raphy (ammonia saturated CHCl3) to give the title compound 9
(379 mg, 92%) as a white amorphous material. IR (KBr, cmꢁ1): 3376,
The treatment of 6a (100.5 mg, 0.2 mmol) under the reaction
conditions A gave the title compound 5a (91.2 mg, 91%) as a colorless
oil. IR (film, cmꢁ1): 3360, 2929, 1722, 1673, 1487, 1279, 754. 1H NMR
(300 MHz, CDCl3):d 0.00e0.07 (m, 2H), 0.36e0.47 (m, 2H), 0.54e0.69
(m, 1H), 1.32 (dd, J¼2.1, 13.5 Hz, 1H), 1.82 (dt, J¼5.7, 12.3 Hz, 1H),
1.91e2.06 (m, 3H), 2.15 (dd, J¼6.6, 12.6 Hz, 1H), 2.30e2.66 (m, 3H),
2.77 (dd, J¼6.6,18.3 Hz,1H), 3.07 (d, J¼18.3 Hz,1H), 3.46 (d, J¼6.3 Hz,
1H), 3.81 (s, 3H), 3.98 (s,1H), 4.34 (dd, J¼4.8,14.4 Hz,1H), 4.61 (s,1H),
4.70(dd, J¼7.2,14.7 Hz,1H), 5.75 (s,1H), 6.60 (d, J¼8.1 Hz,1H), 6.66 (d,
J¼8.4 Hz, 1H), 7.20e7.38 (m, 5H), 7.80e7.90 (m, 2H). 13C NMR
2922, 1638, 1499, 749, 698. 1H NMR (300 MHz, CDCl3):
d 0.06e0.21
(m, 2H), 0.43e0.57 (m, 2H), 0.76e0.90 (m, 1H), 1.65 (dd, J¼6.0,
12.9 Hz,1H),1.83 (dd, J¼2.4,13.2 Hz,1H), 2.00 (dt, J¼5.7,12.6 Hz,1H),
2.27e2.48(m,4H), 2.57(dd, J¼6.0, 9.6Hz,1H), 2.71(dd, J¼4.8,12.0Hz,
1H), 3.03e3.17 (m, 2H), 3.56 (d, J¼6.6 Hz,1H), 3.69e3.88 (m,1H), 3.81
(s, 3H), 4.33 (d, J¼1.2 Hz, 1H), 4.43 (d, J¼5.7 Hz,1H),5.47 (d, J¼8.7 Hz,
1H), 5.76 (d, J¼8.7 Hz, 1H), 6.46e6.56 (m, 2H), 6.62 (d, J¼8.1 Hz, 1H),
7.19e7.35 (m, 5H). (A proton was not observed.) 13C NMR (75 MHz,
(75 MHz, CDCl3): d 3.4, 4.0, 9.3, 27.0, 31.4, 32.2, 33.5, 42.5, 43.2, 45.4,
55.8, 56.0, 59.7, 60.8, 80.2, 84.1, 109.3, 118.1, 124.8, 127.3, 128.0, 128.5,
129.6, 138.0, 142.3, 144.9, 170.9, 207.7. HRMS (ESI): calcd for
C30H35N2O5 [MþH]þ: 503.2546. Found: 503.2525.
CDCl3): d 3.4, 4.1, 9.4, 23.2, 30.0, 33.2, 42.9, 43.6, 43.9, 45.7, 47.4, 56.4,
57.1, 59.8, 76.0, 96.8,112.9,119.6,127.3,127.6,128.2,128.6,129.0,134.6,
136.4, 138.3, 141.8, 147.9, 172.6. HRMS (ESI): calcd for C31H35N2O4
[MþH]þ: 499.2597. Found: 499.2584.
4.6. (1S,3aS,5aS,6R,11bR,11cR)-14-(Cyclopropylmethyl)-3a,11-
dihydroxy-10-methoxy-3-phenyl-1,3,3a,4,5,6,7,11c-octahydro-
2H-6,11b-(iminoethano)-1,5a-epoxynaphtho[1,2-e]indol-2-
one (1b), (4R,4aR,10R,10aS,12S)-13-(cyclopropylmethyl)-5-hyd-
roxy-6-methoxy-3-oxo-N-phenyl-1,2,3,4,9,10-hexahydro-10,-
4a-(iminoethano)-10a,4-(epoxymethano)phenanthlen-12-car-
boxyamide (7b), and (4R,4aR,10R,10aS,12R)-13-(cyclopropylm-
ethyl)-5-hydroxy-6-methoxy-3-oxo-N-phenyl-1,2,3,4,9,10-
hexahydro-10,4a-(iminoethano)-10a,4-(epoxymethano)phen-
anthlen-12-carboxyamide (5b)
4.8. (5R,6R,7S,9R,13S,14S)-N-Benzyl-17-(cyclopropylmethyl)-
4,5-epoxy-6-hydroxy-3-methoxy-6,14-ethanomorpinan-7-
carboxamide (10)
To the solution of 9 (99.7 mg, 0.20 mmol) in MeOH (15 mL) was
added 10% Pd/C (21.3 mg) and stirred at 50 ꢀC for 24 h under a H2
atmosphere (0.5 MPa). The reaction mixture was filtered through
Celite pad and obtained filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (ammonia saturated CHCl3) to give the title
compound 10 (89.6 mg, 90%) as a colorless oil. IR (film, cmꢁ1): 3337,
The treatment of 4b (488.6 mg, 1.0 mmol) under the reaction
conditions A gave a mixture of 1b and 7b (353.7 mg, 72%), and 5b
(50.2 mg, 10%) as colorless oils. A mixture of 1b and 7b: IR (film,
cmꢁ1): 3378, 2928,1692,1488,1279, 752. 1H NMR (300 MHz, CDCl3):
2924, 1632, 1500, 1451, 731. 1H NMR (300 MHz, CDCl3):
d 0.05e0.14
(m, 2H), 0.42e0.53 (m, 2H), 0.59e0.86 (m, 2H), 1.22e1.37 (m, 2H),
1.63e1.74 (m, 1H), 2.01e2.40 (m, 6H), 2.46e2.69 (m, 3H), 2.87 (ddd,
J¼3.9, 11.4, 13.5 Hz, 1H), 3.00 (d, J¼18.3 Hz, 1H), 3.11 (d, J¼6.3 Hz,
1H), 3.88 (s, 3H), 4.25 (d, J¼2.1 Hz, 1H), 4.49 (d, J¼5.7 Hz, 2H), 6.53
(br t, J¼5.7 Hz, 1H), 6.59 (d, J¼8.1 Hz, 1H), 6.71 (d, J¼8.1 Hz, 1H),
7.21e7.34 (m, 5H). (A proton was not observed.) 13C NMR (75 MHz,
d
0.06e0.22 (m, 2H), 0.43e0.67 (m, 2H), 0.84e1.02 (m, 1.75H),
1.42e2.40 (m, 7.25H), 2.58e2.86 (m, 2.25H), 2.95 (dd, J¼6.6, 18.3 Hz,
0.75H), 3.09e3.19 (m,1H), 3.50 (d, J¼5.7 Hz, 0.75H), 3.76 (d, J¼6.6 Hz,
1H), 3.79 (s, 0.75H), 3.84 (s, 2.25H), 4.08 (d, J¼5.7 Hz, 0.25H), 4.83 (d,
J¼6.6 Hz, 0.75H), 5.23 (d, J¼6.0 Hz, 0.25H), 6.63 (d, J¼8.4 Hz, 0.25H),
6.67 (d, J¼8.4 Hz, 0.25H), 6.72 (s, 1.5H), 7.08e7.16 (m, 0.25H),
7.24e7.42 (m, 4.25H), 7.55e7.61 (m, 0.5H), 8.73 (s, 0.25H). (1.75
CDCl3):
d 3.3, 4.1, 9.4, 22.2, 22.8, 28.9, 30.0, 35.0, 35.4, 43.7, 43.8,
45.4, 45.5, 56.4, 58.4, 59.8, 72.5, 95.6, 113.1, 119.5, 127.2, 127.6, 128.5,
128.8, 133.0, 138.5, 141.7, 146.5, 172.5. HRMS (ESI): calcd for
C31H37N2O4 [MþH]þ: 501.2753. Found: 501.2757.
protons were not observed.) 13C NMR (75 MHz, CDCl3):
d 3.2, 3.6, 4.3,
8.9, 26.8, 27.8, 29.8, 31.1, 31.7, 33.8, 36.4, 43.1, 43.4, 43.5, 54.7, 54.8,
55.8, 56.0, 59.3, 59.8 79.3, 80.7, 82.2, 84.3, 92.6, 109.4, 109.5, 118.2,
119.6, 123.6, 124.6, 126.3, 127.7, 128.4, 128.6, 129.0, 129.4, 129.7, 134.4,
136.9,140.8, 142.6, 145.0, 162.5, 168.9,170.3, 206.1. HRMS (ESI): calcd
for C29H33N2O5 [MþH]þ: 489.2390. Found: 489.2402. Compound 5b:
IR (film, cmꢁ1): 3320, 2929, 1725, 1685, 1537, 1280, 733. 1H NMR
4.9. (1S,3aS,5aS,6R,11bS,11cS)-3-Benzyl-14-(cyclopropylme-
thyl)-3a,11-dihydroxy-10-methoxy-1,3,3a,4,5,6,7,11c-octahy-
dro-2H-6,11b-(iminoethano)-1,5a-methanonaphtho[1,2-e]
indol-2-one (11)
(300 MHz, CDCl3): d 0.12e0.28 (m, 2H), 0.50e0.64 (m, 2H), 0.86e1.04
(m,1H),1.37e1.49 (m,1H),1.87e2.19 (m, 5H), 2.40 (dd, J¼6.3,12.6 Hz,
1H), 2.50 (dd, J¼6.6, 12.9 Hz, 1H), 2.56e2.71 (m, 2H), 2.84 (dd, J¼6.3,
18.3 Hz,1H), 3.15 (d, J¼18.3 Hz,1H), 3.61 (d, J¼6.3 Hz,1H), 3.80 (s, 3H),
4.01 (s,1H), 4.68 (s,1H), 5.79 (br s,1H), 6.63 (d, J¼8.4 Hz,1H), 6.66 (d,
J¼8.4 Hz, 1H), 7.07e7.16 (m, 1H), 7.28e7.39 (m, 2H), 7.58e7.69 (m,
The treatment of 10 (50.1 mg, 0.1 mmol) under the reaction
conditions A gave the title compound 11 (38.8 mg, 77%) as a yellow
oil. IR (film, cmꢁ1): 3410, 2935, 1667, 1486, 1278, 733. 1H NMR
(300 MHz, CDCl3): d 0.02e0.18 (m, 2H), 0.37e0.56 (m, 2H), 0.71e1.07
(m, 3H), 1.20e1.64 (m, 4H), 1.73 (dt, J¼4.8, 12.6 Hz, 1H), 1.88e2.03
(m,1H), 2.18e2.39 (m, 2H), 2.50e2.67 (m,1H), 2.92 (d, J¼2.7 Hz, 2H),
3.08e3.23 (m, 2H), 3.27e3.44 (m, 2H), 3.82 (s, 3H), 4.36
2H), 9.45 (s, 1H). 13C NMR (75 MHz, CDCl3):
d 3.8, 4.1, 9.7, 27.1, 31.7,
32.2, 33.5, 42.8, 45.4, 55.8, 56.4, 60.1, 61.1, 80.2, 84.6,109.4,118.2,119.5,

6688
K. Hayashida et al. / Tetrahedron 67 (2011) 6682e6688
(d, J¼15.0 Hz, 1H), 4.51 (d, J¼15.0 Hz, 1H), 6.66 (s, 2H), 7.13e7.29 (m,
3H), 7.39 (d, J¼6.9 Hz, 2H). (Two protons were not observed.) 13C
residue was added the saturated NaHCO3 aqueous solution and
extracted with AcOEt. The combined organic layers were washed
with brine and dried over anhydrous Na2SO4 followed by removing
the solvent under reduced pressure. The resulting residue was pu-
rified by silica gel column chromatography (CHCl3/MeOH/
NH4OH¼100/0/0 to 100/3/0.3) to give the title compound 16
(141 mg, 85%) as an amorphous material. IR (film, cmꢁ1): 2940,1768,
1743, 1718, 1487, 1216, 1042, 753. 1H NMR (300 MHz, CDCl3):
NMR (75 MHz, CDCl3): d 3.7, 9.5, 24.6, 30.5, 30.6, 32.6, 39.0, 42.0, 43.9,
44.2, 44.5, 55.4, 55.9, 56.8, 59.9, 92.5,108.4,119.4,126.9,128.1,128.2,
129.0, 130.9, 139.3, 140.3, 144.6, 176.0. HRMS (ESI): calcd for
C31H37N2O4 [MþH]þ: 501.2753. Found: 501.2752.
4.10. (30R,5R,6S,9R,13S,14S)-17-(Cyclopropylmethyl)-4,5-
epoxy-30-hydroxymethyl-3-methoxyspiro[morphinane-6,20-
oxirane]-14-ol (12)
d
0.06e0.19 (m, 2H), 0.45e0.63 (m, 2H), 0.84e1.02 (m,1H),1.28e1.44
(m, 1H), 1.64e1.81 (m, 1H), 1.91e2.28 (m, 6H), 2.08 (s, 3H), 2.31 (s,
3H), 2.54e2.70 (m, 1H), 2.74 (dd, J¼4.8, 12.6 Hz, 1H), 2.91 (dd, J¼6.6,
18.6 Hz, 1H), 3.18 (d, J¼18.6 Hz, 1H), 3.26 (d, J¼5.7 Hz, 1H), 3.76 (s,
3H), 3.84 (d, J¼8.4 Hz, 1H), 4.04 (dd, J¼7.5, 12.0 Hz, 1H), 4.26 (dd,
J¼3.6, 12.0 Hz, 1H), 4.82 (m, 1H), 6.82 (d, J¼8.4 Hz, 1H), 7.02 (d,
Under an Ar atmosphere, to a solution of 2 (16.4 g, 36.2 mmol) in
MeOH (200 mL) was added NaBH4 (6.85 g, 181.2 mmol) at 0 ꢀC and
stirred at rt for 1 h. To the reaction mixture was added NaBH4 (2.74 g,
72.5 mmol) and stirred at rt for 2 h. After addition of 50% AcOH
aqueous solution, the resulting mixture was poured into saturated
NaHCO3 aqueous solution and extracted with CHCl3. The combined
organic layers were washed with brine and dried over anhydrous
Na2SO4 followed by removing the solvent under reduced pressure.
The resulting residue was crystallized from MeOH solution to give
the title compound 12 (13.5 g, 94%) as colorless needles. Mp 140 ꢀC.
J¼8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 2.8, 4.9, 8.9, 20.8, 20.9,
26.7, 30.4, 31.4, 33.7, 43.4, 45.4, 54.0, 55.9, 59.7, 59.8, 64.5, 77.3, 82.0,
111.1,125.6,129.5,132.0,136.7,149.5,168.4,170.5, 208.4. HRMS (ESI):
calcd for C27H34NO7 [MþH]þ: 484.2335. Found: 484.2334.
Acknowledgements
IR (film, cmꢁ1): 3388.1H NMR (CDCl3, 300 MHz)
d 0.10e0.15 (m, 2H),
We acknowledge the Institute of Instrumental Analysis of
Kitasato University, School of Pharmacy for its facilities. We also
acknowledge Nippon Chemiphar Co., Ltd. for financial support.
0.16e0.58 (m, 2H), 0.78e0.90 (m, 1H), 1.52e1.66 (m, 4H), 1.70e1.77
(m, 1H), 2.17e2.26 (m, 2H), 2.30e2.43 (m, 2H), 2.63 (dd, J¼18.0,
6.5 Hz, 2H), 3.08 (d, J¼19.5 Hz, 1H), 3.13 (d, J¼7.5 Hz, 1H), 3.24 (dd,
J¼8.0, 4.5 Hz, 1H), 3.27e3.29 (m, 1H), 3.54e3.61 (m, 1H), 3.85e3.95
(m,1H), 3.88 (s, 3H), 4.25 (s,1H), 5.41 (br s,1H), 6.60 (d, J¼8.0 Hz,1H),
References and notes
6.75 (d, J¼8.0 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d 3.7, 4.0, 9.3, 18.6,
1. DeLander, G. E.; Portoghese, P. S.; Takemori, A. E. J. Pharmacol. Exp. Ther. 1984,
231, 91.
22.8, 29.1, 33.1, 43.2, 48.4, 56.8, 59.4, 59.7, 59.8, 60.4, 61.7, 70.5, 91.9,
114.8, 118.7, 125.9, 130.4, 141.9, 146.7. HRMS (FAB) calcd for
C23H30NO5 [MþH]þ: 400.2124. Found: 400.2133.
2. (a) Nagase, H.; Hayakawa, J.; Kawamura, K.; Kawai, K.; Takezawa, Y.; Matsuura,
H.; Tajima, C.; Endo, T. Chem. Pharm. Bull. 1998, 46, 366; (b) Kawai, K.; Hay-
akawa, J.; Miyamoto, T.; Imamura, Y.; Yamane, S.; Wakita, H.; Fujii, H.; Kawa-
mura, K.; Matsuura, H.; Izumimoto, N.; Kobayashi, R.; Endo, T.; Nagase, H.
Bioorg. Med. Chem. 2008, 16, 9188; (c) Nakao, K.; Mochizuki, H. Drugs Today
2009, 45, 323; (d) Nagase, H.; Fujii, H. Top. Curr. Chem. 2011, 299, 29.
3. (a) Piercy, M. F.; Lahti, R. A.; Schroeder, L. A.; Einspahr, F. J.; Barsuhu, C. Life Sci.1982,
31,1197; (b) Szmuszkovicz, J.; Von Voigtlander, P. F. J. Med. Chem.1982, 25,1125; (c)
Von Voigtlander, P. F.; Lahti, R. A.; Ludens, J. H. J. Pharmacol. Exp. Ther. 1983, 224, 7.
4. (a) Mucha, R. F.; Herz, A. Psychopharmacology 1985, 86, 274; (b) Millan, M. J.
Trends Pharmacol. Sci. 1990, 11, 70.
5. Tsuji, M.; Takeda, H.; Matsumiya, T.; Nagase, H.; Narita, M.; Suzuki, T. Life Sci.
2001, 68, 1717.
6. (a) Yamaotsu, N.; Fujii, H.; Nagase, H.; Hirono, S. Bioorg. Med. Chem. 2010, 18,
4446; (b) Yamaotsu, N.; Hirono, S. Top. Curr. Chem. 2011, 299, 277.
7. Nemoto, T.; Fujii, H.; Narita, M.; Miyoshi, K.; Nakamura, A.; Suzuki, T.; Nagase,
H. Bioorg. Med. Chem. Lett. 2008, 18, 6398.
8. (a) Nagase, H.; Watanabe, A.; Nemoto, T.; Yamaotsu, N.; Hayashida, K.; Nakajima,
M.; Hasebe, K.; Nakao, K.; Mochizuki, H.; Hirono, S.; Fujii, H. Bioorg. Med. Chem.
Lett. 2010, 20, 121; (b) Nemoto, T.; Yamamoto, N.; Watanabe, A.; Fujii, H.; Hasebe,
K.; Nakajima, M.; Mochizuki, H.; Nagase, H. Bioorg. Med. Chem. 2011, 19, 1205.
9. Casy, A. F.; Parfitt, R. T. Opioid Analgesics; Plenum: New York, NY, 1986.
10. Hasebe, K.; Nakajima, M.; Nagase, H. JP Patent 196,933A, 2009; Chem. Abstr.
2009, 151, 328932.
4.11. (5R,6S,7R,9R,13S,14S)-17-(Cyclopropylmethyl)-6,14-ethano-
7-hydroxymethyl-3-methoxy-8-oxamorphinan-6-ol (13)
Under an Ar atmosphere, to a suspension of NaH (60% in oil,
8.52 g, 213 mmol) in DMF (100 mL) was added 12 (12.9 g, 32.3 mmol)
at rt and stirred at the same temperature for 22 h. The reaction
mixture was poured into distillated water and acidified with 2 M
HCl, andthenwashedwith Et2O. Theaqueouslayerwasbasified with
4 M NaOH aqueous solution and extracted with CHCl3. The com-
bined organic layers were washed with brine and dried over anhy-
drous Na2SO4 followed by removing the solvent under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (CHCl3/MeOH¼100/1 to 30/1) and crystallized
from MeOH solution to give the title compound 13 (10.2 g, 79%) as
colorless crystals. Mp 211 ꢀC. IR (film, cmꢁ1): 3375. 1H NMR (CDCl3,
11. Although the N-hydroxymethylamide structure seemed to be labile, various
natural products with the structure were reported. (a) Kakeya, H.; Takahashi, I.;
Okada, G.; Isono, K.; Osada, H. J. Antibiot. 1995, 48, 773; (b) Singh, S. B.; Goetz,
M. A.; Jones, E. T.; Bills, G. F.; Giacobbe, R. A.; Herranz, L.; Stevens-Miles, S.;
Williams, D. L., Jr. J. Org. Chem. 1995, 70, 7040; (c) Kakeya, H.; Kageyama, S.; Nie,
L.; Onose, R.; Okada, G.; Beppu, T.; Norbury, C. J.; Osada, H. J. Antibiot. 2001, 54,
850; (d) He, H.; Yang, H. Y.; Bigelis, R.; Solum, E. H.; Greenstein, M.; Carter, G. T.
Tetrahedron Lett. 2002, 43, 1633; (e) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.;
Matsizaki, H.; Osada, H. Org. Lett. 2002, 4, 2845; (f) Agatsuma, T.; Akama, T.;
Nara, S.; Matsumiya, S.; Nakai, R.; Ogawa, H.; Otaki, S.; Ikeda, S.; Saitoh, Y.;
Kanda, Y. Org. Lett. 2002, 4, 4387; (g) Isaka, M.; Rugseree, N.; Maithip, P.;
Kongsaeree, P.; Prabpai, S.; Thebtaranonth, Y. Tetrahedron 2005, 61, 5577; (h)
Yang, Y.-L.; Lu, C.-P.; Chen, M.-Y.; Chen, K.-Y.; Wu, Y.-C.; Wu, S.-H. Chem.dEur. J.
2007, 13, 6985; (i) Kontnik, R.; Clardy, J. Org. Lett. 2008, 10, 4149; (j) Tapiolas, D.
M.; Bowden, B. F.; Abou-Mansour, E.; Willis, R. H.; Doyle, J. R.; Muirhead, A. N.;
Liptort, C.; Llewellyn, L. E.; Wolff, C. W. W.; Wright, A. D.; Motti, C. A. J. Nat. Prod.
2009, 72, 1115; (k) Lu, X.-H.; Shi, Q.-W.; Zheng, Z.-H.; Ke, A.-B.; Zhang, H.;
Huo, C.-H.; Ma, Y.; Ren, X.; Li, Y.-Y.; Lin, J.; Jiang, Q.; Gu, Y.-C.; Kiyota, H. Eur. J.
Org. Chem. 2011, 802.
300 MHz)
d 0.06e0.15 (m, 2H), 0.43e0.65 (m, 2H), 0.83e0.94 (m,
2H), 1.40e1.51 (m, 1H), 1.57e1.84 (m, 4H), 2.06 (dd, J¼8.0, 13.0 Hz,
1H), 2.24e2.44 (m, 3H), 2.66e2.71 (m, 1H), 2.75e2.80 (m, 2H), 3.18
(d, J¼18.0 Hz, 1H), 3.53 (d, J¼6.5 Hz, 1H), 3.82e4.04 (m, 3H), 3.89 (s,
3H), 4.45 (d, J¼2.0 Hz, 1H), 6.57 (d, J¼8.0 Hz, 1H), 6.72 (d, J¼8.0 Hz,
1H). 13C NMR (75 MHz, CDCl3):
d 2.4, 5.2, 8.6, 20.2, 24.5, 28.9, 34.6,
43.8, 46.7, 56.4, 56.7, 59.4, 61.9, 71.9, 73.2, 76.0, 94.6, 114.4, 119.8,
128.1, 132.7, 142.0, 147.4. MS (FAB) m/z 400 [MþH]þ. HRMS (FAB)
calcd for C23H30NO5 [MþH]þ: 400.2124. Found: 400.2115.
4.12. ((4R,4aR,10R,10aS,12S)-5-Acetoxy-13-(cyclopropylmethyl)-
6-methoxy-3-oxo-1,2,3,4,9,10-hexahydro-10,4a-(iminoethano)-
10a,4-(epoxymethano)phenanthren-12-yl)methyl acetate (16)
The treatment of 13 (799 mg, 2.0 mmol) under the reaction
conditions A gave the mixture of compounds 14 and 15 (704 mg).
Underan Aratmosphere, a solution of the obtainedmixture(120 mg,
0.3 mmol) in Ac2O (2 mL) was stirred at 60 ꢀC for 6 h. After con-
centration of the reaction mixture under reduced pressure, to the
12. Crystal data for compound 1a: C30H34N2O5, MW: 502.61, orthorhombic, P212121,
3
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ꢀ
ꢀ
a¼10.8197(3) A, b¼12.3710(4) A, c¼18.2439(7) A, V¼2441.95(13) A , Z¼4, Dcalcd¼1.
367 g/cm3. Crystallographic data have been deposited with the Cambridge Crys-
tallographic Data Center as supplementary publication number CCDC 816177.
13. Fujii, H.; Narita, M.; Mizoguchi, H.; Murachi, M.; Tanaka, T.; Kawai, K.; Tseng, L.
F.; Nagase, H. Bioorg. Med. Chem. 2004, 12, 4133.