Approach to the stereoselective synthesis of melatonin receptor agonist Ramelteon via asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2005.11.005

Asymmetric synthesis of a novel non-benzodiazepine hypnotic drug Ramelteon (TAK-375) was accomplished via asymmetric hydrogenation. Development of the substrate design revealed that a novel class of substrate, allylic acylamine 4a, was hydrogenated with a Ru-BINAP catalyst in 95% ee and 98% yield. The effectiveness and robustness of the reaction were demonstrated on a 700-g scale.

Full text of DOI:10.1016/j.tetasy.2005.11.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 184–190
Approach to the stereoselective synthesis of melatonin
receptor agonist Ramelteon via asymmetric hydrogenation
Toru Yamano,* Masayuki Yamashita, Mari Adachi, Mitsutaka Tanaka,
Kiyoharu Matsumoto, Mitsuru Kawada, Osamu Uchikawa,
Kohji Fukatsu and Shigenori Ohkawa
Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd,
Osaka 532-8686, Japan
Received 30 August 2005; revised 2 November 2005; accepted 4 November 2005
Abstract—Asymmetric synthesis of a novel non-benzodiazepine hypnotic drug Ramelteon (TAK-375) was accomplished via asym-
metric hydrogenation. Development of the substrate design revealed that a novel class of substrate, allylic acylamine 4a, was hydro-
genated with a Ru-BINAP catalyst in 95% ee and 98% yield. The effectiveness and robustness of the reaction were demonstrated on
a 700-g scale.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
sleep medication that is not designated as a controlled
substance by the US Drug Enforcement Administration
(DEA).
The chemical synthesis of enantiomerically pure com-
pounds is crucial in the development of new drugs.
The pertinent question in this context is not only how
to prepare them in a pure state, but also how to prepare
them economically. In addition, safety and environmen-
tal issues as well as the availability of the starting mate-
rials and key intermediates are important factors that
determine the reaction feasibility. When a new chemical
entity is selected as a drug candidate, the preliminary
exploration of a wide range of possible reactions is inev-
itable in the early stages. Ramelteon (TAK-375) [(S)-N-
[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]-
propionamide] is a novel, selective melatonin MT1/MT2
receptor agonist and is expected to be useful in the treat-
ment of circadian rhythm sleep disorders (Scheme 1). It
constitutes a new class of prescription drugs that do not
cause adverse effects typically associated with the use of
benzodiazepine, such as learning and memory impair-
ment and drug dependence.1 Recently, the US Food
and Drug Administration (FDA) approved a new drug
application (NDA) for Ramelteon (ROZEREMTM) for
the treatment of insomnia characterized by difficulty
with sleep onset. It is also the first and only prescription
O
1
N
H
O
8
(S)
4
Ramelteon
Scheme 1.
Ramelteon has a simple but unique chemical structure,
comprising of a three-fused-ring system with an asym-
metric center at the benzylic position. In order to obtain
enantiomerically pure Ramelteon, we investigated vari-
ous synthetic approaches based on asymmetric hydro-
genation,2 enzymatic resolution,3 diastereomer salt
resolution, and simulated moving bed (SMB) resolu-
tion.4 With the objective of obtaining a practical synthe-
sis, we focused our efforts on asymmetric hydrogenation
using readily available and versatile Ru-BINAP cata-
lysts.5 We presumed that excellent yield, enantioselectiv-
ity, and productivity could be achieved by the
appropriate design of substrates rather than the screen-
ing of catalysts. Herein, we report our synthetic
approaches to Ramelteon based on chelation-controlled
asymmetric hydrogenation using Ru-BINAP catalysts.
*
Corresponding author. Tel.: +81 663006328; fax: +81 663006151;
e-mail: Yamano_tooru@takeda.co.jp
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.11.005

T. Yamano et al. / Tetrahedron: Asymmetry 17 (2006) 184–190
185
O
O
1
N
H
R
N
R
H
O
O
H2, Ru(OAc)2[(S)-binap]
1a-e
2a-e
Scheme 2.
2. Results and discussion
2.1. Hydrogenation of allylic acylamines 1a–e
tion. In addition, the faint effect of the R groups on the
reactivities and enantioselectivities indicates that any R
group located outside the metal chelation could not con-
tribute to improving the outcome of the reaction.
Prioritizing synthetic effectiveness, we selected tricyclic
exo allylic acylamines 1a–e,6 which were the most direct
precursors for Ramelteon, as shown in Scheme 2 and
Table 1. Substrates with various acyl groups (RCO),
including the propionyl group, which is the substituent
on Ramelteon, were examined. However, none of them
yielded satisfactory enantioselectivities and conversions.
Enantioselective hydrogenation with Ru-BINAP cata-
lysts is generally considered to proceed via metal com-
plexes in which an unsaturated bond and an electron-
donating heteroatom are simultaneously coordinated
to the Ru atom.2 According to the proposed reaction
mechanism, the poor enantioselectivities in the reactions
with 1a–e might suggest that the steric hindrance of the
C1 methylene moiety in 1a–e inhibited the desired chela-
The objective of our substrate design was to realize effec-
tive chelation for hydrogenation, as outlined in Scheme
3. When the carbonyl group in 1 coordinated to Ru in
the usual manner, chelation was presumed to be realized
at the congested side according to the trajectory of coor-
dination. Therefore, we presumed that relocation of the
double bond and the carbonyl group, as depicted in
amide 3 would result in a change in the coordination,
thereby favoring the less hindered side. On the other
hand, the bicyclic substrates 4a–d that lack the undesir-
able C1 methylene moiety were expected to chelate in a
less congested fashion.
2.2. Hydrogenation of carboxamide 3
The synthesis of carboxamide 3 was carried out as
shown in Scheme 4. 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]-
furan-8-one 51 was converted to nitrile 6 by Horner–
Emmons condensation. The treatment of nitrile 6 with
alkaline hydrogen peroxide yielded endo-amide 3 via
hydration and isomerization. The endo geometry was
established by a NOESY experiment by 1H NMR.
The results of the asymmetric hydrogenation of carbox-
amide 3 using (R)-BINAP catalysts are summarized
in Table 2. The binuclear complex [Et2NH2]+-
[Ru2Cl5(binap)2]ꢀ,7 which is a highly effective catalyst
for the asymmetric hydrogenation of ketones such as
Table 1. Asymmetric hydrogenation of allylic acylamines 1a–ea
R
eeb (%)
Yieldb (%)
Et (1a)
H (1b)
n-Pr (1c)
n-Bu (1d)
OBz (1e)c
42
12
32
18
37
18
35
23
29
Racemic
a The reaction was conducted with 10 mol % Ru(OAc)2(binap) at 50 °C
for 6 h under H2 (10 MPa).
b Determined by HPLC analysis with chiral stationary phases.
c [Et2NH2]+[Ru2Cl5(binap)2]ꢀ was utilized.
R
P
HN
O
Ru
NH2
*
P
O
P
Ru
R'O
*
O
P
R
R
O
NH
NH2
O
NH
P
Ru
P
P
*
P
Ru
*
O
O
R'O
O
P
Ru
*
P
1
4a-d
3
Scheme 3.

186
T. Yamano et al. / Tetrahedron: Asymmetry 17 (2006) 184–190
CN
O
(EtO)2P(O)CH2CN
O
O
H2O2, KOH
NaH, THF
83%
32%
5
6
CONH2
CONH2
1) NaBH4, BF3.OEt2
2) HCl
O
O
O
H2, Ru-(R)-BINAP
up to 98% ee
(S)
63%
7
3
8
NH2
.
HCl
EtCOCl, Et3N
Ramelteon
Scheme 4.
Table 2. Asymmetric hydrogenation of carboxamide 3a
Ru-BINAP
H2 (MPa)
Temp (°C)
eeb (%)
Yieldb (%)
[Et2NH2]+[Ru2Cl5(binap)2]ꢀ
[Et2NH2]+[Ru2Cl5(binap)2]ꢀ
Ru(OAc)2[(R)-binap]
10
10
10
5
50
70
50
50
98
97
92
96
20
21
92
86
Ru(OAc)2[(R)-binap]
a The reaction was conducted with 5 mol % Ru for 6 h.
b Determined by HPLC analysis with a chiral stationary phase.
3-oxobutanoate, gave excellent ees but poor yields. Con-
versely, satisfactory ees and yields were obtained when
the mononuclear complex Ru(OAc)2[(R)-binap] was uti-
lized. The effects of pressure and temperature were insig-
nificant. It is noteworthy that (R)-BINAP generated the
desired enantiomer with S-configuration. The opposite
stereochemistry obtained in the hydrogenation of 1a–e
and in the hydrogenation of 3 is most likely due to a dif-
ference in the coordination mode of the chiral catalyst,
as depicted in Scheme 3.8 Hence, the six-membered che-
late complex 3, in which the Ru(II) atom interacts with
carbonyl oxygen, and an olefinic double bond would be
formed on the right side of the existing olefinic double
bond. The reduction of carboxamide 7 followed by acyl-
ation in a conventional manner yielded Ramelteon.
However, carboxamide 3 appeared to be inadequate
for large-scale application because of its insufficient
solubility.
pressure of 9–10 MPa with an excellent enantioselectiv-
ity of 95%. The alkoxy groups (OR0), which were
located outside the chelation, had little effect on the
enantioselectivities. However, the amide alkyl groups
(R) had a substantial effect on both the enantioselectiv-
ity and reactivity. The replacement of the methyl group
with the electron-withdrawing trifluoromethyl group (9c
vs 9d) resulted in a drastic deterioration in ee and yield.
This finding clearly indicates that the chelation of Ru
onto the carbonyl group is crucial for the reaction
(Table 3). Allylic acylamines 4a–d required (S)-BINAP
in order to obtain the desired stereochemistry in accor-
dance with acylamine 1. This observation also reinforces
the feasibility of the working hypothesis depicted in
Scheme 3. The steric hindrance of a rather remote moi-
ety in 1—C1 methylene—exerts a decisive influence on
the chelation, as shown in Scheme 6. It is clear that a
consideration of the entire structure of the compounds
is essential for designing an effective asymmetric hydro-
genation process.
2.3. Hydrogenation of allylic acylamines 4
The bicyclic exo allylic acylamines 4a–d1,9 were sub-
jected to asymmetric hydrogenation (Scheme 5).
The sense of chirality can be rationalized by the two pre-
sumed transition structures schematically illustrated in
Scheme 7. The protruding quasi-equatorial phenyl rings
(colored light blue) are believed to play a crucial role in
stereoselection with BINAP.2,10 The reaction presum-
The reaction proceeded successfully with 10 mol % of
the catalyst precursor at 50–70 °C under an initial H2
NHCOR
R'O
NHCOR
R'O
H2, Ru(OAc)2[(S)-binap]
4a- d
9a-d
Scheme 5.

T. Yamano et al. / Tetrahedron: Asymmetry 17 (2006) 184–190
187
the selectivity. To the best of our knowledge, this is
the first example of the asymmetric hydrogenation of
allylic acylamines. The conversion of the hydrogenated
product 9a to Ramelteon was carried out without
racemization.1
3. Conclusions
Among the three types of substrates, 1a–e, 3, and 4a–d
designed for the practical synthesis of Ramelteon, car-
boxamide 3 and allylic acylamines 4a and b were found
to exhibit superior performances. Additionally, an acyl-
amine in the allylic position proved to play a role as a
directive functional group for asymmetric hydrogena-
tion with the Ru-BINAP catalyst. In conclusion, the
development of highly effective chiral ligands along with
the sophisticated design of substrates has fulfilled the
goal of excellent yields and ees by asymmetric hydro-
genation. This is encouraging for the development of
more efficient processes.
Scheme 6.
Table 3. Asymmetric hydrogenation of allylic acylamines 4a–da
R
R0
Product
eeb (%)
Yieldb (%)
Et
Et
Me
CF3
Me
Et
Me
Me
9a
9b
9c
9d
95
95
81
22
98
88
82
16
a The reaction was conducted with 10 mol % Ru(OAc)2(binap) at 50 °C
for 6 h under H2 (9–10 MPa).
b Determined by HPLC analysis with chiral stationary phases.
4. Experimental
4.1. General
Melting points were determined using a Yanako micro
melting point apparatus and are uncorrected. Infrared
spectra were obtained using PARAGON 1000—a Per-
1
kin–Elmer FT-IR spectrometer. H NMR spectra were
recorded on JEOL JMTC0400/5 (400 MHz), JEOL
JNM-A500 (500 MHz), or Bruker DMX-600
(600 MHz) with tetramethylsilane as an internal refer-
ence. MS were recorded using Hitachi M-2000.
Ru(OAc)2[(S)-binap] and [Et2NH2]+[Ru2Cl5(binap)2]ꢀ
were prepared according to the methods described in
the literature.11 All manipulations involving air- and
moisture-sensitive organometallic compounds were car-
ried out by using the standard Schlenk technique under
purified argon by passing them through a column of
activated copper at 80 °C. Chiral stationary phase col-
umns—CHIRALPAK AS and CHIRALCEL OB-H—
were obtained from Daicel Chemical Industries, Ltd.
The chiral stationary phase column Ceramospher Chiral
RU-1 was obtained from Shiseido Co., Ltd.
Scheme 7.
4.2. Materials
ably proceeds via the transition structure having lk top-
icity avoiding steric repulsion between the quasi-equato-
rial phenyl groups of (S)-BINAP and indane moiety, as
can be seen in Scheme 7, irrespective of the amide car-
bonyl oxygen coordination mode.
Methanol and ethanol were distilled under argon after
being dried over magnesium alkoxides.
4.3. Asymmetric hydrogenation of N-[2-(1,6,7,8-tetra-
hydro-2H-indeno[5,4-b]furan-8-ylidene)ethyl]propion-
amide 1a
The effectiveness and robustness of the reaction were
undiminished on a preparative scale. In a 20-L auto-
clave, 700 g of allylic acylamine 4a was smoothly hydro-
genated with an ee of 93% and a chemical yield of 99%.
From a practical viewpoint, it is noteworthy that a
reduction in loading of the catalyst was achieved by
employing a higher reaction temperature; this resulted
in an increase in the reaction rate while maintaining
A solution of N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]-
furan-8-ylidene)ethyl]propionamide 1a (257 mg, 1 mmol)
and Ru(OAc)2[(S)-binap] (86 mg, 0.1 mmol) in methanol
(70 mL) was degassed by three freeze–thaw cycles and
then charged into a stainless-steel autoclave. Hydrogen
was introduced (10 MPa), and the mixture stirred at
50 °C. After 6 h, the ee (42%) and chemical yield

188
T. Yamano et al. / Tetrahedron: Asymmetry 17 (2006) 184–190
(37%) were determined by HPLC analysis (Ceramospher
Chiral RU-1, eluted with methanol, 0.5 mL/min).
[(R)-binap] (42 mg, 0.0499 mmol) in EtOH (70 mL)
was degassed by three freeze–thaw cycles and then
charged into a stainless-steel autoclave. Hydrogen was
introduced (10 MPa), and the mixture stirred at 50 °C.
After 6 h, the ee (92%) and chemical yield (92%) were
determined by HPLC analysis (Ceramospher Chiral
RU-1, eluted with methanol, 0.7 mL/min). The reaction
mixture was concentrated under reduced pressure to
yield solids (216 mg). A part of the resulting solids
(136 mg) was subjected to preparative thin-layer chro-
matography to afford (S)-2-(1,6,7,8-tetrahydro-2H-inde-
no[5,4-b]furan-8-yl)acetamide 7 (106 mg). mp: 218 °C
(ethyl acetate). 1H NMR (400 MHz, DMSO-d6): d
1.72–1.78 (1H, m), 2.03–2.17 (2H, m), 2.44–2.50 (1H,
m), 2.67 (1H, m), 2.77–2.83 (1H, m), 3.06–3.10 (1H,
m), 3.14–3.22 (1H, m), 3.42–3.44 (1H, m), 4.43–4.51
(2H, m), 6.52 (1H, d, J = 7.8 Hz), 6.81 (1H, s), 6.90
(1H, d, J = 7.8 Hz), 7.33 (1H, s). IR (KBr): mmax cmꢀ1
3400, 3200, 2950, 1665.
4.4. 2-(1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-
ylidene)acetonitrile 6
Sodium hydride (65% dispersion in mineral oil, 17.7 g)
was added to a solution of diethyl cyanomethylphosph-
onate (84.5 g, 0.477 mol) in tetrahydrofuran (600 mL) at
room temperature. The mixture was stirred at room
temperature for 30 min and this added dropwise to a
solution of 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-
one 5 (69.3 g, 0.398 mol) in tetrahydrofuran (1300
mL). After being stirred at room temperature for 2 h,
ice water (500 mL) was added and the mixture was con-
centrated to dryness under reduced pressure. The resi-
due was dissolved in ethyl acetate (2000 mL), and the
solution was washed twice with water (1000 mL) and
once with brine in succession and then dried over mag-
nesium sulfate. The filtrate was treated with activated
charcoal (14 g) and the resulting solution concentrated
under reduced pressure to yield crystals, which were
washed with diisopropyl ether (1000 mL) to afford 2-
(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ace-
tonitrile 6 (49.6 g, 63%). Diisopropyl ether washings
were concentrated to yield crystals, which were washed
again with diisopropyl ether to afford the second crop
(15.8 g, 20%). mp: 146–151 °C. 1H NMR (400 MHz,
DMSO-d6): d 3.05–3.12 (4H, m), 3.30 (2H, t, J =
8.8 Hz), 4.66 (2H, t, J = 8.8 Hz), 5.45 (1H, s), 6.85
(1H, t, J = 8.0 Hz), 7.10 (1H, t, J = 8.0 Hz). IR (KBr):
mmax cmꢀ1 2207, 1602.
4.7. (S)-2-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-
yl)ethylamine hydrochloride 8
Boron trifluoride diethyl etherate (3.47 mL, 27.6 mmol)
was dissolved in dry tetrahydrofuran (25 mL) and
stirred at ꢀ10 °C. Sodium borohydride (1.04 g, 27.6
mmol) was added portionwise to this solution, and the
mixture stirred at room temperature for 1 h. After cool-
ing to 0 °C, (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]-
furan-8-yl)acetamide 7 (1.0 g, 4.6 mmol) was added
and stirred at room temperature for 24 h. The mixture
was concentrated under reduced pressure to yield
solids, which were dissolved in ethyl acetate and treated
with 1 M hydrochloric acid (25 mL). The mixture
was concentrated to dryness, and the resulting residue
was washed with diisopropyl ether to afford (S)-2-
(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl-
amine hydrochloride 8 (0.70 g, 63% yield). mp: 270 °C.
1H NMR (400 MHz, DMSO-d6): d 1.60–1.75 (2H, m),
2.08–2.23 (2H, m), 2.65–2.84 (4H, m), 3.10–3.21 (2H,
m), 4.42–4.57 (2H, m), 6.55 (1H, d, J = 8.0 Hz), 6.91
(1H, d, J = 8.0 Hz), 8.09 (2H, br s). IR (KBr): mmax
cmꢀ1 2920, 2000. The absolute stereochemistry of 8
was established by X-ray crystallographic analysis of
its salt with L-malic acid. Crystallographic data for the
structure in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 286073. Copies of the
data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44 (0)123 336033 or e-mail: deposit@ccdc.cam.
ac.uk].
4.5. 2-(1,6-Dihydro-2H-indeno[5,4-b]furan-8-yl)acet-
amide 3
A 30% hydrogen peroxide solution (10 mL) was added
dropwise to a solution of 2-(1,2,6,7-tetrahydro-8H-inde-
no[5,4-b]furan-8-ylidene)acetonitrile 6 (1.14 g, 5.93 mmol)
and potassium hydroxide (5.0 g) in DMSO (25 mL)
and water (30 mL); the mixture was then stirred at room
temperature for 3 h. The reaction mixture was extracted
with ethyl acetate, and the extract dried over sodium
sulfate. Concentration under reduced pressure afforded
solids, which were recrystallized from ethyl acetate to
yield
2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)acet-
amide 3 (0.395 g, 32%). mp: 204 °C (ethyl acetate).
1H NMR (400 MHz, DMSO-d6): d 3.39 (2H, s), 3.40
(2H, t, J = 8.6 Hz), 3.58 (2H, s), 4.60 (2H, t, J =
8.6 Hz), 5.37 (1H, br s), 5.67 (1H, br s), 6.51 (1H, s),
6.70 (1H, d, J = 7.9 Hz), 7.20 (1H, d, J = 7.9 Hz).
NOESY cross-peaks were observed between H-1 to H-
2, H-2 to H-70, H-70 to H-60, and H-60 to H-50. IR
(KBr): mmax cmꢀ1 3400, 3200, 1650. MS (SIMS): m/z
215 (MH+).
4.8. Asymmetric hydrogenation of N-[2-(6-methoxy-2,3-
dihydro-1H-inden-1-ylidene)ethyl]propionamide 4a
N-[(2E)-2-(6-Methoxy-2,3-dihydro-1H-inden-1-ylidene)-
ethyl]propionamide 4a (700 g, 2.85 mol), Ru(OAc)2[(S)-
binap] (24 g, 28.7 mmol), and methanol (15 L) were
charged into a stainless-steel autoclave. The mixture
was bubbled with nitrogen. Hydrogen was introduced
(9 MPa), and the mixture stirred at 70 °C. After 1 h,
4.6. Asymmetric hydrogenation of 2-(1,6-dihydro-2H-
indeno[5,4-b]furan-8-yl)acetamide 3
A solution of 2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-
yl)acetamide 3 (214 mg, 0.994 mmol) and Ru(OAc)2-

T. Yamano et al. / Tetrahedron: Asymmetry 17 (2006) 184–190
189
the ee (93%) and chemical yield (99%) were determined
by HPLC analysis (CHIRALPAK AS, eluted with
n-hexane/2-propanol/trifluoroacetic acid = 9:1:0.01, 1.0
mL/min). In the same manner, 300 g of N-[(2E)-2-(6-
methoxy-2,3-dihydro-1H-inden-1-ylidene)ethyl]propion-
amide 4a was treated to obtain 95% ee and 98% chemical
yield. The combined reaction mixture was concentrated
under reduced pressure to yield a residue, which was sub-
jected to silica-gel column chromatography (n-hexane/
ethyl acetate = 4:1) followed by recrystallization from
n-hexane and ethyl acetate (4:1) to afford (S)-N-[2-(6-
methoxy-2,3-dihydro-1H-inden-1-yl)ethyl]propionamide
9a (801 g, 79%, 99% ee). mp: 76–77 °C (n-hexane/ethyl
0.56 mmol) and Ru(OAc)2[(R)-binap] (40 mg, 0.048 mmol)
in methanol (70 mL) was degassed by three freeze–
thaw cycles and then charged into
a stainless-
steel autoclave. Hydrogen was introduced (10 MPa),
and the mixture was stirred at room temperature.
After 6 h, the ee (22%) and chemical yield (16%)
were determined by HPLC analysis (CHIRALCEL
OB-H, eluted with n-hexane/2-propanol = 4:1, 0.7 mL/
min).
Acknowledgements
1
acetate). H NMR (500 MHz, CDCl3): d 1.15 (3H, t,
J = 8 Hz), 1.57–1.78 (2H, m), 2.02–2.09 (1H, m), 2.19
(2H, q, J = 8 Hz), 2.29–2.36 (1H, m), 2.74–2.89 (2H,
m), 3.08–3.14 (1H, m), 3.37–3.41 (2H, m), 3.34 (3H, s),
We are indebted to Dr. Shohei Hashiguchi for construc-
tive discussions. We also thank Mr. Akira Fujishima
and Ms. Keiko Higashikawa for their help in the deter-
mination of the single-crystal X-ray structure.
5.53 (1H, br s), 6.71 (1H, dd, J = 2 and 8 Hz), 6.75
25
(1H, d, J = 2 Hz), 7.10 (1H, d, J = 8 Hz). ½aꢁD ¼ ꢀ4:4
(c 1, CHCl3). IR(KBr): mmax cmꢀ1 3317, 2940, 1633,
1550. Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56;
N, 5.66. Found: C, 72.59; H, 8.50; N, 5.84. The absolute
configuration of 9a was deduced from X-ray crystallo-
graphic analysis of the p-bromobenzoate derivative, as
described in the previous literature.1
References
1. (a) Fukatsu, K.; Uchikawa, O.; Kawada, M.; Yamano, T.;
Yamashita, M.; Kato, K.; Hirai, K.; Hinuma, S.; Miya-
maoto, M.; Ohkawa, S. J. Med. Chem. 2002, 45, 4212; (b)
Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; Kawada, M.;
Matsumoto, K.; Imai, Y.; Hinuma, S.; Kato, K.; Nishi-
kawa, H.; Hirai, K.; Miyamoto, M.; Ohkawa, S. J. Med.
Chem. 2002, 45, 4222.
4.9. Asymmetric hydrogenation of N-[(2E)-2-(6-ethoxy-
2,3-dihydro-1H-inden-1-ylidene)ethyl]propionamide 4b
2. For reviews see: (a) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; John Wiley & Sons: New York, 1993;
(b) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000; (c) Gawley, R. E.;
A
solution of N-[(2E)-2-(6-ethoxy-2,3-dihydro-1H-
inden-1-ylidene)ethyl]propionamide 4b (240 mg, 0.93
mmol) and Ru(OAc)2[(S)-binap] (78 mg, 0.093 mmol)
in methanol (70 mL) was degassed by three freeze–thaw
cycles and then charged into a stainless-steel autoclave.
Hydrogen was introduced (10 MPa), and the mixture
was stirred at 50 °C. After 6 h, the ee (95%) and chemi-
cal yield (88%) were determined by HPLC analysis
(CHIRALPAK AS, eluted with n-hexane/2-propa-
nol = 9:1, 1.0 mL/min).
´
Aube, J. Principles of Asymmetric Synthesis; Pergamon:
Oxford, 1996; (d) Tang, W.; Zhang, X. Chem. Rev. 2003,
103, 3029; (e) Shimizu, H.; Nagasaki, I.; Saito, T.
Tetrahedron 2005, 61, 5405.
3. (a) Tarui, N.; Nagano, Y.; Sakane, T.; Matsumoto, K.;
Kawada, M.; Uchikawa, O.; Ohkawa, S.; Nakahama, K.
J. Biosci. Bioeng. 2002, 93, 44; (b) Tarui, N.; Watanabe,
H.; Fukatsu, K.; Ohkawa, S.; Nakahama, K. Biosci.
Biotech. Biochem. 2002, 66, 464; For reviews see: (c)
Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic
Organic Chemistry; Pergamon: Oxford, 1994; (d) Enzy-
matic Reactions in Organic Media; Koskinen, A. M. P.,
Klibanov, A. M., Eds.; Blackie Academic & Professional:
London, 1996.
4.10. Asymmetric hydrogenation of N-[(2E)-2-(6-meth-
oxy-2,3-dihydro-1H-inden-1-ylidene)ethyl]acetamide 4c
(synthesis of an intermediate for the distomer)
A solution of N-[(2E)-2-(6-methoxy-2,3-dihydro-1H-
inden-1-ylidene)ethyl]acetamide 4c (119 mg, 0.5 mmol)
and Ru(OAc)2[(R)-binap] (40 mg, 0.050 mmol) in meth-
anol (70 mL) was degassed by three freeze–thaw
cycles and then charged into a stainless-steel autoclave.
Hydrogen was introduced (10 MPa), and the mixture
stirred at 50 °C. After 6 h, the ee (81%) and chemical
yield (82%) were determined by HPLC analysis (CHIR-
ALPAK AS, eluted with n-hexane/2-propanol = 9:1,
1.0 mL/min).
4. For reviews see: (a) Nagamatsu, S.; Murazumi, K.;
Matsumoto, H.; Makino, S. Proceedings of the Chiral
Europe Õ96 Symposium, Basel, 1996; (b) Bojarski, J.;
Aboul-Enein, H. Y.; Ghanem, A. Curr. Anal. Chem.
2005, 1, 59.
5. (a) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.;
Noyori, R. J. Org. Chem. 1987, 52, 3174; (b) Kumoba-
yashi, H.; Miura, T.; Sayo, N.; Saito, T.; Zhang, X. Synlett
2001, Special Issue, 1055.
6. The geometry of 1a was confirmed to be E by the fact that
NOESY cross-peaks were observed between H-1 to vinyl
proton.
7. DiMichele, L.; King, S. A.; Douglas, A. W. Tetrahedron:
Asymmetry 2003, 14, 3427.
4.11. Asymmetric hydrogenation of 2,2,2-trifluoro-
N-[(2E)-2-(6-methoxy-2,3-dihydro-1H-inden-1-yl-
idene)ethyl]acetamide 4d
8. The stereochemical outcome of the anchor-triggered
asymmetric hydrogenation is highly dependant on the
geometry of the substrate, as can be seen in the hydro-
genation of geraniol/nerol with Ru-BINAP catalyst.2 The
relationship between the substrate geometry, BINAP
A solution of 2,2,2-trifluoro-N-[(2E)-2-(6-methoxy-2,3-
dihydro-1H-inden-1-ylidene)ethyl]acetamide 4d (159 mg,

190
T. Yamano et al. / Tetrahedron: Asymmetry 17 (2006) 184–190
chirality, and configuration of the products is distinct, as
shown below.
9. The geometry of 4a was confirmed by differential NOE
experiments, in which NOE was observed between vinyl
proton (H-2) to phenyl proton (H-70).
10. (a) Ohta, T.; Takaya, H.; Noyori, R. Inorg. Chem. 1988,
27, 566; (b) Kitamura, M.; Tsukamoto, M.; Bessho, Y.;
Yoshimura, M.; Kobs, U.; Widhalm, M.; Noyori, R. J.
Am. Chem. Soc. 2002, 124, 6649.
H2,
(S)-BINAP-Ru
OH
geraniol
OH
(R)-citronellol
11. (a) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Org.
Chem. 1992, 57, 4053; (b) Ohta, T.; Miyake, T.; Takaya,
H. J. Chem. Soc., Chem. Commun. 1992, 1725.
H2,
nerol
(R)-BINAP-Ru
OH