Total synthesis of (+)- and (-)-galanthamine

Article abstract of DOI:10.3987/COM-10-S(E)27

The stereoselective total synthesis of (+)-galanthamine [(+)-1], an antipode of the natural product, and (-)-galanthamine [(-)-1] starting from D-glucose is described. The cyclohexene unit in (+)-1 was prepared in an optically active form from D-glucose using Ferrier's carbocyclization reaction, and the benzylic quaternary carbon was stereoselectively generated via chirality transfer by Johnson-or Eschenmoser-Claisen rearrangement. The dibenzofuran skeleton was effectively constructed by the bromonium ion-mediated intramolecular dealkylating etherification. After the introduction of a carbon-carbon double bond, the Pictet-Spengler type cyclization, followed by reduction of an amide function afforded (+)-1. Starting from D-glucose, (-)-galanthamine [(-)-1] was also totally synthesized. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)27

HETEROCYCLES, Vol. 82, No. 1, 2010
563
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 563 - 579. © The Japan Institute of Heterocyclic Chemistry
Received, 11th May, 2010, Accepted, 10th June, 2010, Published online, 11th June, 2010
DOI: 10.3987/COM-10-S(E)27
TOTAL SYNTHESIS OF (+)- AND (–)-GALANTHAMINE
Tomoaki Kato, Hiroki Tanimoto,1 Hisako Yamada, and Noritaka Chida*
Department Applied Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
1
Yokohama 223-8522, Japan (e-mail: chida@applc.keio.ac.jp); Present address:
Graduate School of Material Science, Nara Institute of Science and Technology,
8916-5 Takayama, Ikoma, Nara 630-0192, Japan
This paper is dedicated to Professor Dr. Albert Eschenmoser on occasion of his
85th birthday.
Abstract – The stereoselective total synthesis of (+)-galanthamine [(+)-1], an
antipode of the natural product, and (–)-galanthamine [(–)-1] starting from
D-glucose is described. The cyclohexene unit in (+)-1 was prepared in an
optically active form from D-glucose using Ferrier’s carbocyclization reaction,
and the benzylic quaternary carbon was stereoselectively generated via chirality
transfer by Johnson- or Eschenmoser-Claisen rearrangement. The dibenzofuran
skeleton was effectively constructed by the bromonium ion-mediated
intramolecular dealkylating etherification.
After the introduction of a
carbon-carbon double bond, the Pictet-Spengler type cyclization, followed by
reduction of an amide function afforded (+)-1. Starting from D-glucose,
(–)-galanthamine [(–)-1] was also totally synthesized.
INTRODUCTION
(–)-Galanthamine [(–)-1], an alkaloid isolated from some species of the Amaryllidaceae family,1,2 has
been reported to be a centrally acting acetylcholinesterase inhibitor3 and an allosteric modulator of the
neuronal nicotinic receptor for acetylcholine.4
On the basis of these biological activities,
(–)-galanthamine was developed as a medicine for Alzheimer’s disease and has been clinically used in
Europe and the USA.2c,3b Its important and significant biological activity as well as its interesting
structure have naturally received considerable attention from the synthetic community, and several
synthetic approaches to 1 have been reported to date.2,5,6 A number of successful total syntheses of

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HETEROCYCLES, Vol. 82, No. 1, 2010
galanthamine, employing the biomimetic oxidative bisphenol coupling,2,5a,6a intramolecular Heck
reaction,2,5b,6b,6d,6e,6f semipinacol rearrangement,5c double Michael-Claisen reaction cascade of acetone
derivatives with acrylates,5d and intramolecular para-alkylation of a phenol derivative,5e for construction
of the characteristic tetracyclic skeleton possessing a benzylic quaternary carbon, have appeared, however,
reports of the chiral syntheses of 1 are rather limited.6 Due to the scarce supplies of galanthamine from
natural sources7 and the necessity for preparing structural analogues for the development of more potent
drugs, it is still important to establish a chiral and effective synthetic route to the alkaloid from readily
available materials. In this paper, we report a stereoselective total synthesis of (+)-galanthamine [(+)-1]
and its natural enantiomer (–)-1 starting from D-glucose.8
3
MeO
MeO
1
12
11
9
4
O
NMe
O
NMe
8a
6
4a
7
OH
OH
(–)-galanthamine [(–)-1]
(+)-galanthamine [(+)-1]
MeO
MeO
MeO
MeO
O
O
MeO
MeO
OBn
C R
OBn
O
NMe
OBn
MeO
D-glucose
(+)-1
+
O
M
HO
OTBS
OH
OTBS
OTBS
(M = Li, MgBr)
(+)-5
3a R = OEt
3b R = NMe2
4
2
Bn = -CH2Ph, TBS = -SiMe2(t-Bu)
Figure 1. Structures of galanthamine and its retrosynthetic analysis.
RESULTS AND DISCUSSION
Our earlier reports of the total synthesis of (+)-vittatine and (+)-haemanthamine, Amaryllidaceae
alkaloids possessing the hexahydroindole skeleton with a 1,3-dioxolane ring at m- and p-positions in the
phenyl group as the core structure, starting from D-glucose revealed that the methodology involving
Claisen rearrangement on the chiral cyclohexenol derived from carbohydrates is effective for the
stereoselective generation of quaternary carbons.9 Taking the successful synthesis of vittatine and
haemanthamine into accounts, our retrosynthetic analysis for (+)-galanthamine (+)-1 suggested that the
tetracyclic lactam 2, which had been utilized in the synthesis of racemic galanthamine by Guillou,5b
would be a suitable intermediate for the total synthesis (Figure 1). The dibenzofuran skeleton in 2 was
expected to be constructed by the bromonium ion-mediated intramolecular dealkylating etherification10 of

HETEROCYCLES, Vol. 82, No. 1, 2010
565
cyclohexene 3 possessing phenolic ether functions at o- and m-positions, whose crucial quaternary carbon
preparation was planned using the Claisen rearrangement9,11 of cyclohexenol derivative 4. The
cyclohexenol 4, in turn, was envisioned to be synthesized by the coupling reaction of an aryl metal
species with cyclohexenone (+)-5, which is a known compound12 and has been prepared in the optically
pure form starting from D-glucose by way of the Ferrier’s carbocyclization.13 Since the enantiomeric
cyclohexenone (–)-5 could also be synthesized from D-glucose,12 the synthetic way to (+)-galanthamine
would be readily applicable to the synthesis of a natural enantiomer of galanthamine.
The treatment of (4R,6S)-6-benzyloxy-4-[(tert-butyldimethylsilyl)oxy]-2-cyclohexenone12 (+)-5, prepared
from commercially available methyl 4,6-O-benzylidene-!-D-glucopyranoside 6 utilizing the catalytic
Ferrier’s carbocyclization13c as the key transformation in a total of 8 steps with 38% overall yield, with
2,3-dimethoxyphenylmagnesium bromide at –78 °C gave 1,2-adducts 7 in 85% yield as a diastereomeric
mixture (7a : 7b = 4 : 1) (Scheme 1). The configuration of C-1 in 7a was assigned by the observed NOE
between H-6 and OH at C-1. When cyclohexenone (+)-5 was reacted with 2,3-dimethoxyphenyllithium
in the presence of TMEDA, compound 7 was obtained in 60% yield with a reverse stereoselectivity (7a :
7b = 1 : 3).
MeO
Ph
O
MeO
MeO
MeO
MeO
OH
OBn
OH
O
MeO
OBn
OBn
O
1
4
6
O
8 steps
M
+
3
(38%)
(ref. 12)
solvent
–78 °C
HO
OMe
OTBS
OTBS
OTBS
OH
7a
7b
(+)-5
6
yield (%)
85
solvent additive
MgBr THF --
Li Et2O TMEDA
7a / 7b
M
4/1
1/3
60
TMEDA = N,N,N'N'-tetramethylethylenediamine
Scheme 1
The oxidation of a mixture of 7a and 7b (4 : 1) with pyridinium chlorochromate (PCC) in the presence of
molecular sieves 4A (MS4A) afforded cyclohexenone 8 in 75% yield,14 which was reduced under the
conditions of Luche15 at –78 °C to give cyclohexenol 4 and its C-1 epimer in 89 and 9% isolated yields,
respectively (Scheme 2). The observed coupling constants in 4 (J1,6 = 7.8 Hz) and its C-1 epimer (J1,6 =
4.1 Hz) supported their assigned configurations. With cyclohexenol 4 possessing the desired
stereochemistry in hand, the crucial Claisen rearrangement was next investigated. Johnson-Claisen
rearrangement16 of 4 in triethyl orthoacetate in the presence of 2-nitrophenol9b,17 in a sealed tube at 140 °C
for 52 h successfully afforded the rearranged product 3a in 80% yield. It is important to note that the

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HETEROCYCLES, Vol. 82, No. 1, 2010
Johnson-Claisen rearrangement of 4, possessing an o-methoxy substituent in the phenyl group, proceeded
in a high yield when 2-nitrophenol was employed as the acid catalyst. It has been reported that the
conventional Johnson-Claisen rearrangement (using propionic acid as the catalyst) of the simple
cyclohexenol systems similar to 4 resulted in the very poor yields of the rearranged products, probably
due to the acid sensitivity of the substrates and the steric congestion at the reaction center caused by the
presence of the o-methoxy substituent in the phenyl group.10,11b,18 Indeed, the Johnson-Claisen
rearrangements of 4 in the presence of propionic acid (10 ~ 130 mol% to 4) at 140 °C gave 3 in less than
40% yields, and the formation of a significant amount of unidentified by-products was observed. The
acidity of 2-nitrophenol (pKa = 7.04) would be appropriate for the Johnson-Claisen rearrangement of 4; its
weaker acidity than that of propionic acid (pKa = 4.62) suppressed the decomposition of the acid-labile
substrate but could catalyze the formation of a ketene acetal. On the other hand, Eschenmoser-Claisen
rearrangement19 of 4 (N,N-dimethylacetamide dimethyl acetal in o-xylene in a sealed tube at 150 °C)
cleanly afforded 3b in an excellent yield (92%).
MeO
MeO
MeO
MeO
MeO
MeO
CO2Et
OBn
2-nitrophenol
(130 mol% to 4)
PCC
MS4A
NaBH4
CeCl3•7H2O
4
OBn
OBn
7a + 7b
1
6
(CH2Cl)2
60 °C
CH3C(OEt)3
140 °C, 52 h
(80%)
MeOH / CH2Cl2
(2 / 3)
–78 °C
(89%, epimer 9%)
O
HO
OTBS
OTBS
OTBS
3a
(75%)
8
4
MeO
MeO
MS4A = molecular seives 4Å
CH3C(OMe)2NMe2
(11 equiv)
CONMe2
OBn
o-xylene
150 °C, 23 h
(92%)
OTBS
3b
Scheme 2
Next, we turned out attention to construct the dibenzofuran skeleton from 3a and 3b. The treatment of
3a with N-bromosuccinimide (NBS) in DMF induced the intramolecular dealkylating etherification via aꢀ
bromonium ion intermediate10 3a’ to give bromo-dibenzofuran derivative 9 as a single product in 84%
yield (Scheme 3). Similar reaction of 3b with NBS, however, afforded no dibenzofuran product and
resulted in the formation of many unidentified products. Among them, "-lactone 10 was isolated in 37%
yield. It is known that the formation of a cyclic bromonium ion intermediate in the congested alkene
systems is a reversible step, and the subsequent nucleophilic opening of the bromonium ion is a
rate-determining one.10,20 The carbonyl group in amide 3b is more nucleophilic than the phenolic ether

HETEROCYCLES, Vol. 82, No. 1, 2010
567
oxygen, thus providing lactone 10 via the epimeric cyclic bromonium ion intermediate 3b’.
Hydrogenolysis of 9 in the presence of Pd on carbon and potassium carbonate in EtOH under atmospheric
pressure of H2 caused the debromination as well as the deprotection of the O-benzyl group to provide 11.
However, under these basic conditions, the de-O-benzylation process was found to be very sluggish, and
resulted in the low yield of 11 (less than 40%). In contrast, under similar hydrogenolytic conditions
without potassium carbonate, deprotection of the O-benzyl group smoothly proceeded, but the
debromination process became slow. After some attempts, it was found that the two-steps in a one-pot
reaction gave satisfactory results. Thus, deprotection of the O-benzyl group in 9 under neutral
conditions (Pd on carbon, atmospheric pressure of H2 in EtOH) was first carried out. After completion
of the de-O-benzylation (TLC monitoring), potassium carbonate was added to the reaction mixture and
the hydrogenolysis of the C-Br bond was further continued in the same reaction vessel to give 11 in 85%
yield. The structure of 11 was confirmed by NMR analyses of the derived benzoate 12; the observed
large coupling constants (J5a,6ax, J6ax,7, J7,8ax and J8ax,9) revealed that the substituents at C-5a, C-7 and C-9
are all in the equatorial positions, and NOE experiments (correlations between H-5a and C-2’methylene,
and H-9 and C-2’ methylene) clearly assigned the stereochemistry of the quaternary carbon at C-9a as R.
Hydrogenolysis of 10 in the absence of potassium carbonate similarly removed the O-benzyl group, and
under the reaction conditions, the O-TBS group was also detached to give bromo-diol 13 (25% yield from
1
3b). The IR spectrum of 13 suggested the presence of hydroxy and "-lactone groups, and the H NMR
analysis assigned the structure of 13 as depicted in Scheme 3.
MeO
MeO
MeO
OMe
MeO
O
Me2N
O
Me
NBS
NBS
O
CO2Et
OBn
3
3a
CO2Et
OBn
3b
O
OMe
OR1
3a
4
O
DMF
0 °C
(37%)
DMF
0 °C
(84%)
7a
OBn
Br
Br
6
7
Br
Br
OR2
OTBS
OTBS
3b'
OTBS
3a'
10 R1 = Bn, R2 = TBS
9
H2, Pd/C
EtOH
13 R1 = R2 = H
(25% from 3b)
H2, 10% Pd/C then H2, 10% Pd/C
EtOH
K2CO3, EtOH
MeO
O
(85%)
H
7a
HO
6
Br
HO
MeO
O
7
H
J
5a,6ax = 8.9 Hz
J5a,6eq = 6.5 Hz
J6ax,7 = 10.2 Hz
J7,8ax = 10.4 Hz
J8ax,9 = 11.9 Hz
J8eq,9 = 3.9 Hz
OMe
OMe
O
5a
4
5
6
9a
CO2Et
8
H
H
TBSO
2'
CO2Et
O
3
O
H 9
Bz
7
H
OR
H
J4,5 = 3.4, 3.7 Hz
J5,6 = 2.7, 3.2 Hz
J6,7 = 2.7 Hz
9a
H
5a
9
H
11 R = H
BzCl
pyridine
(100%)
6
7
8
NOE
! = 3450, 1780 cm-1
J7,7a = 9.5 Hz
12 R = Bz
OTBS
Selected NMR data of 12
Selected spectral data of 13
Bz = -C(O)Ph
Scheme 3

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HETEROCYCLES, Vol. 82, No. 1, 2010
To introduce the requisite carbon-carbon double bond, compound 11 was treated with
(thiocarbonyl)diimidazole and DMAP in dichlorobenzene at 180 °C21 to afford 14 in 72% yield (Scheme
4). Hydrolysis of the ethyl ester function in 14, followed by condensation with methylamine under the
conditions of Shioiri,22 provided amide 15 in 93% yield. The Pictet-Spengler type reaction of 15 with
paraformaldehyde in the presence of TFA5b,5c generated the methano-bridge between the amide nitrogen
and C-1, and induced the deprotection of the O-TBS group to give tetracyclic lactam 2, which is known
as the intermediate for the synthesis of racemic galanthamine reported by the Guillou5b and Tu5c in 67%
yield. However, the reproducibility of the reaction was found to be rather poor, and the yields of 2
sometimes dropped to 20-40%. Fortunately, it was found when the same reaction conditions were
applied to allylic alcohol 16, compound 2 was obtained in better yields with good reproducibility.
Removal of the O-TBS group in 15 afforded the known alcohol 16,5c whose reaction with
paraformaldehyde and TFA provided 2 in 71% overall yield from 15. Finally, reduction of 2 with
1
13
LiAlH4 cleanly afforded (+)-galanthamine [(+)-1] in 88% yield. The H and C NMR data of the
synthetic 1 were totally identical with those of natural (–)-galanthamine and the [!]D value of the
24
20
synthetic compound {[!]D +112 (c 0.50, EtOH): lit.,1c [!]D –118.8 (c 1.378, EtOH)} confirmed its
unnatural absolute configuration. Thus, total synthesis of (+)-galanthamine starting from D-glucose has
been accomplished. Starting from the enantiomeric cyclohexenone (–)-512 obtained from 6 in 12 step
reactions, (–)-galanthamine [(–)-1] {[!]D23 –112 (c 0.19, EtOH)} was also totally synthesized via the same
reaction sequence.
MeO
4
4
MeO
MeO
N C
2
S
1
1
N
5
O
Bu4NF
1) LiOH, MeOH-H2O
11
O
NHMe
O
NHMe
CO2Et
DMAP
1,2-dichlorobenzene
2) MeNH2•HCl, Et3N
(EtO)2P(O)CN
THF, –10 °C
THF
9a
7
5a
5a
O
O
(100%)
8
7
rt - reflux
(72%)
(93%)
OTBS
14
OTBS
OH
16
15
(CH2O)n
TFA
(CH2O)n
TFA
(CH2Cl)2
(71%)
DMAP = 4-(dimethylamino)pyridine
(CH2Cl)2
(67%)
MeO
MeO
3
MeO
1
O
the same
reaction
sequence
11
OBn
9
O
NMe
O
NMe
12 steps
(20%)
4
LiAlH4
O
NMe
6
THF
reflux
(88%)
O
4a
(ref. 12)
7
6
OTBS
OH
OH
(–)-5
OH
2
(–)-galanthamine
(+)-galanthamine
(–)-1
(+)-1
Scheme 4

HETEROCYCLES, Vol. 82, No. 1, 2010
569
CONCLUSIONS
In summary, a new and non-biomimetic synthetic route to optically active galanthamine starting from
D-glucose has been established. This synthesis, required 12 steps with a 13.6% overall yield from (+)-5
(20 steps, 5.2% overall yield from commercially available 6) for the synthesis of (+)-galanthamine, and
24 steps with 2.7% overall yield from 6 for the synthesis of (–)-galanthamine, demonstrated that the
methodology involving the Claisen rearrangement on chiral cyclohexenol derived from D-glucose is
effective for the chiral and stereoselective synthesis of galanthamine-type alkaloids. It was shown that
the Eschenmoser-Claisen rearrangement is a powerful method for the construction of the sterically
hindered quaternary carbon. The effectiveness of 2-nitrophenol as the acid catalyst for the
Johnson-Claisen rearrangement is particularly noteworthy. It was also revealed that the intramolecular
dealkylating etherification using NBS is a useful procedure for the construction of benzofuran skeletons
that are commonly found in galanthamine-type as well as morphine-type biologically significant
alkaloids.
EXPERIMENTAL
General. Melting points were determined on a Mitamura-Riken micro hot stage and were not corrected.
Optical rotations were recorded using a sodium lamp (589 nm) with a JASCO DIP-370 instrument with 1
dm tube. Infrared (IR) spectra were measured with a JASCO FT/IR-200 spectrometer with a KBr cell.
1H NMR spectra were recorded at 300 MHz on a Varian MVX-300 spectrometer for solutions in CDCl3,
unless otherwise noted. Chemical shifts are reported as # values in ppm. Abbreviations used are: b
(broad peak), s (singlet), d (doublet), t (triplet), q (quartet) and m (complex multiplet). 13C NMR spectra
were recorded at 75 MHz on a Varian MVX-300ꢀspectrometer for solutions in CDCl3, unless otherwise
noted. Chemical shifts are reported as # values in ppm. Mass spectra are measured by a JEOL GC
Mate spectrometer with EI (70 eV) or FAB (glycerol matrix) mode. Organic extracts were dried over
anhydrous Na2SO4 and concentrated below 40 °C under reduced pressure. Column chromatography was
carried out with silica gel (Merck Kieselgel 60 F254, 230-400 mesh). Preparative TLC was performed
with Merck PLC plate (Kieselgel 60 F254, 0.5 mm thickness).
(1R,4R,6S)-6-Benzyloxy-4-[(tert-butyldimethylsilyl)oxy]-1-(2,3-dimethoxyphenyl)-2-cyclohexen-1-ol
(7a) and Its (1S)-Epimer (7b). Preparation with Grignard reagent: To a solution of (+)-5 (42.0 mg,
0.126 mmol) in THF (2.1 mL) under argon at –78 ºC was added 2,3-dimethoxyphenylmagnesium
bromide (0.5 M solution in THF, 0.80 mL, 0.40 mmol). After being stirred at –78 ºC for 4 h, the
reaction mixture was quenched with saturated aqueous NH4Cl solution at –78 ºC and the products were
extracted with EtOAc. The extract was washed with saturated aqueous NaHCO3 solution and dried.
The organic solvent was concentrated to give a residue, which was purified by column chromatography (3

570
HETEROCYCLES, Vol. 82, No. 1, 2010
28
g, toluene then EtOAc/toluene = 1/100 as an eluent) to afford 7a (40.3 mg, 68%) as a colorless oil: [!]D
1
+3.4 (c 1.54, CHCl3); IR (neat) $max = 3440, 2950, 2930, 2880, 2860, 1470, 1260, 1070 cm-1; H NMR #
7.34–7.22 (5H, m), 7.02 (1H, dd, J = 8.1 and 7.8 Hz), 6.94 (1H, dd, J = 7.8 and 1.8 Hz), 6.89 (1H, dd, J =
8.1 and 1.8 Hz), 6.62 (1H, s), 5.81 (1H, ddd, J = 10.1, 1.7 and 0.9 Hz), 5.61 (1H, dd, J = 10.1 and 1.8 Hz),
4.67 and 4.62 (each 1H, 2d, J = 12.3 Hz), 4.37 (1H, dddd, J = 9.1, 6.3, 1.8 and 1.7 Hz), 3.85 and 3.84
(each 3H, 2s), 3.74 (1H, dd, J = 12.6 and 3.2 Hz), 2.09 (1H, dddd, J = 12.6, 6.3, 3.2 and 0.9 Hz), 1.59 (1H,
ddd, J = 12.6, 12.6 and 9.1 Hz), 0.90 (9H, s), 0.09 and 0.06 (each 3H, 2s); 13C NMR # 152.6, 148.9, 138.5,
132.4, 132.3, 131.9, 128.2, 128.0, 127.5, 123.1, 122.7, 112.4, 82.4, 79.1, 71.7, 67.8, 61.5, 55.9, 34.6, 25.9,
18.2, –4.57, –4.64; HRMS (FAB) m/z calcd for C27H39O5Si (M+H)+ 471.2567, found 471.2571. Anal.
Calcd for C27H38O5Si: C, 68.90; H, 8.14%. Found: C, 68.60; H, 8.04%. Further elution gave 7b (10.1
20
mg, 17%) as a colorless oil: [!]D +111 (c 1.04, CHCl3); IR (neat) $max = 3520, 2950, 2930, 2860, 1470,
1
1270, 1090 cm-1; H NMR # 7.16–7.24 (4H, m), 7.07 (1H, dd, J = 8.0 and 8.0 Hz), 6.98–7.04 (2H, m),
6.90 (1H, dd, J = 8.0 and 1.5 Hz), 5.86 (1H, ddd, J = 10.0, 2.0 and 1.2 Hz), 5.66 (1H, dd, J = 10.0 and 2.2
Hz), 4.40 (1H, dddd, J = 10.1, 5.3, 2.2 and 2.0 Hz), 4.32 and 4.13 (each 1H, 2d, J = 11.7 Hz), 4.06 (1H,
dd, J = 12.0 and 3.9 Hz), 3.92 (1H bs), 3.87 and 3.73 (each 3H, 2s), 2.11 (1H, dddd, J = 12.0, 5.3, 3.9 and
1.2 Hz), 1.98 (1H, ddd, J = 12.0, 12.0 and 10.1 Hz), 0.92 (9H, s), 0.11 and 0.10 (each 3H, 2s); 13C NMR #
152.9, 146.4, 139.0, 138.0, 133.6, 130.9, 128.1, 127.6, 127.5, 123.4, 119.5, 111.8, 78.5, 72.5, 72.2, 68.2,
60.5, 55.8, 35.0, 25.8, 18.2, –4.68, –4.67; HRMS (FAB) m/z calcd for C27H39O5Si (M+H)+ 471.2567,
found 471.2561. Anal. Calcd for C27H38O5Si: C, 68.90; H, 8.14%. Found: C, 68.62; H, 8.23%.
Preparation with aryllithium reagent: To a solution of 1,2-dimthoxybenzene (1.23 g, 8.90 mmol) in Et2O
(8.6 mL) at 0 ºC under Ar were added TMEDA (1.34 mL, 8.90 mmol) and n-BuLi (1.52 M hexane
solution, 5.86 mL, 8.90 mmol). After being stirred at 0 °C for 45 min, the resultant yellow suspension
was cooled to –78 ºC. To this mixture at –78 ºC under Ar was added a solution of (+)-5 (296.1 mg,
0.891 mmol) in Et2O (1.5 mL) dropwise through a cannula. After being stirred at –78 °C for 30 min, the
mixture was quenched with saturated aqueous NH4Cl solution at –78 ºC and the products were extracted
with EtOAc. The extract was washed successively with saturated aqueous NH4Cl aqueous solution and
saturated aqueous NaHCO3 solution, and then dried. The organic solvent was concentrated to give a
residue, which was purified by column chromatography (15 g, EtOAc/toluene = 1/100 ꢀ 1/50 ꢀ 1/2
as an eluent) to afford 7a (61.1 mg, 15%), 7b (188.5 mg, 45%), and recovered starting material (+)-5
(80.1 mg, 27% recovery).
(4S,6R)-4-Benzyloxy-6-[(tert-butyldimethylsilyl)oxy]-3-(2,3-dimethoxyphenyl)-2-cyclohexen-1-one
(8). To a solution of a diastereomeric mixture of 7a and 7b (7a : 7b = 4:1, 679.0 mg, 1.443 mmol) in
1,2-dichloroethane (34 mL) at rt were added activated MS4A (679 mg) and PCC (1.24 g, 5.77 mmol), and
the mixture was stirred at 60 ºC for 1 h. Silica gel (10 g) was added to the reaction mixture and the

HETEROCYCLES, Vol. 82, No. 1, 2010
571
resulting mixture was stirred vigorously at rt for 5 min. The mixture was diluted with Et2O and the
insoluble material was removed by filtration through a pad of silica gel. The filtrate was concentrated to
give a residue, which was purified by column chromatography (20 g, EtOAc/toluene = 1/50 as an eluent)
29
to afford 8 (504.9 mg, 75%) as a colorless oil: [!]D –125 (c 1.34, CHCl3); IR (neat) $max = 2950, 2930,
1
2860, 1690, 1470, 1270, 1160, 1110 cm-1; H NMR # 7.23–7.16 (3H, m), 7.08 (1H, dd, J = 8.1 and 7.7
Hz), 7.01–6.92 (3H, m), 6.80 (1H, dd, J = 7.7 and 1.5 Hz), 6.09 (1H, d, J = 2.2 Hz), 5.03 (1H, ddd, J =
10.7, 5.0 and 2.2 Hz), 4.47 (2H, s), 4.32 (1H, dd, J = 13.2 and 5.0 Hz), 3.90 and 3.81 (each 3H, 2s), 2.65
(1H, ddd, J = 11.8, 5.0 and 5.0 Hz), 2.24 (1H, ddd, J = 13.2, 11.8 and 10.7 Hz), 0.95 (9H, s), 0.22 and
0.12 (each 3H, 2s); 13C NMR # 198.0, 162.2, 152.4, 146.1, 137.9, 132.1, 128.1, 127.6, 127.5, 127.4, 124.2,
121.5, 113.2, 74.8, 72.9, 71.1, 60.9, 56.0, 39.7, 25.8, 18.5, –4.3, –5.4; HRMS (FAB) m/z calcd for
C27H37O5Si (M+H)+ 469.2410, found 469.2411. Anal. Calcd for C27H36O5Si: C, 69.20; H, 7.74%.
Found: C, 68.97; H, 7.87%.
(1R,4S,6R)-4-Benzyloxy-6-[(tert-butyldimethylsilyl)oxy]-3-(2,3-dimethoxyphenyl)-2-cyclohexen-1-ol
(4) and Its (1S)-Epimer. To a solution of 8 (13.3 mg, 0.0284 mmol) in MeOH (0.2 mL) and CH2Cl2
(0.3 mL) was added cerium chloride heptahydrate (15.9 mg, 0.0427 mmol) at rt. After being stirred for
1 h, the reaction mixture was cooled to –78 ºC. To the mixture was added NaBH4 (1.1 mg, 0.029 mmol)
at –78 ºC, and the resulting mixture was stirred at –78 °C for 30 min. The reaction mixture was
quenched with water at –78 ºC and the products were extracted with EtOAc. The extract was washed
with brine and then dried. The organic solvent was concentrated to give a residue, which was purified
by column chromatography (1 g, EtOAc/toluene = 1/100 as an eluent) to afford 4 (11.9 mg, 89%) as a
colorless oil: [!]D28 –82 (c 0.84, CHCl3); IR (neat) $max = 3450, 2960, 2930, 2890, 2860, 1580, 1470, 1260,
1100 cm-1; 1H NMR # 7.22–7.14 (3H, m), 7.02 (1H, dd, J = 8.0 and 7.7 Hz), 7.00–6.93 (2H, m), 6.89 (1H,
dd, J = 8.0 and 1.4 Hz), 6.81 (1H, dd, J = 7.7 and 1.4 Hz), 5.73 (1H, dd, J = 2.1 and 2.0 Hz), 4.83 (1H,
dddd, J = 10.0, 5.9, 2.1 and 2.0 Hz), 4.39 and 4.33 (each 1H, 2d, J =11.3 Hz), 4.28 (1H, ddd, J = 7.8, 2.0
and 2.0 Hz), 3.88 and 3.78 (each 3H, 2s), 3.71 (1H, ddd, J = 12.2, 7.8 and 3.4 Hz), 2.28 (1H, ddd, J =
12.2, 5.9 and 3.4 Hz), 2.22 (1H, bs), 1.82 (1H, ddd, J = 12.2, 12.2 and 10.0 Hz), 0.93 (9H, s), 0.14 and
0.13 (each 3H, 2s); 13C NMR # 152.5, 146.6, 140.6, 138.6, 134.4, 129.7, 128.0, 127.6, 127.2, 123.9, 122.6,
111.8, 75.6, 74.3, 73.6, 70.9, 60.6, 55.9, 37.5, 25.8, 18.1, –4.3, –4.5; HRMS (FAB) m/z calcd for
C27H39O5Si (M+H)+ 471.2567, found 471.2572. Anal. Calcd for C27H38O5Si: C, 68.90; H, 8.14%.
Found: C, 68.62; H, 8.08%. Further elution afford the 1-epimer of 4 (1.2 mg, 9%) as a colorless oil:
21
[!]D –37 (c 0.64, CHCl3); IR (neat) $max = 3540, 2960, 2930, 2880, 2860, 1580,1470, 1260, 1230, 1090
cm-1; 1H NMR # 7.21–7.11 (3H, m), 7.02 (1H, dd, J = 8.3 and 7.1 Hz), 6.96–6.85 (4H, m), 5.94 (1H, dd, J
= 5.1 and 1.9 Hz), 4.71 (1H, dddd, J = 10.2, 6.0, 1.9 and 0.6 Hz), 4.36 (2H, s), 4.13 (1H, dddd, J = 5.0,
4.1, 1.0 and 0.6 Hz), 3.88 (1H, ddd, J = 11.6, 4.1 and 4.1 Hz), 3.87 and 3.79 (each 3H, 2s), 2.77 (1H, bs),

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HETEROCYCLES, Vol. 82, No. 1, 2010
2.13 (1H, ddd, J = 11.6, 11.6 and 10.2 Hz), 2.00 (1H, dddd, J = 11.6, 6.0, 4.1 and 1.0 Hz), 0.93 (9H, s),
13
0.14 (6H, s); C NMR # 152.3, 146.6, 144.4, 138.7, 134.3, 127.9, 127.5, 127.09, 127.06, 123.9, 122.7,
112.0, 74.8, 69.9, 68.8, 66.2, 60.6, 56.0, 31.9, 25.8, 18.1, –4.4, –4.8; HRMS (FAB) m/z calcd for
C27H39O5Si (M+H)+ 471.2567, found 471.2569.
(1S,4R,6S)-6-Benzyloxy-4-[(tert-butyldimethylsilyl)oxy]-1-(2,3-dimethoxyphenyl)-2-cyclohexene-1-
acetic Acid Ethyl Ester (3a). To a solution of 4 (71.7 mg, 0.152 mmol) in triethyl orthoacetate (10 mL)
was added 2-nitrophenol (27.6 mg, 0.198 mmol) at rt. This mixture in a sealed tube filled with Ar was
heated at 140 ºC for 52 h. The reaction mixture was diluted with EtOAc and washed with saturated
aqueous NaHCO3 solution, and then dried. The organic solvent was concentrated to give a residue,
which was purified by column chromatography (4.5 g, EtOAc/hexane = 1/30) to afford 3a (65.9 mg,
80%) as a colorless oil: [!]D26 –7.2 (c 0.38, CHCl3); IR (neat) $max = 2960, 2940, 2860, 1730, 1580, 1470,
1260, 1230, 1100 cm-1; 1H NMR # 7.35–7.21 (6H, m), 6.95 (1H, dd, J = 8.0 and 8.0 Hz), 6.83 (1H, dd, J =
8.0 and 1.4 Hz), 6.03 (1H, dd, J = 10.2 andꢀ1.7 Hz), 5.66 (1H, ddd, J = 10.2, 1.5 and 1.0 Hz), 4.66 and
4.53 (each 1H, 2d, J = 11.7 Hz), 4.30 (1H, dddd, J = 9.3, 6.8, 1.7 and 1.5 Hz), 4.00 (2H, q, J = 7.1 Hz),
3.83 (1H, dd, J = 12.2 and 2.7 Hz), 3.82 and 3.75 (each 3H, 2s), 3.26 and 3.03 (each 1H, 2d, J = 14.9 Hz),
2.06 (1H, dddd, J = 12.2, 6.8 Hz, 2.7 and 1.0 Hz), 1.83 (1H, ddd, J = 12.2, 12.2 and 9.3 Hz), 1.13 (3H, t, J
13
= 7.1 Hz), 0.87 (9H, s), 0.05 and 0.03 (each 3H, 2s); C NMR (CDCl3, 75 MHz) # 171.8, 153.2, 149.5,
138.7, 134.2, 133.0, 130.4, 128.1, 127.9, 127.4, 124.1, 122.1, 111.6, 78.6, 71.7, 68.2, 60.3, 59.8, 55.8,
48.2, 42.4, 33.2, 25.9, 18.2, 14.1, –4.5, –4.6; LRMS (EI) m/z 540 (M+, 5%), 483 (4), 406 (41), 402 (15),
175 (31), 115 (19), 91 (77), 75 (100); HRMS (EI) m/z calcd for C31H44O6Si (M+) 540.2907, found
540.2908. Anal. Calcd for C31H44O6Si: C, 68.85; H, 8.20%. Found: C, 68.74; H, 8.19%.
2-[(1S,4R,6S)-6-Benzyloxy-4-[(tert-butyldimethylsilyl)oxy]-1-(2,3-dimethoxyphenyl)-2-cyclohexene-
1-yl]-N,N-dimethylacetamide (3b). To a solution of 4 (112.2 mg, 0.2384 mmol) in o-xylene (11.2 mL)
was added N,N-dimethylacetamide dimethyl acetal (0.350 mL, 2.66 mmol) at rt. This mixture in a
sealed tube filled with Ar was heated at 150 ºC for 23 h. The reaction mixture was concentrated to give
a residue, which was purified by column chromatography (5 g, EtOAc/toluene = 1/3) to afford 3b (118.3
26
mg, 92%) as a colorless oil: [!]D +5.8 (c 0.60, CHCl3); IR (neat) $max = 2930, 2960, 2860, 1650, 1470,
1260, 1100 cm-1; 1H NMR # 7.46 (1H, dd, J = 8.0 and 1.5 Hz), 7.38–7.21 (5H, m), 6.97 (1H, dd, J = 8.0
and 8.0 Hz), 6.81 (1H, dd, J = 8.0 and 1.5 Hz), 6.21 (1H, dd, J = 10.2 and 1.7 Hz), 5.61 (1H, ddd, J =
10.2, 2.0 and 1.2 Hz), 4.71 and 4.50 (each 1H, 2d, J = 12.1 Hz), 4.40 (1H, dddd, J = 9.5, 6.3, 2.0 and 1.7
Hz), 4.08 (1H, dd, J = 12.2 and 2.4 Hz), 3.83 and 3.78 (each 3H, 2s), 3.40 and 2.74 (each 1H, 2d, J = 15.6
Hz), 2.92 and 2.86 (each 3H, 2s), 2.15 (1H, dddd, J = 12.2, 6.3, 2.4 and 1.2 Hz), 1.96 (1H, ddd, J = 12.2,
13
12.2 and 9.5 Hz), 0.86 (9H, s), 0.044 and 0.035 (each 3H, 2s); C NMR # 171.4, 153.2, 148.9, 139.0,
136.0, 133.9, 129.8, 128.2, 127.9, 127.3, 123.7, 122.5, 111.0, 78.4, 71.4, 68.7, 60.3, 55.7, 48.7, 39.2, 37.6,

HETEROCYCLES, Vol. 82, No. 1, 2010
573
35.3, 33.4, 25.9, 18.2, –4.5, –4.6; LRMS (EI) m/z 539 (M+, 15.4%), 508 (59.2), 448 (66.0), 405 (100), 333
(69.2), 316 (43.0), 199 (59.9); HRMS (EI) m/z calcd for C31H45NO5Si (M+) 539.3067, found 539.3065.
(5aS,6R,7R,9S,9aS)-9-Benzyloxy-6-bromo-7-[(tert-butyldimethylsilyl)oxy]-6,7,8,9-tetrahydro-4-
methoxy-9a(5aH)-dibenzofuranacetic Acid Ethyl Ester (9). To a solution of 3a (66.3 mg, 0.123
mmol) in DMF (4.3 mL) was added NBS (43.6 mg, 0.245 mmol) at 0 ºC. After being stirred at 0 °C for
12 h, the reaction mixture was quenched with saturated aqueous NaHCO3 solution at 0 ºC and the
products were extracted with EtOAc. The extract was washed with saturated aqueous NaHCO3 solution
and then dried. The organic solvent was concentrated to give a residue, which was purified by column
chromatography (3 g, EtOAc/toluene = 1/100 as an eluent) to afford 9 (62.3 mg, 84%) as a colorless oil:
[!]D26 +26 (c 1.78, CHCl3); IR (neat)ꢀ$max = 2960, 2930, 2860, 1730, 1640, 1590, 1490, 1460, 1260, 1200,
1
1140, 1090 cm-1; H NMR # 7.44–7.28 (5H, m), 7.22 (1H, dd, J = 6.8 and 1.4 Hz), 6.82–6.76 (2H, m),
5.18 (1H, d, J = 7.6 Hz), 4.71 and 4.52 (each 1H, 2d, J = 11.6 Hz), 4.19–4.00 (3H, m), 3.87 (3H, s),
3.76–3.62 (2H, m), 2.89 and 2.48 (each 1H, 2d, J = 16.1 Hz), 2.27 (1H, ddd, J = 12.7, 3.4 and 3.4 Hz),
1.53 (1H, m), 1.22 (3H, t, J = 7.2 Hz), 0.86 (9H, s), 0.13 and 0.07 (each 3H, 2s); 13C NMR # 171.0, 146.6,
145.9, 138.1, 132.0, 128.5, 127.81, 127.78, 122.3, 118.8, 113.2, 90.2, 75.4, 72.1, 69.8, 60.5, 60.1, 56.3,
54.5, 39.7, 36.3, 25.7, 18.0, 14.1, –4.4, –4.5; LRMS (EI) m/z 606 [M+ (81Br), 4%], 604 [M+ (79Br), 4], 549
(4), 547 (4), 531 (4), 529 (3), 337 (42), 247 (93), 91 (100), 73 (39); HRMS (EI) m/z calcd for
C30H4179BrO6Si (M+) 604.1856, found 604.1857.
(5aR,7R,9S,9aS)-7-[(tert-Butyldimethylsilyl)oxy]-6,7,8,9-tetrahydro-9-hydroxy-4-methoxy-9a(5aH)-
dibenzofurnacetic Acid Ethyl Ester (11). To a solution of 9 (27.0 mg, 0.0447 mmol) in EtOH (1.5
mL) was added 10 % Pd on carbon (12 mg) and the mixture was stirred under an atmospheric pressure of
H2 at rt for 1 h. After confirming the disappearance of 9 by TLC analysis, potassium carbonate (6.2 mg,
0.045 mmol) was added to the mixture and the resulting mixture was further stirred under an atmospheric
pressure of H2 at rt for 1 h. The reaction mixture was filtrated through a pad of Celite. The filtrate was
concentrated to give a residue, which was purified by column chromatography (1.5 g, EtOAc/toluene =
1/30 as an eluent) to afford 11 (16.6 mg, 85%) as a colorless oil: [!]D23 +44 (c 0.56, CHCl3); IR (neat) $max
1
= 3530, 2950, 2940, 2860, 1730, 1620, 1590, 1490, 1450, 1260, 1190, 1180, 1120 cm-1; H NMR # 7.15
(1H, dd, J = 7.0 and 2.0 Hz), 6.83 (1H, dd, J = 8.1 and 7.0 Hz), 6.78 (1H, dd, J = 8.1 and 2.0 Hz), 4.75
(1H, dd, J = 8.6 and 6.4 Hz), 4.06 (3H, m), 3.86 (3H, s), 3.75 (1H, dddd, J = 9.8, 9.8, 4.7 and 4.4 Hz),
3.47 (1H, d, J = 4.4 Hz), 2.90 and 2.59 (each 1H, 2d, J = 14.8 Hz), 2.23 (1H, dddd, J = 12.7, 6.4, 4.7 and
1.7 Hz), 2.04 (1H, dddd, J = 10.7, 4.4, 4.4 and 1.7 Hz), 1.73-1.52 (2H, m), 1.16 (3H, t, J = 7.1 Hz), 0.83
(9H, s), 0.033 and 0.025 (each 3H, 2s); 13C NMR # 172.2, 147.2, 145.6, 131.2, 121.6, 118.5, 112.3, 85.5,
71.2, 65.1, 60.9, 56.0, 52.7, 42.3, 39.6, 37.5, 25.7, 18.0, 14.0, –4.8 (2C); LRMS (EI) m/z 436 (M+, 26%),
379 (32), 287 (61), 241 (85), 235 (78), 234 (89), 213 (100), 199 (66), 161 (76), 75 (63), 73 (56); HRMS

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HETEROCYCLES, Vol. 82, No. 1, 2010
(EI) m/z calcd for C23H36O6Si (M+) 436.2281, found 436.2280. Anal. Calcd for C23H36O6Si: C, 63.27; H,
8.31%. Found: C, 62.98; H, 8.25%.
(5aR,7R,9S,9aR)-9-Benzoyloxy-7-[(tert-butyldimethylsilyl)oxy]-6,7,8,9-tetrahydro-4-methoxy-
9a(5aH)-dibenzofurnacetic Acid Ethyl Ester (12). To a solution of 11 (7.5 mg, 0.017 mmol) in
pyridine (0.5 mL) were added benzoyl chloride (3.0 µL, 0.026 mmol) and DMAP (0.2 mg, 2 µmol) at rt.
After being stirred at rt for 27 h, the reaction mixture was quenched with saturated aqueous NH4Cl
solution and the products were extracted with Et2O. The extract was washed with brine and then dried.
The organic solvent was concentrated to give a residue, which was purified by column chromatography
23
(0.5 g, EtOAc/hexane = 1/50 as an eluent) to afford 12 (11.3 mg, 100%) as a colorless oil: [!]D –38 (c
0.42, CHCl3); IR (neat) $max = 2950, 2930, 2860, 1730, 1490, 1455, 1270, 1095 cm-1; 1H NMR # 8.11 (2H,
m), 7.63 (1H, m), 7.52 (2H, m), 7.27 (1H, dd, J = 7.5 and 1.0 Hz), 6.92 (1H, dd, J = 7.5 and 8.0 Hz), 6.83
(1H, dd, J = 8.0 and 1.0 Hz), 5.55 (1H, dd, J = 11.9 and 3.9 Hz), 5.23 (1H, dd, J = 9.0 and 6.4 Hz),
4.10-4.00 (2H, m), 3.88 (3H, s), 3.94 - 3.82 (1H, m), 2.67 and 2.57 (each 1H, 2d, J = 15.3 Hz), 2.37 (1H,
dddd, J = 13.4, 6.4, 4.9 and 1.7 Hz), 2.24 (1H, dddd, J = 11.9, 4.6, 3.9 and 1.7 Hz), 1.69 (1H, ddd, J =
11.9, 11.9 and 10.5 Hz), 1.61 (1H, ddd, J = 13.4, 10.2 and 9.0 Hz), 1.19 (3H, t, J = 7.1 Hz), 0.82 (9H, s),
13
0.05 and 0.03 (each 3H, 2s); C NMR # 170.7, 165.9, 147.2, 145.9, 133.2, 131.4, 130.7, 129.6, 128.6,
121.8, 117.7, 112.2, 84.1, 72.0, 64.6, 60.6, 55.9, 52.3, 40.1, 38.1, 37.1, 25.7, 17.9, 13.9, –4.78, –4.81;
LRMS (EI) m/z 540 (M+, 5%), 483 (18), 343 (35), 241 (35), 179 (32), 105 (100), 77 (38); HRMS (EI) m/z
calcd for C30H40O7Si (M+) 540.2543, found 540.2539.
(3aS,4S,6R,7R,7aR)-7-Bromo-3a-(2,3-dimethoxyphenyl)-4,6-dihydroxy-hexahydro-2(3H)-
benzofuranone (13). To a solution of 3b (29.1 mg, 0.0539 mmol) in DMF (3.5 mL) was added NBS
(18.2 mg, 0.102 mmol) at 0 ºCꢀand the mixture was stirred at rt. After being stirred for 3 h, NBS (18.2
mg, 0.102 mmol) was added at 0 ºC and mixture was further stirred at rt for 2 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 solution at 0 ºC and the products were extracted with
EtOAc. The extract was washed with saturated aqueous NaHCO3 solution and then dried. Removal of
the solvent left a residue, which was purified by column chromatography (1.5 g, EtOAc/toluene = 1/100
as an eluent) and further purified by preparative TLC (EtOAc/toluene =1/5) to afford 10 (11.8 mg, 37%)
as a colorless oil. Compound 10 (11.8 mg, 0.199 mmol) was dissolved in EtOH (2 mL). To the
mixture was added 10 % Pd on carbon (8 mg) and the mixture was stirred under an atmospheric pressure
of H2 at rt for 2 h. The mixture was filtrated through a pad of Celite and the filtrate was concentrated to
give a residue, which was purified by column chromatography (1 g, EtOAc/toluene = 1/1 as an eluent) to
24
afford 13 (5.3 mg, 25% from 3b) as an amorphous solid: [!]D –14 (c 0.27, CHCl3); IR (neat)ꢀ$max
=
3450, 1780, 1470, 1270 cm-1; 1H NMR # 7.07 (1H, dd, J = 8.5 and 8.3 Hz), 6.95 (1H, dd, J = 8.3 and 1.5
Hz), 6.90 (1H, dd, J = 8.5 and 1.5 Hz), 5.54 (1H, d, J = 9.5 Hz), 4.89 (1H, dd, J = 3.7 and 3.4 Hz), 4.34

HETEROCYCLES, Vol. 82, No. 1, 2010
575
(1H, ddd, J = 3.2, 2.7 and 2.7 Hz), 4.15 (1H, dd, J = 9.5 and 2.7 Hz), 3.95 and 3.87 (each 3H, 2s), 2.95
and 2.76 (each 1H, 2d, J = 17.3 Hz), 2.57 (1H, ddd, J = 15.6, 3.7 and 3.2 Hz), 2.15 (1H, ddd, J = 15.6, 3.4
and 2.7 Hz); 13C NMR # 173.7, 153.4, 147.5, 131.6, 123.8, 119.5, 113.3, 81.9, 71.1, 68.9, 60.4, 57.9, 55.8,
55.1, 38.4, 32.3; LRMS (EI) m/z 388 [M+ (81Br), 9%], 386 [M+(79Br), 9], 356 (92), 354 (100), 289 (10),
243 (31), 189 (53), 77 (47); HRMS (EI) m/z calcd for C16H1979BrO6 (M+) 386.0365, found 386.0369.
(5aR,7S,9aR)-7-[(tert-Butyldimethylsilyl)oxy]-6,7-dihydro-4-methoxy-9a(5aH)-dibenzofuranacetic
Acid Ethyl Ester (14) To a solution of 11 (12.4 mg, 0.0284 mmol) in 1,2-dichlorobenzene (2.0 mL)
were added thiocarbonyldiimidazole (20.2 mg, 0.113 mmol) and DMAP (0.4 mg, 0.3 µmol). The
reaction mixture was heated at reflux temperature. After being refluxed for 6 h, the reaction mixture
was cooled to 0 °C and quenched with saturated aqueous NH4Cl solution. The products were extracted
with EtOAc. The extract was washed with saturated aqueous NaHCO3 solution and then dried.
Removal of the solvent left a residue, which was purified by column chromatography (1 g, EtOAc/hexane
28
= 1/10 as an eluent) to afford 14 (8.6 mg, 72%) as a colorless oil: [!]D –22 (c 0.80, CHCl3); IR (neat)
$
max = 2960, 2930, 2860, 1730, 1620, 1590, 1500, 1460, 1260, 1200, 1100 cm-1; 1H NMR # 6.88–6.71 (3H,
m), 5.93 (1H, dd, J = 10.0 and 2.0 Hz), 5.82 (1H, ddd, J = 10.0, 1.8 and 1.2 Hz), 5.24 (1H, dd, J = 11.6
and 5.6 Hz), 4.35 (1H, dddd, J = 10.2, 4.4, 2.0 and 1.8 Hz), 4.08 (2H, q, J = 7.1 Hz), 3.87 (3H, s), 2.62
and 2.54 (each 1H, 2d, J = 14.6 Hz), 2.33 (1H, dddd, J = 11.6, 5.6, 4.4 and 1.2 Hz), 1.70 (1H, ddd, J =
11.6, 11.6 and 10.2 Hz), 1.21 (3H, t, J = 7.1 Hz), 0.85 (9H, s), 0.060 and 0.055 (each 3H, 2s); 13C NMR !
170.4, 145.8, 145.3, 134.6, 133.1, 126.8, 121.5, 115.4, 111.6, 84.4, 65.2, 60.4, 55.9, 48.3, 44.7, 37.0, 25.7,
18.0, 14.2, –4.6, –4.8; LRMS (EI) m/z 418 (M+, 8%), 361 (23), 343 (66), 297 (42), 269 (66), 254 (72),
181 (50), 75 (100); HRMS (EI) m/z calcd for C23H34O5Si (M+) 418.2176, found 418.2173. Anal. Calcd
for C23H34O5Si: C, 65.99; H, 8.19%. Found: C, 65.81; H, 8.22%.
(5aR,7S,9aR)-7-[(tert-Butyldimethylsilyl)oxy]-6,7-dihydro-4-methoxy-N-methyl-9a(5aH)-dibenzo-
furanacetamide (15)ꢁꢀꢀTo a solution of 14 (7.6 mg, 0.018 mmol) in EtOH (0.4 mL) and water (0.1 mL)
was added lithium hydroxide monohydrate (0.9 mg, 0.02 mmol) at rt. After being stirred at rt for 20 h,
the reaction mixture was quenched with saturated aqueous NH4Cl solution at 0 ºC and the products were
extracted with Et2O. The extract was washed with brine and then dried. Removal of the solvent gave a
carboxylic acid as a syrup, which was used for the next reaction without further purification. To a
solution of a crude carboxylic acid in DMF (0.4 mL) were added methylammonium chloride (6.1 mg,
0.091 mmol), diethyl cyanophosphonate (0.027 mL, 0.18 mmol) and Et3N (0.025 mL, 0.18 mmol) at –10
ºC. After being stirred at –10 ºC for 2 h, the reaction mixture was quenched with saturated aqueous
NH4Cl solution and the products were extracted with EtOAc. The extract was washed with brine and
then dried. The organic solvent was concentrated to give a residue, which was purified by column
chromatography (0.5 g, EtOAc/hexane = 1/1) to afford 15 (6.8 mg, 93% for 2 steps) as a crystalline

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HETEROCYCLES, Vol. 82, No. 1, 2010
24
residue: mp 58–60 ºC; [!]D –3.5 (c 0.98, CHCl3); IR (KBr disk) $max = 3310, 2950, 2930, 2860, 1650,
1
1490, 1260, 1090 cm-1; H NMR # 6.83 (1H, dd, J = 8.0 and 7.3 Hz), 6.74 (1H, dd, J = 8.0 and 1.5 Hz),
6.71 (1H, dd, J = 7.3 and 1.5 Hz), 5.99 (1H, dd, J = 10.1 and 2.0 Hz), 5.82 (1H, ddd, J = 10.1, 1.9 and 1.2
Hz), 5.19 (1H, dd, J = 11.6 and 2.0 Hz), 5.18 (1H, bs,), 4.37 (1H, dddd, J = 10.4, 4.9, 2.0 and 1.9 Hz),
3.86 (3H, s), 2.69 (3H, d, J = 4.9 Hz), 2.48 and 2.34 (each 1H, 2d, J = 13.8 Hz), 2.31 (1H, dddd, J = 11.7,
4.9, 2.0 and 1.2 Hz), 1.69 (1H, ddd, J = 11.7, 11.6 and 10.4 Hz), 0.84 (9H, s), 0.054 and 0.047 (each 3H,
2s); 13C NMR # 170.0, 145.9, 145.4, 134.2, 133.3, 127.1, 121.4, 115.4, 111.7, 84.9, 65.2, 56.0, 48.4, 47.0,
36.9, 26.2, 25.7, 18.0, –4.6, –4.8; LRMS (EI) m/z 403 (M+, 9%), 346 (42), 328 (100), 75 (45), 73 (40);
HRMS (EI) m/z calcd for C22H33NO4Si (M+) 403.2179, found 403.2165.
(5aR,7S,9aR)-6,7-Dihydro-7-hydroxy-4-methoxy-N-methyl-9a(5aH)-dibenzofuranacetamide
(16).
To a solution of 15 (7.6 mg, 0.019 mmol) in THF (0.4 mL) was added TBAF (1.0 M THF solution, 0.038
mL, 0.038 mmol) at rt and the mixture was stirred at 40 ºC for 10 h. The reaction mixture was quenched
with saturated aqueous NH4Cl solution and the products were extracted with EtOAc. The extract was
washed with brine and then dried. Removal of the solvent left a residue, which was purified by column
chromatography (0.3 g, EtOAc as an eluent) to afford 16 (5.8 mg, 100%) as a colorless oil: [!]D24 –13 (c
1
0.58, CHCl3); IR (neat) $max = 3310, 3100, 3000, 2940, 2840, 1650, 1490, 1460, 1280, 1070 cm-1; H
NMR # 6.90 (1H, dd, J = 7.8 and 7.8 Hz), 6.80 (1H, dd, J = 7.8 and 1.2 Hz), 6.78 (1H, dd, J = 7.8 and 1.2
Hz), 5.98 (1H, ddd, J = 10.1, 4.6 and 0.5 Hz), 5.73 (1H, ddd, J = 10.1, 1.0 and 1.0 Hz), 5.47 (1H, bs),
5.08 (1H, dd, J = 4.1 and 3.2 Hz), 4.20 (1H, m), 3.86 (3H, s), 2.74 (3H, d, J = 4.9 Hz), 2.61 and 2.57
(each 1H, 2d, J = 14.9 Hz), 2.43 (1H, dddd, J = 14.7, 4.1, 4.1 and 1.0 Hz), 2.22 (1H, ddd, J = 14.7, 4.9
and 3.2 Hz), 2.18 (1H, d, J = 9.7 Hz); 13C NMR ! 169.6, 145.9, 145.2, 133.9, 129.6, 129.2, 122.2, 114.9,
111.9, 86.2, 62.4, 55.9, 47.3, 44.5, 31.9, 26.3; LRMS (EI) m/z 289 (M+, 34%), 216 (100), 201 (33), 199
(42), 103 (39); HRMS (EI) m/z calcd for C16H19NO4 (M+) 289.1314, found 289.1311.
(4aR,6S,8aR)-4a,5,11,12-Tetrahydro-6-hydroxy-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]-
benzazepin-10(9H)-one (2). To a solution of 16 (3.9 mg, 0.014 mmol) in 1,2-dichloroethane (1.2 mL)
were added paraformaldehyde (1.6 mg, 0.054 mmol) and TFA (0.02 mL) at rt. After being stirred at rt
for 2.5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 solution at 0 ºC and the
products were extracted with CHCl3. The extract was washed with brine and then dried. Removal of
the solvent left a residue, which was purified by column chromatography (0.5ꢀꢂꢃꢀMeOH/CHCl3 = 1/200)
to afford 2 (2.9 mg, 71%) as a crystalline residue: mp 213–214 ºC; [!]D25 +115 (c 0.63, CHCl3); IR (KBr
disk) $max = 3450, 2930, 1650, 1640, 1510, 1440, 1280, 1060 cm-1; 1H NMR # 6.70 (2H, s), 6.03 (1H, ddd,
J = 10.1, 5.1 and 1.4 Hz), 5.49 (1H, d, J = 10.1 Hz), 4.74 (1H, dd, J = 2.0 and 1.7 Hz), 4.47 and 4.35
(each 1H, 2d, J = 16.1 Hz ) 4.22 – 4.09 (1H, m), 3.85 and 3.02 (each 3H, 2s), 2.82 and 2.75 (each 1H, 2d,
J = 13.7 Hz), 2.68 (1H, dddd, J = 15.8, 3.9, 1.7 and 1.4 Hz), 2.48 (1H, d, J = 11.5 Hz), 2.12 (1H, ddd, J =

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577
13
15.8 Hz, 5.4 and 2.0 Hz); C NMR # 170.9, 146.6, 144.8, 132.1, 128.3 (2C), 125.1, 120.0, 111.9, 88.3,
61.5, 56.1, 52.0, 43.3, 41.6, 35.9, 29.2; LRMS (EI) m/z 302 [(M+H)+, 9%], 301 (M+, 100), 283 (24), 230
(21), 224 (23), 211 (21), 181 (19), 165 (25), 115 (36), 91 (22), 77 (24); HRMS (EI) m/z calcd for
C17H19NO4 (M+) 301.1314, found 301.1317. Anal. Calcd for C17H19NO4ꢄ1/2H2O: C, 65.79; H, 6.50; N,
4.51%. Found: C, 65.46; H, 6.37; N, 4.50%.
The similar treatment of compound 15 (3.5 mg, 0.0087 mmol) also provided 2 (1.8 mg, 67%).
(+)-Galanthamine [(+)-1]. To a solution of 2 (9.4 mg, 0.031 mmol) in THF (1.5 mL) under Ar at 0 ºC
was added LiAlH4 (2.0 M solution in THF, 0.062 mL, 0.124 mmol) and the mixture was stirred at reflux
temperature for 3 h. The reaction mixture was quenched with 3 mol/L aqueous NaOH solution at 0 ºC
and the products were extracted with CH2Cl2. The extract was washed with brine and then dried over
sodium carbonate. The organic solvent was concentrated to give a residue, which was purified by
column chromatography (0.5 g, MeOH/CHCl3 = 1/20) to afford (+)-1 (7.9 mg, 88%) as a crystalline
23
residue: mp 124–125 ºC (lit.,1c mp 125–126 °C); [!]D +112 (c 0.50, EtOH); IR (KBr disk) $max = 3360,
2920, 1620, 1590, 1510, 1440, 1280, 1050 cm-1; 1H NMR # 6.66 (1H, d, J = 8.3 Hz), 6.62 (1H, d, J = 8.3
Hz), 6.06 (1H, dd, J = 10.3 and 1.2 Hz), 6.00 (1H, ddd, J = 10.3, 4.9 and 1.3 Hz), 4.61 (1H, bs), 4.14 (1H,
dd, J = 4.9 and 4.9 Hz), 4.08 (1H, d, J = 15.1 Hz), 3.83 (3H, s), 3.68 (1H, d, J = 15.1 Hz), 3.26 (1H, ddd,
J = 14.6, 13.0 and 1.7 Hz), 3.05 (1H, ddd, J = 14.6, 3.9 and 3.2 Hz), 2.68 (1H, dddd, J = 15.6, 3.2, 1.5 and
1.3 Hz), 2.40 (3H, s), 2.08 (1H, ddd, J = 13.7, 13.0 and 3.2 Hz), 2.00 (1H, ddd, J = 15.6, 4.9 and 2.4 Hz),
13
1.57 (1H, ddd, J = 13.7, 3.9 and 1.7 Hz); C NMR ! 145.8, 144.2, 133.0, 128.5, 127.7, 126.7, 122.2,
111.2, 88.7, 62.0, 60.4, 55.9, 53.7, 48.1, 41.8, 33.6, 29.9; LRMS (EI) m/z 288 ((M+H)+, 18%), 287 (M+,
100), 286 (84), 269 (14), 230 (20), 174 (19); HRMS (EI) m/z calcd for C17H19NO4 (M+) 287.1521, found
287.1521.
Synthesis of (–)-Galanthamine [(–)-1] from (–)-5. Starting from (–)-5,12 (–)-galanthamine [(–)-1] was
21
synthesized by the same procedure as described for the preparation of (+)-1 from (+)-5. ent-7a: [!]D
24
–4.6 (c 1.40, CHCl3). ent-7b: [!]D21 –116 (c 1.16, CHCl3). ent-8: [!]D24 +120 (c 1.12, CHCl3). ent-4: [!]D
24
+84 (c 1.28, CHCl3). ent-3a: [!]D24 +8.0 (c 0.76, CHCl3). ent-9: [!]D24 –27 (c 0.92, CHCl3). ent-11: [!]D
26
–48 (c 0.76, CHCl3). ent-14: [!]D24 +21 (c 1.11, CHCl3). ent-15: [!]D24 +3.2 (c 1.69, CHCl3). ent-16: [!]D
24
23
20
+11 (c 1.11, CHCl3). ent-2: [!]D –110 (c 0.45, CHCl3). (–)-1: [!]D –112 (c 0.19, EtOH) {lit.,1c [!]D
–118.8 (c 1.378, EtOH)}.
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