One-pot synthesis of chiral bicyclo[3.3.0]octatrienes using diphenylprolinol silyl ether-mediated ene-type reaction

Article abstract of DOI:10.1016/j.tet.2010.03.010

Chiral bicyclo[3.3.0]octatrienes with excellent enantioselectivity were synthesized from the simple starting materials of α,β-unsaturated aldehyde and cyclopentadiene via one-pot operation, which consisted of a diphenylprolinol silyl ether-mediated ene-type reaction, intramolecular addition reaction of cyclopentadiene moiety with aldehyde and dehydration reaction.

Full text of DOI:10.1016/j.tet.2010.03.010

Tetrahedron 66 (2010) 4894–4899
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of chiral bicyclo[3.3.0]octatrienes using diphenylprolinol
silyl ether-mediated ene-type reaction
,b,
Hiroaki Gotoh a, Hiroshi Ogino a, Hayato Ishikawa a, Yujiro Hayashi a
*
a Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
b Research Institute for Science and Technology, Tokyo University of Science Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral bicyclo[3.3.0]octatrienes with excellent enantioselectivity were synthesized from the simple
Received 28 January 2010
Received in revised form 26 February 2010
Accepted 1 March 2010
starting materials of a,b-unsaturated aldehyde and cyclopentadiene via one-pot operation, which con-
sisted of a diphenylprolinol silyl ether-mediated ene-type reaction, intramolecular addition reaction of
cyclopentadiene moiety with aldehyde and dehydration reaction.
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 6 March 2010
Keywords:
Organocatalyst
Asymmetric reaction
One-pot reaction
ene-Reaction
1. Introduction
which was found to possess excellent enantioselectivity (92% ee,
Eq. 1). As the obtained product 2 possesses cyclopentadiene and
One-pot reaction is one of the effective preparation methods of
organic molecules. In a one-pot reaction, several transformations
are performed with the formation of several bonds in a single re-
action apparatus, cutting out the need for several purifications,
minimizing chemical waste generation, and saving time. Recently,
our group has accomplished the three one-pot synthesis of
(ꢀ)-oseltamivir, a neuraminidase inhibitor used in the treatment of
human influenza.1
Bicyclo[3.3.0]octane structure is frequently found in natural
products, such as pentalene, pentalenolactone, hirsutic acid, and
coriolin.2 Bicyclo[3.3.0]octane derivatives are also a precursor of
otherimportantnaturalproducts, especiallymonoterpenes.Thus,the
development of an efficient synthetic preparation method for the
chiral bicyclo[3.3.0]octane framework is considered to be a challenge.
Our group3 and Jørgensen and co-workers4 have independently
developed diarylprolinol silyl ether as an effective organo-
catalyst,5,6 which is widely used in several asymmetric reactions.
aldehyde moieties, it would be a versatile chiral synthetic in-
termediate. In fact, we have converted it to the tricyclic derivative
with excellent enantioselectivity via successive Wittig and Diels–
Alder reactions.3b
It is known that
cyclopentadiene in the presence of pyrrolidine to afford
3-substituted 1-phenyl-1,2-dihydropentalene.7 This is
facile
process of the bicyclo[3.3.0]octane ring system, and is limited to
only phenyl-substituted -unsaturated ketone with only two
b-phenyl-a,b-unsaturated ketone reacts with
a
a,b
examples. We thought that the cyclopentadienyl anion would be
generated by treating a mixture of 2a and 2b with an appropriate
base, which would react with aldehyde moiety intramolecularly to
generate bicyclo[3.3.0]octatriene after
a dehydration reaction
(Scheme 1). In this communication we describe the successful re-
alization of this scenario with the synthesis of chiral bicy-
clo[3.3.0]octatrienes in a one-pot operation.
We chose a mixture of 2a and 2b as a model, and examined the
base. The results were summarized in Table 1. When NaOMe was
used in MeOH, the desired bicyclo[3.3.0]octatriene derivative 3 was
obtained in 23% yield, along with the methoxy adduct 4, which
would be generated by the overreaction of the once-generated 3
with MeOH. When 2a and 2b were treated with DBU, alcohol 5 was
obtained in good yield (84%) with a diastereomeric mixture. On the
other hand, when 2a and 2b were treated with i-Bu2NH and
p-nitrophenol, the desired 3 was obtained in good yield with ex-
cellent enantioselectivity (95% ee), which is higher than that
Recently, we reported on an ene-type reaction of a,b-unsaturated
aldehyde and cyclopentadiene catalyzed by diphenylprolinol silyl
ether 1, affording chiral cyclopentadiene derivatives with a mixture
of position isomers.3b To determine enantioselectivity, cyclo-
pentadiene derivative 2 is converted into cyclopentyl derivative,
* Corresponding author. Tel.: þ81 3 5228 8318; fax: þ81 3 5261 4631; e-mail
address: hayashi@ci.kagu.tus.ac.jp (Y. Hayashi).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.010

H. Gotoh et al. / Tetrahedron 66 (2010) 4894–4899
4895
10 mol%
NH
Ph
Ph
1
OTBS
CHO
CHO
20 mol%
OH
1) NaBH4, MeOH
2)H2, Pd/C, MeOH
p-NO2C6H4OH
CHO
+
+
(1)
Ph
Ph
Ph
Ph
MeOH, 20 h
RT
84%
2a
2b
92% ee
2a:2b =70:30
HO
Ph
CHO
CHO
CHO
base
+
Ph
Ph
Ph
Ph
2a
2b
Scheme 1. The probable reaction mechanism of the formation of bicyclo[3.3.0]octatriene.
Table 1
The effect of base in the reaction of 2 to 3a
RO
Ph
RO
Ph
CHO
CHO
base
+
+
(2)
Ph
Ph
MeOH, RT
Ph
2a
2b
3
4 R = Me
5 R = H
Entry
Base
Additive
Yieldb [%]
ee [%]c
1
NaOMed
DBUd
i-Bu2NH
i-Bu2NH
None
None
None
23e
0h
0
ndf
nd
nd
95
2g
3
4
p-NO2C6H4OHi
75
a
Unless otherwise shown, the reaction conditions: a mixture of 2a and 2b (0.2 mmol), base (0.2 mmol), in MeOH (0.4 mL) at room temperature for 24 h.
b
c
d
e
f
Isolated yield.
ee was determined by HPLC analysis using chiral column.
Base (0.4 mmol) was employed.
Methoxy derivative 4 was obtained in 15% yield.
nd¼not determined.
g
h
i
i-PrOH was used as a solvent.
Hydroxy derivative 5 was obtained in 84% yield.
p-NO2C6H4OH (0.2 mmol) was employed.
reported in the previous ene-type reaction (92% ee, vide infra). In
After optimizing the reaction conditions, the generality of the
one-pot synthesis of bicyclo[3.3.0]octatriene was investigated, and
the results were summarized in Table 2. The reaction has broad
substrate applicability. Not only phenyl, but also a 2-naphthyl-
substituted acrolein derivative gave an excellent result (entry 2).
When the substituent was electron-rich, such as 3,4-methyl-
enedioxyphenyl or p-methoxyphenyl, the reaction also proceeded
efficiently, generating bicyclo[3.3.0]octatrienes with excellent
enantioselectivity values (entries 3 and 4). Acrolein derivatives
possessing electron-deficient aromatic substituents, such as p-bro-
mophenyl were also good substrates, generating an excellent result
(entry 5). Not only aromatic groups, but also heteroaromatic groups,
such as furyl and thienyl were suitable substituents (entries 6 and 7).
The enantiomeric excess values of the ene-type and the present
reaction were found to be different, although the enantio-
discriminating step should be the same. A marked difference was
observed in the reaction of 3-thienylpropenal. That is, in the
cyclopentyl derivative 7, which is prepared by an ene-type reaction
followed by treatment with H2 in presence of Pd/C (Eq. 5),3b only
moderate enantioselectivity (79% ee) is observed, whereas in the
this reaction, both i-Bu2NH and p-nitrophenol are essential, as the
reaction does not proceed in the presence of only one of these two
reagents.8
Next, we investigated a one-pot operation for the synthesis of
bicyclo[3.3.0]octatriene structure. After the treatment of cinna-
maldehyde and cyclopentadiene in the presence of diphenylprolinol
silyl ether 1 and p-nitrophenol for 20 h, i-Bu2NH and p-nitrophenol
were added to the reaction mixture. Further stirring of the reaction
mixture afforded the bicyclo[3.3.0]octatriene 3 in good yield,
without compromising the enantioselectivity (63%, 95% ee, Eq. 3).
10 mol%
Ph
Ph
OTBS
1
NH
i-Bu2NH
20 mol%
p-NO2C6H4OH
p-NO2C6H4OH
CHO
+
(3)
Ph
MeOH, RT, 1 d
MeOH, RT, 20 h
Ph
63%, 95% ee
3

4896
H. Gotoh et al. / Tetrahedron 66 (2010) 4894–4899
ene-type reaction followed by the base treatment to afford bicy-
clo[3.3.0]octatriene derivative 8 (Eq. 6) we obtained excellent
enantioselectivity (98% ee). These data indicate that partial race-
mization occurs in the hydrogenation of cyclopentadiene 6. In the
previous paper,3b we reported the enantioselectivity of ene-type
reaction based on HPLC analysis using chiral column of a cyclo-
pentyl derivative, which was found to be inaccurate. The enantio-
meric excess of the ene-type reaction should be similar to that of
the present bicyclo[3.3.0]octatriene derivative, and they should be
revised to have the same value in Table 2.
2. Experimental section
2.1. General remarks
All reactions were carried out under argon atmosphere and
monitored by thin-layer chromatography using Merck 60 F254
precoated silica gel plates (0.25 mm thickness). FT-IR spectra
were recorded on a JASCO FT/IR-410 spectrometer. 1H and 13C
NMR spectra were recorded on a Brucker AM400 (400 MHz for
1H NMR, 100 MHz for 13C NMR) instrument. Data for 1H NMR are
10 mol%
Ph
Ph
OTBS
1
NH
CHO
CHO
20 mol%
p-NO2C6H4OH
S
S
CHO
S
+
+
MeOH, RT, 20 h
6a
6b
OH
1) NaBH4, MeOH
S
(5)
2) H2, Pd/C, MeOH
7 79% ee
8 98% ee
i-Bu2NH
p-NO2C6H4OH
S
(6)
MeOH, RT, 1 d
Although fulvenes usually react with activated alkenes to provide
Diels–Alder products,9 only in the reaction of 6-aminofulvenes, in
which fulvenes are activated by amino moiety, the [6þ2] cycloaddi-
tion reaction proceeds as reported by Hong and co-workers.10 Even in
activated 6-aminofulvenes, dimethyl acetylenedicarboxylate fails to
react in a [6þ2] cycloaddition manner. Next, bicyclo[3.3.0]octatriene
was treated with alkyne. When 3 was treated with dimethyl acety-
lenedicarboxylate under reflux condition in toluene, the [6þ2]
cycloaddition reaction proceeded smoothly to provide tricy-
clo[5.2.1.04.10]decane derivative 9 in 65% yield without compromising
the enantioselectivity (Eq. 7). This is one of the very rare successful
[6þ2] cycloaddition reactions of a fulvene derivative and dimethyl
acetylenedicarboxylate to afford a chiral tricyclic compound.
reported as chemical shift
(
d
ppm), multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet), coupling con-
stant (Hz), and integration. Data for 13C NMR are reported as
chemical shift. High-resolution mass spectral analyses (HRMS)
were carried out using Bruker ESI-TOF MS and APCI-TOF MS.
Preparative thin-layer chromatography was performed using
Wakogel B-5F purchased from Wako Pure Chemical Industries,
Tokyo, Japan. Flash chromatography was performed using silica
gel 60 N of Kanto Chemical Co. Int., Tokyo, Japan. HPLC analysis
was performed on a HITACHI Elite LaChrom Series HPLC, UV
detection monitored at appropriate wavelength, respectively,
using Chiralcel OJ-H (0.46 cmꢁ25 cm), Chiralpak OD-H
(0.46 cmꢁ25 cm).
MeO2C
H
toluene
reflux
CO2Me
MeO2C
+
(7)
CO2Me
H
Ph
Ph
65%, 95% ee
3
9
In summary, we have accomplished a one-pot synthesis of chiral
bicyclo[3.3.0]octatrienes with excellent enantioselectivity via suc-
cessive reactions, namely the diphenylprolinol silyl ether-mediated
ene-type reaction, the intramolecular addition reaction of cyclo-
pentadiene moiety with aldehyde, and dehydration. As the bicy-
clo[3.3.0]octatrienes were prepared in a one-pot operation, using
only inexpensive starting materials with excellent enantioselectivity,
the present method would be useful for the preparation of chiral
synthetic intermediates.
2.2. The synthesis of (S)-1-phenyl-1,2-dihydropentalene from
cinnamaldehyde and cyclopentadiene (Table 2, entry 1)
To a solution of catalyst 1 (22.1 mg, 0.06 mmol) and p-nitro-
phenol (16.7 mg, 0.12 mmol) in MeOH (1.2 mL) was added
(E)-cinnamaldehyde (74.8
solution was stirred for 1 min before the addition of cyclo-
pentadiene (147 L, 1.8 mmol). After stirring the reaction mixture
for 20 h at room temperature, excess cyclopentadiene was
mL, 0.6 mmol) at room temperature. The
m

H. Gotoh et al. / Tetrahedron 66 (2010) 4894–4899
4897
1H NMR (CDCl3)
d
3.00 (1H, d, J¼20.0 Hz), 3.67 (1H, ddd, J¼2.4,
Table 2
Thegeneralityoftheone-potreactionoftheformationofchiralbicyclo[3.3.0]octatrienea
6.4, 20.0 Hz), 4.17 (1H, d, J¼6.4 Hz), 5.91 (1H, d, J¼1.2 Hz), 6.23 (1H,
10 mol%
Ph
dd, J¼4.8 Hz), 6.83 (1H, d, J¼1.6 Hz), 6.90 (1H, d, J¼4.4 Hz), 7.16–
7.24 (3H, m), 7.25–7.32 (2H, m); 13C NMR (CDCl3)
d 42.1, 51.5, 112.4,
Ph
OTBS
1
NH
116.6, 126.2, 127.2 (2C), 128.5 (2C), 140.9, 142.2, 144.5, 153.6 (2C); IR
n
2921, 1628, 1491, 1471, 1452, 1320, 815, 698 cmꢀ1; HRMS
i-Bu2NH
20 mol%
(neat)
p-NO2C6H4OH
p-NO2C6H4OH
(APCI): [MþH]þ calculated for C14H13: 181.1012, found: 181.1010;
CHO
+
(4)
R
23
MeOH, RT
Yieldb [%]
63
MeOH, RT
[a
]
þ18.6 (c 0.71, CHCl3).
D
R
Entry
Product
eec [%]
2.2.1. (S)-2-(1,2-Dihydropentalen-1-yl)naphthalene (Table 2, entry
2). To a solution of catalyst 1 (22.1 mg, 0.06 mmol) and p-nitro-
phenol (16.7 mg, 0.12 mmol) in MeOH (1.2 mL) was added 3-(2-
naphthyl)propenal (109.3 mg, 0.6 mmol) at room temperature. The
solution was stirred for 1 min before the addition of cyclo-
1
95
Ph
pentadiene (147 mL, 1.8 mmol). After stirring the reaction mixture
for 20 h at room temperature, excess cyclopentadiene was azeo-
tropically removed with benzene from the reaction mixture. To
a solution of crude mixture in MeOH (1.2 mL) were added
2
79
67
98
2-Nap
p-nitrophenol (83.5 mg, 0.6 mmol) and diisobutylamine (107.7 mL,
0.6 mmol) at room temperature. The solution was stirred for 24 h.
The resulting mixture was quenched with pH 7.0 phosphate buffer.
The organic materials were extracted with AcOEt and dried over
anhydrous Na2SO4, then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to afford
(S)-2-(1,2-dihydropentalen-1-yl)naphthalene (109.1 mg, 0.47 mmol,
79%) as a yellow solid.
3
99
O
O
Enantiomeric excess was determined by HPLC using a Chiralpak
OJ-H column (100/1 hexane/i-PrOH; flow rate 1.0 mL/min, tR1¼14.9
(minor), tR2¼20.0 (major) min).
4
5
66
70
99
99
p-MeOPh
1H NMR (CDCl3)
d
3.00 (1H, dt, Jd¼20.0 Hz, Jt¼2.4 Hz), 3.63 (1H,
ddd, J¼2.8, 6.8, 20.0 Hz), 4.23 (1H, d, J¼6.4 Hz), 5.84 (1H, d,
J¼1.6 Hz), 6.17 (1H, d, J¼5.2 Hz), 6.76 (1H, q, J¼2.8 Hz), 6.83 (1H,
d, J¼4.4 Hz), 7.16 (1H, dd, J¼2.0, 8.4 Hz), 7.29–7.37 (2H, m), 7.59
(1H, d, J¼0.8 Hz), 7.63–7.72 (3H, m); 13C NMR (CDCl3)
d 42.3, 51.4,
p-BrPh
112.5, 116.8, 125.3 (2C), 125.9, 126.0, 127.6 (2C), 128.3, 132.3, 133.6,
140.9, 141.8, 142.3, 153.6, 153.7; IR (neat)
n 2926, 1715, 908, 818,
733 cmꢀ1; HRMS (APCI): [MþH]þ calculated for C18H15: 231.1168,
25
found: 231.1163; [
a
]
þ67.1 (c 1.8, CHCl3).
6
51
43
97
98
D
O
2.2.2. (S)-5-(1,2-Dihydropentalen-1-yl)benzo[d][1,3]dioxole (Table 2,
entry 3). To a solution of catalyst 1 (22.1 mg, 0.06 mmol) and
p-nitrophenol (16.7 mg, 0.12 mmol) in MeOH (1.2 mL) was added
3-(3,4-methylenedioxyphenyl)propenal (105.7 mg, 0.6 mmol) at
room temperature. The solution was stirred for 1 min before the
7
S
addition of cyclopentadiene (147 mL, 1.8 mmol). After stirring the
reaction mixture for 20 h at room temperature, excess cyclo-
pentadiene was azeotropically removed with benzene from the
reaction mixture. To a solution of crude mixture in MeOH (1.2 mL)
were added p-nitrophenol (83.5 mg, 0.6 mmol) and diisobutyl-
a
The reaction conditions:
a
,
b
-unsaturated aldehyde (0.6 mmol), cyclopentadiene
(1.8 mmol), p-nitrophenol (0.12 mmol), and catalyst
1
(0.06 mmol) in MeOH
(1.2 mL) at room temperature. After the first reaction, i-Bu2NH (0.6 mmol) and p-
nitrophenol (0.6 mmol) were added and the reaction mixture was further stirred for
one day at room temperature.
amine (107.7 mL, 0.6 mmol) at room temperature. The solution was
b
Isolated yield.
stirred for 24 h. The resulting mixture was quenched with pH 7.0
phosphate buffer. The organic materials were extracted with
AcOEt and dried over anhydrous Na2SO4, then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography to afford compound (S)-5-(1,2-dihydropentalen-
1-yl)benzo[d][1,3]dioxole (90.2 mg, 0.40 mmol, 67%) as a yellow
solid.
c
ee was determined by HPLC analysis using chiral column.
azeotropically removed with benzene from the reaction mixture.
To a solution of crude 2a, 2b in MeOH (1.2 mL) were added
p-nitrophenol (83.5 mg, 0.6 mmol) and diisobutylamine (107.7 mL,
0.6 mmol) at room temperature. The solution was stirred for 24 h.
The resulting mixture was quenched with pH 7.0 phosphate
buffer. The organic materials were extracted with AcOEt and dried
over anhydrous Na2SO4, then concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography to afford compound 3 as a yellow solid (68.1 mg,
0.38 mmol, 63%).
Enantiomeric excess was determined by HPLC using a Chiralpak
OD-H column (100/1 hexane/i-PrOH; flow rate 1.0 mL/min, tR1¼4.8
(major), tR2¼5.8 (minor) min).
Enantiomeric excess was determined by HPLC using a Chiralpak
OD-H column (100/1 hexane/i-PrOH; flow rate 1.0 mL/min, tR1¼8.0
(minor), tR2¼10.4 (major) min).
1H NMR (CDCl3)
d
2.96 (1H, d, J¼20.0 Hz), 3.63 (1H, ddd, J¼2.4,
6.4, 20.0 Hz), 4.09 (1H, d, J¼6.4 Hz), 5.89–5.94 (1H, m), 5.91 (2H, s),
6.21 (1H, d, J¼5.2 Hz), 6.63–6.75 (3H, m), 6.78–6.84 (1H, m), 6.89
(1H, d, J¼4.8 Hz); 13C NMR (CDCl3)
d 41.8, 51.6, 100.8, 107.5, 108.0,
112.4, 116.6, 120.1, 138.4, 140.9, 142.1, 145.9, 147.8, 153.5 (2C); IR
(neat)
n
2995, 1627, 1488, 1442, 1247, 1039, 936, 807 cmꢀ1; HRMS

4898
H. Gotoh et al. / Tetrahedron 66 (2010) 4894–4899
(APCI): [MþH]þ calculated for C15H13O2: 225.0910, found:
with benzene from the reaction mixture. To a solution of crude
mixture in MeOH (1.2 mL) were added p-nitrophenol (83.5 mg,
0.6 mmol) and diisobutylamine (107.7 mL, 0.6 mmol) at room tem-
24
225.0914; [
a
]
þ20.1 (c 0.22, CHCl3).
D
2.2.3. (S)-1-(4-Methoxyphenyl)-1,2-dihydropentalene (Table 2, entry
4). To a solution of catalyst 1 (22.1 mg, 0.06 mmol) and p-nitro-
phenol (16.7 mg, 0.12 mmol) in MeOH (1.2 mL) was added 3-(4-
methoxyphenyl) propenal (97.3 mg, 0.6 mmol) at room tempera-
ture. The solution was stirred for 1 min before the addition of
perature. The solution was stirred for 24 h. The resulting mixture
was quenched with pH 7.0 phosphate buffer. The organic materials
were extracted with AcOEt and dried over anhydrous Na2SO4, then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to afford (R)-2-(1,2-dihy-
dropentalen-1-yl)furan (52.1 mg, 0.31 mmol, 51%) as a yellow solid.
Enantiomeric excess was determined by HPLC using a Chiralpak
OD-H column (100/1 hexane/i-PrOH; flow rate 0.3 mL/min,
tR1¼26.4 (major), tR2¼30.6 (minor) min).
cyclopentadiene (147 mL, 1.8 mmol). After stirring the reaction
mixture for 20 h at room temperature, excess cyclopentadiene was
azeotropically removed with benzene from the reaction mixture. To
a solution of crude mixture in MeOH (1.2 mL) were added
p-nitrophenol (83.5 mg, 0.6 mmol) and diisobutylamine (107.7
mL,
1H NMR (CDCl3)
d
3.20 (1H, dd, J¼2.4, 20.0 Hz), 3.58 (1H, ddd,
0.6 mmol) at room temperature. The solution was stirred for 24 h.
The resulting mixture was quenched with pH 7.0 phosphate buffer.
The organic materials were extracted with AcOEt and dried over
anhydrous Na2SO4, then concentrated under reduced pressure.
The residue was purified by silica gel column chromatography to
afford (S)-1-(4-methoxyphenyl)-1,2-dihydropentalene (83.3 mg,
0.40 mmol, 66%) as a yellow solid.
J¼2.4, 6.4, 20.0 Hz), 4.25 (1H, d, J¼6.4 Hz), 6.06–6.11 (2H, m), 6.24
(1H, d, J¼4.8 Hz), 6.29 (1H, dd, J¼1.6, 3.2 Hz), 6.79 (1H, d, J¼1.6 Hz),
6.91 (1H, d, J¼5.2 Hz), 7.35 (1H, s); 13C NMR (CDCl3)
d 35.3, 47.6,
104.4, 110.0, 112.8, 116.9, 140.4, 141.5, 142.0, 150.2, 153.0, 156.5; IR
(neat)
n ;
2914, 1629, 1590, 1505, 1473, 1323, 1009, 815, 734 cmꢀ1
HRMS (APCI): [MþH]þ calculated for C12H11O: 171.0804, found:
23
171.0807; [
a
]
ꢀ19.6 (c 1.6, CHCl3).
D
Enantiomeric excess was determined by HPLC using a Chiralpak
OD-H column (100/1 hexane/i-PrOH; flow rate 0.3 mL/min,
tR1¼31.7 (minor), tR2¼34.6 (major) min).
2.2.6. (R)-2-(1,2-Dihydropentalen-1-yl)thiophene (Table 2, entry 7). To
a solution of catalyst 1 (22.1 mg, 0.06 mmol) and p-nitrophenol
(16.7 mg, 0.12 mmol) in MeOH (1.2 mL) was added 3-thienyl-pro-
penal (82.9 mg, 0.6 mmol) at room temperature. The solution was
1H NMR (CDCl3)
d
2.99 (1H, d, J¼20.0 Hz), 3.66 (1H, ddd, J¼2.8,
6.8, 20.0 Hz), 3.80 (3H, s), 4.15 (1H, d, J¼6.4 Hz), 5.92 (1H, s), 6.24
(1H, d, J¼4.8 Hz), 6.80–6.85 (1H, m), 6.85 (2H, d, J¼8.8 Hz), 6.92
stirred for 1 min before the addition of cyclopentadiene (147 mL,
(1H, d, J¼4.8 Hz), 7.14 (2H, d, J¼8.8 Hz); 13C NMR (CDCl3)
d
41.4, 51.6,
1.8 mmol). After stirring the reaction mixture for 20 h at room
temperature, excess cyclopentadiene was azeotropically removed
with benzene from the reaction mixture. To a solution of crude
mixture in MeOH (1.2 mL) were added p-nitrophenol (83.5 mg,
55.2, 112.3, 113.9 (2C), 116.4, 128.1 (2C), 136.5, 140.9, 142.1, 153.5,
153.9, 158.1; IR (neat)
n ;
2906, 1511, 1248, 1177, 1036, 812 cmꢀ1
HRMS (APCI): [MþH]þ calculated for C15H15O: 211.1117, found:
24
211.1119; [
a
]
þ20.9 (c 2.1, CHCl3).
0.6 mmol) and diisobutylamine (107.7 mL, 0.6 mmol) at room tem-
D
perature. The solution was stirred for 24 h. The resulting mixture
was quenched with pH 7.0 phosphate buffer. The organic materials
were extracted with AcOEt and dried over anhydrous Na2SO4, then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to afford (R)-2-(1,2-dihy-
dropentalen-1-yl)thiophene (48.1 mg, 0.26 mmol, 43%) as a yellow
solid.
2.2.4. (S)-1-(4-Bromophenyl)-1,2-dihydropentalene (Table 2, entry
5). To a solution of catalyst 1 (22.1 mg, 0.06 mmol) and p-nitro-
phenol (16.7 mg, 0.12 mmol) in MeOH (1.2 mL) was added 3-(4-
bromophenyl)propenal (126.6 mg, 0.6 mmol) at room temperature.
The solution was stirred for 1 min before the addition of cyclo-
pentadiene (147 mL, 1.8 mmol). After stirring the reaction mixture
for 20 h at room temperature, excess cyclopentadiene was azeo-
tropically removed with benzene from the reaction mixture. To
a solution of crude mixture in MeOH (1.2 mL) were added p-
Enantiomeric excess was determined by HPLC using a Chiralpak
OD-H column (100/1 hexane/i-PrOH; flow rate 0.3 mL/min,
tR1¼32.8 (major), tR2¼38.0 (minor) min).
nitrophenol (83.5 mg, 0.6 mmol) and diisobutylamine (107.7
mL,
1H NMR (CDCl3)
d
3.16 (1H, d, J¼20.0 Hz), 3.71 (1H, ddd, J¼1.6,
0.6 mmol) at room temperature. The solution was stirred for 24 h.
The resulting mixture was quenched with pH 7.0 phosphate buffer.
The organic materials were extracted with AcOEt and dried over
anhydrous Na2SO4, then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to afford
(S)-1-(4-bromophenyl)-1,2-dihydropentalene (108.8 mg, 0.42 mmol,
70%) as a yellow solid.
6.4, 20.0 Hz), 4.47 (1H, d, J¼6.4 Hz), 6.09 (1H, s), 6.25 (1H, d,
J¼5.2 Hz), 6.79 (1H, s), 6.89–6.98 (3H, m), 7.15 (1H, d, J¼4.8 Hz); 13C
NMR (CDCl3) d 37.0, 51.6, 112.7, 117.2, 123.3, 123.5, 126.6, 140.1, 142.0,
147.8,152.5,153.0; IR (neat) n ;
2924,1628,1472,1321, 813, 696 cmꢀ1
HRMS (APCI): [MþH]þ calculated for C12H11S: 187.0576, found:
25
187.0577; [
a
]
ꢀ15.1 (c 0.18, CHCl3).
D
Enantiomeric excess was determined by HPLC using a Chiralpak
OD-H column (100/1 hexane/i-PrOH; flow rate 0.3 ml/min, tR1¼31.7
(minor), tR2¼34.6 (major) min).
2 . 2 . 7 . ( S ) - D i m e t hyl - 5 - p h e nyl - 2 a , 5 , 6 , 6 a - t e t ra h y d r o -
cyclopenta[cd]pentalene-1,2-dicarboxylate 4. To a toluene solution
(4.9 mL) of compound 3 (88.2 mg, 0.49 mmol) was added dimethyl
1H NMR (CDCl3)
d
2.97 (1H, d, J¼20.0 Hz), 3.66 (1H, ddd, J¼2.4,
acetylenedicarboxylate (89.7 mL, 0.732 mmol) at room tempera-
6.4, 20.0 Hz), 4.12 (1H, d, J¼6.4 Hz), 5.90 (1H, d, J¼0.8 Hz), 6.23 (1H,
d, J¼5.2 Hz), 6.80 (1H, d, J¼1.6 Hz), 6.89 (1H, d, J¼4.4 Hz), 7.08 (2H,
ture. After stirring the reaction mixture for 10 h at 130 ꢂC, the
resulting mixture was concentrated under reduced pressure at
room temperature. The residue was purified by silica gel column
chromatography to afford compound 4 (101.7 mg, 0.32 mmol, 65%).
Enantiomeric excess was determined by HPLC using a Chiralpak IA
column (20/1 hexane/i-PrOH; flow rate 1.0 mL/min, tR1¼5.6 (mi-
nor), tR2¼6.0 (major) min).
d, J¼8.4 Hz), 7.40 (2H, d, J¼8.4 Hz); 13C NMR (CDCl3)
d 41.5, 51.4,
112.6, 116.8, 119.9, 129.0 (2C), 131.5 (2C), 140.7, 142.2, 143.6, 153.0,
1487, 1011, 808 cmꢀ1; [
a
]
þ17.4 (c 0.51, CHCl3).
23
153.5; IR (neat)
n
D
2.2.5. (R)-2-(1,2-Dihydropentalen-1-yl)furan (Table 2, entry 6). To
a solution of catalyst 1 (22.1 mg, 0.06 mmol) and p-nitrophenol
(16.7 mg, 0.12 mmol) in MeOH (1.2 mL) was added 3-furyl-prope-
nal (73.3 mg, 0.6 mmol) at room temperature. The solution was
stirred for 1 min before the addition of cyclopentadiene (147 mL,
1.8 mmol). After stirring the reaction mixture for 20 h at room
temperature, excess cyclopentadiene was azeotropically removed
1H NMR (CDCl3)
d
2.75 (1H, ddd, J¼2.0, 4.4, 16.4 Hz), 3.12 (1H,
ddd, J¼2.0, 9.2, 16.4 Hz), 3.77 (3H, s), 3.87 (3H, s), 3.91 (1H, dd,
J¼4.4, 9.2 Hz), 4.46 (1H, t, J¼2.0 Hz), 4.51 (1H, d, J¼2.8 Hz), 6.43 (1H,
d, J¼5.2 Hz), 6.80 (1H, d, J¼2.8, 4.8 Hz), 7.20 (2H, d, J¼7.2 Hz), 7.21–
7.27 (1H, m), 7.33 (2H, t, J¼7.2 Hz); 13C NMR (CDCl3)
d 41.8, 45.4,
49.8, 52.0, 81.1, 93.7, 126.3, 128.1 (2C), 128.4 (2C), 141.2, 142.8, 143.3,

H. Gotoh et al. / Tetrahedron 66 (2010) 4894–4899
4899
2008, 47, 6634; (i) Hayashi, Y.; Okano, T.; Ioth, T.; Urushima, T.; Ishikawa, H.;
Uchimaru, T. Angew. Chem., Int. Ed. 2008, 47, 9053; (j) Hayashi, Y.; Toyoshima,
M.; Gotoh, H.; Ishikawa, H. Org. Lett. 2009, 11, 45; (k) Hayashi, Y.; Obi, K.; Ohta,
Y.; Okamura, D.; Ishikawa, H. Chem. Asian J. 2009, 4, 246; (l) Gotoh, H.; Hayashi,
Y. Chem. Commun. 2009, 3083; (m) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett.
2009, 11, 3854; (n) Gotoh, H.; Okamura, D.; Ishikawa, H.; Hayashi, Y. Org. Lett.
2009, 11, 4056.
149.3, 156.3, 164.0, 165.7, 167.1; IR (neat)
n 1715, 1607, 1435, 1270,
1197 cmꢀ1; HRMS (ESI): [MþNa]þ calculated for C20H18O4Na:
23
345.1097, found: 345.1079; [
a]
ꢀ17.3 (c 0.37, MeOH).
D
Relative stereochemistry was determined by NOE experiment
after reduction of ester.
4. (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2005, 44, 794; (b) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjasgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703 Recent reports, see: (c)
Nielsen, M.; Borch, J. C.; Paixao, M. W.; Holub, N.; Jørgensen, K. A. J. Am. Chem.
Soc. 2009, 131, 10581.
5. Reviews of diarylprolinol silyl ether, see: (a) Palomo, C.; Mielgo, A. Angew.
Chem., Int. Ed. 2006, 45, 7876; (b) Mielgo, A.; Palomo, C. Chem. Asian J.
2008, 3, 922.
Acknowledgements
This work was partially supported by Grant-in-Aid for Creative
Scientific Research from The Ministry of Education, Culture, Sports,
Science, and Technology (MEXT).
6. Selected reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138; (b) Asymmetric Organocatalysis; Berkessel, A.,
Groger, H., Eds.; Wiley-VCH: Weinheim, 2005; (c) Hayashi, Y. J. Synth. Org.
Chem., Jpn. 2005, 63, 464; (d) List, B. Chem. Commun. 2006, 819; (e) Marigo, M.;
Jørgensen, K. A. Chem. Commun. 2006, 2001; (f) Gaunt, M. J.; Johansson, C. C. C.;
McNally, A.; Vo, N. T. Drug Discovery Today 2007, 12, 8; (g) Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007; (h) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (i) Barbas, C. F.,
III. Angew. Chem., Int. Ed. 2008, 47, 42; (j) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 4638; (k) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G.
Angew. Chem., Int. Ed. 2008, 47, 6138; (l) Bertelsen, S.; Jørgensen, K. A. Chem. Soc.
Rev. 2009, 38, 2178.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.03.010.
References and notes
1. Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304.
2. Review, see Singh, V.; Thomas, B. Tetrahedron 1998, 54, 3647.
7. Griesbeck, A. G. J. Org. Chem. 1989, 54, 4981.
3. (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44,
4212; (b) Gotoh, H.; Masui, R.; Ogino, H.; Shoji, M.; Hayashi, Y. Angew. Chem., Int.
Ed. 2006, 45, 6853; (c) Gotoh, H.; Hayashi, Y. Org. Lett. 2007, 9, 2859; (d)
Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46,
4922; (e) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307; (f) Hay-
ashi, Y.; Gotoh, H.; Masui, R.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 4012;
(g) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47,
4722; (h) Hayashi, Y.; Samanta, S.; Gotoh, H.; Ishikawa, H. Angew. Chem., Int. Ed.
8. Combination of amine and acid was used as a catalyst in a recent Pihko’s paper
and in Knoevenagel condensation. (a) Erkkila, A.; Pihko, P. M. Eur. J. Org. Chem.
2007, 4205; (b) Jones, G. Org. React. 1967, 15, 204.
9. (a) Gugelchuk, M. M.; Chan, P. C.-M.; Sprules, T. J. J. Org. Chem. 1994, 59, 7723;
(b) Nair, V.; Kumar, S. Tetrahedron 1996, 52, 4029; (c) Hong, B.-C.; Chen, F.-L.; Chen,
S.-H.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2005, 7, 557 and the references cited therein.
10. Hong, B.-C.; Shr, Y.-J.; Wu, J.-L.; Gupta, A. K.; Lin, K.-J. Org. Lett. 2002, 4, 2249.