Organocatalytic activity of 4-hydroxy-prolinamide alcohol with different noncovalent coordination sites in asymmetric Michael and direct aldol reactions

Article abstract of DOI:10.1016/j.tetlet.2008.10.122

4-Hydroxy-prolinamide alcohol with different noncoordination sites as a molecule showed excellent asymmetric catalytic activity in both the Michael reaction (up to 98% ee) and the direct aldol reaction (up to >99% ee), and the catalyzing reactions with hi

Full text of DOI:10.1016/j.tetlet.2008.10.122

Tetrahedron Letters 50 (2009) 193–197
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Organocatalytic activity of 4-hydroxy-prolinamide alcohol
with different noncovalent coordination sites in asymmetric
Michael and direct aldol reactions
a
a
a,
*
Yuko Okuyama a, Hiroto Nakano a, , Yuki Watanabe , Mika Makabe , Mitsuhiro Takeshita
,
*
Koji Uwai a, Chizuko Kabuto b, , Eunsang Kwon
b
*
a Department of Organic Reaction Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
b Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Hydroxy-prolinamide alcohol with different noncoordination sites as a molecule showed excellent
asymmetric catalytic activity in both the Michael reaction (up to 98% ee) and the direct aldol reaction
(up to >99% ee), and the catalyzing reactions with high enantioselectivity are supported by a DFT
theoretical study of their transition state.
Received 17 October 2008
Accepted 23 October 2008
Available online 30 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
4-Hydroxy-prolinamide alcohol
Michael reaction
Aldol reaction
DFT calculations
Asymmetric organocatalysis has emerged as an important and
rapidly growing field in synthetic organic chemistry, and excellent
covalent and noncovalent organocatalysts have been developed for
use in a wide range of reactions.1 In these organocatalysts, proline-
based covalent organocatalysts have been developed and applied
in several reactions.1 Previously reported proline-based catalysts2,3
usually have one covalent site or both a covalent and a noncovalent
site in a molecule. However, to the best of our knowledge, an
example of proline-based catalyst that properly uses the plural
noncovalent coordination site in the molecule at each reaction
has not been reported. In the present study, we planned to develop
an organocatalyst that properly uses the noncoordination sites by
the substrate used. For the design of the planned catalyst, we paid
close attention to the reports of Palomo et al.4 and Singh and co-
workers5 They have recently developed the proline-based organo-
catalysts 1 and 2, respectively, for use in Michael and direct aldol
reactions. These compounds feature both a covalent site and a non-
covalent site, the latter of which activates the substrate molecule
via hydrogen-bonding interactions. Thus, trans-4-hydroxyprolina-
mide 2 is able to hydrogen bond with a substrate molecule through
the hydroxyl group at the 4-position on the pyrrolidine ring,
making it effective in Michael reactions, and the amide moiety
at the 2-position on the pyrrolidine ring acts to control the
equilibrium between enamine conformers and blocks one enamine
face to afford a high enantioselectivity. Conversely, the amide alco-
hol at the 2-position on the pyrrolidine ring in 2-prolinamide alco-
hol 1 facilitates hydrogen bonding with the substrate and results in
effective catalysis in direct aldol reactions. However, as described
below, 2 did not work effectively in aldol reactions and 1 did not
work in Michael reactions in the present study. Given these advan-
tages and disadvantages of catalysts 1 and 2, we designed a series
of 4-hydroxy-prolinamide alcohols 3a–e with different noncova-
lent coordination sites in the molecules (Scheme 1).
Compounds 3a–e contain one covalent site and three noncova-
lent binding sites in a single molecule. For example, the hydroxyl
group at the 4-position on the pyrrolidine ring might bind a sub-
strate, and other noncovalent sites at 2-position might act to con-
trol the equilibrium between enamine conformers and block one
enamine face when the catalyst is used in a Michael reaction. On
the other hand, the amide-alcohol substituent at the 2-position
on the same molecule might bind a substrate and might catalyze
a direct aldol reaction.
This report focuses on the characterization of organocatalysts
having one covalent site and two noncovalent sites on a molecule
that properly uses the two noncovalent coordination sites by the
Michael or direct aldol reactions. The Michael6 and direct aldol7
reactions have attracted a great deal of attention because of the
important role these reactions play in carbon–carbon bond forma-
tion in synthetic organic chemistry.
* Corresponding authors. Tel.: +81 22 727 0147; fax: +81 22 275 2013 (H.N.).
E-mail address: catanaka@tohoku-pharm.ac.jp (H. Nakano).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.122

194
Y. Okuyama et al. / Tetrahedron Letters 50 (2009) 193–197
HO
HO
O
Ph
R
O
a: R=CH2Ph
b: R=Ph
c: R=CH2CH(CH3)2
R
O
4
Ph
Ph
2
OH
N
Ph
Ph
N
H2N
OH
N
H
N
Z
N
H
H
Ph
5a-c
HO
2,4-trans-4a
1
Ph
2
or
+
HO
a: R=CH2Ph
b: R=CH2CH(CH3)2
Ph
O
Ph
OH
HO
Ph
Ph
O
N
Z
H2N
OH
5d
HO
N
H
2,4-cis-4b
O
R
N
Ph
H
4
Z=CO2CH2Ph
HO
Ph
Ph
2
N
H
3a: 88%
N
3d
H
EDC, HOBt
CH2Cl2
H2, Pd-C
HO
3b: 72%
3c: 78%
3d: 80%
3e: 83%
[6a-e]
HO
Ph
O
rt, MeOH, 24h
3a-c
a: R=CH2Ph, b: R=Ph
c: R=CH2CH(CH3)2
Ph
Ph
N
N
H
Scheme 2. Preparations of organocatalysts.
H
HO
3e
model Michael reaction was run in CHCl3 containing 20 mol % of
catalyst 1a,b. Butyraldehyde 7 and b-nitrostyrene 8 were used as
the Michael donor and acceptor, respectively (Table 1). The model
aldol reaction consisted of benzaldehyde 10 and neat acetone 11 in
the presence of 10 mol % catalyst 2 (Table 3). As a result, catalysts
1a and 1b did not produce the Michael adduct 9 in satisfactory
chemical yields, and exhibited negligible enantioselectivity (Table
1, entries 1 and 2). Likewise, catalyst 2 exhibited little catalytic
activity when applied to the direct aldol reaction (Table 3, entry
1). These results imply that the amino and hydroxyl groups at
the 2-position in catalysts 1a and 1b do not effectively make a
hydrogen bond with substrate 8 in the Michael reaction. The hy-
droxyl group at the 4-position on catalyst 2 is similarly ineffective
in forming hydrogen bonds with substrate 11 in the direct aldol
reaction.
Non-Covalent sites
O
HO
4
2
N
H
N
H
O
H
Covalent site
3
O
H
O
R1
R2
R2
N
NO2
N
The Michael and aldol reactions were repeated with the
4-hydroxy-prolinamide alcohols 3a–e as catalysts. The Michael
reaction was performed at room temperature using aldehydes 7
H
O
H
O
R
Michael
reaction
aldol
reaction
R
Table 1
The effect of the catalyst in the Michael reaction of butyraldehyde with nitrostyrenea
Scheme 1. Concept of catalyst design.
Ph
O
O
NO2
catalyst
CHCl3
NO2
+
We report herein that 4-hydroxy-2-prolinamide alcohol 3
H
H
Ph
exhibits a high degree of enantioselectivity in both the Michael
(up to 98% ee) and direct aldol (up to >99% ee) reactions using sev-
eral substrates. This is the first example of a catalyst that makes
proper use of coordination site itself during a reaction, and also
changes from the coordination site to a substituent for a steric
control.
7
8
9
Entry Catalyst
(mol %)
Temp
(°C)
Time
(h)
Yieldb
(%)
drc syn/
anti
eed (%)
1
2
la (20)
lb (20)
rt
rt
20
48
75
65
93:7
94:6
41
57
The 2,4-trans- and 2,4-cis-catalysts, 3a–e, respectively, were
prepared by the condensation of 2,4-trans- or 2,4-cis-1-Cbz-hydro-
xy-2-prolines, 4a and 4b, with the corresponding b-amino alcohols
5a–d in the presence of stoichiometric amounts of HOBt and EDC.
The N-protected compounds 6a–e were then debenzyloxycarbony-
lated using H2 and Pd–C (10%) at yields up to 88% (Scheme 2).
To ascertain the efficacy of organocatalysts 3a–e, the relative
cross-reactivity of known catalysts 1a,b and 2 was examined in
the direct aldol and Michael reactions, respectively. Catalyst 2, hav-
ing the hydroxy group at the 4-position on the pyrrolidine ring,
which has been shown to be effective in direct aldol reactions,
was applied to the Michael reaction, and catalyst 1, having an
amido-alcohol substituent at the 2-position, which is generally
used in Michael reactions, was applied to the aldol reaction. A
3
4
5
3a (20)
3b (20)
3c (20)
rt
rt
rt
20
20
20
99
99
61
93:7
95:5
93:7
90
61
74
6
7
8
9
3a (20)
3a (10)
3a (5)
À45 to 0
À45 to 0
À45 to 0
8
20
20
48
72
98
89
72
54
95:5
96:4
95:5
93:7
98
96
98
98
3a (2.5)
10
11
3d (5)
3e (5)
À45 to 0
À45 to 8
20
20
95
52
96:4
88:12
80
37
a
All reactions were conducted in CHC13 (1 mL) using nitrostyrene (0.34 mmol), a
catalyst (5–20 mol %), and aldehyde (1.7 mmol).
b
Isolated yields.
c
The syn/anti ratio was determined by 1H-NMR and HPLC.
d
The ee of the syn isomer was determined by chiral HPLC using a Daicel OD-H
column.

Y. Okuyama et al. / Tetrahedron Letters 50 (2009) 193–197
195
Table 2
Table 3
Solvent effect to the Michael reactiona
The effect of the catalyst in the aldol reaction of benzaldehyde with acetonea
OH
O
cat.3a 10 mol%
O
H
9
7
+
8
O
catalyst
solvent
+
Entry
Solvent
Temp (°C)
Time (h)
Yieldb (%)
drc syn/anti
eed (%)
11
10
12
1
2
3
4
CH2C12
Hexane
MeOH
Brine
À45 to 0
À45 to 0
À45 to 0
0
20
48
20
20
82
85
60
95
96:4
97:3
88:12
94:6
96
95
85
84
Entry
1
Catalyst (mol %)
Temp (°C)
Time (h)
24
Yieldb (%)
eec (%)
2 (10)
0
Trace
2
3
4
3a (10)
3b (10)
3c (10)
0
0
0
24
24
24
83
87
—
89
85
—
a
All reactions were conducted in
a solvent (1 mL) using nitrostyrene
(0.34 mmol), catalyst 3a (0.034 mmol), and aldehyde (1.7 mmol).
b
Isolated yields.
The syn/anti ratio was determined by 1H-NMR and HPLC.
The ee of the syn isomer was determined by chiral HPLC using Daicel OD-H
5
6
3a (10)
3b (10)
À25
24
24
72
90
98
>99
c
25
d
7
8
3a (5)
3b (5)
À25
À25
24
33
71
99
99
>99
column and AD-H column.
9
10
3a (2.5)
3b (2.5)
À25
À25
46
46
72
68
98
97
and 8 (Table 1). As shown in Scheme 1, compounds 3a–c differed
according to the substituent group at the a-carbon, an (S)-config-
11
12
3d (5)
3e (5)
0
0
36
36
20
36
52
34
ured chiral center, while the gem-diphenyl group was present at
the b-carbon for all three species. The relative efficacy of these
compounds is shown in Table 1. Catalyst 3a, which bears a benzyl
a
A solution of a catalyst (0.05 mmol) in dry acetone (0.5 mL) was stirred at a
suitable temperature for half an hour. An aldehyde (0.5 mmol) was added and the
resulting mixture was stirred at 0 °C or À25 °C for 24–46 h.
b
Isolated yields.
group at the
good enantioselectivity (90% ee). Catalyst 3b, with a phenyl group
at the -carbon, demonstrated excellent catalytic activity, but the
enantioselectivity was greatly reduced (61% ee). Catalyst 3c, with
an iso-butyl group at the -carbon, was not completely soluble,
a-carbon, afforded excellent chemical yield (99%) and
c
Determined by chiral HPLC using a Daicel AD-H column.
a
oselectivity of 83% and 89% ee, respectively. However, both of these
factors were reduced with catalyst 3b. Catalyst 3c did not show
any catalytic activity.
a
producing a moderate chemical yield (61%) and enantioselectivity
(74% ee). Thus, catalyst 3a was deemed effective in the Michael
reaction. Efficacy was further increased by lowering the reaction
temperature to between À45 and 0 °C, and decreasing the amount
of catalyst to 20 mol %. Under these conditions, a dramatic increase
in enantioselectivity was observed (98% ee) together with excellent
chemical yields (98%).
The molar ratio of catalyst in the reaction mixture was an
important variable. Reaction mixtures containing 10 mol % 3a were
equally enantioselective as reactions containing 20 mol %, but the
chemical yield decreased to 89%. At 5 mol % 3a, the reaction prod-
ucts exhibited excellent asymmetric induction and were obtained
in good yield. At 2.5 mol %, the reaction was sluggish and the
chemical yield was moderate even after 72 h. Despite the poor
yield, however, the enantioselectivity (98% ee) was comparable
to that obtained at higher levels of catalyst loading.
The same reactions were then performed at À25 °C using only
catalysts 3a and 3b. The results in Table 3 show that the enantiose-
lectivity was significantly enhanced. Further enhancement was
realized by reducing the molar ratio of catalyst in the reaction mix-
ture. At 5 mol %, both 3a and 3b exhibited almost complete enanti-
oselectivity (3a: 99% ee, 3b: >99% ee). In addition, 3b afforded the
corresponding product 12 in quantitative yield. These catalysts
maintained their efficiency even at 2.5 mol %, but the diastereo-
meric isomers of 3a, 3d, and 3e did not show sufficient asymmetric
catalytic activity.
According to the results shown in Tables 1 and 3, organocatalyst
3a demonstrated superior asymmetric induction in the Michael
reaction of butyraldehyde 7 with nitrostyrene 8 and the direct al-
dol reaction of 10 with 11.
The nature of the substrate also plays a critical role in the effi-
cacy of the catalyst. Therefore, Michael and direct aldol reactions
were examined using several substrates. Michael reactions per-
formed with a variety of aldehydes and nitrostyrenes were carried
out from À45 to 0 °C using 10 mol % of catalyst 3a (Table 4). The
The catalytic activities of both the 2,4-trans-catalyst 3d, bearing
a (R)-benzyl group at the
a-carbon, and the 2,4-cis-catalyst 3e,
with a (S)-benzyl group at the
a-carbon, were also evaluated (Table
1). Catalyst 3d was no more effective than catalyst 3a, and 3e was
unsatisfactory in both chemical yield and enantioselectivity.
To determine the extent of solvent effects on the catalytic activ-
ity of these materials, the same reaction was performed using 7
and 8 in different organic and aqueous solvents between À45
and 0 °C or between À25 and 0 °C in the presence of 10 mol % of
catalyst 3a. As shown in Table 2, the enantioselectivity was highly
dependent on the nature of the solvent. High chemical yields and
enantioselectivities were obtained in dichloromethane and hexane,
while the same reaction performed in MeOH yielded poor results.
The reaction in brine resulted in a dramatic increase in the produc-
tion of 9 with an excellent chemical yield (95%) and good enanti-
oselectivity (84% ee) after 20 h. Generally, the organocatalyzed
Michael reaction in water did not proceeds smoothly and generally
required the addition of TFA to increase the reaction rate, as stated
previously.2e
Table 4
The catalytic asymmetric Michael reaction of aldehydes with nitroalkenesa
R2
O
O
NO2
cat. 3a 10 mol %
CHCl3, -45-0 °C
R1
NO2
+
H
H
R2
R1
Entry
R1
R2
Time (h)
Yieldb (%)
drc syn/anti
eed (%)
1
2
CH3
CH3
Ph
4-ClC6H4
48
48
71
65
99:1
96:4
93
94
3
4
a
n-C3H7
n-C3H7
20
48
96
72
—
95
93
S
c-CH2Ph
95:5
All reactions were conducted in CHCl3 (1 mL) using a nitroolefin (0.34 mmol),
catalyst 3a (0.034 mmol) and aldehyde (1.7 mmol).
The activity of catalysts 3a–e was then evaluated in a direct al-
dol reaction consisting of 10 mol % catalyst with benzaldehyde 10
and acetone 11 at 0 °C. The results are shown in Table 3. Catalyst
3a was fairly effective in the aldol reaction, with a yield and enanti-
b
Isolated yields.
c
The syn/anti ratio was determined by 1H-NMR and HPLC.
d
The ee of the syn isomer was determined by chiral HPLC using a Daicel OD-H
column and AD-H column.

196
Y. Okuyama et al. / Tetrahedron Letters 50 (2009) 193–197
Table 5
Michael reaction of butylaldehyde 7 with b-nitrostyrene 8 and
the aldol reaction of benzaldehyde 10 with acetone 11 using cata-
lyst 3a. For the determination of transition state (TS) models, we
referred to recent quantum mechanistic calculations performed
for the Michael4 and direct aldol8 reactions, which assume active
hydrogen bonding between the substrate and catalyst.
The catalytic asymmetric aldol reaction of aldehydes with acetonea
OH
O
cat. 3a
O
O
5 mol %
+
R1
R1
H
-25 °C
11
Entry
Rl
Time (h)
Yieldb (%)
eec (%)
In the Michael reaction, two acyclic TS models with hydrogen
bonding are assumed, as indicated by Palomo et al.4 One is the
si-face approach of donor 8 in the anti-enamine, which is defined
by the relative position between the double bond and the chiral
carbon atom (C3) of the pyrrolidine ring, and the other is the re-
face approach of 8 in the syn-enamine (Fig. 1). However, more con-
formations are possible in the present enamine, due in part to rota-
tions of the amide-alcohol substituent and the benzyl ring.
Furthermore, we assumed that b-nitrostyrene 8 forms aldol-type
hydrogen bonds. Optimization of the TS energetics yielded two
main models, mic-TS1-anti and mic-TS2-anti, which led to the
product 9 by the formation of a C–C bond on the si-face. The former
model consists of a NHÁÁÁOH hydrogen bond, which forms a five-
membered ring, while the latter involves a C@OÁÁÁHO hydrogen
bond to form a seven-membered ring. The difference in activation
1
2
3
4
5
4-MeOC6H4
4-FC6H4
2-ClC6H4
4-ClC6H4
C6H11
36
36
40
36
46
95
82
95
92
48
98
99
97
97
99
a
A solution of catalyst 3a (0.025 mmol) in dry acetone (0.5 mL) was stirred at a
suitable temperature for half an hour. An aldehyde (0.5 mmol) was added and the
resulting mixture was stirred at À25 °C for 36–46 h.
b
Isolated yields.
Determined by chiral HPLC using a Daicel AD-H column.
c
catalytic activity was moderate in reactions between propionalde-
hyde and 4-chlorobenxaldehyde or 8, while excellent enantio-
selectivity and chemical yield was obtained for reactions
between valeraldehyde and 2-(2-nitrovinyl)thiophene or aliphatic
(3-nitro-2-propenyl)benzene.
energy (DEa) between these two models is only 0.39 kcal/mol.
Thus, two mechanistic routes to the formation of product 9 are
plausible. The alternative re-syn TS models (mic-TS1-syn and
mic-TS2-syn) are unstable by 2.66 and 3.23 kcal/mol, respectively,
in the activation energy (Ea). These results agree with the high
enantioselectivity observed in the present Michael reaction. The
The effects of the substrate on the catalytic activity in direct
aldol reactions were also evaluated using several different alde-
hydes with ketones (Tables 5 and 6). In nearly all cases using ace-
tone (Table 5), an excellent enantioselectivity (97–99% ee) and
relatively good chemical yields (82–95%) were obtained. Almost
complete enantioselectivity was realized with the aliphatic cyclo-
hexanecarboxaldehyde (99% ee), but the reaction was sluggish
and the chemical yield was low even after 46 h. Using cyclohexa-
none as a donor, good chemical yields and fairly good to excellent
enantioselectivities were obtained with different aromatic alde-
hydes, except for the chemical yield of electron-deficient 4-nitro-
benzaldehyde (Table 6, entries 1–3). Furthermore, the reactions
with biologically important heterocyclic ketones afforded good
chemical yields and excellent enantioselectivities (entry 4: 70%,
96% ee, entry 5: 52%, 98% ee). In addition, the reaction of 4-pyr-
idinecarboxaldehyde with cyclohexanone also gave a good chemi-
cal yield and a fairly good enantioselectivity (68%, 93% ee, entry 6).
To better understand these experimental results, mechanistic
studies of these reactions were performed with density functional
theory (DFT) calculations at the B3LYP/6-31G* level (the details are
given in Supplementary data). As model reactions, we chose the
D
Ea values described here represent the energetic difference be-
tween the initial complex (IC) and the TS. Noteworthy is that the
IC of the si-anti approach is more stabilized than that of the re-
syn approach (
D
E is ꢀ2 kcal/mol in the complex stabilization). In
contrast, the mechanistic route via an aldol-type transition state
(mic-TS-5-anti) could be rejected because of the high energy
barrier (DEa is 5.30 kcal/mol).
DFT calculations for the aldol reaction predict only one confor-
mation of the TS per product due to the steric hindrance of the two
gem-diphenyl groups of 3a.
DEa for the two enantiomeric products
of the aldol reaction, al-TS1-(R) and al-TS1-(S), is 5.27 kcal/mol.
This result agrees with the high enantioselectivity observed in
the direct aldol reaction (Fig. 2).
In summary, we have demonstrated the organocatalytic activ-
ity of a new class of 4-hydroxy-L-prolinamide alcohols having one
covalent site and two different noncovalent coordination sites on
a molecule and observed excellent asymmetric catalysis in both
Michael and direct aldol reactions. Of the compounds evaluated,
catalyst 3a exhibited the highest chemical yield and enantioselec-
tivity in both reactions and on a variety of substrate molecules. In
addition, catalyst 3a maintained these characteristics at only
2.5 mol % in the Michael reaction and 5 mol % in the aldol reac-
tion. These results suggest that two noncovalent sites on a single
catalyst molecule can be specific for two distinct substrates. Thus,
the catalyst 3a might make proper use of the noncovalent coordi-
nation site itself by the substrate. Thus, when the hydroxy group
at the 4-position on the pyrrolidine ring makes a hydrogen bond
with a substrate molecule in Michael reactions, the amide moiety
at the 2-position on the pyrrolidine ring acts to control the equi-
librium between enamine conformers and blocks one enamine
face to afford a high enantioselectivity. Conversely, the amide
alcohol moiety at the 2-position on the pyrrolidine ring facilitates
hydrogen bonding with the substrate in direct aldol reactions.
Moreover, theoretical study of the transition state structure of
both the Michael and direct aldol reactions also provides insight
into the origins of the concept to afford the observed high enanti-
oselectivity in both reactions. Further studies, including catalyst
design modifications and mechanistic investigations, are in
progress.
Table 6
The catalytic asymmetric aldol reaction of some ketones and aldehydesa
OH
O
O
cat. 3a
O
5 mol %
R1
+
R1
MeOH
H
X
X
-10 °C, 20 h
Entry
R1
Ph
X
Yieldc (%)
anti/synd
eee (%)
1
CH2
CH2
CH2
0
S
CH2
70
43
77
70
52
68
96:4
94
96
90
96
98
93
2
4-NO2C6H4
3-MeOC6H4
Ph
89:11
83:17
92: 8
>99:1
83:17
3b
4
5
6
Ph
4-Pyridinyl
a
The reaction was performed with an aldehyde (0.4 mmol), a ketone (1.2 mmol),
catalyst 3a (0.02 mmol), and dry MeOH (0.2 mL) at À10 °C for 20 h.
b
The reaction was carried out in water at room temperature.
c
Isolated yields.
The syn/anti ratio was determined by 1H NMR and HPLC.
d
e
The ee of the anti isomer was determined by chiral HPLC using a Daicel AD-H
column and Daicel OD-H column.

Y. Okuyama et al. / Tetrahedron Letters 50 (2009) 193–197
197
Supplementary data
O1
O
O1
O
H
H1
H1
C8
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.122.
H4
O4
H
O3
H2
O2
C3
C7
C5
O2
C6
N3
O4
C4
Ph
Ph
C4
N1
C3
N1
H2
Ph
Ph
N2
N2
N3
H
C5
C7
C6
References and notes
O3
H4
C1
C1
C2
C2
1. For general reviews of asymmetric organocatalysts, see: (a) Seayad, J.; List, B.
Org. Biomol. Chem. 2005, 3, 719; (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138; (c) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37,
580; (d) List, B. Synlett 2001, 1675.
C8
2. For references regarding L-proline-catalyzed Michael reaction, see: (a) Xu, D.-Q.;
mic-TS1-anti
mic-TS2-anti
Wang, B.-T.; Luo, S.-P.; Yue, H.-D.; Wang, Li.-P.; Xu, Z.-Y. Tetrahedron: Asymmetry
2007, 18, 1788; (b) Vishnumaya; Singh, V. K. Org. Lett. 2007, 9, 1117; (c) Luo, S.
Z.; Mi, X. L.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J. P. Angew. Chem., Int. Ed. 2006, 45,
3093; (d) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624–9625; (e)
Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2006, 128, 4966; (f) Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L. Org.
Lett. 2006, 8, 6135; (g) Zu, L. S.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077;
(h) Zhu, M.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. Tetrahedron: Asymmetry
2006, 17, 491; (i) Yan, Z. Y.; Niu, Y. N.; Wei, H. L.; Wu, L. Y.; Zhao, Y. B.; Liang, Y.
M. Tetrahedron: Asymmetry 2006, 17, 3288; (j) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212; (k) Wang, W.; Wang, J.; Li, H.
Angew. Chem., Int. Ed. 2005, 44, 1369.
Ea = 10.39 kcal/mol
Ea = 10.78 kcal/mol
C7
H
Ph
Ph
O3
O1
C8
C6
H4
N3
O4
H1
C5
H2
H2
N3
C7
C6
C4
C4
Ph
Ph
O4
H1
O1
O2
N1
H4
C3
C3
C5
O
N2
C2
O2
H
O
H
O3
N2
N1
3. For references on L-proline-catalyzed direct aldol reaction, see: (a) Enders, D.;
C1
C1(S)
Gasperi, T. Chem. Commun. 2007, 88; (b) He, L.; Jiang, J.; Tang, Z.; Cui, X.; Mi, Ai.-
Q.; Jinag, Y.-Z.; Gong, L.-Z. Tetrahedron: Asymmetry 2007, 18, 265; (c) Ma, G.-N.;
Zhang, Y.-P.; Shi, M. Synthesis 2007, 197–208; (d) Hayashi, Y.; Sumiya, T.;
Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45,
958; (e) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858; (f) Casas,
J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Cordova, A. Angew. Chem., Int. Ed. 2005,
44, 1343; (g) Nyberg, A. I.; Usano, A.; Pihko, P. M. Synlett 2004, 1891; (h)
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798; (i)
Bogevig, A.; Kumaragurubaran, N.; Jorgensen, K. A. Chem. Commun. 2002, 620; (j)
Darbre, T.; Machuqueiro, M. Chem. Commun. 2003, 1090; (k) Wu, Y.-S.; Chen, Y.;
Deng, D.-S.; Cai, J. Synlett 2005, 1627; (l) Wang, W.; Li, H.; Wang, J. Tetrahedron
Lett. 2005, 46, 5077.
C2(R)
mic-TS1-syn
Ea = 13.05 kcal/mol
mic-TS5-anti
Ea = 15.69 kcal/mol
Figure 1. TS models in the Michael reaction.
4. Palomo, C.; Vera, S.; Mielgo, A.; Gomez-Bengoa, E. Angew. Chem., Int. Ed. 2006, 45,
5984.
C8
C8
5. Raj, M.; Vishnumaya; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097.
6. For recent reviews of asymmetric Michael additions, see: (a) Tsogoeva, S. B. Eur.
J. Org. Chem. 2007, 1701; (b) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877; (c) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171; (d)
Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688.
7. For reviews of asymmetric aldol reaction using chiral organocatalysis, see: (a)
List, B. Acc. Chem. Res. 2004, 37, 548; (b) Allemann, C.; Gordillo, R.; Clemente, F.
R.; Cheong, P.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558; (c)
Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570–579.
C7
C7
C5
O3
O3
C3
Ph
Ph
C6
O2
C6
O2
C5
H
N1
H2
H
C4
N1
H2
C4
Ph
Ph
C3
H1
Me
HO
H1
N2
C02
Me
C2
HO
N2
C02
O1
O1
H
H
8. Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, Ai.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5755.
C2
C1
C1
C01
C01
al-TS1-(R)
al-TS1-(S)
ΔEa = 15.10 kcal/mol
Figure 2. TS models in the direct aldol reaction.
ΔEa = 9.83 kcal/mol