Synthesis of galanthamine analogs as acetylcholinesterase inhibitors via intramolecular heck cvclization

Article abstract of DOI:10.1002/jccs.200300071

A novel approach towards the construction of the galanthamine skeleton was demonstrated by the Pdcatalyzed cyclization of N-[2-(l,4-dioxa-spiro[4,5]dec-7- en-8-yl)-ethyl]-2-iodo-4-methoxy-N-methylbenzamide (23), with formation of the benzazepine ring and creation of a quaternary carbon.

Full text of DOI:10.1002/jccs.200300071

Journal of the Chinese Chemical Society, 2003, 50, 449-456
449
Synthesis of Galanthamine Analogs as Acetylcholinesterase Inhibitors via
Intramolecular Heck Cyclization
Pi-Hui Liang (
), Ling-Wei Hsin* (
), Sung-Ling Pong (
),
Chia-Huei Hsu (
) and Chen-Yu Cheng (
)
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University,
Taipei100, Taiwan, R.O.C.
A novel approach towards the construction of the galanthamine skeleton was demonstrated by the Pd-
catalyzed cyclization of N-[2-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-ethyl]-2-iodo-4-methoxy-N-methyl-
benzamide (23), with formation of the benzazepine ring and creation of a quaternary carbon.
Keywords: Alzheimer’s disease; Galanthamine; Intramolecular Heck reaction.
INTRODUCTION
Galanthamine (1), an alkaloid isolated from the
membered azepine ring in galanthamine by Heck reaction has
not been documented yet.
Amaryllidaceae species,1-2 is structurally related to morphine
(2) in its topology. It has been shown to be a potent acetyl-
cholinesterase (AChE) inhibitor, which terminates the neuro-
transmission by catalyzing the cleavage of acetylcholine at
cholinergic synapses. Galanthamine is currently used in the
clinic for the treatment of Alzheimer’s disease.3-5 However,
the production of galanthamine from natural sources is lim-
ited.6 A number of total syntheses of galanthamine have ap-
peared in the literature.7-13 Most of them utilize a biomimetic
oxidative bisphenol coupling to create the critical spiro quar-
ternary carbon of galanthamine. Based on our experience in
applying an intramolecular Heck reaction for the construc-
tion of a morphine skeleton,14-16 we set out to look for an effi-
cient synthetic route for galanthamine. Here, we report the
synthesis of spiro-cyclohexanebenzazepine derivatives rep-
resented by 3 as simplified analogs of galanthamine (Fig. 1).
Based on our knowledge, the direct construction of the seven-
RESULTS AND DISCUSSION
An initial retrosynthetic analysis of compound 3 identi-
fied compound 5 as a potential intermediate for the intended
Heck cyclization to form the azepine-containing tricyclic
system (Scheme I). Compound 5 may be synthesized via the
reductive amination of 2-iodo-4-methoxybenzaldehyde (20)
with 2-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)ethylamine (11),
which was prepared as shown in Scheme II.
1,4-Cyclohexanedione monoethylene ketal (6) under-
went Reformasky reaction with ethyl bromoacetate to give
ester 7 in 93% yield. Compound 7 was reduced with LiAlH4
to afford diol 8, which was then reacted with phthalimide un-
der Mitsunobu condition17 to provide compound 9 and its de-
hydration product 10 in a total yield of 75%. Dehydration of
the remaining tertiary cabinol 9 was achieved via treatment
with p-TsOH. Phthalimide 10 was then treated with hydra-
zine to provide 11 in 92% yield. As a model study, the des-
methoxy analog of 5, namely compound 13, was prepared via
the reductive amination of 2-iodobenzaldehyde with amine
11, followed by protection of the resulting secondary amine
12 with (Boc)2O. However, all attempts to effect the desired
intramolecular Heck reaction of 13 failed, resulting primarily
in dehalogenated products. The failed Heck reaction condi-
tions included Pd(OAc)2 with ligand (PPh3), different bases
(K2CO3, NEt3, Ag2CO3, or proton sponge), with or without
MeO
MeO
H3CO
NMe
NMe
O
O
NMe
H
HO
OH
OH
galanthamine (1)
morphine (2)
3
Fig. 1
* Corresponding author. Tel: +886-2-2395-2310; fax: +886-2-2351-2086; e-mail: lwh@ha.mc.ntu.edu.tw

450 J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003
Liang et al.
Scheme I
MeO
MeO
MeO
NH2
NMe
NMe
N-Boc
OMe
I
+
I
O
O
O
CHO
O
OH
O
20
5
4
11
3
synthesize compound 3 as shown in Scheme IV. 2-Iodo-4-
methoxy-benzaldehyde (20) was prepared from p-anisal-
dehyde (18) in 2 steps: protection of the aldehyde function as
its dimethyl acetal followed by lithium-iodide exchange,
with acidic workup. Compound 20 was then oxidized with
KMnO4 to give 21 in 99% yield. Compound 21 was reacted
with thionyl chloride, followed by coupling with amine 11, to
provide amide 22 in 67% yield. Methylation of 22 with NaH
and CH3I gave compound 23. When compound 23 was sub-
jected to the Heck reaction condition, the desired 7-exo-trig
product 24 was obtained in 66% yield. Remarkably, this was
the first reported example of the direct construction of the
seven-membered azepine ring in galanthamine by Heck reac-
tion.
Scheme II
OH
O
O
O
OH
O
O
a
c
b
OH
O
O
O
O
6
8
7
NH2
O
O
N
O
N
O
e
HO
O
+
O
O
O
O
O
Compound 24 was then hydrolyzed to the correspond-
ing enone 25. Chemoselective reduction of enone 25 was
achieved by the use of L-selectride, and gave compound 26
in 46% yield.21 Reduction of 26 with LiAlH4 then provided
target compound 3 in 66% yield.
11
10
9
d
Reagents and conditions: (a) Zn, ethyl bromoacetate, THF, re-
flux, 93%. (b) LiAlH4, Et2O, rt, 87%. (c) phthalimide, DEAD,
PPh3, THF, rt, 75%. (d) p-TsOH, toluene, reflux, 89%. (e)
N2H4×H2O, ethanol, reflux, 92%.
The inhibitory activities of compound 3 against acetyl-
cholinesterase (AChE) and butyrylcholinesterase (BChE)
were evaluated using the spectroscopic method of Ellmann et
al.22 Compound 3 was found to have weak activity against
AChE, with an IC50 of 150 mM, while galanthamine and tacrine
were active at 2.4 mM and 0.5 mM, respectively. As an at-
tempt to explain the activity difference between galanth-
amine and compound 3, we superimposed the bound confor-
mation of (-)-galanthamine at the active site of Torpedo
californica acetylcholinesterase23 and the energy-minimized
conformation of compound 3 (Fig. 2). It became obvious that
the c-ring hydroxy groups of both molecules do not occupy
the same position in space. Because the hydroxy group in
galanthamine may be involved in hydrogen bonding with the
enzyme, the inability or reduced ability of compound 3 to
form such hydrogen bonding during the ligand-enzyme inter-
action may have contributed to the observed decrease in
anti-AChE activity.
phase transfer catalysts ((n-Bu)4NCl, (n-Bu)4NBr, or (n-
Bu)4NI),18 and different solvents (CH3CN, THF, DMF). Ear-
lier reports suggested that compounds with endo-amide favor
the intramolecular Heck reaction due to the conformational
restriction.19-20 Therefore, we turned our attention to endo-
amide intermediates such as compound 16.
As shown in Scheme III, compound 16 was prepared
via the coupling of 2-iodobenzoic acid with amine 11, fol-
lowed by N-methylation with CH3I and NaH. As expected,
compound 16 underwent Pd-catalyzed cyclization smoothly
to provide 17 in 67% yield. It is noteworthy that the desired
cyclization was not observed when the bromo-analog of 16
was subjected to the same Heck reaction conditions.
Based on the success with compound 16, we went on to

Synthesis of Galanthamine Analogs
J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003 451
Scheme III
NH2
N-Boc
NH
N-BOC
c
a
b
I
I
O
O
O
O
O
O
O
O
12
13
14
11
O
O
I
O
CH3
N
f
N
N
e
d
H
CH3
I
O
O
O
O
O
O
17
16
15
Reagents and Conditions: (a) 2-iodobenzaldehyde, CH2Cl2, rt, 1 h; then NaBH4, MeOH, rt, 30 min,
55%. (b) (Boc)2O, NaHCO3, MeOH, rt, 2 h, 53%. (c) Heck reaction conditions. (d) 2-iodobenzoic acid
with SOCl2, THF, -23 °C, 30 min; then 11, NEt3, THF, -23 °C to rt, 4 h, 63%. (e) NaH, CH3I, THF, rt, 2 h,
76%. (f) Pd(OAc)2, PPh3, K2CO3, CH3CN, 130 °C, 36 h, 67%.
Scheme IV
O
I
O
H
H3CO OCH3
O
H
COOH
I
N
H
I
c
d
a
b
H3CO
OCH3
O
O
OCH3
OCH3
OCH3
22
19
20
21
18
O
CH3
N
O
O
N
CH3
N
g
f
e
H3CO
CH3
H3CO
H3CO
I
O
O
O
O
23
O
25
24
O
CH3
CH3
N
N
i
h
H3CO
H3CO
HO
HO
26
3
Reagents and Conditions: (a) trimethyl orthoformate, p-TsOH, CH2Cl2, rt, 1 day. (b) n-butyllithium, I2,
THF, -78 °C, 53%. (c) KMnO4, acetone-H2O, rt, 1 day, 99%. (d) SOCl2, THF, -23 °C, 30 min; then 11,
NEt3, THF, -23 °C to rt, 4 h, 67%. (e) NaH, CH3I, THF, rt, 2 h, 100%. (f) Pd(OAc)2, PPh3, K2CO3,
CH3CN, 130 °C, 35 h, 66%. (g) 1 N HCl, methanol, rt, 1 h, 88%. (h) L-selectride, THF, -78 °C, 30 min,
46%. (i) LiAlH4, dioxane, reflux, 2 days, 66%.

452 J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003
Liang et al.
added activated Zn powder (15.0 g, 231 mmol); the resulting
mixture was heated at 55 °C and then ethyl bromoacetate
(19.6 mL, 176 mmol) was added dropwise. The reaction mix-
ture was heated at reflux for 8 hours and then cooled. The re-
sulting mixture was filtered through Celite®, and the filtrate
was evaporated. The residue was treated with CH2Cl2 (250
mL) and ammonia water (60 mL). The organic layer was sep-
arated and the aqueous layer was extracted further with
CH2Cl2 (40 mL). The combined extracts were dried over
MgSO4 and evaporated. The crude residue was chromato-
graphed (silica gel; CH2Cl2:MeOH = 20:1) to afford 7 (36.3
g, 93%) as a colorless oil. 7: 1H NMR (200 MHz, CDCl3) d
1.18 (t, J = 7 Hz, 3H), 1.46-1.98 (m, 8H), 2.40 (s, 2H), 3.37
(s,1H), 3.79-3.93 (m, 4H), 4.10 (q, J = 7 Hz, 2H); 13C NMR
(50 MHz, CDCl3) d 14.0, 30.1, 34.6, 45.2, 60.5, 64.0, 64.2,
68.7, 108.4, 172.8; EIMS m/e (relative intensity) 244 (M+, 5),
Fig. 2. (a) The bound conformation of (-)-galanth-
amine in the active site of Torpedo californica
acetylcholineasterase. (b) The energy-mini-
mized conformation of compound 3 obtained
by calculations using the Tripos force field in
Sybyl 6.5. (c) Superimposition of compound 3
and (-)-galanthamine.
In summary, we have successfully demonstrated a
novel synthetic route to spiro-cyclohexanebenzazepine de-
rivatives such as compound 3 as simplified analogs of galan-
thamine. The key step of the synthesis is the formation of the
seven-membered azepine ring via a Pd-catalyzed intramo-
lecular cyclization. Compound 3 was found to possess the de-
sired, albeit weak, activity against AChE. Further work to-
wards a total synthesis of (-)-galanthamine and other galanth-
amine analogs is currently underway in our laboratory.
+
99 (100), HRMS calcd for C12H20O5 244.1311, found
244.1300.
8-(2-Hydroxy-ethyl)-1,4-dioxa-spiro[4,5]decan-8-ol (8)
To a stirred slurry of LiAlH4 (30 mg, 0.80 mmol) in
ether (15 mL) was added a solution of 7 (130 mg, 0.53 mmol)
in ether (10 mL) dropwise. The mixture was stirred at rt for 6
h. Then, the mixture was cooled to 0 °C and 1 mL of water
was added with stirring, followed by filtration. The mixture
was extracted with a solution of isopropanol/CHCl3 (1:4; 20
mL) and H2O (10 mL). The combined organic layers were
dried over MgSO4, filtered and evaporated. The residue was
chromatographed (silica gel; CH2Cl2:MeOH = 15:1) to afford
8 (93 mg, 87%) as colorless oil: 1H NMR (200 MHz, CDCl3)
d 1.48-1.91 (m, 10H), 3.28 (s, 1H, OH), 3.78-3.84 (t, J = 7 Hz,
2H), 3.87 (s, 4H); 13C NMR (50 MHz, CDCl3) d 30.7, 35.1,
42.5, 59.4, 64.5, 71.3, 109.2; EIMS m/e (relative intensity)
202 (M+, 5), 100 (100); HRMS calcd for C10H18O4+ 202.1205,
found 202.1205.
EXPERIMENTAL SECTION
General Procedures
Melting points were taken in a capillary tube with a
MEL-TEMP II apparatus by Laboratory Devices. NMR spec-
tra were recorded on a Bruker DPX-200 & AMX-400 NMR
spectrometer; chemical shifts were recorded in parts per mil-
lion downfield from Me4Si. Mass spectra were recorded on a
Jeol JMS-D300 mass spectrometer; HRMS were obtained
with a Jeol JMS-HX110 spectrometer. Elemental analysis
was performed with a Perkin-Elmer 2400-CHN instrument.
TLC was performed on Merck (art. 5715) silica gel plates and
visualized under UV light (254 nm). Flash column chroma-
tography was performed with Merck (art. 9385) 40-63 mm sil-
ica gel 60. Anhydrous tetrahydrofuran was distilled from so-
dium-benzophenone prior to use.
2-[2-(8-Hydroxy-1,4-dioxa-spiro[4,5]dec-8-yl)-ethyl]-
isoindole-1,3-dione (9)
To a stirred solution of 8 (1.5 g, 7.40 mmol), phthal-
imide (1.28 g, 9.65 mmol), and PPh3 (2.5 g, 9.65 mmol) in
THF (80 mL) at rt under N2 was added dropwise diethyl
azodicarboxylate (DEAD, 1.5 mL, 9.65 mmol, 40% in hex-
ane). The resulting mixture was allowed to stir at rt for 2
hours. The solvent was then evaporated and the residue was
extracted with CH2Cl2 (150 mL) and H2O (30 mL). The or-
ganic layer was separated, dried over MgSO4, filtered, and
evaporated. The residue was chromatographed (silica gel;
(8-Hydroxy-1,4-dioxa-spiro[4,5]dec-8-yl)-acetic acid ethyl
ester (7)
To a stirred solution of 1,4-cyclohexanedione mono-
ethylene ketal (6) (25.0 g, 160 mmol) in 150 mL THF was

Synthesis of Galanthamine Analogs
J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003 453
EtOAc:n-hexane = 2:3) to afford 9 (905 mg, 37%) and 10
(881 mg, 38%) as yellow oils. 9: 1H NMR (200 MHz, CDCl3)
d 1.54-2.02 (m, 10H), 3.81 (t, J = 7 Hz, 2H), 3.89 (s, 4H),
7.63-7.67 (m, 2H), 7.75-7.80 (m, 2H); 13C NMR (50 MHz,
CDCl3) d 30.3, 33.3, 34.7, 40.4, 64.1, 64.2, 69.6, 108.6,
123.2, 132.1, 133.9, 168.5; EIMS m/e (relative intensity) 331
(M+, 10), 232 (100), HRMS calcd for C18H21NO5+ 331.1420,
found 331.1424.
mmol) and stirred for 30 min to generate the acyl chloride in-
termediate. When the temperature was raised to -20 °C, a so-
lution of 11 (1.2 g, 6.56 mmol) and Et3N (2.3 mL, 18.1 mmol)
in THF (15 mL) was added. The mixture was stirred for 6
hours and meanwhile the temperature was slowly raised to rt.
The solvent was then evaporated and the residue was ex-
tracted with CH2Cl2 (50 mL) and H2O (20 mL). The organic
layer was separated, dried over MgSO4, filtered and evapo-
rated. The residue was chromatographed (silica gel; EtOAc:
n-hexane = 3:2) to afford 15 (1.58 g, 63%) as a yellow oil: Rf
= 0.39 (EtOAc:n-hexane = 3:2). To a solution of compound
15 (1.58 g, 3.82 mmol) in 100 mL THF was added NaH (60%
in oil, 230 mg, 5.73 mmol) and then stirred for 30 min at rt.
Then, iodomethane (0.47 mL, 5.04 mmol) was added. The
mixture was stirred for 2 hours. The solvent was then evapo-
rated and the residue was extracted with CH2Cl2 (100 mL)
and H2O (60 mL). The organic layer was separated, dried
over MgSO4, filtered and evaporated. The residue was pumped
dry to afford 16 (1.24 g, 76%) as a yellow oil: 1H NMR (200
MHz, CDCl3) d 1.60 (t, J = 6 Hz, 1H), 1.72 (t, J = 6 Hz, 1H),
1.86 (m, 1H), 2.0-2.3 (m, 5H), (2.72, 3.04) (s, 3H), 3.07 (m,
1H), 3.58 (m, 1H), (3.87, 3.90) (s, 4H), (5.16, 5.38) (s, 1H),
6.98 (m, 1H), 7.12 (m, 1H), 7.27-7.31 (m, 1H), 7.71-7.77 (m,
1H); 13C NMR (50 MHz, CDCl3) d 27.3, (30.9, 32.4), 34.0,
(35.6, 36.3), 45.3, 49.4, 64.2, (92.1, 92.6), (107.4, 107.7),
(120.2, 120.8), (126.8, 127.2), (128.0, 128.2), (129.8, 129.9),
(133.3, 134.4), 138.9, (142.4, 142.8), (170. 170.6); IR (neat)
cm-1 3450, 2926, 1636, 1488; EIMS m/e (relative intensity)
427 (M+), 166 (100).
2-[2-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-ethyl]-isoindole-
1,3-dione (10)
To a 100-mL two-necked flask equipped with a Dean-
Stark and a condenser was placed 9 (900 mg, 2.72 mmol) and
p-toluenesulfonic acid (p-TsOH) (55 mg, 0.29 mmol), and
then toluene (50 mL) was added. The mixture was stirred at
reflux under N2 for 1 day. The solvent was evaporated and the
residue was partitioned with CH2Cl2 (60 mL) and water (30
mL). The organic layer was separated, dried over MgSO4, fil-
tered and evaporated. The residue was chromatographed (sil-
ica gel; EtOAc:n-hexane = 1:4) to afford 10 (757 mg, 89%) as
a yellow oil: 1H NMR (200 MHz, CDCl3) d 1.65 (t, J = 6 Hz,
2H), 2.0 (s, 2H), 2.19 (t, J = 6 Hz, 2H), 2.24 (t, J = 6 Hz, 2H),
3.68 (t, J = 7 Hz, 2H), 3.86 (s, 4H), 5.20 (s, 1H), 7.58-7.64 (m,
2H), 7.69-7.74 (m, 2H); 13C NMR (50 MHz, CDCl3) d 27.5,
31.4, 35.8, 35.9, 36.7, 64.7, 108.2, 121.4, 123.4, 132.4,
134.2, 134.4, 168.5; EIMS m/e (relative intensity) 313 (M+,
10), 86 (100), HRMS calcd for C18H19N O4+ 313.1321, found
313.1321.
2-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-ethylamine (11)
To a stirred mixture of 10 (1.0 g, 3.19 mmol) in ethanol
(50 mL) was added hydrazine-monohydride (240 mg, 4.79
mL). The reaction mixture was heated at reflux for 3 hours.
The solvent was evaporated and the residue was dissolved in
CH2Cl2 and filtered through a thin pad of Celite®. The filtrate
was extracted with a solution of isopropanol/CHCl3 (1:4, 40
mL ´ 2) and H2O (15 mL). The combined organic layers were
dried over MgSO4, filtered and evaporated to afford 11 (537
mg, 92%) as a yellow oil: 1H NMR (200 MHz, CDCl3) d 1.74
(t, J = 6 Hz, 2H), 2.01-2.24 (m, 6H), 2.76 (t, J = 6 Hz, 2H),
3.94 (s, 4H), 5.34 (s, 1H); 13C NMR (50 MHz, CDCl3) d 27.6,
31.4, 36.0, 40.0, 41.4, 64.7, 108.4, 120.5, 135.2; EIMS m/e
(relative intensity) 183 (M+, 10), 167.2 (100).
2-Iodo-4-methoxybenzalehyde (20)
To p-anisaldehyde (18) (32.0 g, 235 mmol) in CH2Cl2
(150 mL) was added trimethyl orthoformate (75 mL) and a
catalytic amount of p-TsOH (4.0 g, 23 mmol) and then stirred
for 1 day. The resulting mixture was evaporated to remove
CH2Cl2 and excess trimethyl orthoformate. The intermediate
19 in THF was cooled to -78 °C and then t-butyl lithium (176
mL, 282 mmol, 1.6 M in pentane) was added. After stirring
for 30 min, iodine (60.2 g, 235 mmol) in THF was added
dropwise during 1 hour, and the color of the mixture was
changed from colorless to slightly brown. After 2 hours, the
mixture was evaporated and 1 N HCl (30 mL) and methanol
(30 mL) were added. After stirring for 30 min, the mixture
was evaporated, and treated with CH2Cl2 (250 mL) and 15%
Na2S2O3 (80 mL). The organic layer was separated, dried
over MgSO4, filtered and evaporated. The residue was re-
crystallized from CH2Cl2 to give 20 (32.6 g, 53%) as a color-
less crystal: 20: mp 105-107 °C; 1H NMR (200 MHz, CDCl3)
N-[2-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-ethyl]-2-iodo-N-
methyl-benzamide (16)
To a solution of 2-iodobenzoic acid (1.5 g, 6.04 mmol)
in 50 mL THF at -78 °C was added SOCl2 (0.7 mL, 6.64

454 J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003
Liang et al.
d 3.80 (s, 3H), 6.89 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 7.35 (d, J =
2.5 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 9.84 (s, 1H); 13C NMR
(50 MHz, CDCl3) d 56.3, 102.7, 115.1, 125.8, 128.9, 131.9,
164.7, 194.7; IR (neat) cm-1 1662, 1582, 1244; EIMS m/e
(relative intensity) 262 (M+, 100).
mL THF was added NaH (93 mg, 3.78 mmol) and stirred for
30 min at rt. Then, iodomethane (0.47 mL, 5.04 mmol) was
added and the mixture was stirred for 2 hours. The solvent
was evaporated and the residue was extracted with CH2Cl2
(50 mL) and H2O (20 mL). The organic layer was separated,
dried over MgSO4, filtered and evaporated. The residue was
pumped dry to afford 23 (1.15 g, 99%) as a yellow oil: 1H
NMR (400 MHz, CDCl3) d 1.60 (t, J = 3 Hz, 1H), 1.86 (m,
1H), 2.11-2.29 (m, 6H), (2.69, 3.01) (s, 3H, NCH3), 3.15 (m,
1H), 3.55 (m, 1H), 3.71 (s, 3H, OCH3), 3.82-3.90 (m, 4H,
ketal), (5.15, 5.35) (s, 1H), 6.79-6.83 (m, 1H), 6.98-7.05 (m,
1H), 7.24-7.28 (m, 1H); 13C NMR (100 MHz, CDCl3) d 27.8,
(31.2, 31.4), 33.0, 36.1, 45.9, 50.1, 55.9, 64.7 (ketal), (93.0,
93.5), (108.0, 108.3), (114.6, 114.8), (120.6, 121.3), 124.5,
(128.1, 128.4), 133.9, (135.0, 135.7), 160.0, (170.8, 171.3);
EIMS m/e (relative intensity) 457 (M+, 9), and 261 (100);
HRMS calcd for C19H24INO4+ 457.0750, found 457.0765.
2-Iodo-4-methoxybenzoic acid (21)
Compound 20 (1.58 g, 6.04 mmol) in CH2Cl2 (30 mL)
was added KMnO4 (3.86 g, 22.8 mmol) and (n-Bu)4NBr (423
mg, 2.85 mmol) and stirred for 1 day. The mixture was fil-
tered and the filtrate was acidified with 3 N HCl (15 mL), and
extracted with a solution of isopropanol/CHCl3 (1:4; 40 mL ×
2). The combined organic layers were dried over MgSO4, fil-
tered, and evaporated to afford the crude product as a yellow
solid. The solid was recrystallized from CH2Cl2 to give 21
(1.67 g, 99%) as a colorless crystal: mp 170-172 °C; 1H NMR
(200 MHz, CDCl3) d 3.81 (s, 3H), 6.97 (dd, J = 8.7 Hz, 2.5
Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H); 13
C
NMR (50 MHz, CDCl3) d 54.2, 93.9, 112.2, 125.8, 126.9,
131.6, 161.2, 167.0; EIMS m/e (relative intensity) 278 (M+,
81).
10-Methoxy-14-methyl-1,4-dioxa-14-aza-benzo[j]dispiro-
[4.2.6.2]hexadec-6-en-13-one (24)
A solution of 23 (1.2 mg, 2.62 mmol), a catalytic
amount of Pd (OAc)2 (64 mg, 0.26 mmol), PPh3 (275 mg, 1.05
mmol), and K2CO3 (722 mg, 5.23 mmol) in acetonitrile (130
mL) was heated in a sealed round bottle at 115 °C for 36 h.
The mixture was cooled, filtered, and evaporated. The result-
ing residue was extracted with CH2Cl2 (50 mL) and H2O (20
mL). The organic layer was separated, dried over MgSO4, fil-
tered and evaporated. The residue was chromatographed (sil-
ica gel; EtOAc:n-hexane:NH4OH = 4:1:0.5%) to afford com-
pound 24 (564 mg, 66%) as a light yellow oil: 1H NMR (400
MHz, CDCl3) d 1.43 (td, J = 10, 2 Hz, 1H), 1.62 (m, 1H), 1.80
(dt, J = 10, 2 Hz, 1H), 1.95 (td, J = 10, 2 Hz, 1H), 2.13 (m,
1H), 2.22 (m, 1H), 3.09 (m, 1H), 3.10 (s, 3H, N-CH3), 3.39
(td, J = 10, 4 Hz, 1H), 3.77 (s, 3H, OCH3), 3.89 (m, 4H), 5.69
(d, J = 10 Hz, 1H), 5.86 (d, J = 10 Hz, 1H), 6.78 (m, 2H), 7.63
(d, J = 8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 30.6, 34.7
(N-CH3), 37.6, 43.0, 43.7, 48.9, 55.7 (O-CH3), 64.8 , 65.0,
105.4, 111.2, 114.7, 128.1, 128.6, 132.3, 139.9, 143.6, 161.3,
171.4; EIMS m/e (relative intensity) 329 (M+, 18), and 277
N-[2-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-ethyl]-2-iodo-4-
methoxy-benzamide (22)
A mixture of 21 (1.42 g, 5.10 mmol), SOCl2 (0.6 mL,
5.6 mmol), DMF (3 drops), and THF (30 mL) was stirred at
-78 °C for 30 min. The temperature was raised to -40 °C, and
then a solution of 11 (1.13 g, 6.18 mmol) and Et3N (1.78 mL,
12.7 mmol) in THF (15 mL) was added. The mixture was
stirred and the temperature was slowly raised to rt. The sol-
vent was then evaporated and the residue was extracted with
EtOAc (3 × 15 mL) and H2O (10 mL). The combined organic
extracts were dried over MgSO4, filtered and evaporated. The
residue was chromatographed (silica gel; EtOAc:n-hexane =
1
3:2) to afford 22 (1.52 g, 67%): mp 96 °C; H NMR (200
MHz, CDCl3) d 1.75 (t, J = 6 Hz, 2H), 2.28 (m, 6H), 3.49 (dd,
J = 6.5, 5.8 Hz, 2H), 3.76 (s, 3H), 3.92 (s, 4H), 5.41 (s, 1H),
5.88 (br s, 1H, NH), 6.83 (dd, J = 8, 2 Hz, 1H), 7.30 (m, 2H);
13C NMR (50 MHz, CDCl3) d 27.5, 31.4, 36.0, 36.7, 38.0,
56.0, 64.8, 93.5, 108.3, 114.3, 121.5, 125.5, 129.9, 133.5,
134.7, 160.9, 169.3; EIMS m/e (relative intensity) 443 (M+,
20), and 166 (100). Anal. calcd for C18H22NO4I: C, 48.77; H,
5.00; N, 3.16; found: C, 48.53; H, 5.07; N, 3.14.
+
(100); HRMS calcd for C19H23NO4 329.1627, found
329.1617.
8-Methoxy-12-methyl-12-aza-benzo[h]spiro[5.6]dodec-1-
en-3,11-dione (25)
N-[2-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-ethyl]-2-iodo-4-
methoxy-N-methyl-benzamide (23)
A solution of 24 (210 mg, 0.64 mmol) and 1 N HCl (5
mL) in methanol (10 mL) was stirred at rt for 1 hour. The mix-
ture was evaporated and extracted with CH2Cl2 (50 mL) and
To a solution of compound 22 (1.12 g, 2.53 mmol) in 30

Synthesis of Galanthamine Analogs
J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003 455
H2O (20 mL). The organic layer was separated, dried over
MgSO4, filtered and evaporated. The residue was chromato-
graphed (silica gel; EtOAc:n-hexane = 4:1) to afford com-
pound 25 (160 mg, 88%) as a light yellow oil: 1H NMR (400
MHz, CDCl3) d 2.10 (m, 3H), 2.27 (m, 3H), 3.09 (s, 3H), 3.19
(t, J = 10 Hz, 1H), 3.41 (td, J = 10, 4Hz, 1H), 3.76 (s, 3H),
6.02 (d, J = 10 Hz, 1H), 6.72 (d, J = 2 Hz, 1H), 6.82 (dd, J = 2,
NMR (50 MHz, CDCl3) d 28.9, 30.99, 38.4, 43.2, 44.4, 54.6,
55.5, 62.3, 67.3, 109.8, 117.9, 129.5, 130.3, 133.2, 138.0,
147.3, 158.6; EIMS m/e (relative intensity) 273 (M+, 60);
HRMS calcd for C17H23NO2+ 273.1729, found 273.1736.
ACKNOWLEDGEMENTS
8 Hz, 1H), 6.87 (d, J = 10 Hz, 1H), 7.68 (d, J = 8 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) d 34.3, 34.4 , 37.9, 42.2, 43.8, 48.2,
55.3, 111.1, 114.0, 127.8, 129.0, 132.4, 141.1, 156.3, 161.1,
170.5, 198.7; EIMS m/e (relative intensity) 285 (M+, 100),
This research was supported by the National Science
Council of the R.O.C. under grant no. NSC 89-2113-M002-019.
+
257 (60); HRMS calcd for C17H19NO3 285.1365, found
Received November 26, 2002.
285.1365.
3,6-cis-3-Hydroxyl-8-methoxy-12-methyl-12-aza-benzo[h]-
spiro[5.6]dodec-1-en-11-one (26)
REFERENCES
A solution of compound 25 (270 mg, 0.95 mmol) in
THF (10 mL) was added dropwise to a solution of L-
selectride (1.68 mL, 1.0 M in hexane) in 10 mL THF at -78 °C
and stirred for 30 min. The mixture was quenched with water,
evaporated, and then extracted with CH2Cl2 (40 mL) and H2O
(20 mL). The organic layer was separated, dried over MgSO4,
filtered and evaporated. The residue was chromatographed
(silica gel; CH2Cl2:methanol = 50:3) to afford 26 (124 mg,
46%) as a light yellow oil: 1H NMR (200 MHz, CDCl3) d 1.75
(3H, m), 2.04-2.15 (m, 3H), 3.06 (m, 1H), 3.09 (s, 3H), 3.48
(m, 1H), 3.78 (s, 3H), 4.16 (m, 1H), 5.68 (d, J = 10 Hz, 1H),
5.85 (dd, J = 10, 1 Hz, 1H), 6.78 (dd, J = 8, 4 Hz, 1H), 6.86 (d,
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CDCl3) d 29.5, 34.8, 37.7, 43.6, 43.9, 49.0, 55.7, 67.5, 109.9,
115.4, 128.0, 132.2, 132.3, 136.8, 144.7, 161.2, 171.6; EIMS
m/e (relative intensity) 287 (M+, 20), 270 (100); HRMS calcd
for C17H21NO3+ 287.1521, found 287.1519.
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