The application of a specific morphinan template to the synthesis of galanthamine

Article abstract of DOI:10.1016/j.tet.2017.08.014

(–)-Galanthamine (4) was synthesized from naltrexone (1) in 18 steps with 3% total yield by overcoming many specific side reactions derived from the 4,5-epoxymorphinan skeleton. The key features are cleavage of the D-ring by the Hofmann elimination and the following the one-pot C9–C10 and C9–14 bond cleavages concomitant with the C9 removal by the OsO₄–NaIO₄ combination reaction. Then, the treatment with zinc powder in acetic acid led to not only removal of the 2,2,2-trichloroethoxycarbonyl (Troc) group, but also reductive amination of the resulting imine to give the desired 7-membered ring.

Full text of DOI:10.1016/j.tet.2017.08.014

Accepted Manuscript
The application of a specific morphinan template to the synthesis of galanthamine
Naoshi Yamamoto, Takahiro Okada, Yukimasa Harada, Noriki Kutsumura, Satomi
Imaide, Tsuyoshi Saitoh, Hideaki Fujii, Hiroshi Nagase
PII:
S0040-4020(17)30834-7
10.1016/j.tet.2017.08.014
TET 28908
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 June 2017
Revised Date: 27 July 2017
Accepted Date: 10 August 2017
Please cite this article as: Yamamoto N, Okada T, Harada Y, Kutsumura N, Imaide S, Saitoh T, Fujii
H, Nagase H, The application of a specific morphinan template to the synthesis of galanthamine,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.08.014.
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The application of a specific morphinan
template to the synthesis of galanthamine
Leave this area blank for abstract info.
Naoshi Yamamotoa, Takahiro Okadab, Yukimasa Haradac,
Noriki Kutsumuraa, Satomi Imaidec, Tsuyoshi Saitoha, Hideaki Fujiic, Hiroshi Nagasea,b,c,*
aInternational Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai,
Tsukuba, Ibaraki 305-8575, Japan
bGraduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-
8571, Japan
cLaboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku,
Tokyo 108-8641, Japan

1
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Tetrahedron
journal homepage: www.elsevier.com
The application of a specific morphinan template to the synthesis of galanthamine
Naoshi Yamamotoa, Takahiro Okadab, Yukimasa Haradac, Noriki Kutsumuraa, Satomi Imaidec, Tsuyoshi
Saitoha, Hideaki Fujiic, and Hiroshi Nagasea,b,c,*
aInternational Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
bGraduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan
cLaboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
(–)-Galanthamine (4) was synthesized from naltrexone (1) in 18 steps with 3% total yield by
overcoming many specific side reactions derived from the 4,5-epoxyymorphinan skeleton. The
key features are cleavage of the D-ring by the Hofmann elimination and the following the one-
pot C9–C10 and C9–14 bond cleavages concomitant with the C9 removal by the OsO4–NaIO4
combination reaction. Then, the treatment with zinc powder in acetic acid led to not only
removal of the 2,2,2-trichloroethoxycarbonyl (Troc) group, but also reductive amination of the
resulting imine to give the desired 7-membered ring.
Available online
Keywords:
naltrexone
(–)-galanthamine
morphinan
2009 Elsevier Ltd. All rights reserved
.
double C–C bond-cleavage
1. Introduction
naltrexone (1) as the starting material to synthesize the
nalfurafine. Naltrexone (1) is also a medication that reverses the
effects of opioids and is used primarily in the management of
alcohol and opioid dependence in the USA.5 The commercially
available compound 1 has also been using as a readily available
drug-like compound. Therefore, we have utilized 1 as a template
to create many novel compounds.9
Three types of opioid receptors (µ (MOR), δ (DOR), κ
(KOR)) are well established not only by pharmacological studies
but by molecular biological studies.1 Narcotic addiction is
believed to be derived from MOR type, and therefore KOR and
DOR types are promising drug targets for analgesics without
addiction.2 To obtain ideal analgesics without addiction and other
side effects derived from the MOR, we have synthesized various
kinds of naltrexone derivatives by use of the specific reactivity of
the morphinan template and have reported some selective ligands
for the KOR3 and DOR4 receptors. One of our designed KOR
selective agonists, nalfurafine hydrochloride (TRK-820, Scheme
1) prepared via 5 steps from the MOR antagonist, naltrexone (1),5
was launched in Japan as an antipruritic for patients undergoing
dialysis in 2009 and for patients with hepatic disease in 2015. On
the other hand, other KOR agonists, aryl-acetamide derivatives
such as U-50488H6 and U-695937 were synthesized and
developed (Figure 1). However, all the aryl-acetamide derivatives
were eliminated from clinical trials not only as analgesics, but
also as antipruritics because of their serious side effects like
psychotomimetic and aversive reactions.8 Notably, nalfurafine
has neither aversive nor addictive effects. We postulated that the
absence of aversion may derive from the partial structure, the
tyrosine moiety in nalfurafine, which is the N-terminal structure
in the endogenous KOR agonist, dynorphin. The aforementioned
aryl-acetamide derivatives have no tyrosine moiety. Focusing on
the possible importance of the tyrosine moiety, we utilized
Scheme 1. Nalfurafine (KOR agonist) was synthesized from
naltrexone (1, MOR antagonist).
Figure 1. Structures of U-50488H, U-69593, 2 and 3.
Corresponding author. Tel.: +81-29-853-6437; fax: +81-29-853-6437; e-mail: nagase.hiroshi.gt@u.tsukuba.ac.jp

2
Tetrahedron
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The specific structural features in naltrexone (1), the 4,5-
to synthesize (–)-homogalanthamine15 instead of (–)-4. After
reporting the synthesis of (–)-homogalanthamine, we discovered
that the C9 removal method cited in the synthesis of
mesembrane21 was applicable to the synthesis of (–)-4. In
consideration of the key step, we proposed a retrosynthetic
pathway of (–)-4 that differed from that of (–)-homogalanthamine
in Scheme 2. The D-ring in 1 can be cleaved by the Hofmann
elimination to give an allyl alcohol 7. A keto-aldehyde 6 would
be transformed from 7, and then, deprotection of the 2,2,2-
epoxy ring, four sequential asymmetric centers, two hydroxy
groups (14-OH and phenolic OH) and a basic nitrogen, have led
to many intramolecular interactions resulting in unexpected
complex rearrangement reactions. A noteworthy characteristic of
the skeleton is the abnormal stability of the enol form of the 6-
keto group in 2 (Figure 2).10 The stability is derived from the
rigid and highly strained 4,5-epoxy morphinan skeleton
(especially, the 4,5-epoxy ring which plays an important role).
Furthermore, the 17-basic nitrogen intramolecularly abstracts the
hydrogen in 14-hydroxy group and the resulting hydroxide ion
can drag away the 7-axial hydrogen to afford enol form 2. The
compound 2 was acetylated with acetic anhydride/pyridine at
room temperature to give triacetates 3.10
We easily synthesized the representative δ and κ receptor
selective antagonists (NTI,11 NTB,12 TRK-85113 and nor-BNI14)
using the stable enol formation (Figure 2). On the other hand, the
abnormally strained structure accelerated the undesired cleavage
reaction of 4,5-epoxy ring to disturb the reductive removal of the
6-keto-group of 1 in the synthesis of (–)-homogalanthamine.15
Thus, the abnormal reactivity needed to be effectively controlled
to utilize the antagonist as a template. The above-mentioned
knowledge of many specific and abnormal reactions derived from
the skeleton should help investigators utilize the naltrexone (1) as
a template. Recently, we have considered the common features
between the partial structures of naltrexone (1) and the target
molecules, (–)-homogalanthamine, mesembrane, and (–)-
galanthamine (4) (red part of the structures, Figure 2).
trichloroethoxycarbonyl (Troc) group of
6 and reductive
amination of the resulting imine would lead to ketone 5 with a 7-
membered ring. Finally, the ketone group would be converted to
the desired allyl alcohol moiety to accomplish synthesis of (–)-4.
However, again, we encountered the formidable side reactions
derived from the reactivity of the naltrexone in the synthesis of (–
)-4 from 1. We overcame these side reactions and attained the
synthesis of (–)-4. Herein, we report the two synthetic methods
for (–)-4 from 1.
N
N
OH
OH
F
X
N
Scheme 2. Retrosynthesis of (–)-4 from naltrexone (1).
O
O
2. Results and discussion
OH
OH
NTI (X = NH)
NTB (X = O)
TRKꢀ851
Naltrexone (1) was converted to the methyl ether 8 with
methyl iodide. It was our bitter experience that the direct removal
of the ketone group by either the Clemmensen-type22 or the
Wolff–Kishner reductions23 led to the cleavage reaction of the
4,5-epoxy ring. Therefore, we applied the longer indirect method
as follows: (1) reduction of the ketone with sodium triacetoxy
borohydride, (2) mesylation of the resulting α-hydroxy
compound with mesyl chloride, and (3) treatment of the mesylate
9 with sodium iodide followed by treatment with DBU to give
the isomeric mixtures of double bond 10 and 11. The obtained
mixtures were reduced with Wilkinson's catalyst in benzene to
afford a saturated single compound 12 in 73% yield over six
steps (Hydrogenation of compound 10 with heterogeneous
catalysts like PtO2 or Pd/C led to the 4,5-epoxy ring opening).15
The key compound 12 obtained via this laborious route was
subjected to the Hofmann elimination reaction with methyl
iodide followed by treatment with sodium hydroxide to give the
9–17 bond cleaved product 7 in 99% yield in two steps. The
resulting allyl alcohol was acetylated with Ac2O/pyridine
followed by treatment with TrocCl to give acetate 14 in 94%
yield in two steps (Scheme 3).21
N
N
OH
OH
OH
N
O
N
O
H
O
O
OH
OH
OH
norꢀBNI
naltrexone (1)
Me
N
OH
H
OH
N
Me
O
N
O
Me
OMe
OMe
(–)ꢀgalanthamine (4)
OMe
(–)ꢀhomogalanthamine
OMe
mesembrane
Figure 2. Structures of NTI, NTB, TRK-851 and nor-BNI. The
common features between naltrexone (1), (–)-homogalanthamine,
mesembrane and (–)-galanthamine (4).
(–)-Galanthamine (4),16 an alkaloid isolated from the
Caucasian snowdrop Galanthus woronowii, and also from
another species of the Amaryllidaceae family, Lycoris radiata, is
a prescription drug for the treatment of Alzheimer’s disease in
Europe, the United States and Japan.17 The mechanism of the
anti-Alzheimer’s disease effect is derived from the dual action on
the cholinergic system, not only inhibiting acetylcholinesterase
(AChE) activity but also allosterically modulating the nicotinic
acetylcholine receptor.18 Many reports have described the
synthesis of 419 and its derivatives.20 We were also interested in
efficient synthesis of 4 maximizing the similarities with the
partial structure of naltrexone (1). However, at that time, the lack
of a method to remove the carbon (C9) from 1 inevitably led us

3
Next, we attempted to protect the tertiary amine of 5 using
OH
OH
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N
N
TrocCl or methyl chloroformate to obtain the corresponding
carbamate 21 because of the protection of the 17-amino group
from the oxidation of the sulfide with mCPBA in the next step,
which is needed for formation of α,β-unsaturated ketone 22 by β-
elimination of sulfoxide at the following stage. However, an
undesirable ring-cleavage reaction proceeded to give 18, which
was the four-step prior product, in 99% yield (Scheme 5).
1) NaBH(OAc)3
AcOH, rt
MeI
K2CO3
O
(–)ꢀ1—HCl
O
O
OMs
2) MsCl, Py
0 °C
DMF
rt
OMe
OMe
9
8
OH
N
OH
N
1) NaI, DMF
100 °C
RhCl(PPh3)3
H2
+
O
O
PhH, rt
2) DBU, DMF
100 °C
73% (6 steps)
OMe
OMe
11
10
I
Me
OH
OH
N
N
NaOH aq
MeI
1,4ꢀdioxane
O
O
80 °C
DMF
99% (2 steps)
80 °C
OMe
OMe
OAc
12
13
Me
N
Me
OH
N
Troc
Scheme 5. Undesired side reaction of 5.
1) Ac2O, 70 °C
O
O
2) TrocCl, Et3N
CH2Cl2, rt
94% (2 steps)
The undesired side reaction led us to protect the 17-amino
group with acid in the oxidation of the sulfide instead of
performing the amidation. After treatment of 5 with LDA and
diphenyl disulfide, we then performed the protection of the
tertiary amine by protonation under acidic condition (CSA)
followed by mCPBA oxidation of the sulfide and the β-
elimination of the resulting sulfoxide afforded a desired α,β-
unsaturated ketone 23 (Scheme 6). The Luche reduction of 23
gave a diastereomeric mixture of allyl alcohols 24 and 25 (58%
and 28% yields, respectively). The structure of the obtained 24
was determined by X-ray crystallographic analysis (see
supplementary data). Finally, mesylation of 24 and the following
elimination gave (–)-galanthamine (4) in 48% and the
diastereomer 26 in 23%.24 The structure of the obtained 4 was
determined by X-ray crystallographic analysis (see
supplementary data).
OMe
OMe
7
14
Scheme 3. Synthesis of 14 from (–)-1·HCl.
Then, the obtained acetate 14 was subjected to ozonolysis to
afford a dialdehyde 15 followed by methanolysis to produce a
dialdehyde-alcohol 16 in quantitative yield. The obtained 16 was
reduced with LiBH4 in MeOH followed by treatment with NaIO4
to afford a keto-alcohol 18, in which the one carbon (C9) was
removed, via an intermediate triol 17 in 72% yield in two steps.
The keto-alcohol 18 was oxidized with MnO2 to give a keto-
aldehyde 6 in 92%. The ketone group was treated with ethylene
glycol to give an acetal compound 19 in 91%. The deprotection
of the Troc group by using a Zn–acetic acid system and the
subsequent cyclization of the resulting secondary amine gave 20.
Finally, hydrolysis with HCl aq. gave the important intermediate
ketone 5 (Scheme 4).
Scheme 6. Synthesis of (–)-galanthamine (4).
Although we obtained the final objective (–)-4, the synthetic
steps, especially the removal step of the one carbon at the C9
position was extremely long. Therefore, we earnestly examined
the alternative shorter synthetic route. We tried to directly obtain
a keto-aldehyde 27 from the Hofmann elimination product 7
(Scheme 7). As we expected, the Lemieux–Johnson oxidation of
Scheme 4. Synthesis of intermediate 5.

4
Tetrahedron
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7 afforded the desired C9-carbon removal to give 27 in 80%.25
mL) was added and the mixture was extracted with Et2O (800,
The cyclopropylmethyl group of 27 was removed with TrocCl to
give the compound 6. The resulting keto-aldehyde 6 was
converted to the objective (–)-galanthamine (4) via the same
routes shown in Schemes 4 and 6. As a result, the alternative
synthetic pathway succeeded to give the final product (–)-4 by a
five-step shortcut, compared to the previous route.
300, 100, 100 mL). The organic layer was washed with brine and
the water layer was extracted with Et2O (100 mL). The combined
organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The crude product (28.8 g, white solid) was
used in the next step without further purification. To a stirring
solution of the crude product (28.8 g) in AcOH (300 mL) was
added NaBH(OAc)3 (25.4 g, 120 mmol), and the mixture was
stirred at room temperature under an argon atmosphere. After 0.5
h, acetone (50 mL) was added. After stirring for 2 h, the reaction
mixture as concentrated under reduced pressure, and then
azeotropically dried with toluene two times to remove the
remained AcOH. The residue was basified with H2O (100 mL)
and K2CO3 (pH 9). The mixture was poured to H2O (150 mL)
and extracted with CHCl3 (200, 100, 50 mL). The organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
The crude product (27.3 g, white solid) was used in the next step
without further purification. The crude product (27.3 g) was
dissolved in pyridine (200 mL) and cooled to 0 °C under an
argon atmosphere. To the solution was added MsCl (12 mL, 155
mmol), and the mixture was stirred for 0.5 h. The reaction
mixture was poured to crushed ice and basified with K2CO3 (pH
9–10). The mixture was poured to H2O (300 mL) and extracted
with CHCl3 (400, 200, 100, 100 mL). The organic layer was
washed with brine, dried over Na2SO4 and concentrated under
reduced pressure. The crude product (35.9 g, brown amorphous
material) was used in the next step without further purification.
To a solution of the crude product (35.9 g) in DMF (300 mL) was
added NaI (229.7 g, 1.53 mol), and the mixture was stirred at 100
°C for 15 h under an argon atmosphere. Before cooling to room
temperature, the hot reaction mixture was poured to H2O,
basified with NaHCO3 and extracted with CHCl3 (600, 300, 150,
100 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude product (35.4 g,
brown solid) was used in the next step without further
purification. To a solution of the crude product (35.4 g) in DMF
(300 mL) was added DBU (44.5 mL, 298 mmol), and the mixture
was stirred at 100 °C for 21 h under an argon atmosphere. The
reaction mixture was poured to saturated aqueous NaHCO3
solution (300 mL)/H2O (400 mL) and extracted with Et2O (400,
200, 200, 100 mL). The organic layer was washed with brine,
dried over Na2SO4 and concentrated under reduced pressure. The
crude product (30.6 g, brown amorphous material) was used in
the next step without further purification. To a mixture of the
crude product (4.96 g) and RhCl(PPh3)3 (1.34 g, 1.45 mmol) was
added degassed benzene (80 mL). The mixture was stirred at
room temperature for 40 h under a hydrogen atmosphere, and
then concentrated under reduced pressure. The crude residue was
purified by column chromatography on amino silica gel
(EtOAc/n-hexane = 0/1 → 1/4); then silica gel (0–20% (28%
NH3 aq.:MeOH:CPME = 1:9:90)/n-hexane) to afford compound
12 (4.01 g, 73% in 6 steps) as a brown oil.
Scheme 7. Alternative synthesis of 6 from 7.
3. Conclusion
We have described the specific reactions of naltrexone (1)
which were sometimes useful and which also sometimes
interfered with the pathway to the successful synthesis of (–)-
galanthamine (4). Especially, we often encountered the cleavage
reaction of the 4,5-epoxy ring, the reductive removal of the
ketone group at the C6 position, and the reduction of the double
bonds in C5–C6 and C6–C7 positions in the case of synthesis of
both (–)-homogalanthamine and (–)-4. Thus, we had no other
choice except the laborious long reaction sequence. Another
unexpected side reaction was the azepane ring cleavage reaction
which gave compound 18, which we had prepared four steps
earlier in the conversion of 5. This awkward side reaction was
circumvented by the protection of the tertiary amine with acid
instead of by urethane formation. Furthermore, we found a five-
step shorter synthetic route to obtain the key intermediate, keto-
aldehyde 6 which led to the effective synthesis of (–)-4.
The description of the above side reactions is expected to be
helpful information for medicinal chemists who could use the
4,5-epoxymorphinan skeleton to prepare useful compounds.
4. Experimental section
4.1. General
All melting points were determined on a Yanaco MP melting
point apparatus and are uncorrected. H and 13C NMR spectral
1
data were obtained with a JEOL JNM-ECS 400 instruments and
an Agilent Technologies VXR-400NMR. Chemical shifts are
quoted in ppm using tetramethylsilane (δ = 0 ppm) and CD3OD
(δ = 3.31 ppm) as the reference for 1H NMR spectroscopy,
CDCl3 (δ = 77.0 ppm) and CD3OD (δ = 49.0 ppm) for 13C NMR
spectroscopy. Mass spectra were measured with a JEOL JMS-
T100LP spectrometer. Column chromatography was carried out
on silica gel (spherical, neutral, 40–50 µm, Kanto Chemical Co.,
Japan) and amino silica gel (60µm, Fuji Silysia Chemical Ltd.,
Japan). Thin layer chromatography (TLC) and preparative TLC
were performed on Merck TLC and PLC silica gel 60 F254 (0.25
mm and 0.5 mm) plates.
4.3. (4aS,4a1S,7aR)-4a1-{2-
[(Cyclopropylmethyl)(methyl)amino]ethyl}-3-methoxy-
4a,5,6,7-tetrahydrophenanthro[4,5-bcd]furan-7a(4a1H)-ol (7)
4.2. (4R,4aS,7aS,12bS)-3-(Cyclopropylmethyl)-9-methoxy-
1,2,3,4,5,6,7,7a-octahydro-4aH-4,12-methanobenzofuro[3,2-
e]isoquinolin-4a-ol (12)
To a solution of compound 12 (1.0 g, 2.93 mmol) in DMF (10
mL) was added MeI (10 mL, 161 mmol), and the mixture was
stirred at 80 °C under an argon atmosphere for 72 h. Additional
MeI (3.0 mL, 48.2 mmol) was added. After stirring for 24 h, the
reaction mixture was concentrated under reduced pressure. The
crude residue was dissolved in 1,4-dioxane (12 mL), and 1 M
aqueous NaOH solution (12 mL) was added. The mixture was
stirred for 2 h at 80 °C under an argon atmosphere. The reaction
mixture was poured to H2O (20 mL) and extracted with CHCl3
(50, 30, 20 mL). The organic layer was dried over Na2SO4 and
Compound 12 was synthesized by a modified procedure of the
reported method.15
To a suspension of naltrexone hydrochloride (30.2 g, 79.9
mmol) in DMF (200 mL) was added K2CO3 (27.6 g, 200 mmol)
and MeI (5.24 mL, 83.9 mmol), and the mixture was stirred at
room temperature under an argon atmosphere. After 11 h, MeI
(0.2 mL, 3.20 mmol) was added. After stirring for 13 h, H2O (600

5
evaporated under reduced pressure. The crude product was
purified by column chromatography on silica gel (0–2% (28%
NH3 aq./MeOH = 1:9) in CHCl3) to afford compound 7 (1.03 g,
99%) as a colorless oil.
(m, 1H), 3.41–3.60 (m, 1H), 3.98 (s, 3H), 4.58 (d, J = 12.0 Hz,
ACCEPTED MANUSCRIPT
0.6H), 4.69 (d, J = 12.0 Hz, 0.4H), 4.75 (d, J = 12.0 Hz, 0.4H),
4.90–4.96 (m, 1H), 4.96 (d, J = 12.0 Hz, 0.6H), 6.99 (d, J = 8.4
Hz, 0.4H), 7.00 (d, J = 8.4 Hz, 0.6H), 7.38 (d, J = 8.4 Hz, 1H),
9.56 (s, 1H), 9.67 (s, 0.6H), 9.68 (s, 0.4H). 13C NMR (100 MHz,
CDCl3): δ 14.3, 14.4, 20.7, 20.8, 20.83, 21.2, 21.4, 28.7, 29.3,
34.3, 35.2, 46.1, 46.5, 54.7, 54.73, 56.1, 75.0, 75.02, 87.8, 88.0,
88.5, 95.7, 111.2, 123.7, 124.0, 128.6, 128.7, 131.9, 132.1, 150.2,
150.3, 153.8, 154.2, 169.8, 169.81, 191.7, 191.8, 197.0. HRMS–
ESI (m/z): [M + Na]+ Calcd for C23H26Cl3NO8Na: 572.0621;
Found 572.0635.
1H NMR (400 MHz, CDCl3): δ 0.08–0.18 (m, 2H), 0.48–0.59
(m, 2H), 0.82–0.93 (m, 1H), 1.21 (ddd, J = 13.6, 13.6, 2.8 Hz,
1H), 1.25–1.39 (m, 2H), 1.47–1.61 (m, 1H), 1.70–1.82 (m, 2H),
1.84–1.95 (m, 1H), 2.15–2.32 (m, 4H), 2.34 (s, 3H), 2.41–2.51
(m, 1H), 3.87 (s, 3H), 4.78 (dd, J = 9.6, 8.0 Hz, 1H), 5.68 (d, J =
9.2 Hz, 1H), 6.24 (d, J = 9.2 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H),
6.69 (d, J = 8.0 Hz, 1H), 8.02 (brs, 1H). 13C NMR (100 MHz,
CDCl3): δ 3.8, 4.2, 8.4, 15.6, 29.6, 34.2, 36.3, 41.6, 50.3, 52.9,
56.1, 62.2, 73.7, 92.0, 112.2, 117.2, 121.9, 124.1, 131.7, 140.4,
143.8, 145.2. HRMS–ESI (m/z): [M + H]+ Calcd for C22H30NO3:
356.2226; Found: 356.2221.
4.6. 2,2,2-trichloroethyl {2-[(5aS,9S,9aS)-1,9-diformyl-9-
hydroxy-4-methoxy-6,7,8,9-tetrahydrodibenzo[b,d]furan-
9a(5aH)-yl]ethyl}(methyl)carbamate (16)
To a solution of compound 15 (100 mg, 0.182 mmol) in
MeOH (2.5 mL) was added Et3N (35 ꢀL, 0.251 mmol), and the
mixture was stirred at room temperature for 2 h. The reaction
mixture was concentrated under reduced pressure and the crude
product was purified by column chromatography on silica gel
(EtOAc/n-hexane = 1/3 → 3/1) to afford compound 16 (93 mg,
quant.) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.57–1.89 (m, 3H), 1.92–2.16
(m, 3H), 2.37–2.58 (m, 1H), 2.72–3.02 (m, 2H), 2.92 (s, 1.8H),
2.96 (s, 1.2H), 3.39–3.63 (m, 1H), 3.98 (s, 1.8H), 3.99 (s, 1.2H),
4.54–4.73 (m, J = 12.0 Hz, 2.4H), 4.85 (d, J = 12.0 Hz, 0.6H)
4.88–4.97 (m, 1H), 6.95 (d, J = 8.4 Hz, 0.4H), 6.96 (d, J = 8.4
Hz, 0.6H), 7.48 (d, J = 8.4 Hz, 1H), 9.26 (s, 0.6H), 9.30 (s, 0.4H),
9.93 (s, 0.6H) 9.94 (s, 0.4H). 13C NMR (100 MHz, CDCl3): δ
16.6, 16.9, 23.6, 23.64, 26.1, 26.9, 29.3, 29.6, 34.2, 35.0, 45.8,
46.4, 53.6, 56.2, 75.0, 79.1, 79.2, 87.0, 87.1, 95.6, 111.4, 127.4,
128.8, 128.9, 129.2, 129.4, 148.8, 148.9, 150.6, 150.63, 153.7,
154.1, 191.3, 191.4, 201.6, 201.8. HRMS–ESI (m/z): [M + Na]+
Calcd for C21H24Cl3NO7Na: 530.0516; Found 530.0531.
4.4. (4aS,4a1S,7aR)-3-methoxy-4a1-(2-{methyl[(2,2,2-
trichloroethoxy)carbonyl]amino}ethyl)-4a,5,6,7-
tetrahydrophenanthro[4,5-bcd]furan-7a(4a1H)-yl acetate (14)
A mixture of compound 7 (175 mg, 0.492 mmol) in Ac2O (1
mL) was stirred at 70 °C for 3 h under an argon atmosphere. The
reaction mixture was concentrated under reduced pressure and
the remained Ac2O was azeotropically removed with toluene. To
a solution of the residue in CH2Cl2 (2 mL) was added Et3N (206
ꢀL, 1.48 mmol) and 2,2,2-trichloroethyl chloroformate (136 ꢀL,
0.988 mmol) under cooling with ice-water, and the mixture was
stirred at room temperature for 0.5 h. Saturated aqueous NaHCO3
solution (5 mL) was added, and the mixture was extracted with
CHCl3 (15, 12, 9 mL). The organic layer was dried over Na2SO4
and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (EtOAc/n-
hexane = 1/6 → 2/1) to afford compound 14 (241 mg, 94%) as a
colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.19–1.43 (m, 4H), 1.93 (dt, J
= 12.4, 5.2 Hz, 0.4H), 2.02 (dt, J = 12.8, 4.8 Hz, 0.6H), 2.07–
2.36 (m, 2H), 2.10 (s, 1.8H), 2.13 (s, 1.2H), 2.76–2.89 (m, 1.6H),
2.81 (s, 1.2H), 2.83 (s, 1.8H), 3.11–3.30 (m, 0.8H), 3.55 (dt, J =
13.6, 4.4 Hz, 0.6H), 3.88 (s, 3H), 4.53 (d, J = 12.0 Hz, 0.6H),
4.66 (d, J = 12.0 Hz, 0.4H), 4.72 (d, J = 12.0 Hz, 0.4H), 4.79 (d,
J = 12.0 HZ, 0.6H), 4.89–4.97 (m, 1H), 6.32 (d, J = 10.0 Hz,
1H), 6.46 (d, J = 10.0 Hz, 0.6H), 6.49 (d, J = 10.0 Hz, 0.4H),
6.63–6.74 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 15.3, 22.4,
29.5, 29.6, 30.1, 30.3, 31.6, 31.9, 33.9, 34.9, 45.6, 46.2, 49.1,
56.0, 74.8, 87.5, 88.0, 90.2, 90.6, 95.5, 95.7, 112.66, 112.7,
118.1, 118.3, 122.7, 122.8, 123.9, 124.0, 127.8, 128.2, 129.5,
129.7, 143.9, 145.2, 145.3, 154.0, 154.1, 169.8, 170.1. HRMS–
ESI (m/z): [M + Na]+ Calcd for C23H26Cl3NO6Na: 540.0723;
Found 540.0743.
4.7. 2,2,2-trichloroethyl {2-[(5aS,9aS)-1-(hydroxymethyl)-4-
methoxy-9-oxo-6,7,8,9-tetrahydrodibenzo[b,d]furan-9a(5aH)-
yl]ethyl}(methyl)carbamate (18)
To a stirred solution of compound 16 (245 mg, 0.482 mmol)
in MeOH (12 mL) was added LiBH4 (240 mg, 11.0 mmol) at –
40 °C. After 0.5 h, the reaction mixture was warmed to 0 °C and
stirred for 0.5 h. The reaction was quenched with saturated
aqueous NaHCO3 solution (30 mL) and the mixture was
extracted with CHCl3 (24, 18, 12 mL). The organic layer was
dried over Na2SO4 and concentrated under reduced pressure. To a
solution of the residue in DME/H2O (3/1, 16 mL) was added
NaIO4 (300 mg, 1.40 mmol), and the mixture was stirred at room
temperature. After 12 h, H2O (6 mL) was added and the mixture
was extracted with CH2Cl2 (15, 12, 7 mL). The organic layer was
dried over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by chromatography on silica gel
(EtOAc/n-hexane = 1/3 → 3/1) to afford compound 18 (166 mg,
72%) as a colorless oil.
4.5. (1S,4aS,9bS)-1,9-diformyl-6-methoxy-9b-(2-
{methyl[(2,2,2-trichloroethoxy)carbonyl]amino}ethyl)-
1,2,3,4,4a,9b-hexahydrodibenzo[b,d]furan-1-yl acetate (15)
A solution of compound 14 (1.65 g, 3.18 mmol) in CH2Cl2
(400 mL) was stirred at –78 °C, and a stream of O3 was
introduced through a pipet for 8 min. The remained O3 was
removed by sparging N2 gas for 20 min, and cooled Me2S (–
78 °C, 7.0 mL, 95.3 mmol) was added. After sparging N2 gas for
20 min, the mixture was stirred at room temperature for 3 h, and
then concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (EtOAc/n-
hexane, gradient) to afford compound 15 (1.59 g, 91%) as a
colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.74–1.89 (m, 2H), 1.97–2.13
(m, 2H), 2.20–2.31 (m, 1H), 2.36–2.57 (m, 3H), 2.85–3.00 (m,
0.5H), 2.93 (s, 1.5H), 2.98 (s, 1.5H), 3.01–3.27 (m, 1H), 3.47–
3.59 (m, 0.5H), 3.90 (s, 3H), 4.43–4.74 (m, 3.5H), 4.84 (d, J =
12.0 Hz, 0.5H), 5.00–5.10 (m, 1H), 6.83 (d, J = 8.4 Hz, 0.5H),
6.85 (d, J = 8.4 Hz, 0.5H), 6.89 (d, J = 8.4 Hz, 0.5H), 6.95 (d, J =
8.4 Hz, 0.5H). One proton (OH) was not observed. 13C NMR
(100 MHz, CDCl3): δ 17.5, 17.6, 28.1, 28.2, 31.3, 32.1, 34.4,
35.0, 38.0, 38.2, 44.9, 45.7, 55.8, 60.7, 60.9, 61.2, 75.0, 88.0,
88.2, 95.4, 95.5, 112.3, 112.6, 123.0, 123.2, 125.1, 125.14, 130.5,
131.0, 143.9, 144.2, 149.1, 153.9, 154.3, 211.2, 211.4. HRMS–
1H NMR (400 MHz, CDCl3): δ 1.39–1.54 (m, 1H), 1.68–2.42
(m, 7H), 2.21 (s, 3H), 2.93 (s, 1.8H), 2.96 (s, 1.2H), 3.07–3.21

6
Tetrahedron
ESI (m/z): [M + Na]+ Calcd for C20H24Cl3NO6Na: 502.0567;
Celite and the filtrate was concentrated under reduced pressure.
ACCEPTED MANUSCRIPT
Found 502.0562.
The residue was diluted with H2O (10 mL) and adjusted to pH 8
with ammonia solution, and then extracted with CHCl3 (20, 10, 5,
5 mL). The organic layer was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The crude
residue was purified by chromatography on silica gel (1–7%
(28% NH3 aq.:MeOH = 1:9) in CHCl3) to afford compound 20
(420 mg, 72%) as a yellow oil.
1H NMR (400 MHz, CDCl3): δ 1.56–1.92 (m, 5H), 1.95–2.09
(m, 1H), 2.09–2.18 (m, 1H), 2.21–2.32 (m, 1H), 2.29 (s, 3H),
2.77–2.91 (m, 1H), 3.09 (ddd, J = 7.6, 7.6, 7.6 Hz, 1H), 3.47 (d, J
= 14.4 Hz, 1H), 3.47–3.58 (m, 1H), 3.70–3.84 (m, 2H), 3.85 (s,
3H), 3.92 (ddd, J = 6.8, 6.8, 3.6 Hz, 1H), 4.40 (d, J = 14.4 Hz,
1H), 4.40–4.46 (m, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 18.0, 23.2, 29.3, 29.8,
41.3, 54.5, 54.7, 55.6, 59.4, 63.9, 64.2, 92.7, 110.6, 112.3, 120.9,
130.2, 131.1, 143.6, 148.7. HRMS–ESI (m/z): [M + H]+ Calcd
for C19H26NO4: 332.1862; Found 332.1862.
4.8. 2,2,2-Trichloroethyl {2-[(5aS,9aS)-1-formyl-4-methoxy-9-
oxo-6,7,8,9-tetrahydrodibenzo[b,d]furan-9a(5aH)-
yl]ethyl}(methyl)carbamate (6)
To a solution of compound 18 (150 mg, 0.312 mmol) in 1,2-
dichloroethane (5 mL) was added activated MnO2 (405 mg, 4.66
mmol), and the suspension was stirred at 80 °C for 12 h. After
cooling to room temperature, the mixture was filtered through a
pad of Celite and the filtrate was concentrated under reduced
pressure. The crude product was purified by chromatography on
silica gel (EtOAc/n-hexane = 1/3 → 1/1) to afford compound 6
(138 mg, 92%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.73–2.25 (m, 5H), 2.33–2.59
(m, 3H), 2.77–2.89 (m, 1H), 2.91 (s, 1.8H), 2.94 (s, 1.2H), 3.38–
3.51 (m, 1H), 3.995 (s, 1.2H), 4.00 (s, 1.8H), 4.56 (d, J = 12.0
Hz, 0.6H), 4.66 (d, J = 12.0 Hz, 0.4H), 4.70 (d, J = 12.0 Hz,
0.4H), 4.79 (d, J = 12.0 Hz, 0.6H), 5.06–5.20 (m, 1H), 6.98 (d, J
= 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 0.6H), 7.49 (d, J = 8.4 Hz,
0.4H), 9.90 (s, 0.6H), 9.94 (s, 0.4H). 13C NMR (100 MHz,
CDCl3): δ 18.3, 18.5, 28.2, 32.3, 32.8, 34.2, 35.0, 38.0, 44.9,
45.4, 56.2, 60. 9, 61.0, 74.96, 74.99, 90.0, 90.4, 95.5, 95.6, 111.6,
127.2, 127.3, 127.57, 127.6, 127.9, 149.3, 149.4, 150.4, 153.8,
154.1, 189.8, 208.3, 208.6. HRMS–ESI (m/z): [M + Na]+ Calcd
for C20H22Cl3NO6Na: 500.0410; Found 500.0412.
4.11. (4aS,8aS)-3-Methoxy-11-methyl-4a,5,6,7,9,10,11,12-
octahydro-8H-benzo[2,3]benzofuro[4,3-cd]azepin-8-one (5)
The mixture of compound 20 (229 mg, 0.690 mmol) in MeOH
(3.0 mL) and 2 M HCl (3.0 mL) was stirred at 60 °C for 12 h
under an argon atmosphere. The reaction mixture was adjusted to
pH 10 with K2CO3 and saturated aqueous NaHCO3 solution, and
then extracted with CHCl3 (12, 6, 3, 3 mL). The organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography on
silica gel (3–5% (28% NH3 aq.:MeOH = 1:9) in CHCl3) to afford
compound 5 (195 mg, 98%) as a colorless oil.
4.9. 2,2,2-Trichloroethyl {2-[(4aS,9bS)-9-formyl-6-methoxy-
2,3,4,4a-tetrahydro-9bH-spiro[dibenzo[b,d]furan-1,2'-
[1,3]dioxolane]-9b-yl]ethyl}(methyl)carbamate (19)
To a solution of compound 6 (2.96 g, 6.18 mmol) in 1,2-
dichloroethane (60 mL) were added ethylene glycol (1.8 mL,
32.3 mmol), isopropoxytrimethylsilane (17 mL, 95.7 mmol) and
trimethylsilyl trifluoromethanesulfonate (570 ꢀL, 3.15 mmol).
The mixture was stirred at 60 °C for 6 h under an argon
atmosphere. The reaction mixture was poured to saturated
aqueous NaHCO3 solution (70 mL) and extracted with CHCl3 (60
mL×2). The organic layer was dried over Na2SO4 and evaporated
under reduced pressure. The crude product was purified by
column chromatography on silica gel (EtOAc/n-hexane = 1/2) to
afford compound 19 (2.94 g, 91%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.88 (ddd, J = 14.4, 2.8, 2.8
Hz, 1H), 1.95–2.27 (m, 4H), 2.32–2.55 (m, 3H), 2.35 (s, 3H),
2.97–3.07 (m, 2H), 3.57 (d, J = 14.8 Hz, 1H), 3.85 (s, 3H), 4.42
(d, J = 14.8 Hz, 1H), 4.69–4.76 (m, 1H), 6.64 (d, J = 8.0 Hz, 1H),
6.69 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 20.9,
25.9, 30.2, 38.4, 41.4, 53.8, 55.8, 61.0, 62.4, 91.7, 111.2, 121.6,
129.9, 132.2, 143.4, 146.9, 211.3. HRMS–ESI (m/z): [M + H]+
Calcd for C17H22NO3: 288.1600; Found 288.1599.
4.12. (4aS,8aS)-3-Methoxy-11-methyl-4a,5,9,10,11,12-
hexahydro-8H-benzo[2,3]benzofuro[4,3-cd]azepin-8-one (23)
The 4:6 ratio rotamer derived from the carbamate was
observed.
A solution of compound 5 (195 mg, 0.678 mmol) in THF (4.0
mL) was added to LDA [prepared from freshly distilled
diisopropylamine (0.33 mL) and n-BuLi (1.6 M in n-hexane, 1.27
mL) in THF (4.0 mL)] with stirring at –78 °C under an argon
atmosphere. After 0.5 h, a solution of diphenyl disulfide (740 mg,
3.39 mmol) in THF (4.0 mL) was added at –78 °C, and then the
reaction mixture was stirred at 0 °C for 2 h. The reaction was
quenched with H2O (10 mL), and the mixture was extracted with
CHCl3 (20, 10 mL, 5 mL×2). The organic layer was washed with
brine, dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column
chromatography on silica gel (CHCl3/n-hexane = 9/1 → 0.5–5%
(28% NH3 aq./MeOH = 1:9) in CHCl3) to afford a mixture of α-
and β-phenylsulfide. To a solution of α- and β-phenylsulfide in
CH2Cl2 (5.0 mL) was added (±)-camphor-10-sulfonic acid (103
mg, 0.443 mmol), and the mixture was stirred at room
temperature for 10 min under an argon atmosphere. A solution of
m-CPBA (65%, 118 mg, 0.444 mmol) in CH2Cl2 (4.0 mL) was
added at −78 °C, and the mixture was stirred at –40 °C for 0.5 h.
The reaction was quenched with saturated aqueous Na2S2O3
solution (5.0 mL). The reaction mixture was poured to saturated
aqueous NaHCO3 solution (10 mL) and brine (10 mL), and
extracted with CHCl3 (20, 10, 5, 3 mL). The organic layer was
1H NMR (400 MHz, CDCl3): δ 1.51–1.78 (m, 3H), 1.88–2.06
(m, 3H), 2.20–2.42 (m, 1H), 2.55–2.77 (m, 1H), 2.88–3.04 (m,
1H), 2.95 (s, 1.8H), 2.97 (s, 1.2H), 3.14 (dd, J = 14.8, 7.2 Hz,
0.4H), 3.21 (dd, J = 14.8, 7.2 Hz, 0.6H), 3.42–3.62 (m, 1H),
3.69–3.93 (m, 3H), 3.95 (s, 3H), 4.64 (d, J = 12.0 Hz, 0.6H), 4.70
(d, J = 12.0 Hz, 0.4H), 4.74 (d, J = 12.0 Hz, 0.4H), 4.78–4.91 (m,
1.6H), 6.90 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 0.6H), 7.55
(d, J = 8.4 Hz, 0.4H), 10.25 (s, 0.6H), 10.28 (s, 0.4H). 13C NMR
(100 MHz, CDCl3): δ 17.0, 17.2, 23.4, 23.4, 28.9, 29.1, 29.7, 34.
6, 35.2, 46.2, 46.9, 55.9, 56.2, 56.2, 64.4, 64.5, 64.8, 75.1, 86.9,
87.0, 95.6, 95.6, 110.2, 111.2, 121.8, 122.0, 128.3, 130.6, 131.0,
149.2, 149.8, 154.0, 154.2, 190.4, 190.7. HRMS–ESI (m/z): [M +
Na]+ Calcd for C22H26Cl3NO7Na: 544.0673; Found 544.0661.
4.10. (4aS,8aS)-3-Methoxy-11-methyl-4a,5,6,7,9,10,11,12-
octahydrospiro[benzo[2,3]benzofuro[4,3-cd]azepine-8,2'-
[1,3]dioxolane] (20)
To a solution of compound 19 (921 mg, 1.76 mmol) in AcOH
(15 mL) was added zinc powder (4.6 g, 70.3 mmol), and the
mixture was stirred at room temperature for 22 h under an argon
atmosphere. The reaction mixture was filtered through a pad of

7
washed with brine, dried over Na2SO4 and concentrated under
reduced pressure. The mixture of the crude residue and NaHCO3
(112 mg) in toluene (9.0 mL) was stirred at 110 °C for 2 h under
an argon atmosphere. Saturated aqueous NaHCO3 solution (10
mL) and H2O (10 mL) was added, and the mixture was extracted
with CHCl3 (12, 6, 3, 3 mL). The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The crude
residue was purified by column chromatography on silica gel
(CHCl3/n-hexane = 9/1 → 0–3% (28% NH3 aq.:MeOH = 1:9) in
CHCl3) and PLC ((28% NH3 aq.:MeOH = 1:9)/CHCl3 = 1/15) to
afford compound 23 (79.6 mg, 41%) as a brown amorphous.
1H NMR (400 MHz, CDCl3): δ 1.77 (ddd, J = 14.0, 3.6, 1.6
Hz, 1H), 2.11–2.24 (m, 1H), 2.41 (s, 3H), 2.79 (dddd, J = 20.4,
5.2, 2.8, 2.8 Hz, 1H), 3.01 (ddd, J = 13.6, 2.8, 2.8 Hz, 1H), 3.11
(dd, J = 20.4, 5.6 Hz, 1H), 3.33–3.47 (m, 1H), 3.61 (d, J = 14.8
Hz, 1H), 3.83 (s, 3H), 4.71 (d, J = 14.8 Hz, 1H), 4.74–4.79 (m,
1H), 6.12 (dd, J = 10.0, 1.6 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H),
6.68 (d, J = 8.0 Hz, 1H), 6.79–6.89 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 26.2, 29.5, 41.3, 53.3, 55.8, 57.8, 60.7, 88.6,
111.3, 122.0, 129.5, 130.3, 132.3, 143.2, 144.4, 146.8, 197.3.
HRMS–ESI (m/z): [M + H]+ Calcd for C17H20NO3: 286.1443;
Found 286.1401.
Hz, 1H). 13C NMR (100 MHz, CD3OD): δ 27.9, 31.7, 43.2,
ACCEPTED MANUSCRIPT
53.8, 56.2, 56.6, 61.1, 69.0, 90.9, 113.0, 122.5, 128.0, 129.3,
133.0, 135.1, 145.0, 149.4. HRMS–ESI (m/z): [M + H]+ Calcd
for C17H22NO3: 288.1600; Found 288.1600.
4.14. (4aR,5S,8aR)-3-methoxy-11-methyl-4a,5,9,10,11,12-
hexahydro-8H-benzo[2,3]benzofuro[4,3-cd]azepin-5-ol, (–)-
galanthamine (4); (4aR,5R,8aR)-3-methoxy-11-methyl-
4a,5,9,10,11,12-hexahydro-8H-benzo[2,3]benzofuro[4,3-
cd]azepin-5-ol (26)
To a solution of compound 24 (69 mg, 0.240 mmol) in CH2Cl2
(5.0 mL) were added Et3N (170 ꢀL, 1.22 mmol) and MsCl (60
ꢀL, 0.775 mmol) at 0 °C under an argon atmosphere. The
mixture was stirred at 0 °C for 0.5 h, and then saturated aqueous
NaHCO3 solution (15 mL) was added. After stirring at room
temperature for 1.5 h, the reaction mixture was extracted with
CHCl3 (30, 20, 10 mL). The organic layer was dried over Na2SO4
and evaporated under reduced pressure. The crude product was
purified by PLC ((28% NH3 aq./MeOH = 1:9)/CHCl3 = 2/25) to
afford (–)-galanthamine (4) (33.1 mg, 48%) as a colorless solid
and compound 26 (15.7 mg, 23%) as a colorless amorphous. A
portion of synthesized (–)-galanthamine (4) was recrystallized
from EtOAc/n-hexane to give light yellow needle crystals.
4.13. (4aS,8R,8aR)-3-methoxy-11-methyl-4a,5,9,10,11,12-
hexahydro-8H-benzo[2,3]benzofuro[4,3-cd]azepin-8-ol (24);
(4aS,8S,8aR)-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-
8H-benzo[2,3]benzofuro[4,3-cd]azepin-8-ol (25)
(–)-Galanthamine (4)
mp 128–130 °C (lit.26b; mp 128–129 °C). [α]20 −89.7° (c =
0.6, CHCl3) (lit.26b; [α]25D –93.4° (c = 1, CHCl3)). 1DH NMR (400
MHz, CDCl3): δ 1.51–1.64 (m, 1H), 2.01 (ddd, J = 16.0, 4.8, 2.8
Hz, 1H), 2.09 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 2.40 (s, 3H), 2.50
(brs, 1H), 2.62–2.75 (m, 1H), 2.98–3.14 (m, 1H), 3.19–3.33 (m,
1H), 3.68 (d, J = 15.2 Hz, 1H), 3.83 (s, 3H), 4.09 (d, J = 15.2 Hz,
1H), 4.14 (dd, J = 4.8, 4.8 Hz, 1H), 4.56–4.66 (m, 1H), 6.00 (dd,
J = 10.0, 4.8 Hz, 1H), 6.07 (d, J = 10.0 Hz, 1H), 6.62 (d, J = 8.4
Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 29.9, 33.7, 42.0, 48.1, 53.8, 55.8, 60.6, 62.0, 88.7, 111.0, 122.0,
126.8, 127.5, 129.3, 132.9, 144.0, 145.7. HRMS–ESI (m/z): [M +
H]+ Calcd for C17H22NO3: 288.1600; Found 288.1595.
To a solution of compound 23 (79.6 mg, 0.277 mmol) in
MeOH (2.0 mL) and CH2Cl2 (1.0 mL) was added CeCl3·7 H2O
(314 mg, 0.842 mmol). The mixture was stirred at room
temperature for 10 min under an argon atmosphere, and then
NaBH4 (21.3 mg, 0.563 mmol) was added at –78 °C. The
reaction mixture was stirred at −40 °C for 1 h. The reaction was
quenched with acetone (3 mL). After warming to room
temperature, the mixture was treated with saturated aqueous
NaHCO3 solution (10 mL) and H2O (10 mL), and extracted with
CHCl3 (12, 6 mL, 3 mL×2). The organic layer was washed with
brine and dried over Na2SO4 and evaporated under reduced
pressure. The crude product was purified by PLC ((28% NH3
aq.:MeOH = 1:9)/CHCl3 = 1/10) to afford compound 24 (46.5
mg, 58%) as a colorless amorphous and compound 25 (22.5 mg,
28%) as a colorless oil. A portion of synthesized compound 24
was recrystallized from Et2O/n-hexane to give colorless prism
crystals.
All data are in agreement with the literature values.26
Compound 26
1H NMR (400 MHz, CDCl3): δ 1.65 (ddd, J = 13.6, 13.6, 1.6
Hz, 1H), 1.72 (ddd, J = 13.6, 10.4, 2.4 Hz, 1H), 2.19 (ddd, J =
13.2, 13.2, 3.2 Hz, 1H), 2.38 (s, 3H), 2.79 (dddd, J = 14.0, 5.6,
4.0, 1.6 Hz, 1H), 2.99–3.12 (m, 1H), 3.20–3.33 (m, 1H), 3.63 (d,
J = 15.2 Hz, 1H), 3.84 (s, 3H), 4.07 (d, J = 15.2 Hz, 1H), 4.56–
4.71 (m, 2H), 5.77–5.86 (m, 1H), 6.08 (ddd, J = 10.8, 1.6, 1.6 Hz,
1H), 6.57 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H). One
proton (OH) was not observed. 13C NMR (100 MHz, CDCl3): δ
32.4, 34.3, 42.1, 48.1, 54.0, 55.8, 60.4, 63.3, 88.4, 110.8, 121.5,
126.6, 129.2, 131.5, 132.9, 143.8, 146.6. HRMS–ESI (m/z): [M +
H]+ Calcd for C17H22NO3: 288.1600; Found 288.1590.
Compound 24
1
mp 163–165 °C. H NMR (400 MHz, CD3OD): δ 1.63–1.91
(m, 1H), 2.00–2.11 (m, 1H), 2.29–2.48 (m, 1H), 2.35 (s, 3H),
2.75 (ddd, J = 17.6, 5.6, 2.8 Hz, 1H), 2.84–3.05 (m, 1H), 3.24–
3.45 (m, 1H), 3.52 (d, J = 14.4 Hz, 1H), 3.78 (s, 3H), 4.20–4.46
(m, 2H), 4.57–4.64 (m, 1H), 5.76–5.85 (m, 1H), 5.88–5.96 (m,
1H), 6.59 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H). One
proton (OH) was not observed. 13C NMR (100 MHz, CD3OD): δ
27.4, 36.6, 42.7, 55.1, 56.6, 62.1, 70.0, 90.0, 113.0, 122.6, 125.8,
131.7, 132.7, 133.4, 144.9, 149.8. One carbon was not observed.
HRMS–ESI (m/z): [M + H]+ Calcd for C17H22NO3: 288.1600;
Found 288.1594.
4.15. (5aS,9aS)-9a-{2-
[(Cyclopropylmethyl)(methyl)amino]ethyl}-4-methoxy-9-oxo-
5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furan-1-carbaldehyde
(27)
To a stirred solution of compound 7 (19.8 mg, 55.7 ꢀmol) in
acetone (2.0 mL) and AcOH (0.2 mL) were added a solution of
NaIO4 (60.3 mg, 0.282 mmol) in H2O (2.0 mL) and OsO4 (2.0
mg/mL in t-BuOH, 0.72 mL, 5.66 ꢀmol). The mixture was stirred
at room temperature for 60 h under an argon atmosphere. The
reaction was quenched with saturated aqueous Na2S2O3 solution
(10 mL) and saturated aqueous NaHCO3 solution (15 mL), and
the mixture was extracted with CHCl3 (20, 10, 5 mL). The
organic layer was dried over Na2SO4 and concentrated under
Compound 25
1H NMR (400 MHz, CD3OD): δ 1.70–1.88 (m, 1H), 2.18
(ddd, J = 14.4, 5.6, 2.8 Hz, 1H), 2.34 (s, 3H), 2.53–2.61 (m, 1H),
2.63–2.73 (m, 1H), 2.83–2.95 (m, 1H), 3.25–3.42 (m, 2H), 3.59
(d, J = 14.8 Hz, 1H), 3.79 (s, 3H), 4.26 (d, J = 14.8 Hz, 1H),
4.29–4.39 (m, 1H), 4.52 (dd, J = 4.8, 1.6 Hz, 1H), 5.82–5.92 (m,
1H), 5.94–6.04 (m, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4

8
Tetrahedron
ACCEPTED MANUSCRIPT
11. Portoghese PS, Sultana M, Nagase H, Takemori AE. J. Med.
reduced pressure. The crude product was purified by PLC
Chem. 1988;31:281.
((28% NH3 aq./MeOH = 1:9)/CHCl3 = 1/20) to afford compound
27 (16.0 mg, 80%) as a brown oil.
12. Portoghese PS; Nagase H; MaloneyHuss KE, Lin CE, Takemori
AE. J. Med. Chem. 1991;34:1715.
1H NMR (400 MHz, CDCl3): δ (–0.03)–0.10 (m, 2H), 0.39–
0.51 (m, 2H), 0.69–0.81 (m, 1H), 1.81–2.36 (m, 9H), 2.24 (s,
3H), 2.37–2.56 (m, 3H), 3.98 (s, 3H), 5.09–5.14 (m, 1H), 6.93 (d,
J = 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 10.08 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 4.6 (two carbons), 6.4, 18.7, 28.0,
30.0, 38.1, 40.3, 51.9, 56.3, 61.0, 61.3, 90.4, 112.0, 126.9, 127.1,
128.6, 149.9, 150.5, 190.8, 208.5. HRMS–ESI (m/z): [M + H]+
Calcd for C21H28NO4: 358.2018; Found: 358.2015.
13. Sakami S, Kawai K, Maeda M, Aoki T, Fujii H, Ohno H, Ito T,
Saitoh A, Nakao K, Izumimoto N, Matsuura H, Endo T, Ueno S,
Natsume K, Nagase H. Bioorg. Med. Chem. 2008;16:7956.
14. Portoghese PS; Nagase H; Lipkowski AW, Larson DL, Takemori
AE. J. Med. Chem. 1988;31:836.
15. Yamamoto N, Fujii H, Imaide S, Hirayama S, Nemoto T, Inokoshi
J, Tomoda H, Nagase H. J. Org. Chem. 2011;76:2257.
16. (a) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1987; Vol. 30, pp 251–376. (b) Hoshino, O. In
The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York,
1998; Vol. 51, pp 323–424.
4.16. 2,2,2-Trichloroethyl {2-[(5aS,9aS)-1-formyl-4-methoxy-
9-oxo-6,7,8,9-tetrahydrodibenzo[b,d]furan-9a(5aH)-
yl]ethyl}(methyl)carbamate (6)
17. (a) Sramek JJ, Frackiewicz EJ, Cutler NR. Expert Opin. Invest.
Drugs 2000;9:2393. (b) Heinrich M, Teoh HL. J.
Ethnopharmacol. 2004;92:147.
18. Lilienfeld S. CNS Drug Rev. 2002;8:159.
To a solution of compound 27 (12.5 mg, 34.5 ꢀmol) in 1,2-
dichloroethane (1.0 mL) were added (i-Pr)2NEt (18.3 ꢀL, 0.105
mmol) and 2,2,2-trichloriethyl chloroformate (5.8 ꢀL, 42.1
ꢀmol), and the mixture was stirred at room temperature for 6 h
under an argon atmosphere. Additional (i-Pr)2NEt (18.3 ꢀL,
0.105 ꢀmol) and 2,2,2-trichloroethyl chloroformate (11.5 ꢀL,
42.1 ꢀmol) were added. After 13 h, additional (i-Pr)2NEt (36.5
ꢀL, 0.210 ꢀmol) and 2,2,2-trichloroethyl chloroformate (2.8 ꢀL,
83.5 ꢀmol) were added. Finally, after 3 h, (i-Pr)2NEt (18.3 ꢀL,
0.105 ꢀmol) was added. After stirring for 2 h, the reaction
mixture was poured to saturated aqueous NaHCO3 solution (5.0
mL) and extracted with CHCl3 (5, 3, 2 mL). The organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by PLC (EtOAc/n-hexane = 1/1)
to afford compound 6 (13.6 mg, 81%) as a colorless oil.
19. (a) Marco–Contelles J, Carreiras MC, Rodríguez C, Villarroya M,
García AG. Chem. Rev. 2006;106:116. and the references cited
therein. For recent examples of asymmetric synthesis of
galanthamine, see; (b) Node M, Kodama S, Hamashima Y, Katoh
T, Nishide K, Kajimoto T. Chem. Pharm. Bull. 2006;54:1662. (c)
Satcharoen V, McLean NJ, Kemp SC, Camp NP, Brown, RCD.
Org. Lett. 2007;9:1867. (d) Kato T, Tanimoto H, Yamada H,
Chida N. Heterocycles 2010;82:563. (e) Chen P, Bao X, Zhang
LF, Ding M, Han XJ, Li J, Zhang GB, Tu YQ, Fan CA. Angew.
Chem. Int. Ed. 2011;50:8161. (f) Chen JQ, Xie JH, Bao DH, Liu
S, Zhou QL. Org. Lett. 2012;14:2714. (g) Zang Y, Ojima I. J.
Org. Chem. 2013;78:4013. (h) Choi J, Kim H, Park S, Tae J.
Synlett 2013;24:379. (i) Li L, Yang Q, Wang Y, Jia Y. Angew.
Chem. Int. Ed. 2015;54:6255. (j) Feng Y, Yu Z-X. J. Org. Chem.
2015;80:1952. (k) Liu CH, Yu ZX. Org. Biomol. Chem.
2016;14:5945. (l) Endoma-Arias MAA, Hudlicky T. Chem. Eur. J.
2016;22:14540.
20. For recent examples, see; (a) Knesl P, Yousefi BH, Mereiter K,
Jordis U. Tetrahedron Lett. 2006;47:5701. (b) Perissutti E, Fiorino
F, Severino B, Frecentese F, Massarelli P, Nencini C, Santagada
V, Caliendo G. Pharmazie 2007;62:403. (c) Jia P, Sheng R, Zhang
J, Fang L, He Q, Yang B, Hu Y. Eur. J. Med. Chem. 2009;44:772.
(d) Vezenkov LT, Georgieva MG, Danalev DL, Ivanov TB,
Ivanova GI. Protein Pept. Lett. 2009;16:1024. (e) Bartolucci C,
Haller LA, Jordis U, Fels G, Lamba D. J. Med. Chem.
2010;53:745. (f) Rao VK, Rao AJ, Reddy SS, Raju CN, Rao PV,
Ghosh SK. Eur. J. Med. Chem. 2010;45:203. (g) Simoni E,
Daniele S, Bottegoni G, Pizzirani D, Trincavelli ML, Goldoni L,
Tarozzo G, Reggiani A, Martini C, Piomelli D, Melchiorre C,
Rosini M, Cavalli A. J. Med. Chem. 2012;55:9708. (h) Keglevich
P, Kovács P, Hazai L, Sánta Z, Dubrovay Z, Háda V, Szántay C
Jr, Kalaus G, Szántay C. Heterocycles 2012;84:1171. (i) Lan P,
Jackson CJ, Banwell MG, Willis AC. J. Org. Chem.
Acknowledgments
We acknowledge the Institute of Instrumental Analysis of
Kitasato University, School of Pharmacy, for its facilities. This
work was supported by JSPS KAKENHI (Grant-in-Aid for
Scientific Research (B)) Grant 16H05098 (H.N.).
References and notes
1. Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB,
Portoghese PS, Hamon M. Pharmacol. Rev. 1996;48:567.
2. Delander GE, Portoghese PS, Takemori AE. J. Pharmacol. Exp.
Ther. 1984;231:91.
2014;79:6759.
3. (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, Hayakawa J, Miyamoto T, Imamura Y, Yamane S,
Wakita H, Fujii H, Kawamura K, Matsuura H, Izumimoto N,
Kobayashi R, Endo T, Nagase H. Bioorg. Med. Chem.
2008;16:9188. (c) Nemoto T, Yamamoto N, Watanabe A, Fujii H,
Hasebe K, Nakajima M, Mochizuki H, Nagase H. Bioorg. Med.
Chem. 2011;19:1205.
4. (a) Nagase H, Osa Y, Nemoto T, Fujii H, Imai M, Nakamura T,
Kanemasa T, Kato A, Gouda H, Hirono S. Bioorg. Med. Chem.
Lett. 2009;19:2792. (b) Nagase H, Nemoto T, Matsubara A, Saito
M, Yamamoto N, Osa Y, Hirayama S, Nakajima M, Nakao K,
Mochizuki H, Fujii H. Bioorg. Med. Chem. Lett. 2010;20:6302. (c)
Ida Y, Nemoto T, Hirayama S, Fujii H, Osa Y, Imai M, Nakamura
T, Kanemasa T, Kato A, Nagase H. Bioorg. Med. Chem.
2012;20:949.
5. Sudakin D. J. Med. Toxicol. 2016;12:71.
6. Piercey MF, Lahti RA, Schroeder LA, Einspahr FJ, Barsuhn C.
Life Sci. 1982;31:2257.
7. Lahti RA, Mickelson MM, Mccall JM, Vonvoigtlander PF. Eur. J.
Pharmacol. 1985; 109:281.
8. (a) Mucha RF, Herz A. Psychopharmacology 1985;86:274. (b)
Millan MJ. Trends. Pharmacol. Sci. 1990;11:70.
21. Konoura K, Fujii H, Imaide S, Gouda H, Hirayama S, Hirono S,
Nagase H. Bioorg. Med. Chem. 2015;23:439.
22. Zhang A, li F, Ding C, Yao Q, Knapp BI, Bidlack JM, Neumeyer
JL. J. Med. Chem. 2007;50:2747.
23. (a) Furrow ME, Myers AG. J. Am. Chem. Soc. 2004;126:5436.
(b)Wu H, Thatcher LN, Bernard D, Parrish DA, Deschamps JR,
Rice KC, MacKerell AD Jr., Coop A. Org. Lett. 2005;7:2531. (c)
Qi, H. A.; Yakov, R.; Virendra, K. WO2009/132313, 2009. (d)
Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, Ganorkar R,
VanAlstine MA, Guo C, Cohen DJ, Bidlack JM. Bioorg. Med.
Chem. Lett. 2009;19:2289.
24. Trost BM, Tang W, Toste FD. J. Am. Chem. Soc. 2005;127:14785.
25. (a) Waddell TG, Rambalakos T, Christie KR. J. Org. Chem.
1990;55:4765. (b) Carroll FI, Abraham P, Gaetano K, Mascarella
SW, Wohl RA, Lind J, Petzoldt K. J.Chem. Soc. Perkin Trans. 1
1991:3017. (c) Nakazaki A, Miyamoto H, Henmi K, Kobayashi S.
Synlett 2005:1417. (d) Zurflüh R, Dunham LL, Spain VL, Siddall
JB. J. Am. Chem. Soc. 1970;92:425.
26. (a) Han SY, Sweeney JE, Bachman ES, Schweiger EJ, Forloni G,
Coyle JT, Davis BM, Joullié MM. Eur. J. Med. Chem.
1992;27:673. (b) Shieh WC, Carlson JA. J. Org. Chem.
1994;59:5463.
9. Nagase H, Fujii H. Top Curr. Chem. 2011;299:187.
10. Nagase H, Abe A, Portoghese PS. J. Org. Chem. 1989;54:4120.
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