Simple primary β-amino alcohol catalyzed enantioselective Diels-Alder reaction of 3-hydroxy-2-pyridones

Article abstract of DOI:10.1016/j.tetlet.2016.11.030

The simple primary β-amino alcohol catalyzed Diels-Alder reaction of 3-hydroxy-2-pyridones as dienes with N-substituted maleimides to provide the highly substituted optically active isoquinuclidines as a single diastereomers in excellent enantioselectivities (up to 98%) with excellent chemical yields (up to 95%) was demonstrated. A range of simple β-amino alcohols were synthesized from the corresponding inexpensive amino acids and their catalytic activity was examined for this reaction.

Full text of DOI:10.1016/j.tetlet.2016.11.030

Accepted Manuscript
Simple primary β-amino alcohol catalyzed enantioselective Diels-Alder reac-
tion of 3-hydroxy-2-pyridones
Toshihisa Takahashi, U.V. Subba Reddy, Yoshihito Kohari, Chigusa Seki,
Taniyuki Furuyama, Nagao Kobayashi, Yuko Okuyama, Eunsang Kwon, Koji
Uwai, Michio Tokiwa, Mitsuhiro Takeshita, Hiroto Nakano
PII:
S0040-4039(16)31486-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.030
TETL 48316
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 October 2016
2 November 2016
7 November 2016
Please cite this article as: Takahashi, T., Subba Reddy, U.V., Kohari, Y., Seki, C., Furuyama, T., Kobayashi, N.,
Okuyama, Y., Kwon, E., Uwai, K., Tokiwa, M., Takeshita, M., Nakano, H., Simple primary β-amino alcohol
catalyzed enantioselective Diels-Alder reaction of 3-hydroxy-2-pyridones, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.11.030
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Graphical Abstract
Simple primary β-amino alcohol catalyzed
enantioselective Diels-Alder reaction of 3-
hydroxy-2-pyridones
Leave this area blank for abstract info.
Toshihisa Takahashi, U. V. Subba Reddy, Yoshihito Kohari, Chigusa Seki, Taniyuki Furuyama, Nagao
Kobayashi, Yuko Okuyama, Eunsang Kwon, Koji Uwai, Michio Tokiwa, Mitsuhiro Takeshita, Hiroto Nakano

1
Tetrahedron Letters
Simple primary β-amino alcohol catalyzed enantioselective Diels-Alder reaction
of 3-hydroxy-2-pyridones
Toshihisa Takahashi,a U. V. Subba Reddy,a Yoshihito Kohari,a Chigusa Seki,a Taniyuki Furuyama,b Nagao
Kobayashi,c Yuko Okuyama,d Eunsang Kwon,e Koji Uwai,a Michio Tokiwa,f Mitsuhiro Takeshitaf and
Hiroto Nakanoa
a
Division of Sustainable and Environmental Engineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran 050-
8585, Japan
b
Graduate School of Natural Science and Technology, Kanazawa University,Kakuma-machi, Kanazawa, 920-1192, Japan
c Faculty of Textile Science and Technology, Shinshu University, Ueda, 386-8567, Japan
d Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
c Research and Analytical Center for Giant Molecules, Graduate School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
f Tokiwakai Group, 62 Numajiri Tsuduri-chou Uchigo Iwaki 973-8053, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The simple primary β-amino alcohol catalyzed Diels-Alder reaction of 3-hydroxy-2-pyridones as
dienes with N-substituted maleimides to provide the highly substituted optically active
isoquinuclidines as a single diastereomers in excellent enantioselectivities (up to 98%) with
excellent chemical yields (up to 95%) was demonstrated. A range of simple β-amino alcohols
were synthesized from the corresponding inexpensive amino acids and their catalytic activity
was examined for this reaction.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Primary -amino alcohol
Diels-Alder reaction
3-hydroxy-2-pyridone
Enantioselective organocatalysis
Introduction
intermediates of biologically active validamines6 and
pharmacologically important compounds such as oseltamivir
phosphate (Tamiflu)7(Scheme 1).
From the last 15 years, enantioselective organocatalysis is
emerging as one of the most powerful synthetic paradigm and
also as complementary to metal-catalyzed transformations to
accelerated the development of new methods to construction of
biologically active complex natural products.1 It is always
challenging task for synthetic organic chemists to develop the
general method for the enantioselective synthesis of complex
natural products. The Diels-Alder (DA) reaction is one of the
most important and powerful method as it could provide
carbocyclic compounds containing up to four contiguous stereo
genic centers in a single step.2,3 Usually, chiral Lewis acids are
effective in enantioselective Diels-Alder reaction to produce the
chiral building blocks.4 Recently, the use of optically active
organic Brønsted acids or Brønsted bases have also emerged as
an effective alternative catalysts for catalytic asymmetric DA
reactions.5 The DA reaction of 3-hydroxy-2-pyridones as diene
provides a direct and versatile access to synthetically valuable
multifunctional bicyclic optically active isoquinuclidines
containing hydroxyl group at 4-position (4-hydroxy-2-
azabicyclo[2.2.2]octanes), which are valuable synthetic
———
O
OH
O
R
OH
N
dienophiles
biologically active
compounds
N
R
Diels-Alder
reaction
R1
chiral 4- hydroxy-
isoquinuclidines
3-hydroxy-2-
pyridones
organocatalyst
OH OH
O
O
OEt
OH OH
HO
HO
HN
HO
HO
NH2
H3PO4
O
NH2
oseltamivir (Tamiflu)
(anti-influenza drug)
NH2
2-epi-validamine
(anti-sheath blight disease)
validamine
(anti-glucoside activity)
Scheme 1. Efficacy of asymmetric Diels-Alder reaction of 3-
hydroxy-2-pyridones.
However, as electron-deficient dienes of aromatic character,
3-hydroxy-2-pyridones are known to be reluctant diene partners
for DA reactions. Because of this distinct character of 3-hydroxy-
 Corresponding author. Tel.: +81 143 46 5727; e-mail: catanaka@mmm.muroran-it.ac.jp (H. Nakano)

2
Tetrahedron
2-pyridones, it is challenge for the development of a catalytic
2-pyridones and between the hydroxyl group of ammonium
alcohol intermediate and the carbonyl group at 2-position on the
2-pyridones, then dienophiles might react stereo selectively from
the less steric interaction site of diene to provide the chiral
isoquinuclidines (Scheme 3).
asymmetric variant for this synthetically useful class of DA
reactions. To the best of our knowledge, till the date there are
only few reports for racemic version of this class of DA reaction
using 3-hydroxy-2-pyridones as dienes8 and only one example
for catalytic asymmetric version of this DA reaction reported by
Tan and co-workers using indanol-typed tertiary amino alcohol
as a Brønsted base organocatalyst (Scheme 2).9
Herein, we describe the DA reaction of 3-hydroxy-2-
pyridones as dienes with N-substituted maleimides to afford the
chiral isoquinuclidines in excellent chemical yields (up to 95%)
and enantioselectivity (up to 98% ee) using simple -amino
alcohols as Brønsted base organocatalysts (Scheme 2).
Results and Discussion
Primary amino alcohol catalysts 3a-h, having aliphatic or
aromatic substituents at the -and/or -positions, respectively,
were easily prepared through well-known Grignard reaction.10f, 11
Whereas catalyst 3i was obtained by reduction of the
12
corresponding -amino acid 2.10f, Moreover, both secondary
and tertiary amino alcohols 4a,b, were prepared by treating 3d
with methyl iodide.10f Furthermore, tertiary amino alcohol 4c
containing pyrrolidinyl ring system as an amino group at -
position was prepared by the reaction of 3d with 1,4-
dibromobutane. In addition, amino silyl ether 5 was obtained
from 3d by masking the hydroxyl function with TMS
(trimethylsilyl) group by treating with TMSOTf.10g Furthermore,
,-diamine 6 was prepared by the substitution reaction of the
corresponding 3d with NaN3 followed by catalytic reduction
using Pd/C system.13 Primary amine catalyst 8 without hydroxyl
group was prepared using the well-known method from the
oxazolidinone 710f (Scheme 4).
Scheme 2. Diels-Alder reaction of 3-hydroxy-2-pyridones with
maleimides.
Recently we are developing the simple primary β-amino
alcohols and their derivatives as a new class of organocatalysts,
since they are easy to synthesize, stable on exposure to air, have
the probability of introducing different functional groups and also
alter the steric sites.10 And also, these catalysts could be used as
inexpensive alternatives to other primary amino organocatalysts
such as the chiral diamines and cinchona derived primary amines.
Because of the presence of adjacently positioned bi-functional
groups i.e, Brønsted acid and base sites, these could be used as
iminium precursors and also as hydrogen bond source (Figure 1).
1 = Ph,
1 = Bn,
1 = iPr,
1 = tBu,
:
:
:
:
R1
H2N
Ph
Ph
OH
3a
3b
3c
3d
R
R
R
R
PhMgBr
tBu
HN
Ph
Ph
O
Et2O
0 °C to rt
12 h
R1
H2N
O
3a-d
7
O
OMe
HCl
R1 = tBu
tBu
R
R
OH
:
3e
R = p-Me-Ph
H2
10% Pd/C
(3 atm)
RMgBr
・
1
:
3f R = p-F-Ph
MeOH/AcOH
Et2O
0 °C to rt
12 h
:
3g R = Me
H2N
:
3h R = Et
3e-h
tBu
Ph
Ph
H
NaBH4
I2
tBu
H
H
OH
tBu
H2N
O
H2N
8
THF
0 °C to rt
24 h
H2N
OH
3i
2
3d
Figure 1. Functionality of β-amino alcohols.
Me-I
K2CO3
Br(CH2)4Br
KI, K2CO3
TMSOTf
EtOH
120 oC, 72 h
(sealed tube)
2) H2
MeCN
reflux,48 h
1) NaN3
TFA
CHCl3
-30 oC to rt
24 h
Et3N
10% Pd/C
0 oC to rt MeOH/AcOH
rt, 1 h
In continuation of our interest to synthesize the different β-
amino alcohols and examination of their general applicability in
diverse organic transformations as chiral organocatalysts10 and
due to the importance of chiral isoquinuclidines as synthetic
intermediates, herein we desire to examine the catalytic
efficiency of simple primary β-amino alcohols in DA reaction of
3-hydroxy-2-pyridones with maleimides. The reaction of
tBu
N
Ph
Ph
OH
tBu
Ph
Ph
NH2
tBu
HN
Ph
Ph
OH
tBu
Ph
Ph
OTMS
tBu
Me
Ph
Ph
OH
+
H2N
H2N
N
6
5
Me
Me
4a
4c
4b
Scheme 4. Preparation of β-amino alcohols.
Initially, the catalytic activity of primary amino alcohol
organocatalysts 3a-d comprising aromatic and aliphatic
substituent groups at -position and diphenyl groups at -
position was examined in the DA reaction of 1-mesitylsulfonyl-
3-hydroxy-2-pyridone 9a with N-phenylmaleimide 10a in CH2Cl2
at -50 °C following the same reaction condition of Tan at all,9
and the results were presented (Table 1). All the used catalysts
showed catalytic activities to afforded endo-DA adduct 11a in
low to moderate chemical yields (31-60%) but enantioselectivity
(ee) was differ with substituent group at -position. Thus,
catalyst 3a bearing phenyl group at -position afforded the DA
adduct 11a at moderate chemical yield (51%) and a quite poor
enantioselectivity (8% ee) (entry 1). The bulkier catalyst 3b
having benzyl group improved enantioselectivity to 25% ee,
although the chemical yield was decreased (entry 2). Catalyst 3c
OH
R
R
ionic
hydrogen
bonding
O
O
N
R
O
R
R
R
OH
O
H
R
H2N
-amino alcohol
organocatalyst
HO
3-hydroxy-2-
pyridones
O
N
NH2
N
O
O
R
O
R
steric
influence
+
O
H
R
R
H
R
hydrogen
bonding
O
R
R
R
chiral
isoquinuclidines
transition state A (Ts-A)
O
dienophiles
Scheme 3. Concept for asymmetry induction using β-amino alcohol
organocatalyst.
3-hydroxy-2-pyridones as a diene with maleimides might be
afforded the DA adducts through the transition state Ts-A, in
which the diene could be fixed by the two hydrogen bonding
interactions between the ammonium site on the ammonium
alcohol intermediate and the hydroxyl group at 3-position on the

3
containing iso-propyl group at -position yield the DA adduct
with 37% ee and 60% yield (entry 3). Best enantioselectivity
(57% ee) was obtained by using catalyst 3d with tert-butyl group
at -position, although chemical yield was deeply decreased
(entry 4).
Next, we desire to study the electronic effect of the
substituent group on the phenyl group at the α-position of the
best catalyst 3d. So that, the catalytic activities of β-amino
alcohols 3e,f containing p-methyl (electron-donating) and p-
fluoro (electron-withdrawing) groups on the phenyl groups at the
α-position were tested under the same reaction conditions (Table
3). Catalyst 3e afforded the corresponding DA adduct 11e in low
chemical yield and moderate enantioselectivity (37%, 60% ee)
(entry 1). On the other hand, catalyst 3f brought about fairly good
asymmetric induction (94% ee), but chemical yield was low
(38%) (entry 2). Furthermore, the catalytic activities of amino
alcohols 3g-i containing dimethyl, diethyl and protons,
respectively, at the α-position were also examined under the same
reaction conditions (entries 3-5). However, these catalysts
afforded the DA adduct 11e in only low chemical yields and
enantioselectivities (3g: 46%, 32% ee, 3h: 42%, 40% ee, 3i:
52%, 31% ee). Also, the catalytic abilities of secondary and
tertiary amino alcohols 4a,b, respectively were also examined
(entries 6, 7). As expected, because of stronger basic property
than primary amino alcohols, these catalysts provide the 11e in
good chemical yields with excellent enantioselectivities (4a:
72%, 95% ee, 4b: 87%, 97% ee). However, they did not afford
the better result than the primary amino alcohol catalyst 3d in
respect of enantioselectivity (98% ee). Furthermore, the catalytic
activity of catalyst 4c containing pyrrolidinyl ring system also
tested in this reaction (entry 8). However, only low
enantioselectivity (40% ee) was obtained, although chemical
yield was considerably good (89%). The catalytic activity of ,-
diamine catalyst 5 was also examined (entry 9). We anticipated
that one amino group might act as a base and another amino
group might be used for hydrogen bonding with substrate but
catalyst 5 yielded the DA adduct 11e with moderate chemical
yield and enantioselectivity (51%, 70% ee). Catalyst 6 bearing
masked hydroxyl group with trimethylsilyl brought a great
decrease in chemical yield (31%), but enantioselectivity was
moderate (61% ee) (entry 10). We also examined the reaction
using catalyst 8 with no substitution for the hydroxyl group at the
α-position (entry 11). Although the catalyst 8 afforded 11e in
fairly good enantioselectivity (93% ee), but chemical yield (30%)
was low in comparison with the results of catalyst 3d with
hydroxyl group (61%, 98% ee, entry 5, Table 2).
Table 1. Diels-Alder reaction of 3-hydroxy-2-pyridone 9a with N-
phenylmaleimide 10a using catalysts 3a-d.
By using the superior catalyst 3d (10 mol%), next we carried
out the same reaction at room temperature with various dienes
and dienophiles and results were presented (Table 2). Catalyst 3d
furnished the endo-DA adduct 11a at room temperature with
enhancement of chemical yield and enantioselectivity (42%, 67%
ee) (entry 1). Considering of this result, next we examined the
reaction of 9a with N-methylmaleimide 10b and N-
ethylmaleimide 10c, respectively (entries 2, 3). However, catalyst
3d did not yield the 11b with satisfactory results (entry 2). In
contrast, fairly good enantioselectivity (87% ee) was obtained
when N-ethylmaleimide 10c was used, although chemical yield
was low (entry 3). Furthermore, the reactions of N-tosyl-3-
hydroxy-2-pyridone 9b with N-substituted maleimides 10a-c
were also carried out under the same reaction conditions (entries
4-6). But, N-phenyl-maleimide 10a and N-ethyl-maleimide 10c
did not afford the corresponding endo-DA adducts 11d,f with
satisfactorily results regarding both chemical yield and
enantioselectivity (11d: 32%, 35% ee, 11f: 38%, 65% ee) (entries
4, 6). On the other hand, excellent enantioselectivity (98% ee)
and good chemical yield (61%) was obtained from the reaction of
9b with 10b (entry 5). These results revealed that the use of 3-
hydroxy-2-pyridone 9b and N-methylmaleimide 10b in the
presence of 3d was the best combinations for obtaining chiral DA
adduct with the highest optical purity.
Table 3. Diels-Alder reaction of 9b with 10b using catalysts 3e-i,
4a-c, 5, 6, 8.
Table 2. Diels-Alder reaction of 3-hydroxy-2pyridones 9a,b with N-
substituted maleimides 10a-c using catalyst 3d.

4
Tetrahedron
From the study of catalytic efficiency of all synthesized
other hand, the new DA adduct 11e showed a positive Cotton
effect at around 249.0 nm and a negative Cotton effect at around
232.5 nm. From this experience, the absolute configuration of
11e was determined as [1R, 4R] same as 11a (Scheme 5).
catalysts, we found that catalyst 3d was superior for this reaction
to afford the best enantioselectivity (98% ee) with good chemical
yield. In order to optimize the reaction conditions, next we
examined the effects of the molar ratio of catalyst 3d, solvent,
reaction temperature and reaction time (Table 4). The increase of
catalytic loading of 3d to 20 mol% did not increase the chemical
yield and enantioselectivity (62%, 98% ee) (entry 1). On the
other hand, the decrease of catalytic loading of 3d to 5 and 2.5
O
HO
O
HO
Ts
SO Mes
O
2
O
N
N
SO2Mes
Ts
HO
HO
O
N
N
O
≡
O
O
N
N
Me
O
N
N
Ph
O
Ph
Me
O
O
[1R, 4R] - 11e
[1R, 4R ] - 11a
by X-ray analysis
mol% resulted in
a decrease the chemical yields, but
[ 1R, 4R ] - 7a
[ 1R, 4R ] - 7e
enantioselectivities were maintained at 98% ee and 96% ee,
respectively (entries 2, 3). However, 1 and 0.5 mol% of catalyst
3d brought about a great decrease in both chemical yields and
enantioselectivities (1 mol%: 24%, 69% ee, 0.5mol%: 17%, 37%
ee) (entries 4, 5). When the reaction was carried out at 0 °C, both
chemical yield and enantioselectivity (60%, 97% ee) were almost
similar to the result at room temperature (62, 97% ee) (entry 6).
The same reaction at -20 °C and -50 °C results the great decrease
of the chemical yields (-20°C: 46%, -50°C: 37%) and
enantioselectivities were also slightly decreased (-20°C: 94% ee,
-50°C: 90% ee) (entries 7, 8). Using the best reaction condition
(10 mol% of catalyst 3d, rt), extending the reaction times from 1
to 3 and 6 h led to increase the chemical yields greatly with
excellent enantioselectivity (entries 9, 10). Particularly, when the
reaction was carried out for 6 h, an excellent chemical yield and
enantioselectivity was observed (95%, 98% ee) (entry 10). Next,
we also examined the solvent effects on this reaction. Commonly
used aprotic polar (DMF, MeCN) and protic (MeOH, 2-propanol)
polar solvents were screened (entries 11-14). Unfortunately, no
improvement was observed in enantioselectivity in these solvents
with comparison the use of CH2Cl2.
By X- ray analysis.
absolute configration of [1R, 4R] - 7e
absolute configuration of [1R,4R ] - 11e
252.5 nm (+92.5)
249.0 nm (+16.2)
80%
30%
!20%
7e
11e
7a
11a
232.5 nm (-16.7)
!70%
!120%
235.5 nm (-94.2)
!170%
200%
210%
220%
230%
240%
250%
260%
270%
280%
290%
300%
[nm]
Scheme 5. Determination of absolute stereochemistry of DA adduct
11e using CD spectra.
Based on the observed enantiopurity (98% ee) (entry 10,
Table 4) of the chiral endo-DA adduct 11e that was obtained
from the reaction of 9b with 10b, the model of the
enantioselective reaction course was proposed as follows
(Scheme 6). The endo DA adduct 11e might form through the
transition state Ts-A form the reaction of reaction of 9b with
10b. In Ts-A, the pyridone 9b could be fixed by the two
hydrogen bonding interactions between the ammonium site on
the ammonium alcohol intermediate and the hydroxyl function at
3-position on 9b and between the hydroxyl group on the
ammonium alcohol intermediate and the carbonyl group at 2-
position on 9b, and then maleimide 10b might attack
enantioselectively from the one reaction site of 9b, which shows
a less steric interaction between tert-butyl and phenyl groups on
the ammonium alcohol intermediate and the dienophile 10b,
although the reason is not clear.
Table 4. Optimized conditions for Diels-Alder reaction of 9b with
10b using catalyst 3d.
OH
O
H3C
ionic
hydrogen
bonding
O
N
O
tBu
Ph
Ph
OH
O
N
H
Ts
Ts
HO
O
H2N
N
9b
NH2
3d
N
98% ee
O
O
Ts
steric
influence
+
H
O
N
H
O
hydrogen
bonding
Me
O
N
Me
[ 1R, 4R ] - 11e
O
transition state A (Ts-A)
10b
Scheme 6. Plausible reaction course.
Conclusion
In conclusion, simple optically active primary -amino
alcohol organocatalysts showed a dramatic asymmetric catalytic
activity for affording chiral DA adducts with excellent chemical
yields and enantioselectivities (up to 95% yield, up to 98% ee) in
the DA reactions of 3-hydroxy-2-pyridones with N-substituted
maleimides. In particular, catalyst 3d bearing tert-butyl group at
-position afforded the corresponding chiral endo-DA adduct 11e
with fairly good chemical yield and an excellent
enantioselectivity (95%, 98% ee). These simple -amino alcohol
catalysts might be superior for practical use, because of these
catalysts are stable in air and could be synthesized easily form
inexpensive commercially available amino acids by means of
well-known reactions in few steps. The enantioselective synthesis
of DA adducts using 3-hydroxy-2-pyridones as dienes is
challenging and important task because of the resulted DA
The absolute stereochemistry of the obtained DA adduct 11e
was determined by the CD spectroscopy. Thus, the cotton effect
pattern of the DA adduct 11e was showed to be same as that of
[1R, 4R]-11a whose structure was confirmed by X-ray
diffraction.9 DA adduct 11a with known absolute configuration
showed a positive Cotton effect at around 252.5 nm and a
negative Cotton effect at around 235.5 nm in CD spectra. On the

5
14. Spectral data for new compounds. (S)-(2-dimethylamino)-3,3-
adducts could be used as synthetic precursors for total synthesis
of various biologically active scaffolds. Application of DA
adducts in synthesis of biologically active molecules and
mechanistic studies of these catalysts for this reaction are now in
progress and results will be published in the due course.
Dimethyl-1,1-diphenylbutan-1-ol (4b): White solid, m.p. : 110-115
oC; [α]D = -36.3 (c 0.22, CHCl3); IR (neat) cm-1 : 3626, 3033,
22
2900, 1660, 1447, 1277, 1050;1H NMR (CDCl3, 500 MHz) : δ 7.58-
7.55 (m, 5H), 7.24-7.20 (m 3H), 7.10-7.07 (m, 2H), 3.72 (s,1H),
2.45 (s, 6H), 0.85 (s, 9H); 13C NMR (CDCl3, 125 MHz) : δ 148.6,
128.3, 127.9, 127.5, 127.3, 126.6, 126.5, 126.1, 125.8, 125.6, 125.4,
76.8, 76.2, 40.9, 31.2, 27.8; FAB-MS m/z : 298 [M+H]+; HRMS
(FAB) calcd for C20H28NO : 298.2170 [M + H]+, found : 298.2171.
(S)-3,3-dimethyl-1,1-diphenyl-2-(pyrrolidin-1-ly)buten-1-ol (4c):
Acknowledgment
This research is partially supported by the Adaptable & Seamless
Technology Transfer Program through Target-driven R&D from
Japan Science and Technology Agency, JST (AS231Z01382G).
o
23
Colorless solid, m.p. : 120-124 C; [α]D = -28.0 (c 0.25, CHCl3);
IR (neat) cm-1 : 3058, 2955, 2868, 1735, 1717, 1597, 1489, 1364,
1059; 1H NMR (CDCl3, 500 MHz) : δ 7.63-7.57 (m, 4H), 7.23-7.19
(m, 4H), 7.10-7.04 (m, 2H), 3.98 (s, 1H), 3.07-2.95 (m, 4H), 1.35-
1.24 (m, 4H), 0.88 (s, 9H); 13C NMR (CDCl3, 125 MHz) : δ 128.9,
128.5, 127.8, 127.7, 127.6, 127.4, 127.2, 125.9, 125.7, 125.5, 125.2,
52.1, 41.1, 31.4, 29.2, 26.7; EI-MS m/z : 323 [M]+; HRMS (EI)
calcd for C22H29NO : 323.2249 [M]+, found : 323.2241. (4R)-7-
hydroxy-9-(mesitylsulfonyl)-2-methyl-3a,4,7,7a-tetrahydro-1H-
References and notes
1.
a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. Engl. 2001, 41,
3726–3748; b) List, B. Adv. Synth. and Cat. 2004, 346, 1021; c)
Lopez, E. M.; Herrera, R. P.; Christmann, M. Nat. Prod. Rep. 2010,
27, 1138–1167; d) Atodiresei, I.; Vila, C.; Rueping M. ACS
Catal. 2015, 5, 1972–1985.
4,7-(epiminomethano)isoindole-1,3,8(2H)-trione
(11b):
Pale
°
20
yellow solid, m.p. : 180-182 C; [α]D = -2.7 (c 0.33, CHCl3); The
ee was determined by HPLC [DAICEL chiralpak AS-H column,
hexane/2-propanol = 10/90, flow rate: 0.2 mL/min, tr(major) =
2.
3.
For selective reviews of Diels-Alder reaction, see: a) Henri, B.;
Kagan B.; Riant, O. Chm. Rev. 1992. 92, 1007–1019; b) Corey, E.
J. Angew. Chem. Int. Ed. 2002, 41, 1650–1667.
For application of Diels-Alder reaction in total synthesis, see: a)
Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem. Int. Ed. 2002, 41, 1668–1698; b) Takao, K.;
Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779–4807.
Dias, L. C.; Braz. J. Chem. Soc. 1997, 8, 289–332; b) Ishihara, J.;
47.23 min, tr(minor) = 116.84 min, ee = 29 %]; IR (neat) cm-1
:
1
3329, 2948, 1779, 1735, 1689, 1439,1347, 1166, 1106; H NMR
(CDCl3, 500 MHz) : δ 6.98 (s, 2H), 6.44 (dd, 1H, J = 8.0, 5.7 Hz),
6.37 (dd, 1H, J = 8.0, 1.0 Hz), 5.81-5.79 (m, 1H), 3.74 (dd, 1H, J =
8.1, 4.3 Hz), 3.11 (d, 1H, J = 7.9 Hz), 2.95 (s, 3H), 2.57 (s, 6H),
2.29 (s, 3H); 13C NMR (CDCl3, 125 MHz) : δ 173.5, 173.2, 170.7,
144.9, 141.1, 137.3, 132.3, 131.6, 128.8, 51.3, 48.0, 44.8, 25.4,
22.7, 21.3; FAB-MS m/z : 405 [M + H]+; HRMS (FAB) calcd for
C19H21N2O6S : 405.1120 [M + H]+, found : 405.1115. (4R)-7-
hydroxy-2-phenyl-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7-
(epiminomethano)isoindole-1,3,8(2H)-trione (11d): Pale yellow
solid, m.p. : 190-191 oC; [α]D20 = -6.7 (c 0.24, CHCl3) ; The ee was
determined by HPLC [DAICEL chiralpak AD-H column, hexane/2-
propanol = 10/90, flow rate: 0.2 mL/min, tr(major) = 75.24 min,
tr(minor) = 178.13 min, ee = 35 %]; IR (neat) cm-1 : 3449, 3065,
1781, 1712, 1449, 1351, 1240, 1159, 1107; 1H NMR (CDCl3, 500
MHz) : δ 7.89 (d, 2H, J = 8.4Hz), 7.46-7.38 (m, 3H), 7.36-7.34 (m,
2H), 7.17-7.15 (m, 2H), 6.48 (dd, 1H, J = 7.9, 5.9 Hz), 6.39 (d, 1H,
J = 8.0 Hz), 5.85-5.82 (m, 1H), 4.09 (s, 1H), 3.74 (dd, 1H, J = 8.3,
4.3 Hz), 3.14 (d, 1H, J = 8.3 Hz) , 2.57 (s, 3H); 13C NMR (CDCl3,
125 MHz): δ 17 2.5, 169.7, 146.4, 136.8, 134.5, 131.1, 130.0,
129.4, 129.3, 129.2, 128.2, 126.2, 52.4, 47.3, 21.8; FAB-MS m/z :
439 [M+H]+; HRMS (FAB) calcd for C22H18N2O6S : 439.0964 [M
4.
5.
Nakadachi, S.; Watanabe, Y.; Hatakeyama, S.
J. Org.
Chem. 2015, 80, 2037–2041.
Few recently examples. a) Hatano, M.; Goto, Y.; Izumiseki, A.;
Akakura, M.; Ishihara, K. J. Am. Chem. Soc. 2015, 137, 13472–
13475; b) Wang, Y.; Tu, M. S.; Yin, L.; Sun, M.; Shi, F. J. Org.
Chem. 2015, 80, 3223–3232.
6.
a) Kameda, Y.; Kawashima, K.; Takeuchi, M.; Ikeda, K.; Asano,
N.; Matsui, K. Carbohydr Res. 1997, 300, 259–264; b) Takeuchi,
M.; Takai, N.; Asano, N.; Kameda, Y.; Matsui, K. Chem Pharm
Bull. 1990, 38, 1970–1972.
7.
8.
Javier, M. Chem. Rev. 2009, 109, 4398–4438.
a) Kipassa, N. T.; Okamura, H.; Kina, K.; Hamada, T.; Iwagawa, T.
Org. Lett. 2008, 10, 815–816; b) Posner, H. G.; Vinader, V.;
Afarinkia, K. J. J. Org. Chem. 1992, 57, 4088–4097; c) Masato, H.;
Hisao, M.; Reiko, F. Chem. Pharm. Bull. 2008, 56, 480–484; d)
Bohm, M.; Lorthiois, E.; Meyyappan, M.; Vasella, A. Hel V. Chim.
Acta. 2003, 86, 3787–3817.
H]+, found
3a,4,7,7a-tetrahydro-1H-4,7-(epiminomethano)isoindole-
: 439.0970. (4R)-7-hydroxy-2-methyl-9-tosyl-
9.
Julian, Y. S.; Tan. C. H. J. Am. Chem. Soc. 2009, 131, 6904–6905.
+
10. a) Subba Reddy, U. V.; Chennapuram, M.; Seki, C.; Okuyama, Y.;
Kwon, E.; Nakano, H. Eur. J. Org. Chem. 2016, 4124–4143; b)
Kimura, J.; Subba Reddy, U. V.; Kohari, Y.; Seki, C.; Mawatari,
Y.; Uwai, K.; Okuyama, Y.; Kwon, E.; Tokiwa, M.; Takeshita, M.;
Iwasa, T.; Nakano, H. Eur. J. Org. Chem. 2016, 3728–3756; c)
Nakano, H.; Kumagai, J.; Subba Reddy, U. V.; Seki, C.; Okuyama,
Y.; Kwon, E. J. Syn. Org. Chem. 2016, 74, 720–731; d) Kumagai,
J.; Otsuki, T.; Subba Reddy, U. V.; Kohari, Y.; Seki, C.; Uwai, K.;
Okuyama, Y.; Kwon, E.; Tokiwa, M.; Takeshita, M.; Nakano, H.
Tetrahedron: Asymmetry 2015, 26, 1423–1439; e) Otsuki, T.;
Kumagai, J.; Kohari, Y.; Okuyama, Y.; Kwon, E.; Seki, C.; Uwai,
K.; Mawatari, Y.; Kobayashi, N.; Iwasa, T.; Tokiwa, M.; Takeshita,
M.; Maeda, A.; Hashimoto, A.; Turuga, K.; Nakano, H. Eur. J.
Org. Chem. 2015, 7292–7300; f) Kohari, Y.; Okuyama, Y.; Kwon,
E.; Furuyama, T.; Kobayashi, N.; Otuki, T.; Kumagai, J.; Seki, C.;
Uwai, K.; Dai, G.; Iwasa, T.; Nakano, H. J. Org. Chem. 2014, 79,
9500–9511; g) Sakuta, Y.; Kohari, Y.; Hutabarat, N. D. M. R.;
Uwai, K.; Kwon, E.; Okuyama, Y.; Seki, C.; Matsuyama, H.;
Takano, N.; Tokiwa, M.; Takeshita, M.; Nakano, H. Heterocycles
2012, 86, 1379–1389; h) Suttibut, C.; Kohari, Y.; Igarashi, K.;
Nakano, H.; Hirama, M.; Seki, C.; Matsuyama, H.; Uwai, K.;
Takano, N.; Okuyama, Y.; Osone, K.; Takeshita, M.; Kwon, E.
Tetrahedron Lett. 2011, 52, 4745–4748; i) Nakano, H.; Osone, K.;
Takeshita, M.; Kwon, E.; Seki, C.; Matsuyama, H.; Takano, N.;
Kohari, Y. Chem. Comm. 2010, 46, 4827–4829.
1,3,8(2H)-trione (11e): White solid, m.p : 225-227 oC; [α]D = -20.7
(c 0.34, CHCl3); The ee was determined by HPLC [DAICEL
chiralpak AD-H column, hexane/2-propanol = 10/90, flow rate: 0.2
mL/min, tr(mjor) = 49.36 min, tr(minor) = 110.82 min, ee = 98 %];
IR (neat) cm-1: 3456, 3072, 1778, 1709, 1458, 1360, 1238, 1154,
1112; 1H NMR (DMSO-d6, 500 MHz): δ 7.85 (d, 2H, J = 8.5 Hz),
7.33 (d, 2H, J = 8.0 Hz), 6.34 (dd, 1H, J = 6.0, 2.0 Hz), 6.24 (dd,
1H, J = 7.5, 1.0 Hz), 5.76 (m, 1H), 3.58 (dd, 1H, J = 4.5, 3.5 Hz),
3.01 (d, 1H, J = 8.5 Hz), 2.93 (s, 3H), 2.43 (s, 3H); 13C NMR
(DMSO-d6, 125 MHz): δ 174. 7, 173.6, 170.6, 146.0, 136.6, 135.1,
130.3, 130.1, 128.2, 78.7, 52.1, 47.9, 42.0, 25.1, 21.6; FAB-MS
m/z: 377 [M+H]+; HRMS (FAB) calcd for C17H16N2O6S : 377.0807
20
[M
+ : 377.0813. (4R)-2-ethyl-7-hydroxy-9-tosyl-
H]+, found
3a,4,7,7a-tetrahydro-1H-4,7-(epiminomethano)isoindole-
1,3,8(2H)-trione (11f): Colorless solid, m.p. : 201-203 C; [α]D
o
20
=
-8.7 (c 0.35, CHCl3); The ee was determined by HPLC [DAICEL
chiralpak AD-H column, hexane/2-propanol = 10/90, flow rate: 0.2
mL/min, tr(major) = 43.25 min, tr(minor) = 11.73 min, ee = 65 %];
IR (neat) cm-1 : 3445, 2938, 1731, 1638, 1596, 1405, 1344, 1227,
1099, 976;1H NMR (CDCl3, 500 MHz) : δ 7.86 (d, 2H, J = 8.4 Hz),
7.33 (d, 2H, J = 8.0 Hz), 6.34 (dd, 1H, J = 8.0, 5.9 Hz), 6.24 (d, 1H,
J = 7.0 Hz), 5.75-5.73 (m, 1H), 4.06 (s,1H), 3.54 (dd, 1H, J = 8.0,
4.2 Hz), 3.48 (dd, 1H, J = 14.3, 7.1 Hz), 2.96 (d, 1H, J = 8.2 Hz),
2.43 (s, 3H), 1.07 (t, 3H, J = 7.2 Hz); 13C NMR (CDCl3, 125 MHz)
: δ 173.5, 173.2, 170.7, 146.3, 136.6, 134.6, 130.0, 129.3, 129.2,
128.9, 128.2, 77.7, 52.3, 47.3, 43.9, 34.3, 21.9 ; FAB-MS m/z : 391
[M+H]+; HRMS (FAB) calcd for C18H19N2O6S : 391.0964 [M +
H]+, found : 396.0963.
11. Korkmaz, N.; Astley, D.; Astley. S. T. Turk. J. Chem. 2011, 35,
361–374.
12. Malkov, A. V.; Kabeshov, M. A.; Bella, M.; Kysilka, O.;
Malyshev, D. A.; Pluhackova, K.; Kocovsky. P. Org. Lett. 2007, 9,
5473–5476.
13. Uraguchi, D.; Sakaki, S.; Ueki, Y.; Ito, T.; Ooi. T. Heterocycles
2008, 76, 1081–1085.

6
Tetrahedron
Highlights
 A series of simple -amino alcohols were
synthesized via simple organic transformations.
 Successfully utilized these -amino alcohols
as organocatalysts in DA reaction.
 Biologically important isoquinuclidines
were obtained as single diastereomers.

Products were obtained in excellent chemical
yields (95%) and enantioselectivity (98%).

Stereochemistry of products were confirmed by
CD spectra study.