Facile evolution of asymmetric organocatalysts in water assisted by surfactant Br?nsted acids

Article abstract of DOI:10.1016/j.tet.2007.08.096

Simple mixing of chiral amines and surfactant Br?nsted acids such as p-dodecyl benzenesulfonic acid (DBSA) leads to highly effective and selective organocatalysts in water. The in situ generated catalysts catalyze highly stereoselective desymmetrization o

Full text of DOI:10.1016/j.tet.2007.08.096

Tetrahedron 63 (2007) 11307–11314
Facile evolution of asymmetric organocatalysts in water
assisted by surfactant Brønsted acids
a
a
b
b
Sanzhong Luo,a, Hui Xu, Jiuyuan Li, Long Zhang, Xueling Mi,
*
Xiaoxi Zhenga and Jin-Pei Chenga,b,
*
aBeijing National Laboratory for Molecular Sciences (BNLMS), Center for Chemical Biology, Institute of Chemistry,
The Chinese Academy of Sciences, Beijing 100080, China
bDepartment of Chemistry and State-key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071,China
Received 26 June 2007; revised 24 August 2007; accepted 28 August 2007
Available online 1 September 2007
Abstract—Simple mixing of chiral amines and surfactant Brønsted acids such as p-dodecyl benzenesulfonic acid (DBSA) leads to highly
effective and selective organocatalysts in water. The in situ generated catalysts catalyze highly stereoselective desymmetrization of prochiral
ketones via direct aldol reactions (up to >16:1 dr, >99% ee) in water using micelle as reaction media. The current strategy was also applied in
asymmetric Michael addition leading to a catalytic system with good activity and stereoselectivity.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
example of desymmetric direct aldol reactions in water.
Using this strategy, highly active and stereoselective cata-
lysts for Michael addition were also developed in water.
The aqueous phase asymmetric catalysis has attracted inten-
sive research interest in the last decade due to the favorable
features of water as an inexpensive, safe, and environmen-
tally benign medium.1 More recently, chiral amines have be-
come another focus in this field because of their divergent
nature to form either nucleophilic enamines or electrophilic
imminium ions and their structural modifiability to ease
diversity-oriented catalysts discovery.2 Their nontoxic and
robust features as well as mild experimental conditions are
also beneficial to catalytic reactions in aqueous media.3
And indeed, quite a few chiral amine-catalyzed reactions
in homogeneous aqueous media have been reported recently
that showed good stereoselectivity.4 Water was demon-
strated to increase both reactivity and stereoselectivity for
some direct aldol reactions.5
Library of Hydrophobic
Bronsted Acids
H2O
H2O
Library of
Chiral Amines
Library of
e.g.
Catalysts in Water
Et
N
Et
-O3S
C12H25
N
H
H
Stereocontrol Unit Catalyst
Anchor
Hydrophobic part
Scheme 1. Strategy for the construction of chiral amine catalysts in water.
Despite these remarkable achievements, a modular and
efficient methodology that directly transforms the available
chiral amines into effective aqueous-phase chiral catalysts
without any modification should be highly desirable. Herein,
we present a simple strategy for developing asymmetric cat-
alysts that combines chiral amines and surfactant Brønsted
acids (SBAs) via non-covalent acid–base interactions in
water (Scheme 1). The asymmetric organocatalytic systems
obtained here also allowed us to demonstrate the first
2. Result and discussion
2.1. The principle of catalyst evolution in water
Though the combination of chiral amine–Brønsted acid is
known,4a,6 the corresponding aqueous catalysis utilizing sur-
factant Brønsted acids has rarely been attempted.7 In fact,
surfactants are frequently employed in order to perform reac-
tions in water.8 Recently, Barbas et al.,9 Hayashi et al.,10 and
this group11 independently reported tailor-made surfactant-
type chiral amine catalysts wherein the connected surfactant
moieties were shown to be essential for high activity and
Keywords: Aldol; Michael addition; Chiral amine; Surfactant Brønsted
acids.
* Corresponding authors. E-mail addresses: luosz@iccas.ac.cn; chengjp@
mail.most.gov.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.096

11308
S. Luo et al. / Tetrahedron 63 (2007) 11307–11314
enantioselectivity by forming hydrophobic colloidal disper-
sions favorable for the reactions.12 In these cases, the cata-
lysts have to be prepared individually via multiple steps,
and are therefore limited for further evolution. In compari-
son, our approach in the present work takes advantage of
a readily available chiral amine library and the quick and
quantitative acid–base reaction to in situ generate asymmet-
ric catalysts in water, so that a diverse library of asymmetric
catalysts suitable for aqueous catalysis is easily created to
fulfill the requirements of the reactions under study. Further-
more, surfactant Brønsted acid in this design would not only
act as a surfactant, but also as a non-covalent anchor for
chiral amines leading to protonated centers that are critical
for stereocontrol (Scheme 1).
2.2. Evolution of organocatalysts for direct aldol
reaction in water
Asymmetric direct aldol reaction of cyclohexanone was
selected for our initial model reaction. A quick scanning of
surfactant Brønsted acids (SBAs) with chiral diamine 1
was first conducted (Table 1). The combinations 1 and
SBAs could catalyze the reaction with good enantioselectiv-
ity (up to 84% ee, Table 1). In contrast, the reaction with
a non-surfactant Brønsted acid such as p-toluenesulfonic
acid gave a low yield and stereoselectivity (Table 1, entry
6), thus validating our hypothesis. Light microscopic studies
demonstrated that both the in situ-generated catalyst and the
reaction mixture formed good colloidal dispersions in pure
water (Fig. 1), suggesting that the reactions occur in the mi-
celles. The acidity of SBAs was found to be a major factor
influencing the enantioselectivity and among a series of
commercial available surfactant Brønsted acids p-dodecyl
benzenesulfonic acid (DBSA) gave the best performance,
so it was selected for further catalysts’ screening. It is noted
that increasing the loading of DBSA resulted in improve-
ment on enantioselectivity, but with the sacrifice of activity
(Table 1, entries 7–9). This observation suggests the exis-
tence of general base catalysis under these conditions.
Table 1. The acid screeninga
O
O
OH
CHO
1 (10 mol%)
+
Acid (X mol%)
O2N
H2O
NO2
Entry Acidb
X
Time (h) Yieldc (%) anti:synd eee (%)
1
2
3
3
5
6
7
8
9
PFDA
STEA
DDNA
DDPA
10 12
10 12
10 12
10 12
80
93
96
45
59
24
92
59
45
66:34
63:37
62:38
74:26
77:23
78:22
83:17
80:20
82:18
25
17
26
52
65
53
68
81
84
Zn(DS)2 10 12
PTSA
DBSA
DBSA
DBSA
10 12
10 13
12 13
15 13
a
Aldehyde (0.5 mmol), 1 mmol cyclohexanone, 1 mL media.
b
DBSA: 4-dodecylbenzenesulfonic acid; PTSA: 4-methylbenzenesulfonic
acid; DDNA: dodecanoic acid; PFDA: perfluoroundecanoic acid; STEA:
stearic acid; DDPA: didodecyl hydrogen phosphate. DS: dodecyl sulfate.
Isolated yields.
An initial library of chiral diamines was then constructed
since this type of catalysts is frequently used in organo-
catalysis in organic solvent (Fig. 2).2,6 It was found that
successful chiral diamine catalysts in organic solvent could
c
d
e
Determined by 1H NMR.
Determined by HPLC on a chiral column.
Figure 1. Light microscopy of: (a) mixtures of chiral amine 1 (0.05 M) and DBSA (0.05 M) in water; (b) mixtures of chiral amine 1 (0.05 M), DBSA (0.05 M),
cyclohexanone (1 M) and p-NO2PhCHO (0.5 M) in water.
Bu
Bu
O
N
O
N
N
N
n
N
H
N
H
N
H
N
H
N
H
N
H
2
n=1: 3
n=2: 4
n=3: 5
N
6
1
7
BnO
O
O
O
O
2-Py:8
3-Py:9
4-Py:10
N
H
Py
N
N
N
H
N
H
N
N
H
Ph
N
N
H
N
H
H
13
12
11
Figure 2. Selected chiral amines.

S. Luo et al. / Tetrahedron 63 (2007) 11307–11314
11309
Table 2. Selected screening resultsa
contrasting behavior on the basis of the basicity difference
between 3-aminopyridine and 4-aminopyridine (pKa 5.98
vs 9.17).14 However, the geometrical difference and molec-
ular orientation of the chiral amines obviously also played
a pivotal role because of the fact that the basicity of the inert
2-aminopyridinyl 11 is not too much different from that of
the active 3-aminopyridine (pKa 6.86 vs 5.98), so the differ-
ence in their spatial arrangement may be quite substantial in
the surfactant micelle.15
O
OH
O
CHO
Cat. (10 mol%)
+
O2N
DBSA (10 mol%)
H2O or Phosphate buffer
rt
NO2
Entry Cat. Media Time (h) Yieldb (%) anti:sync eed (%)
1
2
3
4
5
6
7
8
1
1
2
3
4
5
6
7
H2O
PB
PB
PB
PB
PB
PB
PB
13
13
12
12
12
12
12
5
92
88
95
95
95
98
19
85
83:17
83:17
76:24
77:23
82:18
80:20
68
81
57
75
79
75
Other notable results in the catalysts screening included the
observation that aniline analogue 12 and N-methylated cat-
alyst 13 were inactive for catalysis; this indicates the impor-
tance of amino-pyridine structure and the amide linkage
(entries 19 and 20). In control reactions, we could also dem-
onstrate that 3(4)-aminopyridinyl catalysts–DBSA com-
plexes were unique for aqueous catalysis as seen from the
poor performance either in the absence of DBSA (entry
13), in the presence of non-surfactant p-toluenesulfonic
acid (entry 16) or under neat conditions (entry 17). It is
thus conceived that besides its role as a surfactant and a cat-
alyst anchor, DBSA should also contribute significantly to
the enhanced activity and enantioselectivity most likely by
protonating the pyridinyl ring that consequently activates
the amide hydrogen-bond donor in hydrophobic micellar
media.
Not determined
32
69:31
9
8
9
9
9
H2O
H2O
PB
Brine
H2O
H2O
PB
H2O
Neat
H2O
H2O
H2O
12
12
12
12
12
12
12
12
12
12
24
24
No reaction
96:4
95:5
10
11
12
13
14
15
16
17
18
19
20
20
92
31
93
88
90
95:5
9
Tracee
92
81
10
10
10
10
11
12
13
94:6
92:8
93
90
Tracef
81
90
95:5
96:4
No reaction
No reaction
90
98
a
Aldehyde (0.5 mmol), 1 mmol cyclohexanone, 1 mL of solvent.
Isolated yields.
b
c
d
e
f
Determined by 1H NMR.
The substrates’ scopes of the identified optimal catalyst 11
were next probed for asymmetric direct aldol reaction in wa-
ter. Cyclohexanone reacted with a range of aromatic alde-
hydes to afford the desired products (14a–14g) with high
yields and stereoselectivity (Table 3, entries 1–6).
Determined by HPLC on a chiral column.
In the absence of DBSA.
Reaction in the presence of p-toluenesulfonic acid (10 mol %). PB: phos-
phate buffer, NaH2PO4–Na2HPO4, 1 M, pH¼7.2.
be transformed into good aqueous catalysts assisted by
DBSA (catalysts 1 and 3–5; Table 2, entries 2 and 4–6).
This validates our design strategy and highlights the impor-
tant role of DBSA (note that the reaction with non-surfactant
Brønsted acid gave low yields and poor stereoselectivity in
water, see Table 1, entry 6 and Table 2, entry 14). The
improved performance in phosphate buffer (1 M, pH¼7.2)
again suggests general base catalysis should also be working
in chiral diamine–DBSA system in pure water (Table 2,
entry 2 vs 1).13
Table 3. Substrate scopesa
O
OH
O
CHO
11 (10 mol%)
+
DBSA (10 mol%)
X
H2O, rt
X
H
R
R
Entry
R
X
Time (h) Yieldb (%) drc
eed (%)
1
2
3
H (14)
b/3-NO2 24
c/2-NO2 24
d/4-CN 24
95
88
93:7 >99
98:2
91:9
95:5
94:6
93:7
>16:1
>16:1
>16:1
96
98
90
93
93
99
98
98
91
98
98
96
97
94
99
>99
81
Bearing this in mind, we next explored a series of chiral
amide catalysts (catalyst 7–11) in order to alleviate the back-
ground catalysis. Additional basic amine groups were
appended in the catalysts to offer proper complex of catalysts
with DBSA. To our delight, among this series of catalysts we
were able to identify an optimal catalyst 11 with conjugate
4-aminopyridinyl group that promoted the model reaction
with 90% yield, 96:4 dr and 98% ee (entry 18) in pure water
using the media of colloid dispersion. Interestingly, the
reaction with the seemingly similar aminopyridinyl catalysts
8, 9, and 10 gave dramatically different results.
4
5
6
e/2-Cl
f/H
g/3-Br
72
72
72
33
78
90
86
7
8
9
Me (15) a/4-NO2 12
b/4-CF3 48
c/2-NO2 16
85
10
11
12
13
14
15
16
17
18
d/4-Cl
e/H
4-NO2
H
a/4-NO2 40
b/4-Cl 72
72
72
31
72
77 (20)e >16:1
41 (56)e >16:1
86 (10)e >16:1
Et (16)
t-Bu (17)
N3 (18)
58
>16:1
69 (20)e >10:1
52
97
99
>16:1
>16:1
>16:1 >99
96
SAc (19) a/4-NO2 36
b/4-CF3 60
Br (20)
4-NO2
40
74 (22)e >16:1
The 2-aminopyridinyl 8 was observed to be totally inactive,
whereas 3-aminopyridinyl 9 and 4-aminopyridinyl 10
showed contrasting preference to reaction media. Catalyst
9 showed a higher activity in phosphate buffer than in pure
water (entry 12 vs 11), whereas catalyst 10 performed better
in pure water than in phosphate buffer (entry 14 vs 15). The
observation that catalyst 9 performed poorly in brine may
rule out the possible salt effect. One may explain the
a
Aldehyde (0.5 mmol) and 1.0 mmol cyclohexanone in 1 mL water at
room temperature with 10 mol % of 11.
b
c
Isolated yields of pure products.
Entries 1–6: dr¼anti:syn, determined by 1H NMR; entries 7–18: dr¼the
ratio of the major isomer shown with all the other isomers based on the
isolated products.
d
e
Determined by HPLC on a chiral column.
Recovered aldehyde.

11310
S. Luo et al. / Tetrahedron 63 (2007) 11307–11314
Table 4. Asymmetric Michael addition in watera
With regard to the aldol donors, a variety of 4-substituted
cyclohexanones were applied in the present reactions. Sig-
nificantly, catalyst 11–DBSA catalyzed the reactions of
4-substituted cyclohexanones to produce predominantly
one single isomer with excellent enantioselectivity (Table
3, entries 7–18, 96 to >99% ee). As known, enantioselective
desymmetrizations using asymmetric catalysis are powerful
ways to generate chiral products with multiple stereogenic
centers.16 While asymmetric transition metal catalysts16a
and enzymes16b have been widely applied in desymmetriza-
tion of meso compounds, the examples using asymmetric
organocatalysts are rare, especially for intermolecular
reactions.17 Our evolved catalyst 11 provided successful
asymmetric desymmetrization of prochiral ketones with
excellent stereoselectivity in water under room temperature.
For the same reactions in organic solvent, the current
well-established organcoatalysts gave either low activity or
poor stereoselectivity.18 The characteristics of our discovery
include: (1) selective formation of one isomer out of eight
possible stereoisomers (>16:1 dr, up to >99% ee), (2)
wide scope of 4-substituted cyclohexanones encompassing
4-alkyl (entries 7–13), and 4-heteroatom functionalized
groups (entries 14–18), and (3) highly enantioselective de-
symmetrizations in pure water conditions. However, the cur-
rent catalyst also has its limitation such as the reactions with
aliphatic aldehydes gave lower yields due to side reactions.
X
O
Chiral amine
O
NO2
15 mol%
NO2
+
DBSA (15 mol%)
X
H2O, rt.
Entry Chiral amine X
Time (h) Yieldb (%) syn:antic eed (%)
1
1
H
24 (36) 85 (95)
95:5
94:6
92:8
90:10
93:7
85
86
83
86
80
2
3
3
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2
3
4
5
6
7
8
9
10
11
12
13
1
1
1
1
1
H
H
H
H
H
H
H
H
24
24
24
24
24
24
24
24
24
24
24
24
48
80
85
72
80
Trace
70
No reaction
16
93
24
87:13
15
95:5
94:6
90:10
18
20
11
H
H
H
H
4-Cl
2-Napth 48
4-MeO 72
3-NO2 24
No reaction
No reaction
81
99
99
67
94
98:2
95:5
96:4
94:6
95:5
85
87
87
81
88
2-Cl
72
a
Nitrostyrene (0.25 mmol), 1 mmol cyclohexanone in 1 mL H2O.
Isolated yields.
b
c
d
Determined by 1H NMR.
Determined by HPLC on a chiral column.
In general, the reactions were started by simple mixing of
11–DBSAwith substrates in bulk water and good colloid dis-
persions were then formed, indicating that the reactions oc-
cur in the micelles. At the end of the reactions the products
normally precipitated out or could be easily extracted with
organic solvents. The relative and absolute configurations
of the optically pure products formed were determined by
X-ray analysis.19 Both of the crystal structures of products
15d and 20 revealed the absolute configurations to be
(10R,2S,4S) (Scheme 2, left). The observed high stereoselec-
tivity may be explained by the proposed transition state as
shown in Scheme 2 (right). This model is in accordance
with that of L-proline catalyzed reaction in DMSO.20 The
unique pyridinium-amide moiety may also contribute to
effect the orientation of the R group besides providing an
activated amide hydrogen-bonding moiety and this hypo-
thesis is under our current investigations.
found to be a proper surfactant Brønsted acid in this reaction.
In the presence of DBSA, simple chiral amines such as 1 were
able to catalyze the Michael addition of cyclohexanone to ni-
trostyrene with high activity and stereoselectivity (Table 4).
Initial screening revealed that chiral diamines performed
better than amide-type catalysts. Amide-type catalysts 7–
13 were ineffective in the Michael addition reaction, pro-
ducing either lower yields or lower enantioselectivity
(Table 4, entries 7–13). With the assistance of DBSA, chi-
ral diamines such as 1–5 could be transformed into effec-
tive aqueous phase catalysts affording the desired Michael
adducts with good yields and good enantioselectivity
(Table 4, entries 1–5, 72–95% yields, 80–87% ee). In con-
trast, a chiral diamine 3 itself or combined with trifluoro-
acetic acid produced only low yields of products (<20%)
as previously reported.9b The applicability of these cata-
lysts was simply demonstrated with chiral diamine 1–
DBSA catalyst in several representative examples, all
showing good activity and good stereoselectivity (Table
4, entries 14–18). Although our results did not outperform
2.3. Asymmetric Michael addition in water
The application of the above strategy in asymmetric Michael
addition in water was briefly explored. DBSA was again
O
OH
2
1'
BnO
O
Cl
4
Me
N
N
15d
H
O
NH
R ≠ H
H
R
O
OH
H
Proposed Transition State
NO2
Br
20
Scheme 2. X-ray crystal structure of 15d and 20 (left) and the proposed transition state (right).

S. Luo et al. / Tetrahedron 63 (2007) 11307–11314
11311
the previous reports, the current catalytic system repre-
sents a much simpler and convenient alternative to many
other synthetic catalysts that work in pure water.4g,9b,11,21
In addition, the chance for better catalyst is still open
through screening other types of chiral amines.
m), 2.76–2.82 (1H, m), 3.21–3.27 (1H, m), 4.03–4.14
(2H, m), 4.43–4.53 (2H, m), 7.28–7.35 (5H, m), 7.50–7.52
(2H, m), 8.46–8.48 (2H, m), 9.88–9.99 (1H, br); 13C NMR
(CDCl3, 75 MHz): d 36.1, 52.6, 60.4, 70.7, 80.3, 113.3,
127.6, 127.8, 128.5, 137.9, 144.5, 150.7, 173.9; HRMS for
C17H20N3O2 (M+H)+, calcd 298.1550, found 298.1547.
3. Conclusion
4.2.2. Spectra data for chiral amines catalysts 7–10 and
13.
In summary, our results show a modular and effective ap-
proach for the discovery of asymmetric organocatalysts in
water by combining chiral amine and surfactant Brønsted
acid. Catalyst 11–DBSA, unique for aqueous catalysis,
was evolved by combinatorial screening of libraries of chiral
amines that provided the first example of asymmetric
desymmetrization reactions in water with excellent dia-
stereoselectivity and enantioselectivity. The current strategy
could be equally applied in the asymmetric Michael addition
in water.
4.2.2.1. (S)-N-((1R,2R)-2-(Dimethylamino)cyclohex-
yl)pyrrolidine-2-carboxamide (7). The title product was
prepared from Boc-protected L-proline and (1R,2R)-N,N-
dimethylcyclohexanediamine according to the general pro-
cedure with 50% yield as white solid. [a]2D0 ꢂ87.8 (c 1.0,
1
CHCl3); H NMR (300 MHz, CDCl3): d 1.01–1.32 (4H,
m), 1.60–1.71 (3H, m), 1.74–1.80 (2H, m), 1.88–2.13 (3H,
m), 2.17 (3H, s), 2.18 (3H, s), 2.24–2.29 (2H, m), 2.81–
2.97 (2H, m), 3.46–3.57 (1H, m), 3.67 (1H, dd, J¼5.3, 5.3,
8.7 Hz), 7.53–7.63 (1H, br); 13C NMR (CDCl3, 75 MHz):
d 22.1, 24.8, 25.3, 25.9, 30.9, 33.0, 40.1, 47.2, 50.4, 60.9,
66.6, 174.9; HRMS for C13H26N3O (M+H)+, calcd
240.2070, found 240.2069.
4. Experimental section
4.1. General information
4.2.2.2. (S)-N-(Pyridin-2-yl)pyrrolidine-2-carbox-
amide (8). The title product was prepared from Boc-protected
L-proline and 2-aminopyridine according to the general
procedure with 86% yield as pale yellow oil. [a]2D0 ꢂ56.0 (c
Commercial reagents were used as received, unless other-
wise stated. Chemical shifts are reported in parts per million
from tetramethylsilane with the solvent resonance as the
internal standard. The following abbreviations were used
to designate chemical shift mutiplicities: s¼singlet, d¼
doublet, t¼triplet, q¼quartet, h¼heptet, m¼multiplet,
br¼broad. All first-order splitting patterns were assigned
on the basis of the appearance of the multiplet. Splitting pat-
terns that could not be easily interpreted are designated as
multiplet (m) or broad (br). Mass spectra were obtained
using fast-atom bombardment (FAB) spectrometer or
electrospray ionization (ESI) mass spectrometer. Optical
rotations were measured using a 1 mL cell with a 1 dm
path length and are reported as follows: [a]rDt (c in g per
100 mL of solvent).
1
1.0, CH3OH); H NMR (300 MHz, CDCl3): d 1.74–1.83
(2H, m), 1.96–2.07 (1H, m), 2.21–2.33 (1H, m), 3.08–3.17
(2H, m), 4.13 (1H, dd, J¼5.5, 5.3, 9.0 Hz), 4.87–5.44 (1H,
br), 6.94–6.98 (1H, m), 7.59–7.65 (1H, m), 8.12 (1H, d, J¼
8.3 Hz), 8.25 (1H, d, J¼4.1 Hz), 10.3 (1H, br); 13C NMR
(CDCl3, 75 MHz): d 25.7, 30.7, 47.0, 60.8, 113.7, 119.6,
138.1, 147.9, 151.0, 173.0; HRMS for C10H14N3O (M+H)+,
calcd 192.1131, found 192.1132.
4.2.2.3. (S)-N-(Pyridin-3-yl)pyrrolidine-2-carbox-
amide (9). The title product was prepared from Boc-protected
L-proline and 3-aminopyridine according to the general proce-
dure with 76% yield as pale yellow oil. [a]2D0 ꢂ53.1 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): d 1.78–1.86 (2H, m),
1.98–2.09 (1H, m), 2.24–2.35 (1H, m), 3.08–3.19 (2H, m),
4.08–4.13 (1H, m), 4.49–5.28 (1H, br), 7.20–7.25 (1H,
m), 8.13–8.18 (1H, m), 8.28–8.32 (1H, m), 8.73–8.76 (1H,
m), 9.79–10.76 (1H, br); 13C NMR (CDCl3, 75 MHz):
d 25.8, 30.6, 47.0, 60.7, 123.5, 126.5, 134.7, 140.9, 144.7,
172.8; HRMS for C10H14N3O (M+H)+, calcd 192.1131,
found 192.1131.
4.2. General procedure for the synthesis of catalysts
4.2.1. Synthesis of (2S,4R)-4-(benzyloxy)-N-(pyridin-4-
yl)pyrrolidine-2-carboxamide (11). To a solution of
(2S,4R)-1-(tert-butoxycarbonyl)-4-(benzyloxy)pyrrolidine-2-
carboxylic acid (1.61 g, 5 mmol) in 20 mL CH2Cl2 was
added DCC (1.06 g, 5.1 mmol), HOBt (0.69 g, 5.1 mmol)
under 0 ꢀC and stirred for 30 min. Pyridin-4-amine (0.47 g,
5 mmol) was added in one portion. After 12 h, the mixture
was filtered through Celite and the resulting solvent was con-
centrated in vacuo to give crude Boc-protected 11 as yellow
oil, which was purified by flash chromatograph on silica gel
to afford pure Boc-protected 11 (1.59 g, 80% yield) as white
solid. This compound was deprotected in 5 M HCl/EtOH to
give the hydrogen chloride salts, which was subsequently
dissolved in CH2Cl2 (10 mL) and then treated with saturated
NaHCO3 solution (50 mL). This mixture was stirred for 1 h.
The aqueous layer was extracted with CH2Cl2 (30 mLꢁ5),
The combined organic phase was dried over anhydrous
Na2SO4, and concentrated in vacuo after filtration to give
essentially pure chiral catalyst 11 (1.1 g, 74% yield overall
steps) as white solid. [a]2D0 ꢂ28.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d 1.94–2.03 (1H, m), 2.49–2.62 (2H,
4.2.2.4. (S)-N-(Pyridin-4-yl)pyrrolidine-2-carbox-
amide (10). The title product was prepared from Boc-
protected L-proline and 4-aminopyridine according to the
general procedure with 89% yield as white solid. [a]D20
ꢂ69.7 (c 1.0, CH3OH); 1H NMR (300 MHz, CDCl3):
d 1.67–1.74 (2H, m), 1.90–2.01 (1H, m), 2.10–2.20 (1H,
m), 2.56 (1H, br), 2.88–3.07 (2H, m), 3.77–3.83 (1H, m),
7.46–7.49 (2H, m), 8.40–8.43 (2H, m), 9.94 (1H, s); 13C
NMR (CDCl3, 75 MHz): d 26.3, 30.7, 47.3, 61.0, 113.3,
144.5, 150.6, 174.5; HRMS for C10H14N3O (M+H)+, calcd
192.1131, found 192.1130.
4.2.2.5. (S)-N-Methyl-N-(pyridin-4-yl)pyrrolidine-2-
carboxamide (13). The title product was prepared from

11312
S. Luo et al. / Tetrahedron 63 (2007) 11307–11314
Boc-protected L-proline and 4-methylaminopyridine accord-
ing to the general procedure with 72% yield as pale yellow
oil. [a]2D0 ꢂ81.6 (c 0.5, CHCl3); 1H NMR (300 MHz,
CDCl3): d 1.99–2.09 (2H, m), 2.23–2.31 (2H, m), 2.77
(1H, s), 2.79 (3H, s), 6.41–6.43 (2H, m), 8.19–8.23 (2H,
m); 13C NMR (CDCl3, 75 MHz): d 23.7, 26.1, 31.2, 48.6,
63.1, 107.9, 149.8, 151.9, 172.8; HRMS for C11H16N3O
(M+H)+, calcd 206.1288, found 206.1285.
36.7, 38.5, 53.0, 69.8, 124.0, 128.5, 128.9, 133.1, 136.7,
148.8, 214.9; HRMS for C14H18NO4 (M+H)+, calcd
264.1230, found 264.1231. The enantiomeric excess was
determined by HPLC with an AD-H column at 254 nm
(2-propanol/hexane¼20:80), 25 ꢀC, 0.8 mL/min; tR¼10.73
(minor), tR¼11.07 (major).
4.4.4. (2S,4S)-2-((R)-Hydroxy(4-chlorophenyl)methyl)-4-
methylcyclohexanone (15d). White solid; ee 91%; [a]D20
1
4.3. General experimental procedure for aldol reaction
in water
ꢂ33.1 (c 0.5, AE); H NMR (300 MHz, CDCl3): d 1.03
(3H, d, J¼6.8 Hz), 1.26–1.35 (1H, m), 1.46–1.55 (1H, m),
1.68–1.77 (1H, m), 1.87–1.99 (1H, m), 2.01–2.08 (1H, m),
2.35–2.56 (2H, m), 2.65–2.74 (1H, m), 3.69 (1H, d, J¼
2.5 Hz), 4.80 (1H, dd, J¼2.3, 2.5, 8.9 Hz), 7.23–7.26 (2H,
m), 7.30–7.33 (2H, m); 13C NMR (CDCl3, 75 MHz): d 18.5,
26.7, 33.2, 36.2, 38.2, 53.4, 74.2, 128.3, 128.7, 133.7, 139.7,
215.2; HRMS for C14H17ClO2 (M+), calcd 252.0917, found
252.0919. The enantiomeric excess was determined by
HPLC with an AS-H column at 280 nm (2-propanol/
hexane¼10:90), 25 ꢀC, 0.8 mL/min; tR¼21.56 (major), tR¼
42.44 (minor).
Catalyst 11 (10 mol %, 0.05 mmol, 14.9 mg) and DBSA
(10 mol %, 0.05 mmol, 16.4 mg) were stirred in water
(1 mL) for 10 min. The corresponding ketone (1 mmol) and
aldehyde (0.5 mmol) was then added and the resulted
mixture was stirred for the time given in Tables 1 and 2 at am-
bient temperature. The aqueous layer was decanted from the
precipitated products and extracted with ether (2 mLꢁ3). The
organic was combined with the precipitant and loaded onto
silica gel. The desired product was obtained by flash chroma-
tography. Products 14a–14g are known compounds.4a,4h,9a
4.4.5. (2S,4S)-2-((R)-Hydroxyphenyl)methyl)-4-methyl-
cyclohexanone (15e). Colorless oil; ee 98%; [a]2D0 ꢂ17.8
4.4. Spectra data for new aldol products
1
(c 0.5, CHCl3); H NMR (300 MHz, CDCl3): d 1.01 (3H,
4.4.1. (2S,4S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)-4-
methylcyclohexanone (15a). White solid; ee 99%; [a]D20
ꢂ39.8 (c 0.5, EA); H NMR (300 MHz, CDCl3): d 1.04
d, J¼6.8 Hz), 1.26–1.35 (1H, m), 1.46–1.55 (1H, m),
1.65–1.73 (1H, m), 1.88–1.99 (1H, m), 2.01–2.09 (1H, m),
2.39–2.54 (2H, m), 2.70–2.79 (1H, m), 3.55–3.59 (1H, br),
4.83 (1H, d, J¼9.4 Hz), 7.27–7.37 (5H, m); 13C NMR
(CDCl3, 75 MHz): d 18.8, 26.7, 33.5, 36.3, 38.3, 53.9,
74.9, 126.9, 128.0, 128.5, 141.2, 215.3; HRMS for
C14H19O2 (M+H)+, calcd 219.1380, found 219.1381. The
enantiomeric excess was determined by HPLC with an
AS-H column at 254 nm (2-propanol/hexane¼20:80),
25 ꢀC, 0.5 mL/min; tR¼17.40 (major), tR¼27.58(minor).
1
(3H, d, J¼7.0 Hz), 1.27–1.35 (1H, m), 1.54–1.64 (1H, m),
1.74–1.82 (1H, m), 1.87–1.99 (1H, m), 2.04–2.11 (1H, m),
2.34–2.43 (1H, m), 2.48–2.59 (1H, m), 2.69–2.78 (1H,
m), 3.90 (1H, d, J¼2.8 Hz), 4.92 (1H, dd, J¼3.2, 3.2, 8.5 Hz),
7.49 (2H, d, J¼8.7 Hz), 8.20 (2H, d, J¼8.7 Hz); 13C NMR
(CDCl3, 75 MHz): d 18.2, 26.6, 32.9, 36.1, 38.2, 52.9,
74.1, 123.6, 127.8, 147.6, 148.4; HRMS for C14H18NO4
(M+H)+, calcd 264.1230, found 264.1230. The enantiomeric
excess was determined by HPLC with an AS-H column at
254 nm (2-propanol/hexane¼30:70), 25 ꢀC, 0.8 mL/min;
tR¼16.05 (major), tS¼22.80 (minor).
4.4.6. (2S,4S)-4-Ethyl-2-((R)-hydroxy(4-nitrophenyl)me-
thyl)cyclohexanone (16). White solid; ee 98%; [a]D20
ꢂ22.1 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 0.79
(3H, t, J¼7.4 Hz), 1.29–1.57 (4H, m), 1.66–1.75 (1H, m),
1.82–1.92 (2H, m), 2.33–2.50 (2H, m), 2.61–2.70 (1H, m),
3.92–3.95 (1H, br), 4.90 (1H, dd, J¼3.0, 3.0, 8.7 Hz),
7.47–7.50 (2H, m), 8.17–8.21 (2H, m); 13C NMR (CDCl3,
75 MHz): d 11.9, 24.9, 30.6, 33.5, 33.7, 38.4, 53.1, 74.1,
123.6, 127.8, 147.6, 148.5, 214.9; HRMS for C15H19NO4
(M+), calcd 277.1314, found 277.1316. The enantiomeric
excess was determined by HPLC with an AD-H column at
254 nm (2-propanol/hexane¼20:80), 25 ꢀC, 0.8 mL/min;
tR¼14.45 (minor), tR¼15.08 (major).
4.4.2. (2S,4S)-2-((R)-Hydroxy(4-trifluoromethylphenyl)-
methyl)-4-methylcyclohexanone (15b). White solid; ee
1
98%; [a]2D0 ꢂ10.0 (c 0.2, CHCl3); H NMR (300 MHz,
CDCl3): d 1.04 (3H, d, J¼7.0 Hz), 1.25–1.33 (1H, m),
1.49–1.58 (1H, m), 1.71–1.78 (1H, m), 1.87–1.98 (1H, m),
2.02–2.09 (1H, m), 2.35–2.55 (2H, m), 2.69–2.77 (1H,
m), 2.83 (1H, d, J¼3.0 Hz), 4.87 (1H, dd, J¼3.0, 2.8, 8.7 Hz),
7.42 (2H, d, J¼8.1 Hz), 7.60 (2H, d, J¼8.1 Hz); 13C NMR
(CDCl3, 75 MHz): d 18.3, 26.6, 33.1, 36.1, 38.1, 53.2,
74.3, 125.3, 125.4, 127.3, 145.1, 215.1; HRMS for
C15H18F3O2 (M+H)+, calcd 287.1253, found 287.1255.
The enantiomeric excess was determined by HPLC with
an AS-H column at 254 nm (2-propanol/hexane¼20:80),
25 ꢀC, 0.5 mL/min; tR¼14.75 (major), tR¼21.53 (minor).
4.4.7. (2S,4S)-4-tert-Butyl-2-((R)-hydroxy(4-nitrophe-
nyl)methyl)cyclohexanone (17). White solid; ee 96%;
1
[a]2D0 ꢂ75.2 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3):
d 0.77 (9H, s), 1.37–1.46 (2H, m), 1.53–1.57 (2H, m),
1.97–2.03 (1H, m), 2.47–2.52 (2H, m), 2.62–2.69 (1H, m),
3.07–3.09 (1H, m), 4.90 (1H, dd, J¼3.2, 3.2, 9.8 Hz),
7.33–7.37 (5H, m); 13C NMR (CDCl3, 75 MHz): d 25.6,
27.1, 27.9, 32.7, 39.2, 42.1, 55.7, 74.8, 126.9, 128.3,
128.6, 141.4, 215.7; HRMS for C17H24O2 (M+), calcd
260.1776, found 260.1779. The enantiomeric excess was
determined by HPLC with an AS-H column at 254 nm
(2-propanol/hexane¼20:80), 25 ꢀC, 0.8 mL/min; tR¼17.63
(major), tR¼23.16 (minor).
4.4.3. (2S,4S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)-4-
methylcyclohexanone (15c). Yellow solid; ee 98%; [a]D20
ꢂ11.4 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.04
(3H, d, J¼7.0 Hz), 1.42–1.50 (1H, m), 1.67–1.98 (3H, m),
2.05–2.10 (1H, m), 2.30–2.51 (2H, m), 2.85–2.92 (1H, m),
3.80–4.13 (1H, br), 5.40 (1H, d, J¼7.2 Hz), 7.37–7.43
(1H, m), 7.57–7.63 (1H, m), 7.69–7.72 (1H, m), 7.78–7.82
(1H, m); 13C NMR (CDCl3, 75 MHz): d 18.3, 26.9, 33.2,

S. Luo et al. / Tetrahedron 63 (2007) 11307–11314
11313
4.4.8. (2S,4S)-4-Azido-2-((R)-hydroxy(4-nitrophenyl)me-
thyl)cyclohexanone (18a). Pale yellow solid; ee 97%; [a]D20
+12.1 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.69–
1.73 (2H, m), 1.89–2.00 (1H, m), 2.22–2.29 (1H, m), 2.36–
2.43 (1H, m), 2.66–2.77 (1H, m), 2.96–3.05 (1H, m), 3.94
(1H, d, J¼3.8 Hz), 3.99–4.04 (1H, m), 4.90 (1H, dd, J¼
3.8, 3.8, 7.9 Hz), 7.49–7.53 (2H, m), 8.19–8.23 (2H, m);
13C NMR (CDCl3, 75 MHz): d 30.9, 34.2, 37.4, 51.5, 55.9,
73.6, 123.7, 127.8, 147.7, 147.8, 212.4; HRMS for
C13H15N4O4 (M+H)+, calcd 291.1088, found 291.1092.
The enantiomeric excess was determined by HPLC with
an AD-H column at 280 nm (2-propanol/hexane¼20:80),
25 ꢀC, 0.8 mL/min; tR¼17.54 (minor), tR¼20.24 (major).
d 1.92–1.97 (2H, m), 2.15–2.26 (1H, m), 2.38–2.46 (2H,
m), 2.99 (1H, td, J¼6.0, 13.8 Hz), 3.27–3.36 (1H, m),
3.80–4.11 (1H, br), 4.65–4.69 (1H, m), 4.97 (1H, d, J¼
7.7 Hz), 7.52 (2H, d, J¼8.3 Hz), 8.21 (2H, d, J¼8.3 Hz);
13C NMR (CDCl3, 75 MHz): d 35.9, 38.0, 38.9, 49.1, 52.2,
73.3, 123.7, 127.8, 147.6, 147.7, 212.1; HRMS for
C13H14BrNO4 (M+), calcd 327.0101, found 327.0100. The
enantiomeric excess was determined by HPLC with an
AD-H column at 254 nm (2-propanol/hexane¼20:80),
25 ꢀC, 0.8 mL/min; tR¼20.21 (major), tR¼23.09 (minor).
4.5. General experimental procedure for Michael
reaction in water
4.4.9. (2S,4S)-4-Azido-2-((R)-hydroxy(4-chlorophenyl)-
methyl)cyclohexanone (18b). White solid; ee 94%; [a]D20
+18.6 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): d 1.55
Catalyst 1 (15 mol %, 0.0375 mmol, 5.9 mg) and DBSA
(15 mol %, 0.0375 mmol, 12.3 mg) were stirred in water
(1 mL) for 10 min. The corresponding nitroolefin
(0.25 mmol) and cyclohexanone (1.0 mmol) was then added
and the resulted mixture was stirred for the time given in
Table 3 at ambient temperature. The aqueous layer was
decanted from the precipitated products and extracted with
ether (2 mLꢁ3). The organic was combined with the precip-
itant and loaded onto silica gel. The desired product was
obtained by flash chromatography. All the Michael adducts
are known compounds.11
1
(1H, td, J¼13.2, 2.8 Hz), 1.66–1.73 (1H, m), 1.86–1.98
(1H, m), 2.18–2.26 (1H, m), 2.34–2.41 (1H, m), 2.69 (1H,
td, J¼13.8, 6.0 Hz), 2.91–3.01 (1H, m), 3.88 (1H, d, J¼
3.2 Hz), 3.95–3.99 (1H, m), 4.77 (1H, dd, J¼3.0, 3.0,
8.3 Hz), 7.23–7.27 (2H, m), 7.31–7.34 (2H, m); 13C NMR
(CDCl3, 75 MHz): d 30.9, 34.1, 37.4, 51.6, 55.9, 73.7,
76.6, 77.1, 77.5, 128.3, 128.8, 133.9, 138.9, 213.0; HRMS
for C13H14ClN3O2 (M+), calcd 279.0775, found 279.0777.
The enantiomeric excess was determined by HPLC with
an AD-H column at 280 nm (2-propanol/hexane¼20:80),
25 ꢀC, 0.8 mL/min; tR¼12.24 (minor), tR¼15.74 (major).
Acknowledgements
This work was supported by National Science Foundation of
China and Institute of Chemistry. We thank Prof. Mei-Xiang
Wang for helpful discussion and Prof. Qiyu Zheng for crys-
tallographic analysis.
4.4.10. S-(1S,3S)-3-((R)-Hydroxy(4-nitrophenyl)methyl)-
4-oxocyclohexyl ethanethioate (19a). Colorless oil; ee
99%; [a]2D0 ꢂ66.3 (c 2.0, CHCl3); 1H NMR (300 MHz,
CDCl3): d 1.62–1.67 (1H, m), 1.83–1.93 (1H, m), 2.12–
2.16 (2H, m), 2.29 (3H, s), 2.41–2.56 (2H, m), 2.75–2.83
(1H, m), 3.85–3.97 (1H, br), 4.00–4.03 (1H, m), 4.91 (1H,
d, J¼7.9 Hz), 7.45–7.48 (2H, m), 8.15–8.18 (2H, m); 13C
NMR (CDCl3, 75 MHz): d 30.9, 32.4, 35.5, 39.1, 39.2,
53.9, 73.4, 123.7, 127.8, 147.6, 147.9, 194.0, 212.3;
HRMS for C15H18NO5S (M+H)+, calcd 324.0900, found
324.0900. The enantiomeric excess was determined by
HPLC with an AD-H column at 280 nm (2-propanol/
hexane¼10:90), 25 ꢀC, 0.8 mL/min; tR¼50.31 (minor),
tR¼59.36 (major).
Supplementary data
It consists of spectra for all new compounds. Supplementary
data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2007.08.096.
References and notes
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4.4.11. S-(1S,3S)-3-((R)-Hydroxy(4-trifluoromethylphe-
nyl)methyl)-4-oxocyclohexyl ethanethioate (19b). Color-
1
less oil; ee >99%; [a]2D0 ꢂ31.8 (c 0.5, CHCl3); H NMR
(300 MHz, CDCl3): d 1.62–1.70 (1H, m), 1.83–1.93 (1H,
m), 2.14–2.20 (2H, m), 2.32 (3H, s), 2.43–2.51 (1H, m),
2.56–2.64 (1H, m), 2.78–2.86 (1H, m), 3.83 (1H, d, J¼
3.0 Hz), 4.02–4.07 (1H, m), 4.88 (1H, dd, J¼3.4, 3.4,
8.1 Hz), 7.44 (2H, d, J¼8.1 Hz), 7.61 (2H, d, J¼8.1 Hz);
13C NMR (CDCl3, 75 MHz): d 30.9, 32.6, 35.5, 39.2, 54.0,
73.8, 124.5 (q, –CF3), 125.4, 125.5, 127.3, 144.5, 194.0,
212.7; HRMS for C16H18F3O3S (M+H)+, calcd 347.0923,
found 347.0922. The enantiomeric excess was determined
by HPLC with an AD-H column at 254 nm (2-propanol/
hexane¼20:80), 25 ꢀC, 0.8 mL/min; tR¼9.51 (minor), tR¼
11.09 (major).
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[a]2D0 +38.4 (c 0.25, CHCl3); H NMR (300 MHz, CDCl3):

11314
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2006, 8, 4653–4655; (d) Chen, X.; Luo, S.; Tang, Z.; Cun,
L.; Mi, A.; Jiang, Y.; Gong, L. Chem.—Eur. J. 2007, 13, 689–
701; (e) Tang, Z.; Yang, Z.; Cun, L.; Gong, L.; Mi, A.; Jiang,
Y. Org. Lett. 2004, 6, 2285–2287; (f) Hayashi, Y.; Aratake,
S.; Itoh, T.; Okano, T.; Sumiya, T.; Shoji, M. Chem.
Commun. 2007, 957–959.
N
H
N
H
H
I
II
15. It is known that 2-aminopyridine is a good molecular recogni-
tion unit for acids. It is therefore likely the complex of DBSA
and catalyst 8 will geometrically facilitate protonation of pyr-
rolidinyl ring, resulting in exclusively formation of species II
(Ref. 14), as a result totally depleting the catalytic activity of
catalyst 8. For pyrrolidinyl pyridines as organocatalysts in
the absence of acidic additives, see: Tang, Z.; Cun, L.-F.;
Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2006,
8, 1263–1266.
16. (a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–
2943; (b) Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev.
2005, 105, 313–354.
17. For a few of examples, see: (a) Ramachary, D.; Barbas, C. F.,
III. Org. Lett. 2005, 7, 1577–1580; (b) Hayashi, Y.; Gotoh,
H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am.
Chem. Soc. 2005, 127, 16028–16029; (c) Liu, Q.; Rovis, T.
J. Am. Chem. Soc. 2006, 128, 2552–2553; During the work
of this manuscript, Gong reported another example similar
with ours, however, the reactions were carried out in organic
solvent under lower (ꢂ40 ꢀC) temperature, see: (d) Jiang, J.;
He, L.; Luo, S.; Cun, L.; Gong, L. Chem. Commun. 2007,
736–738.
6. Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570–579.
7. For examples of surfactant effect in aminocatalysis, see: (a)
Peng, Y. Y.; Ding, Q. P.; Li, Z.; Wang, P. G.; Cheng, J.-P.
Tetrahedron Lett. 2003, 44, 3871–3875; (b) Dziedzic, P.; Zou,
ꢀ
ꢀ
W.; Hafren, J.; Cordova, A. Org. Biomol. Chem. 2006, 4, 38–
40; (c) Guizzetti, S.; Benaglia, M.; Rainondi, L.; Celentano,
G. Org. Lett. 2007, 9, 1247–1250; For examples of surfactant
Brønsted acid catalyzed reactions, see: (d) Shirakawa, S.;
Kobayashi, S. Org. Lett. 2007, 9, 311–314; (e) Shirakawa, S.;
Kobayashi, S. Org. Lett. 2006, 8, 4939–4942; (f) Iimura, S.;
Nobutou, D.; Manabe, K.; Kobayashi, S. Chem. Commun.
2003, 1644–1645; (g) Manabe, K.; Iimura, S.; Sun, X. M.;
Kobayashi, S. J. Am. Chem. Soc. 2002, 124, 11971–11978.
8. Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed.
2005, 44, 7174–7199.
18. Pihko, P. M.; Laurikainen, K. M.; Usano, A.; Nyberg, A. I.;
Kaavi, J. A. Tetrahedron 2006, 62, 317–328 for other exam-
ples, see: Ref. 17d.
19. CCDC 637019 and CCDC 637018 contain the supplementary
crystallographic data for compounds 15d and 20, respectively.
These data can be obtained free of charge from The Cambridge
Crystallo-graphic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif. Crystal data for 15d: C14H13ClO2, colorless block,
Mr¼248.69, crystal size 0.10ꢁ0.10ꢁ0.10 mm3, orthorhombic,
9. (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128,
734–735; (b) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128,
4966–4967.
10. Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.;
Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 5527–5530.
11. Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem. Commun.
2006, 3687–3689.
12. For hydrophobic effect in stereoselective reactions, see:
Breslow, R.; Bandyopadhyay, S.; Levine, M.; Zhou, W.
ChemBioChem 2006, 7, 1491–1496.
13. For general base catalysis in aqueous aminocatalysis, see: Refs.
3b and 9.
14. For pKa of aminopyridines, see: Palmer, M. M. The Structure
and Reaction of Heterocycle Compounds; Edward Arnold:
London, 1982; 2-Aminopyridine: pKa¼6.86; 3-aminopyridine:
pKa¼5.98; 4-aminopyridine: pKa¼9.17. The variation of activ-
ity in different media may be rationalized by the following
equilibrium, where only species I is catalytically active. (The
protonation of pyrrolidinyl nitrogen in a L-prolinamide with
strong acids such as p-toluenesulfonic acid leads to an inert
˚
˚
space group P2(1)/c, a¼6.71893(4) A, b¼10.43752(8) A,
c¼19.1216(4) A, a¼90.00ꢀ, b¼90.00ꢀ, g¼90.00ꢀ, V¼
˚
1340.98(3) A , Z¼4, rcalcd¼1.232 g cmꢂ3, T¼296(2) K. A to-
3
˚
tal of 3074 reflections and 2282 parameters were used for the
full matrix, least-squares refinement on F2. R1¼0.0368
[I>2s(I)], R1¼0.0488 (all data), wR2¼0.0933 [I>2s(I)],
wR2¼0.1002 (all data). Crystal data for 20: C13H14BrNO4, col-
orless prism, Mr¼328.16, crystal size 0.62ꢁ0.24ꢁ0.20 mm3,
˚
orthorhombic, space group P2(1)/c, a¼7.2324(14) A,
ꢀ
ꢀ
˚
˚
b¼9.6314(19) A, c¼19.391(4) A, a¼90.00 , b¼90.00 , g¼
90.00ꢀ, V¼1350.7(5) A , Z¼4, rcalcd¼1.614 g cmꢂ3
,
T¼
3
˚
293(2) K. A total of 3095 reflections and 1651 parameters
were used for the full matrix, least-squares refinement on F2.
R1¼0.0310 [I>2s(I)], R1¼0.0678 (all data), wR2¼0.0716
[I>2s(I)], wR2¼0.0824 (all data).
20. Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am.
Chem. Soc. 2003, 125, 2475–2479.
21. (a) Cao, Y.-J.; Lai, Y.-Y.; Wang, X.; Li, Y.-J.; Xiao, W.-J.
Tetrahedron Lett. 2007, 48, 21–24; (b) Vishnumaya; Singh,
V. K. Org. Lett. 2007, 9, 1117–1119.