The cooperative effect of a hydroxyl and carboxyl group on the catalytic ability of novel β-homoproline derivatives on direct asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tetasy.2011.01.025

Novel β-homoproline derivatives, 2-hydroxy-2-(pyrrolidin-2-yl)acetic acids (R,S)- and (S,S)-1a-d, were synthesized. All of the prepared compounds were used as organocatalysts in the direct asymmetric aldol reaction of 4-nitrobenzaldehyde with several ketones. Among these catalysts, (R)-2-hydroxy-2-((S)-pyrrolidin-2-yl)acetic acid (R,S)-1a showed good catalytic ability in the formation of aldol product 13 (up to 69% ee, 95% yield), which was similar to the results catalyzed by l-proline (71% ee, 96% yield). Relatively low yields and low enantioselectivities were observed in aldol reactions catalyzed by (S,S)-1a, for example, 13 was obtained in 55% yield and 13% ee. The aldol reaction catalyzed by the methyl-protected carboxylic acid 1b and esters 1c,d produced much lower chemical yields and enantioselectivities during the formation of 13. The cooperative effect of the (R)-configured hydroxyl group and the carboxyl group was found to play an important role in inducing enantioselectivity in the aldol reaction. Relatively high diastereoselectivities (anti:syn = 85:15) and enantioselectivity (anti, 83% ee) were observed in the aldol reactions of 4-nitrobenzaldehyde with cyclohexanone, which was catalyzed by (R,S)-1a.

Full text of DOI:10.1016/j.tetasy.2011.01.025

Tetrahedron: Asymmetry 22 (2011) 226–237
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The cooperative effect of a hydroxyl and carboxyl group on the catalytic
ability of novel b-homoproline derivatives on direct asymmetric aldol reactions
Yoshikazu Hiraga a, , Triana Widianti a, Tsuyoki Kunishi a, Manabu Abe a,b
⇑
a Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
b Japan Science and Technology Agency, CREST, 5 Sanbancho, Chiyodaku, Tokyo 102-0075, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel b-homoproline derivatives, 2-hydroxy-2-(pyrrolidin-2-yl)acetic acids (R,S)- and (S,S)-1a–d, were
synthesized. All of the prepared compounds were used as organocatalysts in the direct asymmetric aldol
reaction of 4-nitrobenzaldehyde with several ketones. Among these catalysts, (R)-2-hydroxy-2-((S)-pyrr-
olidin-2-yl)acetic acid (R,S)-1a showed good catalytic ability in the formation of aldol product 13 (up to
Received 8 December 2010
Accepted 25 January 2011
Available online 1 March 2011
69% ee, 95% yield), which was similar to the results catalyzed by L-proline (71% ee, 96% yield). Relatively
low yields and low enantioselectivities were observed in aldol reactions catalyzed by (S,S)-1a, for exam-
ple, 13 was obtained in 55% yield and 13% ee. The aldol reaction catalyzed by the methyl-protected car-
boxylic acid 1b and esters 1c,d produced much lower chemical yields and enantioselectivities during the
formation of 13. The cooperative effect of the (R)-configured hydroxyl group and the carboxyl group was
found to play an important role in inducing enantioselectivity in the aldol reaction. Relatively high dia-
stereoselectivities (anti:syn = 85:15) and enantioselectivity (anti, 83% ee) were observed in the aldol reac-
tions of 4-nitrobenzaldehyde with cyclohexanone, which was catalyzed by (R,S)-1a.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
catalysts would provide useful information regarding the role of
hydrogen bonding interaction involved in the catalytic mechanism
The use of small organic compounds as catalysts has recently
been recognized as a powerful tool for the construction of chiral
building blocks for asymmetric synthesis.1 Amongst the organocat-
of the proline-catalyzed direct aldol reaction. To this end, novel
L-
b-homoproline derivatives bearing a hydroxyl and a carboxyl
group 1a (R1 = R2 = H),
a methoxy and carboxyl group 1b
alysts developed so far for asymmetric reactions,
L-proline and pro-
(R1 = Me, R2 = H), a hydroxyl and methyl ester group 1c (R1 = H,
R2 = Me), or a methoxy and methyl ester groups 1d (R1 = R2 = Me)
were designed (Fig. 1).
line-based compounds are known to be powerful catalysts not only
in direct asymmetric aldol reactions,2,3 but also in Mannich reac-
tions,4 Michael reactions,5
a
-aminations,6 and other reactions.7
On the basis of experimental and theoretical studies of the pro-
line-catalyzed aldol reaction, it is generally accepted that the reac-
tion proceeds through an enamine-mediated mechanism.8
Recently, the detection of enamine intermediates in the proline-
catalyzed aldol reactions using NMR methods has been reported.9
Several models have also been discussed to explain the stereose-
lectivity for the proline-catalyzed aldol reaction. In some models,
the proton of the carboxyl group of the enamine intermediate
was proposed to participate in hydrogen bonding with the aldol
acceptor during the C–C bond formation step in the catalytic cy-
cle.3,8 However, to the best of our knowledge, there are only a
few reports on catalysts bearing a hydroxyl group that participated
in hydrogen bonding with the enamine intermediate and the aldol
acceptor.3 We believed that studies on hydroxyl group-containing
O
O
O
HN
(R)
HN
HN
HN
(S)
OH
OR2
OR2
OH
(S)
(S)
2
OR1
OR1
(S,S)-1
O
(R,S)-1
L-proline 2
L-β-homoproline 3
1a: R1 = R2 = H
1b: R1 = Me, R2 = H
1c: R1 = H, R2 = Me
1d: R1 = R2 = Me
Figure 1. Structures of catalysts.
Herein we report the synthesis of novel organocatalysts (R,S)-
and (S,S)-1a–d and their catalytic ability in some aldol reactions.
Furthermore, the effects of additives and solvents on the catalytic
reaction were investigated and computational studies on a model
transition states were also performed for a model aldol reaction.
⇑
Corresponding author. Tel.: +81 82 424 7434; fax: +81 82 424 7432.
E-mail address: yhiraga@sci.hiroshima-u.ac.jp (Y. Hiraga).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.025

Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
227
respectively. Analysis of the 19F NMR of the MTPA esters also
showed that the enantiomeric ratios of the alcohols 8 and 9 were
both >99:1.
2. Results and discussion
2.1. Synthesis of organocatalysts 1a–d
The Boc-protected alcohols 8 and 9 were then transformed into
organocatalysts (R,S)- and (S,S)-1a–d, respectively, as depicted in
Scheme 2. The saponification of methyl esters 8 and 9 using aque-
ous LiOH in THF,14 followed by deprotection of the Boc group of
(R,S)- and (S,S)-10 by treatment with TFA, gave hydroxyacetic acids
(R,S)- and (S,S)-1a, respectively.15 The hydroxyl groups of 8 and 916
were converted into the ether groups using MeI and Ag2O in
MeCN,16 giving the corresponding methyl ether (R,S)-11 and
(S,S)-11. The saponification of the ester groups of (R,S)- and (S,S)-
11, followed by deprotection of the Boc group of (R,S)- and (S,S)-
12 provided the corresponding (R,S)- and (S,S)-1b, respectively.
The deprotection of the Boc group of 8 and 9 using TFA yielded
the hydroxyl-substituted methyl esters (R,S)- and (S,S)-1c, respec-
tively. The deprotection of the Boc group of the methoxy methyl
esters (R,S)- and (S,S)-11 by treatment with TFA provided the
methoxy-substituted methyl ester (R,S)- and (S,S)-1d in quantita-
tive yields, respectively.
Organocatalysts (R,S)- and (S,S)-1a–d were synthesized from
Boc-L-proline 4, which was prepared from the commercially avail-
able
L
-proline 2. As shown in Scheme 1, Boc-L-proline 4 was treated
with cyanophosphorane 510 to give cyanoketophosphorane 6.
Ozonolysis of ketophosphorane 6 in the presence of methanol
according to the reported methods10b,11 gave the methyl
a
-ketoes-
ter 7 in 9.6% yield (over two steps from 4) as with a high enantio-
meric ratio (>99:1) determined by HPLC. Reduction of methyl
a
-
ketoester 7 with zinc borohydride at ꢀ78 °C afforded a diastereo-
mixture of alcohols 8 and 9.10b,12 Alcohols 8 and 9 could be sepa-
rated by column chromatography on silica gel and isolated in
47% and 17% yield, respectively.
In order to assign the absolute stereochemistry of the C-2 at-
tached hydroxyl group in the diastereomeric alcohols 8 and 9,
the corresponding (R)- and (S)-methoxy trifluoromethyl phenyl
acetic acid (MTPA) esters of 8 and 9 (8-r-Boc, 8-s-Boc, 9-r-Boc,
9-s-Boc) were prepared.13 The Boc group of MTPA esters of 8-r-
Boc, 8-s-Boc, 9-r-Boc, and 9-s-Boc was removed by treatment
with trifluoroacetic acid (TFA) to give the corresponding amines
8-r-NH, 8-s-NH, 9-r-NH, 9-s-NH, respectively. As shown in Table 1,
2.2. The direct asymmetric aldol reaction of 4-
nitrobenzaldehyde with acetone
The catalytic ability of compounds (R,S)- and (S,S)-1a–d was ini-
tially examined in the aldol reaction of 4-nitrobenzaldehyde with
acetone using DMSO as a solvent. Reactions using L-proline 2 and
the
D
dY [d(S)-MTPA ester ꢀ d(R)-MTPA ester] values obtained from
the 1H NMR data of 8-s-NH, 8-r-NH, 9-s-NH, and 9-r-NH indicated
that the absolute configuration at C-2 in 8 and 9 is (R) and (S),
PPh3
b
PPh3
a
Boc
Boc
N
N
Boc
N
OH
CN
CN
O
O
4
5
6
O
O
O
c
Boc
N
Boc
N
OMe
OMe
OMe
OH
OH
O
8
9
7
Scheme 1. Synthesis of alcohols 8 and 9. Reagents and conditions: (a) EDCI, DMAP, CH2Cl2, rt, 24 h; (b) O3, CH2Cl2–MeOH, ꢀ78 °C, 3.5 h, 9.6% (over two steps); (c) Zn(BH4)2,
THF, ꢀ78 °C, 2.5 h, 8 47%, 9 17%.
Table 1
1H NMR spectral data for 8-s-NH, 8-r-NH, 9-s-NH and 9-r-NH (in d) in CD3ODa
4'
5'
3'
2
O
3"
OMe
HN
2'
1'
O
O
F3C
Ph
OMe
H-2
5.60
5.70
ꢀ0.10
H-20
4.09
4.15
ꢀ0.06
H-30
H-40
H-50
H-300
3.80
3.86
ꢀ0.06
8-s-NH
2.25
2.15
+0.10
1.89
1.56
+0.33
2.06
1.66
+0.40
2.00
1.80
+0.20
3.30
3.18
+0.12
3.25
2.87
+0.38
8-r-NH
b
D
dY
9-s-NH
5.58
5.58
0.00
4.09
4.13
ꢀ0.04
2.03
2.20
ꢀ0.17
1.82
1.92
ꢀ0.10
2.03
2.07
ꢀ0.04
1.92
1.98
ꢀ0.06
3.28
3.35
ꢀ0.07
3.06
3.26
ꢀ0.20
3.88
3.82
+0.06
9-r-NH
b
D
dY
a
Chemical shift values are given in ppm. Assignments were confirmed by 1H–1H COSY, HMQC, and HMBC experiments.
d(S)-MTPA ester ꢀ d(R)-MTPA ester.
b

228
Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
O
c
O
O
O
a
c
HN
TFA
Boc
N
Boc
N
HN
TFA
*
*
*
*
OMe
OMe
OH
OH
2
OH
OH
OH
OH
(R,S)-1c
(S,S)-1c
(R,S)-1a
(S,S)-1a
8: (R)-OH
9: (S)-OH
(R,S)-10 (59%)
(S,S)-10 (81%)
b
O
O
O
*
c
O
*
c
a
Boc
N
*
Boc
N
*
HN
TFA
HN
TFA
OH
OMe
OH
OMe
OMe
OMe
OMe
OMe
(R,S)-1d
(S,S)-1d
(R,S)-11 (92%)
(S,S)-11 (71%)
(R,S)-1b
(S,S)-1b
(R,S)-12 (71%)
(S,S)-12 (74%)
Scheme 2. Synthesis of catalysts (R,S) and (S,S)-1a–d. Reagents and conditions: (a) 1 M LiOH, THF, rt, 3 h; (b) Ag2O, MeI, MeCN, rt, 12 h; (c) TFA, rt, 12 h, >99%.
L
-b-homoproline 3 as the catalyst were also carried out for the sake
line 3, while the selectivity in the presence of (R,S)-1a showed
higher enantioselectivity than the -b-homoproline-catalyzed reac-
of comparison. All reactions were performed at 25 °C for 24 h in the
presence of 20 mol % of catalyst and triethylamine. The results are
summarized in Table 2. As shown in Table 2, (R,S)-1a (R1 = R2 = H),
which has a (R)-hydroxyl and a carboxyl group, catalyzed the aldol
reaction, giving the product 13 in 95% yield with 63% ee (entry 1).
The aldol product has the same configuration as those obtained
L
tion. The results indicate that the stereochemistry at the hydroxyl-
substituted carbon is important to enhance the enantioselectivity.
Based on these results, it is suggested that intramolecular hydro-
gen bonding between the hydroxyl group and the carboxyl group,
which increases the acidity of the carboxyl group, plays an impor-
tant role in increasing both the chemical yield of 13 and its enanti-
oselectivity. As the acidity increases, the hydrogen bonding
between the catalyst and aldehyde (aldol acceptor) would become
stronger, and thus the reaction rate and enantioselectivity may
increase.
from L-proline 2 and L-b-homoproline 3 catalyzed reactions (en-
tries 9 and 10).2a On the other hand, in the presence of (S,S)-1a, al-
dol product 13 was obtained in 55% yield with 13% ee (entry 2),
which were much lower values than those observed for the (R,S)-
1a-catalyzed reaction. The aldol reactions catalyzed by (R,S)- and
(S,S)-1b (R1 = Me, R2 = H), which contain a methoxy and a carboxyl
group, gave the aldol product 13 in moderate yields, although the
observed enantioselectivity in 13 was much lower than that cata-
lyzed by (R,S)-1a (entries 3 and 4). The reactions catalyzed by (R,S)-
and (S,S)-1c (R1 = H, R2 = Me) and (R,S)- and (S,S)-1d (R1 = R2 = Me)
were sluggish, giving the aldol product 13 in only small amounts
(entries 5–8). Amongst the catalysts examined herein, catalyst
(R,S)-1a bearing a (R)-configured hydroxyl group showed the best
catalytic activity and enantioselectivity. The results clearly indicate
that the carboxyl group (R2 = H) in catalysts 1 is important for the
catalytic ability. It should be noted that the enantioselectivity cat-
2.3. Influence of the additive on the direct asymmetric aldol
reaction using organocatalysts (R,S)-1a and (R,S)-1b
Since additives have been known to alter the reactivity and
selectivity of organic reactions,17,18 the effect of additives on the al-
dol reaction using catalysts (R,S)-1a and (R,S)-1b was examined.
The addition of additives improved the enantioselectivity of the
catalyst (R,S)-1a and (R,S)-1b. The results of this examination are
shown in Table 3. In the case of the reaction catalyzed by the
TFA salt of (R,S)-1a without an additive, the yield of 13 greatly
decreased, although the enantioselectivity was not so affected
alyzed by (S,S)-1a was lower than that catalyzed by L-b-homopro-
Table 2
The direct asymmetric aldol reaction of 4-nitrobenzaldehyde with acetone in DMSO in the presence of various catalysts
O
O
OH
O
catalyst (20 mol%)
O
+
H
+
DMSO
25°C, 24 h
NO2
NO2
Yielda (%)
NO2
13
14
Entry
Catalyst
ee of 13b (%)
13
14
1
2
3
4
5
6
7
8
9
(R,S)-1ac
(S,S)-1ac
(R,S)-1bc
(S,S)-1bc
(R,S)-1cc
(S,S)-1cc
(R,S)-1dc
(S,S)-1dc
95
55
63
61
6
5
9
0
96
3
2
37
15
0
0
0
0
4
63
13
15
11
31
21
18
—
71
L
-Proline (2)
-b-HomoprolineꢁHCl (3)c
10
79
0
46
L
a
b
c
Determined by 1H NMR analysis of the crude products.
Determined by HPLC using a Daisel CHIRALCEl OJ column (hexane–iPrOH, 75:25).
20 mol % of Et3N was added.

Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
229
Table 3
Table 4
Influence of the additive for the direct asymmetric aldol reaction of 4-nitrobenzal-
Solvent screening for the direct asymmetric aldol reaction of 4-nitrobenzaldehyde
dehyde with acetone using organocatalysts (R,S)-1a and (R,S)-1ba
with acetone using organocatalysts (R,S)-1aa
Entry
Catalyst
Additive
Yieldb (%)
ee of 13c (%)
Entry
Solvent
Yieldb (%)
ee of 13c (%)
13
14
13
14
1
2
3
4
5
6
7
8
9
(R,S)-1ad
(R,S)-1ae
(R,S)-1ad
(R,S)-1ad
(R,S)-1ae
(R,S)-1ad
(R,S)-1ad
(R,S)-1ad
(R,S)-1bg
(R,S)-1bg
None
None
13
87
95
80
56
75
84
52
66
63
4
3
3
19
4
6
57
52
63
65
52
69
69
68
17
15
1
2
3
4
5
6
7
DMSO
THF
CH3CN
Acetone
CH2Cl2
EtOH
95
24
20
49
7
3
0
0
0
4
4
0
63
43
45
39
39
29
2
Et3N (20 mol %)
Morpholine (20 mol %)
Et3NꢁHCl (20 mol %)
MS 3 Å (5 mg)f
MS 4 Å (5 mg)f
MS 5 Å (5 mg)f
None
72
83
4
H2O
11
34
37
a
All reactions were carried out at 25 °C for 24 h in the presence of 20 mol % of
(R,S)-1a and 20 mol % of Et3N.
10
Et3N (20 mol %)
Determined by 1H NMR analysis of the crude products.
b
a
c
All reactions were carried out at 25 °C for 24 h in the presence of 20 mol % of
catalyst.
Determined by HPLC using a Daicel CHIRALCEL OJ column (hexane–iPrOH,
75:25).
Determined by 1H NMR analysis of the crude products.
b
c
Determined by HPLC using a Daisel CHIRALCEL OJ column (hexane–iPrOH,
75:25).
d
When the reaction was performed in either the presence of MS
3 Å or 4 Å, it afforded higher enantioselectivities than those per-
formed in the presence of organic bases, such as triethylamine
and morphorine (entries 6 and 7). In the presence of MS 5 Å, the
enantiomeric excess of 13 was similar to those obtained from the
reaction in the presence of MS 3 Å or 4 Å, whereas the chemical
yield decreased (entry 8). Thus, amongst the additives tested MS
3 Å and 4 Å appear to provide a small improvement in the enanti-
oselectivity of 13. In the case of TFA-(R,S)-1b catalyzed aldol reac-
tions, regardless of the presence or absence of triethylamine as an
additive, there was no significant difference in the chemical yield
or enantioselectivity (entries 9 and 10).
TFA salt form of (R,S)-1a was used.
TFA free form of (R,S)-1a was used.
All molecular sieves were dried using a microwave oven before use.
TFA salt form of (R,S)-1b was used.
e
f
g
(entries 1 vs 2). Previously, it has been reported that the reactivity
and selectivity of aldol reactions in water depend on the pH of the
reaction mixture.2w This fact suggests that when the TFA salt of
(R,S)-1a was used without the addition of an organic base, such
as triethylamine or morpholine, the reactivity and enantioselectiv-
ity are poor due to the high acidity of TFA. On the other hand, when
the TFA-free form of (R,S)-1a was used as the catalyst, both the
chemical yield and enantiomeric excess of 13 slightly decreased
compared to those obtained from the reaction catalyzed by the
TFA salt of (R,S)-1a with triethylamine (entry 3). The slight de-
crease in the chemical yield and enantiomeric excess of the TFA-
free (R,S)-1a catalyzed reaction was probably caused by its poor
solubility in DMSO. When morpholine, which is a weak organic
base, was used as an additive, the chemical yield of the aldol reac-
tion was slightly decreased, although the enantioselectivity was
not affected (entry 4). In order to investigate the role of triethyl-
amine in enhancing the enantioselectivity of 13, the aldol reaction
using the TFA free form of (R,S)-1a as catalyst and triethylammo-
nium chloride as the additive was performed (entry 5). The chem-
ical yield and the enantioselectivity of 13 obtained from the
reaction were 56% and 52%, respectively. Although the enantio-
meric excess of 13 obtained from the reactions catalyzed by the
TFA free form of (R,S)-1a remained unchanged regardless of the ab-
sence or presence of triethylammonium chloride, a decrease in the
chemical yield of 13 was observed by the addition of triethylam-
monium chloride as an additive (entries 2 and 5). Since the TFA
free form of (R,S)-1a hardly dissolved in the reaction mixture,
whereas the TFA salt of (R,S)-1a with triethylamine was dissolved
in the reaction mixture, the yield might be dependent upon the sol-
ubility of the catalyst in the reaction mixture. On the other hand,
the enantioselectivity of the catalyst correlated with the acidity
of the catalyst in the reaction mixture.2y
2.4. Influence of the solvent on the direct asymmetric aldol
reaction using (R,S)-1a as a catalyst
The effect of the organic solvent was investigated in the direct
aldol reaction of 4-nitrobenzaldhyde with acetone at 25 °C in the
presence of 20 mol % of catalyst (R,S)-1a. As can be seen in Table 4,
the yield and enantioselectivity of the aldol product 13 were
slightly decreased when aprotic solvents such as THF, acetonitrile
or acetone were used (entries 2–4). Dichoromethane was found
to be not suitable as a solvent for the aldol reaction (entry 5). When
protic solvents such as ethanol or water were used, the chemical
yield of the aldol product 13 was similar to that obtained from
the reaction in DMSO, although the enantioselectivity was signifi-
cantly decreased (entries 6 and 7). Overall, the aprotic polar sol-
vent, DMSO appeared to be the best solvent amongst the
solvents tested.
2.5. Asymmetric direct aldol reactions of various ketones and 4-
nitrobenzaldehyde using catalyst (R,S)-1a
The catalytic ability of (R,S)-1a was examined in the direct aldol
reaction of either butan-2-one or cyclohexanone with 4-nitrobenz-
aldehyde (Table 5). All reactions were carried out in DMSO at 25 °C
for 24 h in the presence of 20 mol % of the TFA free form of catalyst
(R,S)-1a. When butan-2-one was used, the direct aldol reaction
proceeded slowly, giving the aldol product 15a (8% yield, 70% ee)
together with syn and anti-15b [4% yield; syn:anti = 28:72; 72%
ee (anti)] after 24 h (entry 1). Due to the small amount of syn-
15b, the enantioselectivity of syn-15b was not determined. The
diastereoselectivity and enantioselectivity of this reaction were
Previously, it was reported that the mesoporous molecular
sieves, such as MS 3 Å {K9Na3[(AlO2)12(SiO2)12]}, 4 Å {Na12[(A-
lO2)12(SiO2)12]}, 5 Å {Ca4.5Na3[(AlO2)12]}, could be used to capture
strong protic acids, such as TfOH, owing to their basic charac-
ters.18b Moreover, the molecular sieves were also used as additives
in the organocatalyzed direct aldol reactions to trap water.18c
Water was proven to be the reason as to why the enantiomeric ex-
cess of 13 in the (R,S)-1a catalyzed aldol reaction decreased (Ta-
ble 4, entry 7). In order to trap TFA and water, the reactions were
performed in the presences of the molecular sieves as additives.
similar to those of the L
-proline-catalyzed aldol reaction.2b,v,w The
reaction of cyclohexanone and 4-nitrobenzaldehyde provided the
syn- and anti-aldol products 16 (entry 2). The major diastereomer
anti-16 (83% ee) was obtained in the similar enantioselectivity as
compared with the reported value of the anti-product from the L-

230
Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
Table 5
The direct aldol reaction of various ketones and 4-nitrobenzaldehyde using organocatalyst (R,S)-1aa
Entry
Ketone
Product
Yieldb (%)
drb (anti:syn)
eec (%)
70
O
O
OH
8
—
NO2
15a
1
O
OH
72 (anti)
nd (syn)d
4
72:28
85:15
NO2
15b
O
O
OH
83 (anti)
48 (syn)
2
45
OH
16
a
b
c
All reactions were carried out at 25 °C for 24 h in DMSO in the presence of 20 mol % of TFA free form of (R,S)-1a.
Determined by 1H NMR analysis of the crude products. Yield was calculated by the mole of 4-nitrobenzaldehyde as starting material.
Ee of the products was determined by HPLC using a Daicel CHIRALPAK AS and AD-H columns.
Not determined.
d
proline-catalyzed reaction (89% ee); a higher diastereoselectiviy
The possible structures of the transition states were calculated
for the model reaction of acetone with acetoaldehyde using density
function theory (DFT) at the B3LYP/6-311++G(d,p) level in the gas
phase. All calculations were performed by using the GAUSSIAN 03
program.19
(syn:anti = 15:85) as compared to that of the L-proline catalyzed
reaction (syn:anti = 37:63) was observed.2g,o Thus, it can be seen
that the direct aldol reaction (R,S)-1a of 4-nitrobenzaldehyde and
ketones using organocatalyst gave the corresponding aldol prod-
ucts with similar or higher diastereoselectivity as compared to
Transition states TS-1–6 and TS-10–40 of the re-face and si-face
the
L-proline catalyzed reaction.
attack to the aldehyde acceptor from (R,S)- and (S,S)-1a, and L-b-
homoproline 4, were found in the computations (Fig. 3). As clearly
indicated in Figure 3, the transition states TS-1,3,5 and TS-10,30,
which produce the (R)-aldol product, were calculated to be ener-
getically more stable than the transition states TS-2,4,6 and TS-
20,40 for the si-face attack. For the reaction of the enamine of
(R,S)-1a, the transition states TS-10 and TS-20, which possess the
double hydrogen-bonding at the same oxygen, were more energet-
ically stable than the transition state TS-1 and TS-2. However, tran-
sition states TS-3 and TS-4 were found to be more stable structures
than TS-30 and TS-40 for the reaction of the (S,S)-1a based-enamine.
In our experiments, the enantioselectivity obtained in the (R,S)-1a-
catalyzed reaction was higher than that catalyzed by (S,S)-1a.
However, the calculated energy differences between the transition
states derived from (R,S)-1a, for example, TS-10 and TS-20, were
found to be smaller than those obtained for the transition states
derived from (S,S)-1a, for example, TS-3 and TS-4. Thus, the com-
putations in the gas phase do not reproduce well the experimental
2.6. Computational studies
Our experimental studies can be summarized as follows: (1) the
catalytic ability and the enantioselectivity were largely dependent
upon the configuration of the hydroxyl-substituted carbon. Thus,
the chemical yield and the enantioselectivity obtained by the
(R,S)-1a-catalyzed reaction were much higher than those observed
in the (S,S)-1a-catalyzed reaction (Table 1, entries 1 and 2). (2) The
cooperative effect of the hydroxyl and carboxyl group of the cata-
lysts was observed especially with regard to the enantioselectivity
(Table 1, entries 1 and 3). Thus, the enantioselectivity obtained by
(R,S)-1a was much higher than that in the presence of (R,S)-1b. The
stereochemical outcome for the formation of the (R)-enantiomer of
13 can be explained by the possible transition states TS and TS0
according to the Houk’s model,8a,b,g considering enamine interme-
diate (Fig. 2).
H
O
O
O
N
H
(R)
O
H
HN
O
OH
(R)
R
OH
(R,S)-1a
R'
re-face
H
O
OH
O
O
TS
R
R'
(R)
R
H
R'
O (R)
H
N
H
O
H
O
O
R
R'
re-face
TS'
H
Figure 2. Plausible transition states in the (R,S)-1a catalyzed reaction.

Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
231
Figure 3. Transition state structures for the reaction of acetoaldehyde and acetone catalyzed by (R,S)- and (S,S)-1a and
L-b-homoproline. The relative energies are in the
parentheses at B3LYP/6-311++G(d,p) level in the gas phase. All bond lengths are in angstroms (Å).
observations, although the stereochemical outcome of the major
(R)-configuration was consistent with the experiments. The med-
ium effect, for example, solvent effect, may affect the energetic sta-
bility of the polar structures. Thus, further discussion based on the
gas-phase energies should be avoided. Further computational stud-
ies to understand the cooperative effect on the enantioselectivity
and catalytic ability of the novel organocatalysts 1a are currently
ongoing.

232
Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
ratio (1.6:1.0) was determined by 1H NMR; FAB-HRMS calcd for
30H32N2O3P [M+H]+, 499.2151; found 499.2149.
3. Conclusions
C
In conclusion, we have synthesized novel organocatalysts (R,S)-
and (S,S)-1a–d bearing a b-homoproline skeleton. Amongst these
organocatalysts, (R,S)-1a showed the best catalytic ability and
enantioselectivity for the direct asymmetric aldol reaction of 4-
nitrobenzaldehyde with various ketones. Based on the experimen-
tal and theoretical results, we found that the stereochemistry of
the hydroxyl-substituted carbon in (R,S)-1a plays an important role
in enhancing the enantioselectivity of the aldol reaction while the
carboxylic acid group is an essential factor for the catalytic activity.
The cooperative effect in this study stimulates the molecular de-
sign of organocatalysts for asymmetric reactions. Reaction condi-
tions and the limitations of the substrates are currently under
investigation. We are also currently studying the application of
other organic reactions using catalyst (R,S)-1a.
4.2.2. (2S)-tert-Butyl 2-(20-methoxy-20-oxoacetyl)pyrrolidine-1-
carboxylate 7
A solution of crude 6 (4.50 g) in a mixture of dichloromethane–
methanol (7:3, 30 mL) was treated with ozone at ꢀ78 °C for
40 min. The solution was flushed with nitrogen for 10 min and
then allowed to warm to room temperature. The solvent was evap-
orated and the resulting residue was purified by column chroma-
tography (hexane/EtOAc, 6:1) on silica gel to give 321 mg (9.6%)
of 7 as a colorless liquid; ½a D25
ꢃ
¼ ꢀ32:8 (c 0.884, CHCl3); 1H NMR
(500 MHz, CDCl3) d 4.86 (dd, J = 4.9, 8.5 Hz, minor-0.42H), 4.74
(dd, J = 5.7, 8.7 Hz, major-0.58H), 3.85 (s, major-1.75H), 3.83 (s,
minor-1.25H), 3.53–3.38 (m, 2H), 2.35–2.20 (m, 1H), 2.06–1.81
(m, 3H), 1.42 (s, minor-3.75H), 1.35 (s, minor-5.25H); 13C NMR
(125 MHz, CDCl3) d 193.1 (192.6), 161.3 (161.0), 153.3 (154.5),
80.6 (80.2), 62.5 (62.2), 52.8, 46.7 (46.6), 30.0 (28.9), 28.0 (28.3)
(ꢂ3), 23.7 (24.5) (chemical shift in parentheses is the minor amide
rotational isomer); the amide rotamer ratio (1.4:1.0) was deter-
mined by 1H NMR; FAB-HRMS calcd for C12H20NO5 [M+H]+,
258.1341; found 258.1347. The ee value of 7 was determined by
HPLC analysis using a Daicel CHIRALCEL OJ column (hexane/i-
PrOH, 80:10, kmax 254 nm, flow rate = 0.5 mL/min), tR = 34.4 min
(>99%) and 39.5 min (<1%).
4. Experimental
4.1. General
All chemicals were purchased from Wako Chemicals, Tokyo Ka-
sei, and Sigma–Aldrich in their highest purity. Flash column chro-
matography was performed on 230–430 mesh silica gel. 1H NMR
(500 MHz), 13C NMR (125 MHz), and 19F NMR (372 MHz) spectra
were recorded in CDCl3 and CD3OD with JEOL NM-ECP500, JEOL
NM-LA500, and JEOL NM-AL400 spectrometers. Chemical shifts
in 1H NMR, 13C NMR and 19F NMR are given in parts per million
(ppm) relative to internal TMS (d 0.00 ppm), CDCl3 (d 7.24 ppm),
and CD3OD (d 3.31 ppm) for 1H NMR, TMS (d 0.00 ppm), CDCl3 (d
77.0 ppm), and CD3OD (d 49.0 ppm) for 13C NMR, and external tri-
fluoroacetic acid (d ꢀ76.5 ppm) for 19F NMR. HRMS was recorded
on JEOL SX-102A and Thermo Fisher Scientific LTQ Orbitrap XL
spectrometers. Optical rotations were measured on a Horiba
SEPA-300 polarimeter. Enantioselectivity (%ee) was determined
by HPLC analysis of the reaction mixture with a system consisting
of a Jasco 980-PU pump and a Jasco 970-UV detector.
4.2.3. (2S,10R)- and (2S,10S)-tert-Butyl 2-(10-hydroxy-20-methoxy-
20-oxoethyl)pyrrolidine-1-carboxylate 8 and 9
To a stirred solution of 7 (500 mg, 1.94 mmol) in THF (20 mL), a
freshly prepared solution of zinc borohydride11 (15 mL, 2.2 equiv)
in ether was added under cooling at ꢀ78 °C. The reaction mixture
was stirred for 4 h under an N2 atmosphere at the same tempera-
ture. The reaction mixture was quenched by adding 10 mL of water
and 10 mL of ethyl acetate. The organic phase was separated, and
the aqueous phase was extracted with ethyl acetate (3 ꢂ 10 mL).
The combined organic phase was dried over anhydrous Na2SO4
and evaporated to afford the crude products. Column chromatogra-
phy on silica gel eluting with hexane–ethyl acetate (6:1) afforded 8
(238 mg, 47%) as a colorless liquid; ½a D25
¼ ꢀ49:4 (c 0.516, CHCl3);
ꢃ
4.2. Preparation of organocatalysts 1a–d
1H NMR (CD3OD, 500 MHz) d 4.51–4.45 (m, minor-0.37H), 4.33–
4.28 (m, major-0.63H), 4.16–4.09 (m, major-0.63H), 4.09–4.01
(m, minor-0.37H), 3.72 (s, 3H), 3.42–3.38 (m, 2H), 2.09–1.96 (m,
2H), 1.95–1.74 (m, 2H), 1.46 (s, minor-3.33H), 1.44 (s, major-
5.67H), the hydroxyl proton was not observed because of broaden-
ing of the signal; 13C NMR (CD3OD, 125 MHz) d 175.0, 156.8
(156.3), 80.9 (81.5), 73.1 (72.1), 61.1, 52.6, 48.0 (48.6), 28.8 (ꢂ3),
28.7 (28.3), 24.9 (23.8) (chemical shift in parentheses is the minor
amide rotational isomer); the amide rotamer ratio (1.7:1.0) was
determined by 1H NMR; FAB-HRMS calcd for C12H23NO5 [M+H]+,
260.1498; found 260.1506; ESI-HRMS calcd for C12H21NO5Na
[M+Na]+ 282.1312; found 282.1317.
4.2.1. (2S)-tert-Burtyl 2-(20-cyano-20-
triphenylphosphoranylideneacetyl)pyrrolidine-1-carboxylate 6
To a stirred solution of Boc-L-proline 4 (2.80 g, 13 mmol), 1-(3-
diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
(2.68 g, 14 mmol), and 4-dimethylaminopyridine (0.159 g,
1.3 mmol), (triphenylphosphoranylidene)acetonitrile 510 (8.44 g,
28 mmol) in 60 mL of dichloromethane were added dropwise un-
der cooling in an ice water bath. The stirring was continued for
20 h at room temperature under an N2 atmosphere. The mixture
was then poured over water (5 mL) and the organic phase was sep-
arated. The aqueous phase was extracted with dichloromethane
(25 mL ꢂ 3). The combined organic phase was dried over anhy-
drous Na2SO4. The solvent was evaporated to afford 4.50 g of crude
product containing 6 as yellow oil. The cyanoketophosphorane 6
was used in the next step without purification; 1H NMR
(500 MHz, CDCl3) d (ppm) 7.63–7.45 (m, 15H), 4.93 (dd, J = 8.7,
3.6 Hz, 1H), 3.48–3.32 (m, 2H), 2.35–2.24 (m, 1H), 2.01–1.84 (m,
1H), 1.83–1.76 (m, 1H), 1.44 (s, minor-3.46H), 1.40 (s, major-
5.54H); 13C NMR (125 MHz, CDCl3) d (ppm) 195.8 (195.9) (d,
JCP = 3.1 Hz), 153.9 (154.9), 133.5 (133.6) (d, JCP = 10.3 Hz) (ꢂ6),
133.4 (ꢂ3), 133.1 (132.8) (d, JCP = 2.4 Hz) (ꢂ3), 129.0 (128.9) (d,
JCP = 13.0 Hz) (ꢂ6), 123.0 (123.2) (d, JCP = 93.8 Hz), 121.6 (121.3)
(d, JCP = 16.0 Hz), 78.9 (78.8), 61.6 (61.8) (d, JCP = 9.1 Hz), 46.6
(46.9), 31.4 (30.1), 28.4 (ꢂ3), 23.3 (24.4) (chemical shift in paren-
theses is the minor amide rotational isomer); the amide rotamers
Further elution with hexane–ethyl acetate (5:3) afforded 9
(84 mg, 17%) as a colorless liquid; ½a D25
¼ ꢀ37:8 (c 0.344, CHCl3);
ꢃ
1H NMR (CD3OD, 500 MHz) d 4.59 (m, minor-0.48H), 4.55 (m, ma-
jor-0.52H), 4.08–4.05 (m, 1H), 3.74 (s, minor-1.43H), 3.72 (s, ma-
jor-1.57H), 3.46–3.38 (m, 1H), 3.34–3.26 (m, 1H), 2.04–1.71 (m,
4H), 1.47 (s, minor-4.29H), 1.46 (s, major-4.71H), the hydroxyl pro-
ton was not observed because of broadening of the signal; 13C NMR
(CD3OD, 125 MHz) d 174.8 (174.7), 156.5 (156.1), 80.9 (81.4), 72.0
(72.5), 61.2, 52.6, 48.5 (48.0), 28.8 (ꢂ3), 27.2 (27.0), 25.0 (24.6)
(chemical shift in parentheses is the minor amide rotational iso-
mer); the amide rotamer ratio (1.1:1.0) was determined by 1H
NMR; FAB-HRMS calcd for C12H23NO5 [M+H]+, 260.1498; found
260.1507; ESI-HRMS calcd for C12H21NO5Na [M+Na]+ 282.1312;
found 282.1314.

Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
233
4.2.4. (S)- and (R)-MTPA esters of the alcohols 8 and 9
A solution of 8 (3.7 mg, 0.014 mmol) in dry pyridine (50
mixture was stirred at room temperature for 12 h. The reaction
mixture was concentrated in vacuo to remove the solvent to afford
the TFA salt of (S)-MTPA ester, 8-s-NH (1.1 mg, >99%). The (R)-
MTPA and (S)-MTPA esters, 8-r-NH (1.3 mg), 9-s-NH (1.7 mg),
and 9-r-NH (1.4 mg) were prepared according to the same proce-
dure. The 1H NMR data of 8-s-NH, 8-r-NH, 9-s-NH, and 9-r-NH
are summarized in Table 1.
lL) was
treated with (R)-(ꢀ)-MTPA chloride (10 mg, 0.040 mmol). The
solution was allowed to stand for 10 h. N,N-Dimethyl-1,3-propane-
diamine (5 lL) was added to quench the excess chloride. The sol-
vent was evaporated under reduced pressure to afford the crude
products. This crude product was purified by column chromatogra-
phy on silica gel eluted with hexane–ethyl acetate (5:1) affording
(S)-MTPA ester of 8 (8-s-Boc) (5.5 mg, 78%). The (R)-MTPA ester
of 8-r-Boc (2.5 mg, 85%) and (S)- and (R)-MTPA esters of 9-s-Boc
(1.9 mg, 82%) and 9-r-Boc (1.5 mg, 84%) were prepared according
to the same procedure as described above.
4.2.4.5. 8-s-NH. 1H NMR (500 MHz, CD3OD) d 7.57–7.40 (m, 5H),
5.60 (d, J = 5.7 Hz, 1H), 4.09 (m, 1H), 3.80 (s, 3H), 3.55 (s, 3H),
3.30 (m, 1H), 3.25 (m, 1H), 2.25 (m, 1H), 2.06 (m, 1H), 2.00 (m,
1H), 1.89 (m, 1H), the amine proton was not observed because of
broadening of the signal; 13C NMR (125 MHz, CD3OD) d 167.9,
166.9, 132.4, 131.2, 129.5 (ꢂ2), 128.9 (ꢂ2), 124.5 (d,
J = 287.7 Hz), 86.2 (d, J = 27.8 Hz), 74.1, 60.0, 56.4, 53.8, 47.6,
28.0, 24.8; 19F NMR (372 MHz, CD3OD) d ꢀ76.1 (s, CF3), ꢀ76.5 (s,
CF3COOH); ESI-HRMS calcd for C17H21NO5F3 [M+H]+ 376.1366;
found 376.1371.
4.2.4.1. 8-s-Boc. 1H NMR (500 MHz, CD3OD) d 7.67–7.36 (m, 5H),
5.43–5.38 (m, minor-0.31H), 5.31–5.24 (m, major-0.69H), 4.38–
4.31 (m, major-0.69H), 4.29–4.22 (m, minor-0.31H), 3.77 (s, min-
or-0.94H), 3.74 (s, major-2.06H), 3.51 (s, 3H), 3.43–3.28 (m, 1H),
3.22–3.04 (m, 1H), 2.14–1.63 (m, 4H), 1.45 (s, minor-2.81H), 1.42
(s, major-6.19H); 13C NMR (125 MHz, CD3OD) d 169.5, 167.3,
156.3 (155.8), 133.0 (132.9), 130.9 (131.0), 129.4 (ꢂ2), 129.1
(128.9) (ꢂ2), 124.7 (d, J = 288.6 Hz), 86.1 (d, J = 27.6 Hz), 81.2
(82.0), 76.4 (75.4), 58.5 (58.8), 56.0, 53.1, 48.1 (47.7), 29.1 (28.9),
28.7 (ꢂ3), 24.5 (23.6) (chemical shift in parentheses is the minor
amide rotational isomer); the amide rotamer ratio (2.2:1.0) was
determined by 1H NMR.
4.2.4.6. 8-r-NH. 1H NMR (500 MHz, CD3OD) d 7.63–7.42 (m, 5H),
5.70 (d, J = 4.3 Hz, 1H), 4.15 (m, 1H), 3.86 (s, 3H), 3.70 (s, 3H),
3.18 (m, 1H), 2.87 (m, 1H), 2.15 (m, 1H), 1.80 (m, 1H), 1.66 (m,
1H), 1.56 (m, 1H), the amine proton was not observed because of
broadening of the signal; 13C NMR (125 MHz, CD3OD) d 168.1,
166.8, 133.3, 131.3, 129.7 (ꢂ2), 128.3 (ꢂ2), 124.6 (d,
J = 288.4 Hz), 85.7 (d, J = 27.8 Hz), 73.5, 59.9, 56.8, 54.0, 47.7,
27.7, 24.7; 19F NMR (372 MHz, CD3OD) d ꢀ75.8 (s, CF3), ꢀ76.5 (s,
CF3COOH); ESI-HRMS calcd for C17H21NO5F3 [M+H]+ 376.1366;
found 376.1372.
4.2.4.2. 8-r-Boc. 1H NMR (500 MHz, CD3OD) d 7.61–7.40 (m, 5H),
5.39–5.33 (m, minor-0.31H), 5.23–5.17 (m, major-0.69H), 4.35–
4.29 (m, major-0.69H), 4.17–4.10 (m, minor-0.31H), 3.80 (s, min-
or-0.94H), 3.77 (s, major-2.06H), 3.71 (s, major-2.06H), 3.67 (s,
minor-0.94H), 3.17–3.02 (m, 2H), 2.05–1.28 (m, 4H), 1.45 (s, min-
or-2.81H), 1.42 (s, major-6.19H); 13C NMR (125 MHz, CD3OD) d
169.7, 167.3, 156.2, 133.6 (133.8), 130.9, 129.5 (ꢂ2), 128.3 (ꢂ2),
124.7 (d, J = 288.1 Hz), 85.7 (d, J = 27.6 Hz), 81.1 (82.0), 76.7
(76.7), 58.4 (58.6), 56.5, 53.2, 48.2 (47.8), 29.3 (29.1), 28.7 (ꢂ3),
24.3 (23.4) (chemical shift in parentheses is the minor amide rota-
tional isomer); the amide rotamer ratio (2.2:1.0) was determined
by 1H NMR.
4.2.4.7. 9-s-NH. 1H NMR (500 MHz, CD3OD) d 7.64–7.44 (m, 5H),
5.58 (d, J = 6.4 Hz, 1H), 4.09 (m, 1H), 3.88 (s, 3H), 3.67 (s, 3H),
3.28 (m, 1H), 3.06 (m, 1H), 2.03 (m, 2H), 1.92 (m, 1H), 1.82 (m,
1H), the amine proton was not observed because of broadening
of the signal; 13C NMR (125 MHz, CD3OD) d 168.0, 166.7, 133.0,
131.2, 129.6 (ꢂ2), 128.6 (ꢂ2), 124.6 (d, J = 288.4 Hz), 85.8 (d,
J = 27.8 Hz), 73.6, 59.6, 56.5, 54.1, 47.5, 27.8, 24.4; 19F NMR
(372 MHz, CD3OD) d ꢀ73.1 (s, CF3), ꢀ76.5 (s, CF3COOH); ESI-HRMS
calcd for C17H21NO5F3 [M+H]+ 376.1366; found 376.1374.
4.2.4.3. 9-s-Boc. 1H NMR (500 MHz, CD3OD) d 7.60–7.38 (m, 5H),
5.86–5.83 (m, major-0.55H), 5.79–5.78 (m, minor-0.45H), 4.27–
4.19 (m, 1H), 3.81 (s, major-1.64H), 3.80 (s, minor-1.36H), 3.72
(s, major-1.64H), 3.70 (s, minor-1.36H), 3.12–3.01 (m, 1H), 2.62–
2.40 (m, 1H), 1.95–1.70 (m, 2H), 1.68–1.48 (m, 2H), 1.51 (s, ma-
jor-4.91H), 1.44 (s, minor-4.09H); 13C NMR (125 MHz, CD3OD) d
169.3 (169.5), 167.3 (167.6), 155.1 (155.9), 133.8 (133.9), 130.8
(130.8), 129.7 (129.6) (ꢂ2), 128.0 (128.1) (ꢂ2), 124.7 (d,
J = 288.4 Hz), 85.7 (d, J = 27.8 Hz), 81.9 (81.3), 75.1 (74.6), 58.6,
56.7 (56.6), 53.3 (53.2), 47.6 (47.8), 28.7 (28.7) (ꢂ3), 27.9 (27.0),
24.0 (24.6) (chemical shift in parentheses is the minor amide rota-
tional isomer); the amide rotamer ratio (1.2:1.0) was determined
by 1H NMR.
4.2.4.8. 9-r-NH. 1H NMR (500 MHz, CD3OD) d 7.60–7.45 (m, 5H),
5.58 (d, J = 6.5 Hz, 1H), 4.13 (m, 1H), 3.82 (s, 3H), 3.55 (s, 3H),
3.35 (m, 1H), 2.26 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.98 (m,
1H), 1.92 (m, 1H), the amine proton was not observed because of
broadening of the signal; 13C NMR (125 MHz, CD3OD) d 167.9,
166.7, 132.4, 131.2, 129.5 (ꢂ2), 129.9 (ꢂ2), 124.5 (d,
J = 288.7 Hz), 86.1 (d, J = 27.4 Hz), 73.8, 59.6, 56.3, 53.9, 47.7,
27.9, 24.5; 19F NMR (372 MHz, CD3OD) d ꢀ71.0 (s, CF3), ꢀ76.5 (s,
CF3COOH); ESI-HRMS calcd for C17H21NO5F3 [M+H]+ 376.1366;
found 376.1372.
4.2.5. (2R,20S)-2-[10-(tert-Butoxycarbonyl)pyrrolidin-20-yl]-2-
hydroxyacetic acid (R,S)-10 and (2S,20S)-2-[10-(tert-
4.2.4.4. 9-r-Boc. 1H NMR (500 MHz, CD3OD) d 7.57–7.39 (m, 5H),
5.84–5.78 (m, 1H), 4.31–4.24 (m, 1H), 3.79 (s, major-1.57H), 3.78
(s, minor-1.43H), 3.49 (s, 3H), 3.42–3.12 (m, 2H), 2.02–1.62 (m,
4H), 1.48 (s, major-4.71H), 1.45 (s, minor-4.29H); 13C NMR
(125 MHz, CD3OD) d 169.2 (168.9), 167.5 (167.2), 155.5 (156.0),
133.2, 130.9, 129.5 (129.4) (ꢂ2), 128.7 (128.8) (ꢂ2), 124.6 (d,
J = 287.7 Hz), 86.1 (d, J = 27.6 Hz), 82.1 (81.5), 75.3 (74.6), 58.5
(58.6), 55.9, 53.2 (53.1), 48.1 (48.4), 28.7 (ꢂ3), 27.8 (27.0), 24.0
(24.6) (chemical shift in parentheses is the minor amide rotational
isomer); the amide rotamer ratio (1.1:1.0) was determined by 1H
NMR.
butoxycarbonyl)pyrrolidin-20-yl]-2-hydroxyacetic acid (S,S)-10
To a stirred solution of 8 (131 mg, 0.51 mmol) in tetrahydrofu-
ran (2 mL) was added 1.0 mL of aqueous 1.0 M LiOH solution. The
mixture was stirred at room temperature for 3 h. The reaction mix-
ture was concentrated in vacuo to remove the solvent. The result-
ing residue was purified by silica gel column chromatography
(CHCl3/MeOH, 4:1) to afford (R,S)-10 (73 mg, 59%) as a colorless li-
quid; ½a 2D5
ꢃ
¼ ꢀ35:8 (c 1.47, CH3OH); 1H NMR (500 MHz, CD3OD) d
4.25–3.96 (m, 2H), 3.33–3.19 (m, 2H), 2.14–1.57 (m, 4H), 1.37 (s,
9H), the hydroxyl and carboxyl protons were not observed because
of broadening of the signals; 13C NMR (125 MHz, CD3OD) d 179.1
(178.5), 157.7 (156.5), 81.2, 75.2 (73.7), 61.9 (61.4), 48.3 (48.2),
28.8 (ꢂ3), 28.7 (28.7), 24.6 (23.9) (chemical shift in parentheses
To
a solution of 8-s-Boc (1.4 mg, 0.003 mmol) in CH2Cl2
(1.0 mL) were added 0.1 mL of trifluoro acetic acid. The reaction

234
Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
is the minor amide rotational isomer); the amide rotamer ratio
could not be determined by 1H NMR because of overlapping of
the major and minor signals; ESI-HRMS calcd for C11H19NO5Na
[M+Na]+ 268.1155; found 268.1155.
rotational isomer); the amide rotamer ratio (1.7:1.0) was deter-
mined by 1H NMR; ESI-HRMS calcd for C12H21NO5Na [M+Na]+
282.1312; found 282.1313.
Compound (S,S)-12 was prepared from (S,S)-11 according to the
Compound (S,S)-10 was obtained from 9 in the same manner as
same procedure as above: ½a D25
ꢃ
¼ ꢀ62:2 (c 0.740, CH3OH); 1H NMR
above: ½a 2D5
ꢃ
¼ ꢀ44:4 (c 0.394, CH3OH); 1H NMR (500 MHz, CD3OD)
(500 MHz, CD3OD) d 4.18–4.10 (m, 2H), 3.44–3.32 (m, 5H), 2.04–
1.66 (m, 4H), 1.49 (s, minor-3.75H), 1.46 (s, major-5.25H), the car-
boxyl proton was not observed because of broadening of the sig-
nal; 13C NMR (125 MHz, CD3OD) d 178.6 (178.1), 156.3 (156.3),
83.6 (84.0), 81.0 (81.4), 60.9 (60.8), 59.4 (59.6), 48.5 (48.3), 28.9
(ꢂ3), 27.3 (27.9), 25.2 (24.5) (chemical shift in parentheses is the
minor amide rotational isomer); the amide rotamer ratio
(1.4:1.0) was determined by 1H NMR; ESI-HRMS calcd for
C12H21NO5Na [M+Na]+ 282.1312; found 282.1314.
d 4.67–4.54 (m, 1H), 4.26–4.17 (m, 1H), 3.48–3.25 (m, 2H), 2.07–
1.64 (m, 4H), 1.47 (s, 9H), the hydroxyl and carboxyl protons were
not observed because of broadening of the signals; 13C NMR
(125 MHz, CD3OD) d 179.1, 156.5 (156.5), 81.2 (81.0), 74.4 (74.8),
61.8, 48.4 (48.6), 28.9 (ꢂ3), 27.5 (27.2), 24.9 (25.4) (chemical shift
in parentheses is minor amide rotational isomer); the amide rot-
amer ratio could not be determined by 1H NMR because of overlap-
ping of the major and minor signals; ESI-HRMS calcd for
C
11H19NO5Na [M+Na]+ 268.1155; found 268.1158.
4.3. Organocatalysts (R,S)- and (S,S)-1a–d
4.2.6. (2S,10R)-tert-Butyl 2-(10,20-dimethoxy-20-
oxoethy)pyrrolidine-1-carboxylate (R,S)-11 and (2S,10S)-tert-
butyl 2-(10,20-dimethoxy-20-oxoethy)pyrrolidine-1-carboxylate
(S,S)-11
4.3.1. (2R,20S)-2-Hydroxy-2-(pyrrolidin-20-yl)acetic acid TFA salt
(R,S)-1a
To a solution of (R,S)-10 (72 mg, 0.30 mmol) in CH2Cl2 (3 mL)
was added 0.5 mL of trifluoroacetic acid. The reaction mixture
was stirred at room temperature for 12 h. The reaction mixture
was concentrated in vacuo to remove the solvent to afford the
TFA salt form of (R,S)-1a (71 mg, >99%) as a colorless liquid;
To a stirred solution of 8 (33 mg, 0.127 mmol) in CH3CN
(0.5 mL) was added Ag2O (50 mg) and CH3I (0.5 mL). The mixture
was stirred at room temperature for 12 h. The reaction mixture
was filtered through Celite and concentrated. The residue was
purified by column chromatography on silica gel (hexane/EtOAc,
½
a 2D5
ꢃ
¼ ꢀ9:2 (c 0.546, CH3OH); 1H NMR (500 MHz, CD3OD) d 4.30
5:1) to afford (R,S)-11 (32 mg, 92%) as
a colorless liquid;
(d, J = 4.8 Hz, 1H), 3.88–3.83 (m, 1H), 3.29–3.24 (m, 2H), 2.25–
1.95 (m, 4H), the hydroxyl, carboxyl, and amino protons were
not observed because of broadening of the signals; 13C NMR
(125 MHz, CD3OD) d 174.1, 70.4, 62.9, 47.0, 28.2, 24.9; 19F NMR
(372 MHz, CD3OD) d ꢀ76.5 (s, CF3COOH); ESI-HRMS calcd for
C6H12NO3 [M+H]+ 146.0812; found 146.0813.
½
a 2D5
ꢃ
¼ ꢀ74:2 (c 1.51, CHCl3), 1H NMR (500 MHz, CDCl3) d 4.20–
4.00 (m, 2H) 3.72 (s, 3H), 3.36 (s, 3H), 3.45–3.15 (m, 2H), 2.10–
1.90 (m, 2H), 1.86–1.67 (m, 2H), 1.43 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 171.6, 154.7 (154.1), 80.8 (80.4), 79.3 (79.7), 58.5, 58.4,
52.0, 47.2 (46.6), 28.4 (ꢂ3), 27.2 (27.0), 23.9 (22.9) (chemical shift
in parentheses is the minor amide rotational isomer); the amide
rotamer ratio could not be determined by 1H NMR because of over-
lapping of the major and minor signals; ESI-HRMS calcd for
By the same procedure, the TFA salt forms of (S,S)-1a, (R,S)- and
(S,S)-1b–d were prepared from the corresponding Boc-protected
precursors (S,S)-10, (R,S)-12, (S,S)-12, (R,S)-8, (S,S)-9, (R,S)-11, and
(S,S)-11, respectively.
C
13H23NO5Na [M+Na]+ 296.1468; found 296.1473.
(S,S)-11 was prepared from 9 according to the same procedure
as described above;
½
a 2D5
ꢃ
¼ ꢀ78:5 (c 0.789, CHCl3), 1H NMR
4.3.2. (2S,20S)-2-Hydroxy-2-(pyrrolidin-20-yl)acetic acid TFA salt
(S,S)-1a
(500 MHz, CDCl3) d 4.39–4.33 (m, major-0.63H), 4.19–4.14 (m,
minor-0.37H), 4.12–4.06 (m, major-0.63H), 4.05–4.00 (m, minor-
0.37H), 3.73 (s, minor-1.11H), 3.71 (s, major-1.89H), 3.47–3.39
(m, minor-0.74H), 3.36 (s, 3H), 3.36–3.28 (m, major-1.26H),
2.01–1.86 (m, 2H), 1.82–1.65 (m, 2H), 1.46 (s, minor-3.33H), 1.44
(s, major-5.67H); 13C NMR (125 MHz, CDCl3) d 171.8 (171.6),
154.5 (154.0), 80.3 (81.6), 79.4 (79.7), 59.2 (59.4), 58.9, 51.9, 47.2
(46.8), 28.4 (ꢂ3), 25.9 (26.7), 24.2 (23.6) (chemical shift in paren-
theses is minor amide rotational isomer); the amide rotamer ratio
(1.7:1.0) was determined by 1H NMR; ESI-HRMS calcd for
½
a 2D5
ꢃ
¼ ꢀ9:0 (c 0.558, CH3OH); 1H NMR (500 MHz, CD3OD) d
4.48 (d, J = 4.2 Hz, 1H), 3.97–3.93 (m, 1H), 3.32–3.29 (m, 2H),
2.11–1.97 (m, 4H), the hydroxyl, carboxyl, and amino protons were
not observed because of broadening of the signals; 13C NMR
(125 MHz, CD3OD) d 174.0, 69.3, 62.3, 47.4, 25.5, 24.8; 19F NMR
(372 MHz, CD3OD) d ꢀ76.5 (s, CF3COOH); ESI-HRMS calcd for
C6H12NO3 [M+H]+ 146.0812; found 146.0813.
4.3.3. (2R,20S)-2-Methoxy-2-(pyrrolidin-20-yl)acetic acid TFA salt
(R,S)-1b
C
13H23NO5Na [M+Na]+ 296.1468; found 296.1472.
a 2D5
ꢃ
¼ ꢀ32:7 (c 2.26, CH3OH); 1H NMR (500 MHz, CD3OD) d
4.2.7. (2R,20S)-2-[10-(tert-Butoxycarbonyl)pyrrolidin-20-yl]-2-
methoxyacetic acid (R,S)-12 and (2S,20S)-2-[10-(tert-
½
3.97 (d, J = 6.0 Hz, 1H), 3.82–3.78 (m, 1H), 3.50 (s, 3H), 3.31–3.22
(m, 2H), 2.23–1.90 (m, 4H), the carboxyl and amino protons were
not observed because of broadening of the signals; 13C NMR
(125 MHz, CD3OD) d 172.3, 80.0, 62.1, 59.1, 46.9, 28.0, 24.8; 19F
NMR (372 MHz, CD3OD) ꢀ76.5 (s, CF3COOH); ESI-HRMS calcd for
C7H14NO3 [M+H]+ 160.0968; found 160.0970.
butoxycarbonyl)pyrrolidin-20-yl)-2-methoxyacetic acid (S,S)-12
To a stirred solution of (R,S)-11 (41 mg, 0.15 mmol) in tetra-
hydrofuran (1 mL) was added 0.3 mL of 1.0 M LiOH aqueous
solution. The mixture was stirred at room temperature for 3 h.
The reaction mixture was concentrated to remove the solvent
in vacuo. The resulting residue was purified by silica gel column
chromatography (CHCl3/MeOH, 4:1) to afford (R,S)-12 (28 mg,
4.3.4. (2S,20S)-2-Methoxy-2-(pyrrolidin-20-yl)acetic acid TFA salt
(S,S)-1b
71%) as a colorless liquid; ½a D25
ꢃ
¼ ꢀ36:3 (c 0.564, CH3OH); 1H
½
a 2D5
ꢃ
¼ ꢀ35:8 (c 0.950, CH3OH); 1H NMR (500 MHz, CD3OD) d
NMR (500 MHz, CD3OD) d 4.22–4.06 (m, 1H), 3.97–3.85 (m, min-
or-0.37H), 3.78–3.67 (m, major-0.63H), 3.42–3.33 (m, 2H), 3.40
(s, 3H), 2.14–1.69 (m, 4H), 1.47 (s, 9H), the carboxyl proton
was not observed because of broadening of the signal; 13C
NMR (125 MHz, CD3OD) d 178.6 (177.5), 157.1 (156.4), 84.9
(83.6), 81.3, 59.9 (59.6), 59.0 (58.6), 48.2 (47.8), 28.8 (ꢂ3), 28.8
(28.6), 24.7 (24.0) (chemical shift in parentheses is minor amide
4.11 (d, J = 3.8 Hz, 1H), 3.98–3.94 (m, 1H), 3.49 (s, 3H), 3.31–3.26
(m, 2H), 2.10–1.93 (m, 4H), the carboxyl and amino protons were
not observed because of broadening of the signals; 13C NMR
(125 MHz, CD3OD) d 172.8, 79.0, 61.7, 59.0, 47.4, 25.6, 25.0; 19F
NMR (372 MHz, CD3OD) ꢀ76.5 (s, CF3COOH); ESI-HRMS calcd for
C7H14NO3 [M+H]+ 160.0968; found 160.0970.

Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
235
4.3.5. (2R,20S)-Methyl 2-hydroxy-2-(pyrrolidin-20-yl)acetate TFA
salt (R,S)-1c
aqueous NH4Cl solution (1 mL) and extracted with EtOAc
(5 ꢂ 2 mL). The organic extracts were combined, dried over MgSO4,
and concentrated. The residue was purified by flash column chro-
matography on silica gel (hexane/EtOAc, 1:1) to afford the aldol
adducts.
The relative and absolute configurations of 13 in Tables 2–4,
and 15 and 16 in Table 5 were determined by comparison with
the reported NMR and HPLC data. The enantiomeric excess of aldol
products was determined by HPLC on chiral stationary phase of
CHIRALCEL OJ, AD-H, and AS columns (Daicel Co. Ltd.,
4.6 ꢂ 250 mm).
½
a 2D5
ꢃ
¼ ꢀ22:5 (c 0.778, CH3OH); 1H NMR (500 MHz, CD3OD) d
4.35 (d, J = 4.7 Hz, 1H), 3.88–3.83 (m, 1H), 3.79 (s, 3H), 3.29–3.26
(m, 2H), 2.21–1.93 (m, 4H), the hydroxyl and amino protons were
not observed because of broadening of the signals; 13C NMR
(125 MHz, CD3OD) d 173.0, 70.5, 62.7, 53.1, 47.0, 28.1, 24.9; 19F
NMR (372 MHz, CD3OD) ꢀ76.5 (s, CF3COOH); ESI-HRMS calcd for
C7H14NO3 [M+H]+ 160.0968; found 160.0971.
4.3.6. (2S,20S)-Methyl 2-hydroxy-2-(pyrrolidin-20-yl)acetate TFA
salt (S,S)-1c
½
a 2D5
ꢃ
¼ ꢀ17:7 (c 1.24, CH3OH); 1H NMR (500 MHz, CD3OD) d
4.4.1. 4-Hydroxy-4-(4-nitrophenyl)-2-butanone 132a
4.53 (d, J = 4.3 Hz, 1H), 3.96–3.92 (m, 1H), 3.79 (s, 3H), 3.31–3.28
(m, 2H), 2.11–1.91 (m, 4H), the hydroxyl and amino protons were
not observed because of broadening of the signals; 13C NMR
(125 MHz, CD3OD) d 173.0, 70.5, 62.7, 53.1, 47.0, 28.1, 24.9; 19F
NMR (372 MHz, CD3OD) ꢀ76.5 (s, CF3COOH); ESI-HRMS calcd for
C7H14NO3 [M+H]+ 160.0968; found 160.0967.
1H NMR (500 MHz, CDCl3) d 8.22 (d, J = 8.6 Hz, 2H), 7.54 (d,
J = 8.6 Hz, 2H), 5.29–5.24 (m, 1H), 2.87–2.84 (m, 2H), 2.23 (s, 3H),
the hydroxyl proton was not observed because of broadening of
the signals; HPLC analysis using a Daicel CHIRALCEL OJ column
(hexane/i-PrOH, 75:25, kmax 254 nm, flow rate = 1.0 mL/min),
tR = 11.4 min (major) and 12.7 min (minor).
4.3.7. (2R,20S)-Methyl 2-methoxy-2-(pyrrolidin-20-yl)acetate TFA
salt (R,S)-1d
4.4.2. 4-(4-Nitrophenyl)but-3-en-2-one 14
1H NMR (500 MHz, CDCl3) d 8.26 (d, J = 8.8 Hz, 2H), 7.70 (d,
J = 8.8 Hz, 2H), 7.54 (d, J = 16.3 Hz, 1H), 6.82 (d, J = 16.3 Hz, 1H),
2.42 (s, 3H).
½
a 2D5
ꢃ
¼ ꢀ32:8 (c 0.442, CH3OH); 1H NMR (500 MHz, CD3OD) d
4.06 (d, J = 5.4 Hz, 1H), 3.85–3.79 (m, 1H), 3.81 (s, 3H), 3.49 (s,
3H), 3.31–3.22 (m, 2H), 2.22–1.88 (m, 4H), the amino proton was
not observed because of broadening of the signal; 13C NMR
(125 MHz, CD3OD) d 171.2, 79.8, 61.9, 59.3, 53.1, 47.0, 27.9, 24.8;
19F NMR (372 MHz, CD3OD) ꢀ76.5 (s, CF3COOH); ESI-HRMS calcd
for C8H16NO3 [M+H]+ 174.1125; found 174.1128.
4.4.3. 1-Hydroxy-1-(4-nitrophenyl)pentan-3-one 15a2b
1H NMR (500 MHz, CDCl3) d 8.20 (d, J = 8.4 Hz, 2H), 7.52 (d,
J = 8.4 Hz, 2H), 5.27–5.23 (m, 1H), 3.62 (d, J = 3.3 Hz, 1H), 2.85–
2.76 (m, 2H), 2.49–2.44 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H); ee = 70%,
the ee value was determined by HPLC analysis using a Daicel CHIR-
ALPAK AS column (hexane/i-PrOH, 90:10, kmax 280 nm, flow
rate = 2.0 mL/min), tR = 15.8 min (major) and 35.2 min (minor).
4.3.8. (2S,20S)-Methyl 2-methoxy-2-(pyrrolidin-20-yl)acetate TFA
salt (S,S)-1d
½
a 2D5
ꢃ
¼ ꢀ42:9 (c 0.198, CH3OH); 1H NMR (500 MHz, CD3OD) d
4.25 (d, J = 3.8 Hz, 1H), 3.99–3.94 (m, 1H), 3.80 (s, 3H), 3.49 (s,
3H), 3.32–3.24 (m, 2H), 2.11–1.91 (m, 4H), the amino proton was
not observed because of broadening of the signal; 13C NMR
(125 MHz, CD3OD) d 170.8, 78.7, 61.4, 59.3, 53.0, 47.5, 25.5, 24.9;
19F NMR (372 MHz, CD3OD) ꢀ76.5 (s, CF3COOH); ESI-HRMS calcd
for C8H16NO3 [M+H]+ 174.1125; found 174.1126.
4.4.4. 4-Hydroxy-3-methyl-4-(4-nitrophenyl)butan-2-one syn-
and anti-15b2v,w
1H NMR (500 MHz, CDCl3) d 8.21 (d, J = 8.3 Hz, 2H), 7.50 (d,
J = 8.3 Hz, 2H), 5.27–5.26 (m, syn-0.28H), 4.87–4.84 (m, anti-
0.72H), 3.20 (d, J = 4.8 Hz, 1H), 2.92–2.86 (m, 1H), 2.19 (s, 3H),
1.01 (d, J = 7.4 Hz, 3H); syn:anti = 28:72; ee = 70% (anti), the ee va-
lue of was determined by HPLC analysis using a Daicel CHIRALPAK
AS column (hexane/i-PrOH, 90:10, kmax 280 nm, flow rate = 2.0 mL/
min), tR = 16.2 min (minor) and 22.4 min (major). Due to the small
amount of the syn-15b, the enantiomeric excess could not be
determined.
4.3.9. TFA free form of (2R,20S)-2-hydroxy-2-(pyrrolidin-20-
yl)acetic acid (R,S)-1a
The TFA salt of (R,S)-1a (244 mg, 1.01 mmol) was dissolved in
3 mL of 1.0 M HCl. The solution was then applied to the cation-ex-
change resin, AG 50 W-X8 (200–400 mesh), hydrogen form (Bio-
Rad Laboratories, USA), that had been preequilibrated with
H2O.20 After washing with 100 mL of H2O, 100 mL of 6 M NH4OH
was eluted. The aqueous solution was evaporated to dryness under
reduced pressure to afford the TFA free form of (R,S)-1a (146 mg,
4.4.5. 2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (syn-
and anti-16)2g,o
1H NMR (500 MHz, CDCl3) d 8.19 (d, J = 8.8 Hz, 2H), 7.47 (d,
J = 8.8 Hz, 2H), 5.39–5.37 (m, syn-0.15H), 4.88–4.85 (m, anti-
0.85H), 3.14 (d, J = 3.3 Hz, 1H), 2.64–2.59 (m, 1H), 2.50–2.34 (m,
2H), 2.14–2.06 (m, 1H), 1.87–1.81 (m, 1H), 1.74–1.63 (m, 2H),
1.63–1.49 (m, 2H); syn:anti = 15:85; ee = 48% (syn), 83% (anti), the
ee value was determined by HPLC analysis using a Daicel CHIR-
ALPAK AD-H column (hexane/i-PrOH, 80:20, kmax 254 nm, flow
rate = 0.5 mL/min), syn-diastereomer: tR = 26.5 min (minor) and
27.7 min (major), anti-diastereomer: tR = 30.3 min (minor) and
39.6 min (major).
97%) as a colorless solid; ½a D25
ꢃ
¼ þ13:6 (c 1.03, H2O); 1H NMR
(500 MHz, D2O) d 4.28 (d, J = 5.3 Hz, 1H), 4.27–3.89 (m, 1H),
3.48–3.40 (m, 2H), 2.34–2.27 (m, 1H), 2.24–2.08 (m, 2H), 2.04–
1.96 (m, 1H), the hydroxyl, carboxyl, and amino protons were
not observed because of broadening of the signals; 13C NMR
(125 MHz, CD3OD) d 177.3, 70.7, 62.4, 45.9, 26.8, 23.6; ESI-HRMS
calcd for C6H12NO3 [M+H]+ 146.0812; found 146.0813.
4.4. General procedure for the aldol reactions between acetone
and 4-nitrobenzaldhyde
4.5. Computational methods
To a solution of the chosen catalyst (0.02 mmol) in DMSO
Transition states for the aldol reactions of acetoaldehyde with
(0.80 mL) and Et3N (2.8
l
L, 0.02 mmol) was added ketone
acetone catalyzed by (R,S)- and (S,S)-1a, and L-b-homoproline as
(0.20 mL, 20 vol %). The mixture was stirred at room temperature.
After 10 min of stirring, 4-nitrobenzaldehyde (15.1 mg, 0.10 mmol)
was added to the mixture. The reaction mixture was then stirred at
25 °C for 24 h. The reaction mixture was quenched with saturated
the simple model reactions were explored. All calculations were
implemented in the GAUSSIAN 03 program.19 The geometries of the
transition states of the corresponding enamines and acetone were
optimized using the B3LYP functional with the 6-311++G(d,p) basis

236
Y. Hiraga et al. / Tetrahedron: Asymmetry 22 (2011) 226–237
9631; (f) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, C. F.,
III Org. Lett. 2006, 8, 2839–2842; (g) Valeroa, G.; Balaguera, A.-N.; Moyano, A.;
Rios, R. Tetrahedron Lett. 2008, 49, 6559–6562; (h) Dziedzic, P.; Ibrahem, I.;
Córdova, A. Tetrahedron Lett. 2008, 49, 803–807; (i) Chandler, C.; Galzerano, P.;
Michrowska, A.; List, B. Angew. Chem., Int. Ed. 2009, 48, 1978–1980.
set in the gas phase. At the same level of theory, frequency calcu-
lations were carried out to verify the transition state structure.
Zero-point energies have been taken from unscaled vibrational fre-
quencies. Reported energies in Figure
corrections.
3 include zero-point
5. For some selected examples on Michael reactions catalyzed by L-proline and its
derivatives see: (a) Yamaguchi, M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.;
Hirama, M. Tetrahedron 1997, 53, 11223–11236; (b) List, B.; Pojarliev, P.;
Martin, H. J. Org. Lett. 2001, 3, 2423–2425; (c) Melchiorre, P.; Jørgensen, K. A. J.
Org. Chem. 2003, 68, 4151–4157; (d) Halland, N.; Aburel, P. S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 661–665; (e) Mase, N.; Thayumanavan, R.;
Tanaka, F.; Barbas, C. F., III Org. Lett. 2004, 6, 2527–2530; (f) Wang, W.; Wang, J.;
Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369–1371; (g) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212–4215; (h) Mase, N.;
Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc.
2006, 128, 4966–4967; (i) Yan, Z.-Y.; Niu, Y.-N.; Wei, H.-L.; Wu, L.-Y.; Zhao, Y.-
B.; Liang, Y.-M. Tetrahedron: Asymmetry 2006, 17, 3288–3293; (j) Triana, W.;
Hiraga, Y.; Kojima, S.; Abe, M. Tetrahedron: Asymmetry 2010, 21, 1861–1868; (k)
Roca-Lopez, D.; Sadaba, D.; Delso, I.; Herrera, R. P.; Tejero, T.; Merino, P.
Tetrahedron: Asymmetry 2010, 21, 2561–2601.
Acknowledgments
We are indebted to the Natural Science Center for Basic Re-
search and Development (N-BARD), Hiroshima University, for mea-
surements of NMR and MS, and Hiroshima Prefectural Institute of
Industrial Science and Technology for NMR. This work was sup-
ported by a Grant-in-Aid for Scientific Research (No. 19350021,
20036038, 19020034, 20611012) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
6. For some selected examples on
a-aminations and a-aminoxylations catalyzed
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