Highly diastereo- and enantioselective direct aldol reactions promoted by water-compatible organocatalysts bearing a pyrrolidinyl-camphor structural scaffold

Article abstract of DOI:10.1016/j.tet.2009.02.022

Efficient synthetic routes have been developed for the synthesis of a series of pyrrolidinyl-camphor containing organocatalysts (1-10). Structural modifications were made by varying the stereo- and electronic properties of the camphor scaffold and the aromatic substituents. These readily tunable and amphiphilic organocatalysts were evaluated for the direct asymmetric aldol reaction of various aromatic aldehydes and cyclohexanone either in organic solvents or in the presence of water. The aldol reaction proceeded smoothly with excellent chemical yields (up to 99%), enantioselectivities (up to 99% ee), and anti-diastereoselectivities (up to 99:1) with a catalytical amount of the bifunctional organocatalysts (20 mol %) under optimal reaction conditions. Mechanistic transition models are proposed and the stereochemical bias of the asymmetric aldol reaction is presented.

Full text of DOI:10.1016/j.tet.2009.02.022

Tetrahedron 65 (2009) 2879–2888
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Highly diastereo- and enantioselective direct aldol reactions promoted
by water-compatible organocatalysts bearing a pyrrolidinyl-camphor
structural scaffold
*
Zheng-Hao Tzeng, Hung-Yao Chen, Raju Jannapu Reddy, Ching-Ting Huang, Kwunmin Chen
Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient synthetic routes have been developed for the synthesis of a series of pyrrolidinyl-camphor
containing organocatalysts (1–10). Structural modifications were made by varying the stereo- and
electronic properties of the camphor scaffold and the aromatic substituents. These readily tunable and
amphiphilic organocatalysts were evaluated for the direct asymmetric aldol reaction of various aromatic
aldehydes and cyclohexanone either in organic solvents or in the presence of water. The aldol reaction
proceeded smoothly with excellent chemical yields (up to 99%), enantioselectivities (up to 99% ee), and
anti-diastereoselectivities (up to 99:1) with a catalytical amount of the bifunctional organocatalysts
(20 mol %) under optimal reaction conditions. Mechanistic transition models are proposed and the
stereochemical bias of the asymmetric aldol reaction is presented.
Received 28 November 2008
Received in revised form 12 February 2009
Accepted 12 February 2009
Available online 20 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
enantioselectivities in water9 or in the presence of water.10 Thus,
the design and synthesis of small organic molecules that catalyze
In recent years, the development of small, metal-free privileged
organic molecules that catalyze enantioselective reactions has
emerged as one of the viable strategies for the preparation of chiral
building blocks.1,2 The aldol reaction is one of the most useful
methods for the formation of carbon–carbon bond in organic
chemistry.3,4 Direct asymmetric aldol reactions provide an atom-
enantioselective reactions in water or in the presence of water is
currently a promising research topic in organic chemistry.
In a previous study, we have developed recently, pyrrolidinyl-
camphor based organocatalysts for asymmetric organocatalysis.11
These catalysts were found to be efficient for direct aldol reactions
on water with high diastereo- and enantioselectivities (up to >99:1
dr and >99% ee). We envision that the assembly of a well-defined
structural camphor scaffold12 with a thiourea motif13 and amine
functionalities could constitute a new class of bifunctional orga-
nocatalysts.14 It is postulated that they synergistically activate both
the nucleophilic and electrophilic substrates via enamine formation
and hydrogen bond activation. In addition, the neighboring rigid
bicyclic camphor structural scaffold can serve as an efficient ster-
eocontrolling element. We would like to describe here the design
and synthesis of a series of camphor-based organocatalysts (1–10)
for the asymmetric aldol reaction. High to excellent levels of
chemical yields (up to 95%) and stereoselectivities (up to >99:1 dr
and >99% ee) were obtained and the stereochemical pathway of
the reactions is proposed.
economical approach to form b-hydroxyl carbonyls whilst various
organocatalysts have been developed to achieve high diastereo-
and enantioselectivities.5 The stereoselective transformation in
water or aqueous media6 is an important research subject because
water is an environmentally friendly, safe medium, which avoids
issues of pollution that are inherent with organic solvents. Water
often inhibits the catalyst’s activity or alters enantioselectivity by
interfering with the formation of transition states. Although the
addition of large amount of water generally resulted in low
chemical yields and enantioselectivities of the aldol products,7
excellent stereoselectivities were achieved when the reaction was
carried out in the presence of small amount of water.8 Therefore,
utilizing pure water as a reaction medium for asymmetric aldol
reactions is needed, especially for the discovery of new small
privileged organic molecules as a catalyst. Recently, many research
groups have demonstrated direct asymmetric aldol reactions cat-
alyzed by a variety of organocatalysts with high diastereo- and
2. Results and discussion
2.1. Design and preparation of organocatalysts 1–10
The synthesis of organocatalysts 1–4 began with (S)-tert-butyl
2-(2-aminophenylcarbamoyl)pyrrolidine-1-carboxylate (A), which
* Corresponding author.
E-mail address: kchen@ntnu.edu.tw (K. Chen).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.022

2880
Z.-H. Tzeng et al. / Tetrahedron 65 (2009) 2879–2888
was readily prepared from the Boc-protected
L-proline and o-phe-
On the other hand, the in situ prepared ketopinic acid derived
nylenediamine in CH2Cl2. Treatment of compound A with phenyl
isothiocyanate and 3,5-bis(trifluoromethyl)phenyl isothiocyanate
in CH2Cl2 to give Boc protected 1-(2-aminophenyl)-3-phenylthio-
urea and 1-[3,5-bis(trifluoromethyl)phenyl]-3-(2-aminophenyl)-
thiourea derivatives, which was followed by the addition of TFA to
give the desired organocatalysts 1 and 2 with overall yields of 60%
and 64%, respectively (Scheme 1). The organocatalyst 3 can
be prepared by conventional coupling between A and cam-
phorsulfonyl chloride followed by TFA treatment to produce 3 with
a 65% overall yield. A similar synthetic route was developed for the
preparation of organocatalyst 4 in 62% overall yield by reacting
ketopinic acid chloride with compound A.
isothiocyanate (SOCl2 and NH4SCN) was reacted with o-phenyl-
enediamine to afford 5 (51% yield), which was then converted to
a thiourea-amine catalyst 6 (R¼H) with a relatively high yield (81%)
(Scheme 2). A similar synthetic route was used to prepare the
analogous 4-hydroxy L-proline organocatalyst 7, which was sub-
sequently protected as its tert-butyldiphenylsilyl ether 8. Attempts
to protect the 4-hydroxyl group of the pyrrolidine ring in N-Boc-7
as its benzyl ether failed, which of worth noting, resulted in the
formation of an unexpected benzylisothiourea 9 with a reasonable
chemical yield (61% yield) after removal of the Boc group. A similar
reaction affords (naphthalen-1-yl)methylisothiourea 10 by using
1-(bromomethyl)naphthalene under the same reaction conditions.
Me
Me
O
O
H
S
N
H
N
O
N
H
O
3 (65%)
1. Camphorsulfonyl chloride
Et3N, CH2Cl2, 0 °C, 1 h
R
2. TFA, CH2Cl2, 0 °C, 1 h
R
R
S
1.SCN
H
ClCO2Et / Et3N
CH2Cl2, 0 °C to rt
H
N
NH2
H
N
N
N
H
R
+
OH
N
Boc
N
H
N
Boc
CH2Cl2 / 0 °C to rt
2. TFA, CH2Cl2 , 0 °C
H2N
NH2
O
A
O
O
1 (R = H, 60%)
2 (R = CF3, 64%)
1. Ketopinic chloride
Et3N, CH2Cl2 , 0 °C, 1 h
2. TFA, CH2Cl2, 0 °C, 1 h
Me
Me
O
O
N
H
N
H
N
H
O
4 (62%)
Scheme 1. Synthesis of prolinamide derivatives as an organocatalysts 1–4.
1. N-Boc-L-Proline
(or N-Boc-4-hydroxy-L-Proline)
S
O
O
S
O
O
ethyl chloroformate
R
1. SOCl2, reflux
H
H
(2. TBDPSCl, DMAP, CH2Cl2)
3. TFA, CH2Cl2
H
N
N
N
H
N
N
H
2. NH4SCN, acetone
H2N
3. o-phenylenediamine
O
N
H
O
52-83%
OH
HO
O
5
6 (R = H)
7 (R = OH)
8 (R = OTBDPS)
R
S
O
S
O
O
HO
1. RCH2Br, NaH, THF, 0 °C
2. TFA, CH2Cl2, 0 °C
H
H
N
N
N
H
N
H
N
H
N
O
N
H
N
BOc
O
O
9
(R = Ph, 61%)
N-Boc-7
10 (R = 1-Naphthyl, 45%)
Scheme 2. Synthesis of camphor containing thiourea-prolinamide catalysts 5–10.

Z.-H. Tzeng et al. / Tetrahedron 65 (2009) 2879–2888
2881
the N–H protons of thiourea, which resulted in an increase in
chemical yield and enantioselectivity (Table 1, entry 2). An appre-
ciable increase in reactivity was achieved when a camphorsulfonyl
derived L-proline catalyst (3) was used (Table 1, entry 3). This may
due to the enhanced N–H acidity by the sulfonyl group, which
activates the electrophile. Low chemical yields and moderate
selectivities were observed when organocatalyst 4 was used in tol-
uene (Table 1, entry 4). No desired product was obtained when
organocatalyst 5 was used. This demonstrated the vital role of the
nucleophilic amine in the pyrrolidinyl moiety in the aldol reaction
(Table 1, entry 5). The reaction proceeded smoothly to afford the
anti-aldol product with a 78% yield and good stereoselectivities
when a camphor moiety was incorporated into the thiourea-amine
motif (Table 1, entry 6). Slight improvements in selectivity were
observed when organocatalysts 7 and 8 were used in toluene (Table
1, entries 7 and 8). By screening all the organocatalysts using these
conditions, it was observed that the anti-aldol products dominated
with the newly generated absolute stereochemistry to be (2R,10S).
The assignment of the absolute configuration (2R,10S) of anti-aldol
product is determined on the bases of the literature reports.5j,9a,16a
By analyzing the preliminary data obtained, it is obvious that the
presence of the bifunctional group is essential for the catalytical
reaction. Attention was also paid to the solvent effect of organo-
catalysts 6–10 under similar reaction conditions. Reasonable to
excellent yields and stereoselectivities were obtained under neat
conditions (Table 1, entries 9–11). Reactivity was significantly im-
proved with the organocatalysts (6–10) when hexanes were used
as the solvent (Table 1, entries 12–16). Subsequently, the aldol
reaction was carried out using organocatalysts 6–8 in CH2Cl2 to
improve the reactivities and the stereoselectivities (Table 1, entries
17–19). Good diastereo- and enantioselectivities were obtained
when catalyst 8 was used (Table 1, entry 18). The products were
obtained with low reactivities and good stereoselectivities when
catalyst 7 was used in THF (Table 1, entries 20–22). No significant
improvements were observed when the reaction was carried out in
CH3CN and DMSO (Table 1, entries 23–25 and entries 26–28).
Surprisingly, when using H2O as the reaction medium, high
chemical yields and selectivities were obtained for organocatalysts
Figure 1. ORTEP diagram (50% probability level) of 9 (hydrogen atoms are omitted for
clarity, expect at NH and OH).
The structures of these organocatalysts were fully characterized by
IR, 1H, 13C NMR, and HRMS analyses and compound 9 was further
confirmed by single crystal X-ray data analysis (Fig. 1).15
2.2. Screening of organocatalysts and optimization of
reaction conditions
As a model study, we explored the aldol reaction using cyclo-
hexanone and 4-nitrobenzaldehyde in the presence of the organo-
catalysts 1–10 (Table 1). The probe substrate was treated with
a catalytical amount of 1 (20 mol %) in toluene to give the desired
product with 38% yield in 2 days. The anti-products were obtained
with a reasonable diastereomeric ratio (anti/syn¼73:27) and 51%
enantiomeric excess (Table 1, entry 1). The powerful electron-
withdrawing groups of CF3 substituents in 2 augment the acidity of
Table 1
Diastereo- and enantioselective aldol reaction of cyclohexanone and 4-nitrobenzaldehyde catalyzed by organocatalysts 1–10 in various solvents (1 mL) at ambient
temperaturea
OH
O
OH O
O
2
CHO
Orgcat. 1-10
1'
+
+
solvent, rt
O2N
O2N
O2N
syn
anti
Entry
Cat.
Solvent
t (h)
Yieldb (%)
anti/sync
eed (%)
Entry
Cat.
Solvent
t (h)
Yieldb (%)
anti/sync
eed (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
6
7
8
6
7
8
9
10
6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Neat
48
48
24
72
60
72
48
48
96
96
96
72
72
72
72
72
96
38
48
95
14
NR
78
87
52
65
90
98
98
97
99
99
99
29
73:27
63:37
66:34
79:21
d
51
66
65
71
d
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
7
8
6
7
8
6
7
8
6
7
8
6
6
7
8
9
10
CH2Cl2
CH2Cl2
THF
THF
THF
CH3CN
CH3CN
CH3CN
DMSO
DMSO
DMSO
H2O
Brine
H2O
H2O
96
96
96
48
48
96
96
96
96
48
48
24
24
48
48
72
72
62
97
26
91
37
21
59
73
31
68
43
92
90
89
79
99
99
93:7
88
80
86
89
90
70
88
82
77
88
76
77
79
81
76
85
81
86:14
90:10
94:6
87:13
86:14
92:8
89:11
81:19
95:5
82:18
76:24
76:24
88:12
86:14
91:9
76:24
95:05
88:12
68:32
90:10
85:15
76:24
83:17
86:14
91:9
74
84
84
73
90
86
57
72
85
86
80
68
9
10
11
12
13
14
15
16
17
Neat
Neat
Hexanes
Hexanes
Hexanes
Hexanes
Hexanes
CH2Cl2
89:11
84:16
H2O
H2O
89:11
a
All reactions were carried out using 4-nitrobenzaldehyde (75.5 mg, 0.5 mmol), cyclohexanone (0.1 mL, 1 mmol), and 20 mol % organocatalysts (1–10).
Isolated yield.
Determined by analysis of the crude products with chiral HPLC.
anti-product % of ee was determined by Chiralpak AD-H.
b
c
d

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Z.-H. Tzeng et al. / Tetrahedron 65 (2009) 2879–2888
6–10 (Table 1, entries 29 and 31–34). A comparable result was
achieved when the aldol reaction was carried out in brine (Table 1,
entry 30). The use of a co-solvent system (THF/H2O) was also
studied, but failed to improve the chemical outcomes (data not
shown). Although excellent chemical yields can be obtained by
carrying out the aldol reaction on H2O, the stereochemical results
need further improvement. Thus, we focus our subsequent in-
vestigations on the additive effect and using H2O as the reaction
medium.
then examined under optimum reaction conditions. In most cases,
anti-aldol products with high to excellent diastereo- and enantio-
selectivities were obtained. The reaction rate depended upon the
nature of the substituent on the aromatic group. Excellent selec-
tivities were observed when 2-nitrobenzaldehyde was employed as
the acceptor while the use of 3-nitrobenzaldehyde resulted in
a decrease in both the reactivities and selectivities (Table 3, entries
1 and 2). Excellent enantioselectivity but diminished reactivity was
observed when 4-cyanobenzaldehyde was used (Table 3, entry 3).
The chemical yield was further decreased to 55% when benzalde-
hyde was used (Table 3, entry 4). High enantioselectivities of the
anti-product were observed, for electron-donating substituent ac-
ceptor aldehydes the reactivity decreased dramatically as expected
(Table 3, entries 5–7). High to excellent diastereo- and enantiose-
lectivities were obtained when the reaction with 4-fluo-
robenzaldehyde was catalyzed by organocatalysts 8–10 in the
presence of water with chemical yields of only 29–32% (Table 3,
entries 8, 11, and 14). On the other hand, 4-chloro and 4-bromo-
benzaldehydes provide low reactivities and low to moderate
selectivities when catalyzed by organocatalysts 8–10 (Table 3,
entries 9, 10, 12, 13, 15, and 16). To improve reactivities and
stereoselectivities of 4-halosubstituent acceptors, we have carried
out reaction in hexanes catalyzed by organocatalysts 9 and 10.
4-Fluorobenzaldehyde provides low chemical yields and excellent
stereoselectivities (Table 3, entries 17 and 20), whereas, 4-chloro
and 4-bromobenzaldehydes afford low reactivities and low to
moderate selectivities in hexanes (Table 3, entries 18, 19, 21, and
22). The reactivity for aldehydes with electron-donating sub-
stituents and 4-halobenzaldehydes was dramatically decreased.
This may be depending upon the nature of less reactivity of alde-
hyde acceptors having electron-donating and 4-halosubstituent
group on the aromatic ring.
As mentioned, our aim is to develop an environmentally benign
synthetic method for asymmetric reactions. We envision that
the presence of an additional proton source may help to build the
framework of the hydrogen bonds between substrates and
the catalyst. This may consequently enhance the outcomes of the
stereoselectivities. Excellent chemical yields and good to high
stereoselectivities were obtained when catalyzed by organocatalyst
6 with the addition of 20 mol % of HCl (0.033 M, 1.0 mL) and citric
acid (0.033 M, 1.0 mL) (Table 2, entries 1 and 2). Comparable results
were observed when acetic acid was added (Table 2, entry 3). The
stereoselectivities were further improved when TFA was added as
an additive (Table 2, entry 4). The reactivity decreased when
20 mol % of camphorsulfonic acid was added (Table 2, entry 5). Both
the chemical yields and selectivities were improved by organo-
catalysts 6–8 in the presence of NH4Cl (0.033 M, 1.0 mL) (Table 2,
entries 6–10). Satisfactory results were achieved when dodecyl-
benzenesulfonic acid (DBSA) was added as it serves dual functions
as both an acid promoter and a surfactant to improve the chemical
outcomes. To this end, when organocatalyst 6 was employed in H2O
and DBSA (20 mol %), the anti-product was obtained with excellent
chemical yield (97%) and high stereoselectivity (93:7 anti/syn ratio
and 92% ee) (Table 2, entry 11). Slight improvements in stereo-
selectivities were observed when organocatalysts 7 and 8 were
used (Table 2, entries 12–14). It is worth mentioning that only
2.0 equiv of the donor cyclohexanone to the acceptor aldehyde was
used for the catalytical process using organocatalysts 6–8, which
represented a significant improvement over the conventional aldol
condensation in organic solvents.
Cyclopentanone and butanone were also successfully explored
as aldol donors. The reaction of cyclopentanone and butanone with
4-nitrobenzaldehyde proceeded smoothly in the presence of water
when catalyzed by 8 to give the corresponding aldol products with
isolated yields of 72% and 58%, respectively. The diastereomeric
ratio of anti/syn was 77:23 and 93:7 with enantioselectivities of 82%
and 98% observed for anti-isomer, respectively (Eqs. 1 and 2). Un-
fortunately, inferior results were observed, when we study for ac-
etone (63% yield and 48% ee) and 2-hydroxyacetone (60% yield,
anti/syn ratio 55:45 and 13% ee) donors with 4-nitrobenzaldehyde
under the same reaction conditions.
2.3. Substrate generality
The substrate generality of this aldol reaction using cyclohexa-
none and catalyzed by 8–10 with a series of aromatic aldehydes was
Table 2
OH
O
O
cat. 8 (20 mol%)
Optimization of enantioselective aldol reaction of cyclohexanone and 4-nitro-
benzaldehyde catalyzed by 6–8 on water in the presence of various additivesa
CHO
DBSA (20 mol%)
+
H2O, 0 °C to rt, 2 d
72%
Yieldb (%)
anti/sync
eed (%)
O2N
O2N
Entry
Cat.
Additive
t (h)
anti / syn: 77:23
82% ee (anti)
1
2
3
4
5
6
7
8
6
6
6
6
6
6
7
8
8
8
6
7
8
8
HCl
40
24
24
24
40
40
12
36
36
96
24
36
36
36
91
96
91
93
57
94
94
99
92
65
97
99
89
95
86:14
80:20
84:16
93:7
90:10
91:9
94:6
86:14
91:9
88:12
93:7
95:5
96:4
96:4
90
80
80
93
90
94
89
83
85
94
92
94
98
Citric acid
CH3CO2H
TFA
ð1Þ
(þ)-CSAe
NH4Cl
NH4Cl
OH
O
O
cat. 8 (20 mol%)
NH4Cl (rt)
NH4Cl (0 ꢀC to rt)
NH4Cl (rt, THF)
DBSAf
CHO
DBSA (20 mol%)
9
+
H2O, 0 °C to rt, 5 d
58%
10
11
12
13
14
O2N
O2N
DBSAf
DBSA (rt)
DBSAf
anti / syn: 93:7
98% ee (anti)
>99
ð2Þ
a
Unless otherwise specified, all reactions were carried out using 4-nitro-
benzaldehyde (0.5 mmol), cyclohexanone (1.0 mmol), additive (20 mol %), and cat-
alyst (20 mol %) on water (1 mL) at ambient temperature.
2.4. Transition state models for direct aldol reaction
b
Total isolated yield.
Determined by analysis of the crude products by chiral HPLC.
Determined by chiral HPLC analysis (Chiralpak AD-H).
c
The mechanistic understanding of the catalytical aldol reaction
remains unclear and the transition state models were proposed to
explain the asymmetric induction. The transition state
d
e
D
-(þ)-10-Camphorsulfonic acid.
f
The reaction was carried out at 0 ꢀC with DBSA (dodecylbenzenesulfonic acid).

Z.-H. Tzeng et al. / Tetrahedron 65 (2009) 2879–2888
2883
Table 3
Enantioselective aldol reaction of cyclohexanone and various aromatic aldehydes catalyzed by organocatalysts 8–10a
O
OH
R
O
OH
O
CHO
+
cat. 8-10 / DBSA
H2O (or) Hexanes
S
R
+
R
R
Entry
R
Cat.
t (d)
Yieldb (%)
anti/sync
eed (%)
1
2
3
4
5
6
7
8
2-NO2
3-NO2
4-CN
H
4-Me
4-OMe
1-Naphthyl
4-F
4-Cl
4-Br
4-F
4-Cl
4-Br
4-F
4-Cl
4-Br
4-F
4-Cl
4-Br
4-F
4-Cl
4-Br
8
8
8
8
8
8
8
8
8
8
9
9
2
2
2
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
87
83
75
55
42
26
35
32
25
16
29
18
30
29
27
34
30
24
35
26
44
40
99:1
98
80
94
94
85
80
89
73
29
24
98
83
23
>99
83
41
81:19
88:12
97:3
91:9
85:15
90:10
89:11
42:58
33:67
98:2
91:9
86:14
93:7
9
10
11
12
13
14
15
16
17e
18e
19e
20e
21e
22e
9
10
10
10
9
9
9
10
10
10
92:8
40:60
87:13
95:5
39:61
85:15
33:67
31:69
94
83
33
99
61
22
a
Unless otherwise specified, all reactions were carried out using aldehyde (0.5 mmol), cyclohexanone (1.0 mmol), additive (20 mol %), and catalyst (20 mol %) on water (1 mL
for entries 1–16).
b
Isolated yield.
Determined by chiral HPLC analysis (Chiralpak AD-H).
Determined by chiral HPLC analysis.
Reactions were carried out in hexanes (1 mL for entries 17–22).
c
d
e
conformation was organized by the hydrogen bond formation in-
volving the organocatalyst and the substrate. These together with
the electrostatic as well as the steric interactions may account for
the stereochemical bias of the reaction. The results are in agree-
ment with earlier reports,16 which suggested that the presence of
additional hydrogen bond donors can have a beneficial effect on the
prolinamide catalysts in aldol reactions. As proposed in Figure 2,
the bifunctional organocatalyst (6) pyrrolidine moiety reacts with
the cyclohexanone to form the nucleophilic enamine in the pres-
ence of an acidic additive. The aldehyde is activated by bifurcated
H-bonding with NH of amide as well as NH of thiourea through
hydrogen bond interactions.
(model I). On the other hand, when the reaction was carried out in
an aqueous medium, the water molecules form H-bonding with the
nitro and amide group in a favored transition state model II.6a,9k,10g
In the case of organic solvent, the nucleophilic addition of the en-
amine to the si-face of the carbonyl group leading to the major
(2R,10S)-product. The aromatic substituent of the aldehyde is ori-
ented to avoid the steric interactions with the camphor scaffold.
However, the more fixed transition state model II is established in
the presence of a nitro group. The approach of the enamine to the si-
face of the carbonyl group yields the desired anti-product.
3. Conclusions
We anticipated that in organic solvents, since there is a direct H-
bonding between the aldehyde and the N–H groups of amide and
thiourea, there may be an observed effect of stereochemistry
In conclusion, we have developed a practical alternative method
for the organocatalytic direct aldol reaction using bifunctional
water phase
O
S
N
N
H
N
H
O
O
S
N
H
O
Me
Me
N
N
H
O
N
H
H
O
Me
Me
N
O
H
O
H
I
N
O
O
H
O
II
organic phase
O
H
H
H
O
H
H
water phase
Figure 2. Proposed transition state models for the asymmetric aldol reaction was carried out in organic solvent (I) and in aqueous medium (II) using organocatalyst 6.

2884
Z.-H. Tzeng et al. / Tetrahedron 65 (2009) 2879–2888
thiourea-amine organocatalysts (1–10) bearing a hydrophobic
camphor scaffold structural units. These catalysts are readily pre-
pared from inexpensive starting materials with good overall
chemical yields. The organocatalytic direct asymmetric aldol
reaction was evaluated by employing these structurally tunable and
amphiphilic structural organocatalysts either in organic solvents or
in the presence of water. The anti aldol products were obtained
with excellent chemical yields (up to 99%), and diastereo- and
enantioselectivity (up to 99:1 dr and 99% ee) on water. A reasonable
mechanistic explanation was proposed for the stereochemical bias
of the asymmetric aldol reaction. Further study of these newly
developed camphor containing bifunctional organocatalysts in
asymmetric organocatalysis is under investigation.
on silica gel using MeOH/CH2Cl2 (1:20) as the eluent to furnish pure
product 1 as a yellowish liquid (1.51 g, 70% for 2 steps; overall yield
27
60% for 3 steps). [
a]
ꢂ7.9 (c 2.9, CHCl3); IR (CHCl3):
n
3415, 2969,
10.02 (br
D
2868, 1650, 1531, 1099 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
s, 1H), 8.52 (br s, 1H), 7.72 (d, J¼8.0 Hz, 1H), 7.44–7.32 (m, 5H), 7.30–
7.25 (m, 1H), 7.24–7.21 (m, 1H), 7.17 (td, J¼7.6 and 1.2 Hz, 1H), 3.76
(dd, J¼8.8 and 4.8 Hz, 1H), 2.97 (td, J¼6.8 and 2.0 Hz, 2H), 2.11–2.00
(m, 1H), 1.89–1.78 (m, 1H), 1.72–1.55 (m, 2H); 13C NMR (100 MHz,
CDCl3):
d 180.61, 173.97, 137.46, 133.28, 129.44, 129.35, 128.75,
128.20, 126.68, 125.75, 124.92, 123.33, 60.80, 47.16, 30.93, 26.10;
HRMS m/z 340.1367 (calcd for C18H20N4OS: 340.1358).
4.2.2. Pyrrolidine-2-carboxylic acid-{2-[3-(3,5-bistrifluoro-
methylphenyl)thioureido]phenyl}-amide (2)
4. Experimental section
4.1. General remarks
To a solution of the crude product A (1.00 g, 3.28 mmol) in dry
CH2Cl2 (10 mL) were added 3,5-bis(trifluoromethyl)phenyl iso-
thiocyanate (0.63 mL, 3.44 mmol) and Et3N (0.93 mL, 6.56 mmol)
dropwise at 0 ꢀC. After stirring for 1 h, the reaction mixture was
extracted with CH2Cl2 (2ꢁ20 mL). The combined organic layer was
washed with brine (20 mL), dried over MgSO4, filtered, and the
solvent was removed in vacuo to give the Boc-protected crude
product 2. The crude adduct was treated with TFA (1 mL) in CH2Cl2
(5 mL) at 0 ꢀC for 1 h. The mixture was diluted with H2O (10 mL)
and the resulting solution pH was adjusted to w7 with aqueous
NaHCO3. The mixture was then extracted with CH2Cl2 (2ꢁ10 mL).
The combined organic layer was washed with brine, dried over
MgSO4, filtered, and the solvent was removed in vacuo. The product
was purified by flash column chromatography on silica gel using
All reagents were used as purchased from commercial suppliers
without additional purification. IR spectra were recorded on a
Perkin–Elmer 500 spectrometer. NMR spectra were recorded on
a Bruker Avance 400 NMR spectrometer (400 MHz for 1H and
100 MHz for 13C). Chemical shifts are reported in
d parts per million
referenced to an internal TMS standard for 1H NMR and chloro-
form-d (77.0 ppm) for 13C NMR. Optical rotations were measured
on a JASCO P-1010 polarimeter. HRMS were recorded on JEOL
SX-102A. The X-ray diffraction measurements were carried out at
298 K on a KAPPA APEX II CCD area detector system equipped with
a graphite monochromator and a Mo K
¼0.71073 Å). Routine monitoring of reactions was performed
using silica gel, glass-backed TLC plates (Merck Kieselgel 60 F254
and visualized by UV light (254 nm). Solutions were evaporated to
dryness under reduced pressure on a rotary evaporator and the
residues purified by flash column chromatography on silica gel
(230–400 mesh) with the indicated eluents. Air and/or moisture
sensitive reactions were performed under the inert atmospheric
conditions.
a
fine-focus sealed tube
MeOH/CH2Cl2 (1:20) as the eluent to yield 2 as a colorless liquid
27
(l
(1.17 g, 75% for 2 steps; overall yield 60% for 3 steps). [
4.13, CHCl3); IR (CHCl3):
1131 cmꢂ1 1H NMR (400 MHz, CDCl3):
a
]
ꢂ25.4 (c
D
)
n
3417, 1633, 1519, 1471, 1380, 1278, 1177,
10.02 (br s, 1H), 8.04 (s,
;
d
2H), 7.63 (s, 1H), 7.53 (d, J¼7.6 Hz, 1H), 7.36–7.29 (m, 1H), 7.23 (d,
J¼4.4 Hz, 2H), 3.85 (dd, 1H, J¼9.2 and 5.2 Hz), 3.08–2.92 (m, 2H),
2.18–2.06 (m, 1H), 1.88–1.76 (m, 1H), 1.73–1.56 (m, 2H); 13C NMR
(100 MHz, CDCl3):
d 180.66, 175.64, 140.17, 133.05, 131.80 (q,
J¼33 Hz), 130.53, 128.64, 128.39, 126.99, 125.22, 124.38, 123.61,
121.67, 118.54 (q, J¼37 Hz), 60.69, 47.27, 30.81, 26.15; HRMS m/z
476.1115 (calcd for C20H18F6N4OS: 476.1106).
4.2. Synthesis of organocatalysts 1–10
4.2.1. Pyrrolidine-2-carboxylic acid-[2-(3-phenylthioureido)-
phenyl]-amide (1)
4.2.3. Pyrrolidine-2-carboxylic acid-[2-(7,7-dimethyl-2-oxo-bicyclo-
[2.2.1]hept-1-ylmethanesulfonylamino)phenyl]-amide (3)
To
a
stirred solution of Boc-protected
L
-proline (1.61 g,
To a mixture of camphorsulfonic acid chloride [prepared from
camphorsulfonic acid (1.00 g, 4.31 mmol) and SOCl2 (20 mL)] in dry
CH2Cl2 (10 mL) were added the common intermediate A (1.00 g,
3.28 mmol) and Et3N (1.86 mL, 13.12 mmol) at 0 ꢀC. After stirring
for an additional 1 h, the mixture was extracted with CH2Cl2
(2ꢁ20 mL). The combined organic layer was washed with brine
(20 mL), dried over MgSO4, filtered, and the solvent was removed
under vacuo to give the Boc-protected product 3. This was dissolved
in CH2Cl2 (5 mL) and TFA (1 mL) was added dropwise at 0 ꢀC. After
stirring for 1 h, the mixture was diluted with H2O (10 mL) and the
solution was adjusted to pH¼w7 with aqueous NaHCO3. The mix-
ture was then extracted with CH2Cl2 (2ꢁ10 mL) and the combined
organic layer was washed with brine, dried over MgSO4, filtered,
and the solvent was removed in vacuo. The crude product was
purified by flash column chromatography on silica gel using MeOH/
7.47 mmol) in dry CH2Cl2 (20 mL) at 0 ꢀC were added ethyl chloro-
formate (0.75 mL, 7.84 mmol) and Et3N (1.09 mL, 7.84 mmol)
dropwise. To this o-phenylenediamine (0.85 g, 7.84 mmol) was
added and the resulting mixture was heated to the ambient tem-
perature and then stirred for 30 min. The reaction mixture was
diluted with CH2Cl2 (20 mL) and H2O was added (10 mL). The layers
were separated and the organic layer was washed with brine, dried
over MgSO4, filtered, and the solvent was removed in vacuo to give
product A as a colorless liquid (1.94 g, 85%). To a solution of crude
product A (1.94 g, 6.36 mmol) in dry CH2Cl2 (20 mL) were added
phenyl isothiocyanate (0.91 mL, 7.63 mmol) and Et3N (1.08 mL,
7.63 mmol) dropwise at 0 ꢀC and stirred for 1 h. The mixture was
extracted with CH2Cl2 (2ꢁ20 mL) and the combined organic layer
was washed with brine (20 mL), dried over MgSO4, and filtered. The
solvent was removed under vacuo. The resulting crude product was
dissolved in CH2Cl2 (10 mL) and was added TFA (2 mL) dropwise at
0 ꢀC. After the consumption of the starting material as indicated by
TLC analysis, the reaction mixture was diluted with H2O (10 mL)
and the resulting solution was adjusted to pH¼w7 with aqueous
NaHCO3. The reaction mixture was extracted with CH2Cl2
(2ꢁ20 mL) and the combined organic layer was washed with brine,
dried over MgSO4, filtered and the solvent was removed in vacuo.
The crude product was purified by flash column chromatography
CH2Cl2 (1:20) as the eluent to afford the pure product 3 as a white
29
solid (0.89 g, 65% for 3 steps); mp: 70–72 ꢀC. [
a
]
þ60.7 (c 1.9,
D
CHCl3); IR (CHCl3):
n
3576, 3244, 2962, 2884, 1743, 1668, 1595, 1521,
10.38 (br s,1H),
1455,1336,1150 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
7.88 (dd, J¼7.8 and 1.4 Hz, 1H), 7.34–7.24 (m, 3H), 7.14 (td, J¼7.8 and
1.4 Hz, 1H), 3.92 (dd, J¼9.2 and 5.2 Hz, 1H), 3.58 (d, J¼15.2 Hz, 1H),
3.09 (t, J¼6.8 Hz, 2H), 2.90 (d, J¼15.2 Hz, 1H), 2.45 (dt, J¼18.0 and
4.4 Hz, 1H), 2.32–2.12 (m, 3H), 2.10–1.94 (m, 5H), 1.88–1.70 (m, 2H),
1.52–1.42 (m, 1H), 1.04 (s, 3H), 0.94 (s, 3H); 13C NMR (100 MHz,

Z.-H. Tzeng et al. / Tetrahedron 65 (2009) 2879–2888
2885
CDCl3):
d
217.01, 174.64, 134.27, 128.19, 127.86, 126.44, 125.22,
product was purified by flash column chromatography on silica gel
containing 1% Et3N of EtOAc/hexanes (1:4) as the eluent to furnish
123.28, 61.07, 59.56, 49.57, 48.70, 47.31, 42.93, 42.88, 30.92, 27.01,
26.89, 26.19, 19.91, 19.63; HRMS m/z (MHþ) 420.1949 (calcd for
C21H30N3O4S: 420.1952).
organocatalyst 6 as a white solid (24.0 g, 83% for 2 steps); mp 108–
22
110 ꢀC. [
a
]
D
ꢂ3.5 (c 1.2, CHCl3); IR (CHCl3):
n
3215, 2968, 1731, 1516,
1160 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d 11.83 (s, 1H), 10.81 (s, 1H),
4.2.4. Pyrrolidine-2-carboxylic acid-{2-[(7,7-dimethyl-2-oxo-
bicyclo[2.2.1]heptane-1-carbonyl)amino]phenyl}-amide (4)
The same procedure as described in Section 4.2.3 was followed
with ketopinic acid chloride [prepared from ketopinic acid (0.90 g,
4.94 mmol) and SOCl2 (1.4 mL)] being used instead of cam-
9.98 (s, 1H), 8.06 (d, J¼8.0 Hz, 1H), 7.50 (d, J¼7.8 Hz, 1H), 7.38–7.32
(m,1H), 7.20–7.14 (m,1H), 3.87 (dd, J¼9.2 and 4.9 Hz,1H), 3.05–2.92
(m, 2H), 2.63 (dt, J¼18.9 and 3.6 Hz, 1H), 2.52 (td, J¼11.8 and 3.6 Hz,
1H), 2.29–2.00 (m, 6H), 1.87–1.65 (m, 3H), 1.59–1.50 (m, 1H), 1.31
(s, 3H), 1.08 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 214.31, 179.55,
phorsulfonic acid chloride to afford organocatalyst 4 as a colorless
173.40, 170.01, 133.56, 128.37, 127.78, 126.60, 124.04, 122.03,
64.11, 60.47, 50.43, 46.66, 42.87, 42.72, 30.19, 28.76, 27.18,
25.64, 20.23, 19.81; HRMS m/z 428.1878 (calcd for C22H28N4O3S:
428.1882).
27
liquid (0.75 g, 62% for 3 steps). [
n
a]
ꢂ6.32 (c 1.9, CHCl3); IR (CHCl3):
D
3427, 2969, 2873, 1726, 1651, 1514 cmꢂ1
;
1H NMR (400 MHz,
CDCl3):
d 9.74 (s, 1H), 9.40 (s, 1H), 7.72–7.63 (m, 2H), 7.20–7.12 (m,
2H), 3.92 (dd, J¼9.2 and 5.6 Hz, 1H), 3.08–2.94 (m, 2H), 2.63–2.53
(m, 2H), 2.27–2.04 (m, 5H), 2.00 (d, J¼13.2 Hz, 1H), 1.88–1.68 (m,
3H),1.48 (td, J¼9.2 and 4.0 Hz,1H),1.31 (s, 3H),1.09 (s, 3H); 13C NMR
4.2.7. 4-Hydroxypyrrolidine-2-carboxylic acid-{2-[3-(7,7-
dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-carbonyl)thioureido]-
phenyl}-amide (7)
(100 MHz, CDCl3):
d 216.49, 174.41, 168.06, 130.08, 129.80, 125.87,
125.52, 124.84, 124.12, 65.51, 61.12, 50.27, 47.32, 43.77, 43.44, 30.72,
28.88, 27.73, 26.29, 20.83, 20.57; HRMS m/z 369.2068 (calcd for
C21H27N3O3: 369.2052).
The same procedure as described in Section 4.2.6 was followed
with 4-hydroxy-L-proline (10.0 g, 76.3 mmol) being used instead of
L
-proline to give organocatalyst 7 as a white solid (15.5 g, 79% for 2
22
steps); mp 97–98 ꢀC. [
2968, 2929, 1731, 1676, 1594, 1517, 1161, 750 cmꢂ1
(400 MHz, CDCl3): 11.84 (s, 1H), 10.77 (s, 1H), 9.98 (s, 1H), 8.04 (d,
a
]
ꢂ10.9 (c 1.1, CHCl3); IR (CHCl3):
n
3226,
D
4.2.5. 1-(2-Aminophenyl)-3-(7,7-dimethyl-2-oxo-bicyclo-
[2.2.1]heptane-1-carbonyl)thiourea (5)
;
1H NMR
d
To a mixture of ketopinic acid (10.0 g, 54.9 mmol) and SOCl2
(13.4 mL, 164.7 mmol) was stirred at reflux temperature (60 ꢀC) for
2 h. The mixture was cooled to ambient temperature and the excess
of SOCl2 was removed in vacuo. The crude product was dissolved in
acetone (200 mL) and NH4SCN (8.4 g, 109.8 mmol) was added at
0 ꢀC. The mixture was then stirred for 30 min. To this o-phenyldi-
amine (11.9 g, 109.8 mmol) was added at the same temperature and
stirred for an additional 30 min. The mixture was concentrated,
water (50 mL) was added, and extracted with EtOAc (2ꢁ50 mL).
The combined organic layer was washed with brine (20 mL), dried
over MgSO4, and filtered, after which the solvent was removed in
vacuo. The crude product was purified by flash column chroma-
tography on silica gel using CH2Cl2/hexanes (1:1) as the eluent to
J¼8.1 Hz, 1H), 7.51 (d, J¼7.8 Hz, 1H), 7.37–7.32 (m, 1H), 7.22–7.16 (m,
1H), 4.44 (s, 1H), 4.13 (t, J¼8.3 Hz, 1H), 3.01 (d, J¼12.3 Hz, 1H), 2.92
(dd, J¼12.3 and 2.9 Hz, 1H), 2.68–2.44 (m, 3H), 2.38–2.00 (m, 6H),
1.87–1.78 (m, 1H), 1.58–1.48 (m, 1H), 1.32 (s, 3H), 1.10 (s, 3H); 13C
NMR (100 MHz, CDCl3):
d 214.57, 180.16, 173.34, 170.56, 132.83,
128.84, 128.56, 127.07, 124.89, 122.82, 73.26, 64.73, 60.28, 55.18,
51.01, 43.47, 43.36, 39.81, 29.28, 27.76, 20.80, 20.44; HRMS m/z
444.1830 (calcd for C22H28N4O4S: 444.1831).
4.2.8. 4-(tert-Butyldiphenylsilanyloxy)pyrrolidine-2-carboxylic
acid-2-[3-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-
carbonyl)thioureido]phenyl}-amide (8)
To a stirred solution of N-Boc-protected adduct 7 (5.0 g,
9.2 mmol) in CH2Cl2 (50 mL) were added Et3N (1.5 mL, 11.0 mmol),
TBDPSCl (2.6 mL, 10.1 mmol), and DMAP (0.2 g, 1.8 mmol) at the
ambient temperature. The reaction mixture was allowed to stir for
2 d and was diluted with H2O (20 mL) and extracted with CH2Cl2
(2ꢁ50 mL). The combined organic layer was washed with brine,
dried over MgSO4, filtered, and the solvent was removed in vacuo.
The residue obtained was dissolved in CH2Cl2 (50 mL), and TFA
(7.0 mL, 92.0 mmol) was added dropwise at 0 ꢀC and stirred for 4 h.
The mixture was diluted with H2O (20 mL) and the solution was
adjusted to pH¼w7 with aqueous NaHCO3. The reaction mixture
was extracted with CH2Cl2 (2ꢁ50 mL) and the combined organic
layer was washed with brine, dried over MgSO4, filtered, and the
solvent was removed in vacuo. The crude product was purified by
flash column chromatography on silica gel using EtOAc/hexanes
yield 5 as a white solid (12.0 g, 66% for 3 steps); mp 180–181 ꢀC.
22
[
a]
þ16.9 (c 1.3, CHCl3); IR (CHCl3):
n
3421, 2969, 1730, 1633, 1531,
11.84 (s, 1H), 10.82 (s, 1H),
D
1159 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
7.27 (d, J¼8.0 Hz, 1H), 7.18–7.10 (m, 1H), 6.87–5.98 (m, 2H), 3.95 (s,
2H), 2.62 (dt, J¼14.9, 4.0 Hz, 1H), 2.51 (td, J¼14.9, 3.5 Hz, 1H), 2.29–
2.13 (m, 2H), 2.08 (d, J¼18.9 Hz,1H),1.87–1.76 (m,1H),1.58–1.47 (m,
1H), 1.30 (s, 3H), 1.08 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 214.61,
179.17, 170.65, 141.88, 128.75, 126.99, 124.08, 119.04, 117.42, 64.54,
51.07, 43.45, 43.37, 29.39, 27.79, 20.80, 20.45; HRMS m/z 331.1344
(calcd for C17H21N3O2S: 331.1354).
4.2.6. Pyrrolidine-2-carboxylic acid-{2-[3-(7,7-dimethyl-2-oxo-
bicyclo[2.2.1]heptane-1-carbonyl)thioureido]phenyl}-amide (6)
To a solution of Boc-protected L-proline (16.1 g, 74.7 mmol) in
dry CH2Cl2 (200 mL) were added ethyl chloroformate (7.5 mL,
78.4 mmol) and Et3N (10.9 mL, 78.4 mmol) dropwise at 0 ꢀC. After
15 min stirring, a solution of compound 5 (22.3 g, 67.2 mmol) in
CH2Cl2 (10 mL) was added dropwise at 0 ꢀC. The resulting mixture
was allowed to warm up to ambient temperature and stirred for
6 h. To the reaction mixture were added H2O (100 mL) and CH2Cl2
(200 mL) and the layers were separated. The combined organic
layer was washed with brine, dried over MgSO4, filtered, and the
solvent was removed in vacuo. The crude product obtained was
dissolved in CH2Cl2 (200 mL) and was treated with TFA (55.2 mL,
747.0 mmol) in a dropwise fashion at 0 ꢀC for 4 h. The mixture was
diluted with H2O (50 mL) and the solution was adjusted to pH¼w7
with aqueous NaHCO3. This was extracted with CH2Cl2 (2ꢁ200 mL)
and the combined organic layer was washed with brine, dried over
MgSO4, filtered, and the solvent was removed in vacuo. The crude
(1:2) as the eluent to yield catalyst 8 as a white solid (3.3 g, 52% for
22
3 steps); mp 102–103 ꢀC. [
a
]
þ0.5 (c 1.1, CHCl3); IR (CHCl3):
n
D
3225, 2959, 2931, 1732, 1682, 1593, 1533, 1516, 1111, 750, 703 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
11.80 (s, 1H), 10.75 (s, 1H), 9.94 (s, 1H),
8.02 (d, J¼8.0 Hz, 1H), 7.66–7.59 (m, 4H), 7.52 (d, J¼7.7 Hz, 1H),
7.47–7.29 (m, 7H), 7.20–7.14 (m, 1H), 4.41 (s, 1H), 4.18 (t, J¼8.5 Hz,
1H), 2.91 (d, J¼12.0 Hz, 1H), 2.68 (dd, J¼12.0 and 2.6 Hz, 1H), 2.59
(dt, J¼19.0 and 3.4 Hz,1H), 2.46 (td, J¼14.9 and 3.4 Hz,1H), 2.36 (dd,
J¼13.5 and 8.6 Hz, 1H), 2.25–2.13 (m, 2H), 2.08 (d, J¼19.0 Hz, 1H),
1.88–1.71 (m, 2H),1.58–1.48 (m,1H),1.23 (s, 3H),1.06 (s, 9H), 0.98 (s,
3H); 13C NMR (100 MHz, CDCl3):
d 214.39, 180.05, 173.40, 170.44,
135.59, 135.54, 133.94, 133.60, 132.83, 129.79, 129.71, 128.87, 128.47,
127.73, 127.69, 126.95, 124.76, 122.88, 75.10, 64.56, 60.58, 55.65,
50.95, 43.43, 43.31, 39.88, 29.25, 27.78, 26.89, 20.76, 20.32, 19.07;
HRMS m/z 682.3004 (calcd for C38H46N4O4SSi: 682.3009).

2886
Z.-H. Tzeng et al. / Tetrahedron 65 (2009) 2879–2888
4.2.9. 4-Hydroxypyrrolidine-2-carboxylic acid-{2-[2-benzyl-3-
(7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-carbonyl)-
isothioureido]phenyl}-amide (9)
in vacuo. The crude product was purified by flash column chro-
matography on silica gel using EtOAc/hexanes (1:5) as the eluent to
afford the pure aldol adducts.
To a solution of N-Boc-protected adduct 7 (5.0 g, 9.2 mmol), NaH
(60% in mineral oil, 0.7 g, 18.4 mmol) in THF (50 mL) benzyl bro-
mide (1.3 mL, 11.0 mmol) was added in a dropwise fashion at 0 ꢀC
and was stirred for 3 h. The mixture was diluted with H2O (20 mL)
and the solution was acidified to a pH¼6–7 using a saturated
aqueous NH4Cl solution. The reaction mixture was extracted with
EtOAc (2ꢁ100 mL) and the combined organic layer was washed
with brine, dried over MgSO4, filtered, and the solvent was re-
moved in vacuo. The resulting crude adduct was dissolved in CH2Cl2
(50 mL) and TFA (7.0 mL, 92.0 mmol) was added dropwise at 0 ꢀC
for 4 h. The mixture was diluted with H2O (20 mL) and extracted
with CH2Cl2 (2ꢁ50 mL). The combined organic layer was washed
with brine, dried over MgSO4, filtered, and the solvent was re-
moved under vacuo. The crude product was purified by flash col-
umn chromatography on silica gel using EtOAc/hexanes (4:1) as the
4.3.1. (2R,10S)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone
anti-Diastereomer:5i,9a 1H NMR (400 MHz, CDCl3):
d 8.20 (d,
J¼8.5 Hz, 2H), 7.51 (d, J¼8.5 Hz, 2H), 4.90 (dd, J¼8.2 and 2.6 Hz, 1H),
4.10 (d, J¼2.6 Hz,1H), 2.65–2.55 (m,1H), 2.53–2.44 (m,1H), 2.37 (td,
J¼13.0, 5.9 Hz, 1H), 2.16–2.06 (m, 1H), 1.88–1.78 (m, 1H), 1.75–1.30
(m, 4H); 13C NMR (100 MHz, CDCl3):
d 214.59, 148.38, 147.48,127.81,
123.46, 73.88, 57.10, 42.58, 30.67, 27.56, 24.60; HPLC analysis
Chiralcel AD-H (i-PrOH/hexanes¼5:95, 1.0 mL/min, 254 nm) tR
43.7 min and tR 58.8 min. syn-Diastereomer: 1H NMR (400 MHz,
CDCl3):
d
8.20 (d, J¼8.6 Hz, 2H), 7.49 (d, J¼8.6 Hz, 2H), 5.49 (s, 1H),
3.20 (d, J¼3.2 Hz, 1H), 2.68–2.60 (m, 1H), 2.53–2.45 (m, 1H), 2.40
(td, J¼13.2 and 6.0 Hz, 1H), 2.17–2.06 (m, 1H), 1.90–1.82 (m, 1H),
1.80–1.46 (m, 4H); 13C NMR (100 MHz, CDCl3):
d 213.98, 149.17,
147.07, 126.63, 123.44, 70.13, 56.80, 42.60, 27.83, 25.92, 24.78; HPLC
analysis Chiralcel AD-H (i-PrOH/hexanes¼5:95, 1.0 mL/min,
254 nm) tR 29.9 min and tR 40.0 min.
eluent to give 9 as a white solid (3.0 g, 61% for 3 steps); mp 192–
22
193 ꢀC. [
a
]
D
þ73.9 (c 1.1, CHCl3); IR (CHCl3):
n
3427, 2969, 2929,
1731, 1644, 1591, 1514, 1197 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
10.22 (s, 1H), 10.16 (s, 1H), 8.45 (d, J¼7.7 Hz, 1H), 7.40 (d, J¼7.2 Hz,
4.3.2. (2R,10S)-2-[Hydroxy(2-nitrophenyl)methyl]cyclohexanone
2H), 7.34–7.27 (m, 2H), 7.25–7.10 (m, 3H), 6.90 (d, J¼7.2 Hz, 1H),
4.48–4.33 (m, 3H), 4.09 (t, J¼7.6 Hz, 1H), 3.02 (d, J¼12.3 Hz, 1H),
2.84 (dd, J¼12.3 and 2.6 Hz, 1H), 2.48–2.23 (m, 5H), 2.15–1.94 (m,
3H), 1.89 (d, J¼19.0 Hz, 1H), 1.62–1.51 (m, 1H), 1.43–1.32 (m, 1H),
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.83 (d,
J¼8.2 Hz, 1H), 7.76 (d, J¼7.9 Hz, 1H), 7.63 (t, J¼7.4 Hz, 1H), 7.43 (t,
J¼7.4 Hz, 1H), 5.44 (d, J¼7.1 Hz, 1H), 4.09 (br s, 1H), 2.81–2.71 (m,
1H), 2.50–2.40 (m, 1H), 2.35 (td, J¼13.0 and 5.9 Hz, 1H), 2.14–2.03
1.21 (s, 3H), 0.91 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
215.70,
(m, 1H), 1.89–1.52 (m, 5H); 13C NMR (100 MHz, CDCl3):
d 214.77,
172.86, 168.03, 152.45, 136.21, 136.14, 130.36, 129.56, 128.51, 127.30,
125.09, 124.08, 120.03, 73.26, 64.96, 60.59, 55.33, 50.60, 43.32,
43.20, 39.87, 36.14, 29.64, 29.20, 27.67, 20.67, 20.20; HRMS m/z
(MHþ) 535.2370 (calcd for C29H35N4O4S: 535.2374). Crystal data for
148.70, 136.52, 132.97, 128.96, 128.33, 123.97, 69.64, 57.24, 42.73,
31.01, 27.68, 24.89; HPLC analysis Chiralcel OD-H (i-PrOH/
hexanes¼5:95, 1.0 mL/min, 254 nm) tR 16.5 min and tR 19.6 min.
syn-Diastereomer: 1H NMR (400 MHz, CDCl3):
d
8.00 (d, J¼8.2 Hz,
9
at 296 K: C29H34N4O4S,
M
534.66, orthorhombic, P212121
,
1H), 7.84 (d, J¼7.8 Hz, 1H), 7.65 (t, J¼7.2 Hz, 1H), 7.43 (t, J¼8.2 Hz,
1H), 5.96 (d, J¼1.8 Hz, 1H), 3.22 (br s, 1H), 2.92–2.82 (m, 1H), 2.51–
2.36 (m, 2H), 2.16–2.04 (m, 1H), 1.92–1.76 (m, 2H), 1.74–1.48 (m,
a¼12.1093(9) Å, b¼12.4874(9) Å, c¼18.4317(13) Å, V¼2787.1(3) Å3,
Z¼4,
l
¼0.71073 Å, Dc¼1.274 Mg/m3,
m
¼0.157 mmꢂ1, 19,795 re-
flections, 339 parameters, R¼0.1037, Rw¼0.1282 for all data.
3H); 13C NMR (100 MHz, CDCl3):
d 213.82, 147.07, 137.02, 133.05,
129.54, 127.85, 124.56, 66.54, 54.79, 42.46, 27.87, 26.40, 24.77; HPLC
analysis Chiralcel OD-H (i-PrOH/hexanes¼5:95, 1.0 mL/min,
254 nm) tR 12.0 min and tR 12.5 min.
4.2.10. 4-Hydroxypyrrolidine-2-carboxylic acid-{2-[3-(7,7-
dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-carbonyl)-2-naphthalen-
1-ylmethylisothioureido]phenyl}-amide (10)
The same procedure as described in Section 4.2.9 was followed
with 1-(bromomethyl)naphthalene (2.4 g, 11.0 mmol) being used
4.3.3. (2R,10S)-2-[Hydroxy(3-nitrophenyl)methyl]cyclohexanone
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 8.19 (s,1H), 8.15
instead of benzyl bromide to furnish organocatalyst 10 as a white
(d, J¼8.1 Hz, 1H), 7.67 (d, J¼7.6 Hz, 1H), 7.53 (t, J¼8.1 Hz, 1H), 4.90
(dd, J¼8.4 and 2.7 Hz, 1H), 4.14 (d, J¼2.7 Hz, 1H), 2.69–2.58 (m, 1H),
2.55–2.44 (m, 1H), 2.38 (td, J¼13.0 and 6.1 Hz, 1H), 2.18–2.05 (m,
1H), 1.88–1.78 (m, 1H), 1.77–1.51 (m, 3H), 1.47–1.32 (m, 1H); 13C
22
solid (1.3 g, 45% for 3 steps); mp 104–106 ꢀC. [
a
]
þ53.2 (c 1.3,
D
CHCl3); IR (CHCl3):
n
3360, 3252, 2967, 2933, 1731, 1695, 1666, 1605,
1590, 1513, 1448, 1212, 753 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
10.24 (s, 1H), 10.19 (s, 1H), 8.46 (d, J¼7.8 Hz, 1H), 7.85 (s, 1H), 7.80–
NMR (100 MHz, CDCl3): d 214.75, 148.24, 143.27, 133.15, 129.23,
7.71 (m, 3H), 7.50 (d, J¼8.2 Hz, 1H), 7.45–7.37 (m, 2H), 7.22–7.10 (m,
2H), 6.91 (d, J¼7.4 Hz, 1H), 4.55 (q, J¼12.8 Hz, 2H), 4.30 (s, 1H), 4.00
(t, J¼8.2 Hz, 1H), 2.95 (d, J¼12.1 Hz, 1H), 2.75 (d, J¼10.2 Hz, 2H),
2.43–2.23 (m, 3H), 2.10–1.95 (m, 2H), 1.94–1.79 (m, 2H), 1.58–1.47
(m, 1H), 1.37–1.21 (m, 1H), 1.17 (s, 3H), 0.87 (s, 3H); 13C NMR
122.78,121.95, 73.94, 57.07, 42.59, 30.68, 27.57, 24.59; HPLC analysis
Chiralcel AD-H (i-PrOH/hexanes¼5:95, 1.0 mL/min, 254 nm) tR
32.6 min and tR 41.5 min. syn-Diastereomer: 1H NMR (400 MHz,
CDCl3):
d
8.19 (s, 1H), 8.11 (d, J¼8.1 Hz, 1H), 7.67 (d, J¼7.7 Hz, 1H),
7.52 (t, J¼8.1 Hz, 1H), 5.48 (s, 1H), 3.28 (d, J¼3.2 Hz, 1H), 2.67 (ddd,
(100 MHz, CDCl3):
d 215.78, 173.26, 168.14, 152.44, 136.36, 133.79,
J¼12.6, 5.6, and 1.9 Hz, 1H), 2.53–2.34 (m, 2H), 2.18–2.06 (m, 1H),
133.39,132.64,130.43, 128.36, 128.29, 127.68,126.29,125.99,125.19,
124.26, 120.17, 73.12, 65.05, 60.66, 55.36, 50.66, 43.37, 43.24, 39.86,
36.39, 29.71, 29.23, 27.71, 20.73, 20.27; HRMS m/z (MHþ) 585.2529
(calcd for C33H37N4O4S: 585.2536).
1.92–1.47 (m, 5H); 13C NMR (100 MHz, CDCl3):
d 214.06, 148.33,
143.94, 132.00, 129.15, 122.07, 120.90, 69.91, 56.77, 42.59, 27.85,
25.92, 24.75; HPLC analysis Chiralcel AD-H (i-PrOH/hexanes¼5:95,
1.0 mL/min, 254 nm) tR 25.6 min and tR 29.2 min.
4.3. General procedure for the direct aldol reaction
4.3.4. (2R,10S)-2-[Hydroxy(4-cyanophenyl)methyl]cyclohexanone
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.64 (d,
To a solution of dodecylbenzenesulfonic acid (DBSA, 0.1 mmol)
and H2O (1 mL) were added aldehyde (0.5 mmol) and organo-
catalyst (0.1 mmol) at 0 ꢀC. Cyclohexanone (1.0 mmol) was added
and the mixture was allowed to warm up to the ambient temper-
ature for 1–7 days. The mixture was diluted with brine (5 mL) and
then was extracted with EtOAc (2ꢁ15 mL). The combined organic
layer was dried over MgSO4, filtered, and the solvent was removed
J¼8.2 Hz, 2H), 7.44 (d, J¼8.2 Hz, 2H), 4.83 (dd, J¼8.4 and 3.0 Hz, 1H),
4.05 (d, J¼3.0 Hz, 1H), 2.62–2.43 (m, 2H), 2.36 (td, J¼13.0 and
5.7 Hz, 1H), 2.16–2.04 (m, 1H), 1.88–1.76 (m, 1H), 1.74–1.48 (m, 3H),
1.43–1.29 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 214.71, 146.36,
132.13, 127.73, 118.66, 111.66, 74.16, 57.09, 42.61, 30.68, 27.59, 24.64;
HPLC analysis Chiralcel AD-H (i-PrOH/hexanes¼10:90, 0.5 mL/min,
254 nm) tR 47.8 min and tR 60.8 min. syn-Diastereomer: 1H NMR

Z.-H. Tzeng et al. / Tetrahedron 65 (2009) 2879–2888
2887
(400 MHz, CDCl3):
d
7.62 (d, J¼8.2 Hz, 2H), 7.43 (d, J¼8.2 Hz, 2H),
125.97, 125.52, 125.36, 125.26, 123.96, 72.11, 57.45, 42.83, 31.39,
27.94, 24.90; HPLC analysis Chiralcel OJ-H (i-PrOH/hexanes¼10:90,
0.5 mL/min, 254 nm) tR 23.3 min and tR 28.1 min. syn-Di-
5.43 (s, 1H), 3.27 (s, 1H), 2.64–2.56 (m, 1H), 2.51–2.32 (m, 2H), 2.14–
2.04 (m, 1H), 1.92–1.82 (m, 1H), 1.80–1.46 (m, 4H); 13C NMR
(100 MHz, CDCl3):
d
213.84, 147.14, 131.89, 126.47, 118.76, 110.66,
astereomer: 1H NMR (400 MHz, CDCl3):
d 7.90–7.84 (m, 1H), 7.82–
70.01, 56.65, 42.45, 27.67, 25.77, 24.63; HPLC analysis Chiralcel AD-
H (i-PrOH/hexanes¼10:90, 0.5 mL/min, 254 nm) tR 35.4 min and tR
41.4 min.
7.73 (m, 2H), 7.70 (d, J¼7.2 Hz, 1H), 7.52–7.44 (m, 3H), 6.24 (s, 1H),
3.14 (s, 1H), 2.77 (dd, J¼12.8 and 5.6 Hz, 1H), 2.54–2.48 (m, 1H), 2.38
(td, J¼13.6 and 6.1 Hz, 1H), 2.10–2.00 (m, 1H), 1.90–1.52 (m, 4H),
1.45–1.31 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 214.61, 136.56,
4.3.5. (2R,10S)-2-(Hydroxyphenylmethyl)cyclohexanone
133.63, 129.49,129.10,127.46,125.99,125.32,125.29,124.06,122.34,
66.89, 55.35, 42.61, 27.73, 26.02, 24.73; HPLC analysis Chiralcel OJ-H
(i-PrOH/hexanes¼10:90, 0.5 mL/min, 254 nm) tR 20.7 min and tR
28.9 min.
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.36–7.25 (m,
5H), 4.77 (dd, J¼8.8 and 2.6 Hz, 1H), 3.99 (d, J¼2.6 Hz, 1H), 2.66–
2.55 (m, 1H), 2.50–2.42 (m, 1H), 2.34 (td, J¼12.9 and 6.0 Hz, 1H),
2.10–2.01 (m, 1H), 1.80–1.44 (m, 4H), 1.34–1.21 (m, 1H); 13C NMR
(100 MHz, CDCl3):
d
215.26, 140.90, 128.20, 127.70, 126.88, 74.52,
4.3.9. (2R,10S)-2-[Hydroxy(4-fluorophenyl)methyl]cyclohexanone
57.28, 42.47, 30.67, 27.65, 24.52; HPLC analysis Chiralcel OD-H
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.32–7.25 (m,
(i-PrOH/hexanes¼10:90, 1 mL/min, 254 nm) tR 7.2 min and tR
2H), 7.02 (t, J¼8.7 Hz, 2H), 4.77 (d, J¼8.7 Hz, 1H), 4.03 (d, J¼1.7 Hz,
1H), 2.62–2.52 (m, 1H), 2.51–2.42 (m, 1H), 2.35 (td, J¼12.9, 6.0 Hz,
1H), 2.13–2.02 (m, 1H), 1.88–1.45 (m, 4H), 1.34–1.20 (m, 1H); 13C
11.8 min. syn-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.36–7.21
(m, 5H), 5.38 (s, 1H), 3.12 (d, J¼2.7 Hz, 1H), 2.58 (td, J¼10.2 and
1.6 Hz,1H), 2.47–2.40 (m, 1H), 2.35 (td, J¼13.2 and 5.8 Hz,1H), 2.10–
2.00 (m, 1H), 1.87–1.58 (m, 4H), 1.56–1.43 (m, 1H); 13C NMR
NMR (100 MHz, CDCl3):
d
215.32, 163.59 (d, J¼244.4 Hz), 136.90 (d,
J¼3.1 Hz), 128.69 (d, J¼7.9 Hz), 115.31 (d, J¼21.1 Hz), 74.06, 57.47,
42.63, 30.75, 27.73, 24.68; HPLC analysis Chiralcel OD-H (i-PrOH/
hexanes¼5:95, 1 mL/min, 254 nm) tR 12.9 min and tR 25.9 min. syn-
(100 MHz, CDCl3):
d 214.53, 141.51, 128.02, 126.83, 125.67, 70.47,
57.09, 42.52, 27.78, 25.89, 24.73; HPLC analysis Chiralcel OD-H
(i-PrOH/hexanes¼10:90,1 mL/min, 254 nm) tR 5.6 minandtR 6.3 min.
Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.30–7.23 (m, 2H), 7.01
(t, J¼8.7 Hz, 2H), 5.35 (s, 1H), 3.17 (s, 1H), 2.62–2.51 (m, 1H), 2.50–
4.3.6. (2R,10S)-2-[Hydroxy(4-methylphenyl)methyl]cyclohexanone
2.30 (m, 2H), 2.13–2.02 (m, 1H), 1.92–1.44 (m, 5H); 13C NMR
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d
7.20 (d,
(100 MHz, CDCl3):
d
214.48, 162.96 (d, J¼243.2 Hz), 137.23 (d,
J¼8.0 Hz, 2H), 7.14 (d, J¼8.0 Hz, 2H), 4.74 (dd, J¼8.7 and 2.5 Hz, 1H),
3.90 (d, J¼2.5 Hz, 1H), 2.65–2.55 (m, 1H), 2.51–2.42 (m, 1H), 2.40–
2.29 (m, 4H), 2.12–2.02 (m, 1H), 1.82–1.73 (m, 1H), 1.72–1.46 (m,
J¼3.0 Hz), 127.32 (d, J¼7.8 Hz), 114.96 (d, J¼21.1 Hz), 70.04, 57.05,
42.53, 27.64, 25.93, 24.73; HPLC analysis Chiralcel OD-H (i-PrOH/
hexanes¼5:95, 1 mL/min, 254 nm) tR 9.6 min and tR 9.8 min.
3H), 1.34–1.21 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 215.52, 137.98,
137.48, 129.00, 126.88, 74.48, 57.41, 42.62, 30.83, 27.78, 24.68, 21.10;
HPLC analysis Chiralcel OD-H (i-PrOH/hexanes¼3:97, 1 mL/min,
254 nm) tR 14.3 min and tR 20.7 min. syn-Diastereomer: 1H NMR
4.3.10. (2R,10S)-2-[Hydroxy(4-chlorophenyl)methyl]cyclohexanone
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.31 (d,
J¼8.4 Hz, 2H), 7.25 (d, J¼8.4 Hz, 2H), 4.76 (d, J¼8.7 Hz, 1H), 4.00 (s,
1H), 2.60–2.43 (m, 2H), 2.35 (td, J¼12.9 and 6.0 Hz, 1H), 2.13–2.03
(m, 1H), 1.83–1.75 (m, 1H), 1.71–1.47 (m, 3H), 1.35–1.23 (m, 1H); 13C
(400 MHz, CDCl3):
d
7.18 (d, J¼8.1 Hz, 2H), 7.13 (d, J¼8.1 Hz, 2H),
5.34 (s, 1H), 2.99 (d, J¼3.2 Hz, 1H), 2.61–2.53 (m, 1H), 2.49–2.28 (m,
5H), 2.11–2.02 (m, 1H), 1.88–1.59 (m, 4H), 1.57–1.43 (m, 1H); 13C
NMR (100 MHz, CDCl3): d 215.20, 139.59, 133.57, 128.54, 128.41,
NMR (100 MHz, CDCl3):
d
214.72, 138.51, 136.48, 128.79, 125.66,
74.11, 57.38, 42.66, 30.76, 27.73, 24.71; HPLC analysis Chiralcel OD-H
70.51, 57.21, 42.63, 27.90, 26.06, 24.84, 21.03; HPLC analysis Chir-
alcel OD-H (i-PrOH/hexanes¼3:97, 1 mL/min, 254 nm) tR 10.4 min
and tR 11.1 min.
(i-PrOH/hexanes¼5:95, 1 mL/min, 254 nm) tR 13.7 min and tR
21.9 min. syn-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.30 (d,
J¼8.4 Hz, 2H), 7.23 (d, J¼8.4 Hz, 2H), 5.35 (s, 1H), 3.10 (d, J¼3.2 Hz,
1H), 2.56 (td, J¼9.8 and 1.5 Hz,1H), 2.50–2.30 (m, 2H), 2.14–2.04 (m,
1H), 1.89–1.80 (m, 1H), 1.74–1.44 (m, 4H); 13C NMR (100 MHz,
4.3.7. (2R,10S)-2-[Hydroxy(4-methoxyphenyl)methyl]-
cyclohexanone
CDCl3):
d 214.45, 140.01, 132.62, 128.26, 127.14, 70.07, 56.99, 42.59,
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d
7.15 (d,
27.85, 25.93, 24.80; HPLC analysis Chiralcel OD-H (i-PrOH/
hexanes¼5:95, 1 mL/min, 254 nm) tR 10.2 min and tR 10.6 min.
J¼8.6 Hz, 2H), 6.79 (d, J¼8.6 Hz, 2H), 4.66 (d, J¼8.8 Hz, 1H), 3.86 (d,
J¼2.2 Hz, 1H), 3.72 (s, 3H), 2.57–2.47 (m, 1H), 2.43–2.34 (m, 1H),
2.28 (td, J¼12.8 and 5.9 Hz, 1H), 2.04–1.93 (m, 1H), 1.79–1.39 (m,
4.3.11. (2R,10S)-2-[Hydroxy(4-bromophenyl)methyl]cyclohexanone
4H), 1.24–1.10 (m, 1H); 13C NMR (100 MHz, CDCl3):
d
215.59, 159.28,
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.46 (d,
133.25, 128.17, 113.78, 74.24, 57.54, 55.27, 42.64, 30.84, 27.82, 24.71;
HPLC analysis Chiralcel AD-H (i-PrOH/hexanes¼5:95, 1 mL/min,
254 nm) tR 35.3 min and tR 36.4 min. syn-Diastereomer: 1H NMR
J¼8.4 Hz, 2H), 7.20 (d, J¼8.4 Hz, 2H), 4.75 (dd, J¼8.6 and 2.8 Hz, 1H),
3.98 (d, J¼2.8 Hz, 1H), 2.60–2.43 (m, 2H), 2.35 (td, J¼13.0 and
6.1 Hz, 1H), 2.13–2.04 (m, 1H), 1.84–1.47 (m, 4H), 1.36–1.22 (m, 1H);
(400 MHz, CDCl3):
d
7.13 (d, J¼8.6 Hz, 2H), 6.79 (d, J¼8.6 Hz, 2H),
13C NMR (100 MHz, CDCl3):
d 215.21, 140.08, 131.50, 128.76, 121.72,
5.23 (s, 1H), 3.71 (s, 3H), 2.97 (d, J¼2.9 Hz, 1H), 2.52–2.43 (m, 1H),
74.19, 57.35, 42.67, 30.77, 27.73, 24.73; HPLC analysis Chiralcel OD-H
2.39–2.21 (m, 2H), 2.04–1.93 (m, 1H), 1.81–1.51 (m, 4H), 1.50–1.36
(i-PrOH/hexanes¼5:95, 1 mL/min, 254 nm) tR 14.7 min and tR
(m,1H); 13C NMR (100 MHz, CDCl3):
d
214.78,158.62,133.74,126.95,
21.0 min. syn-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 7.45 (d,
113.58, 70.39, 57.30, 55.26, 42.67, 27.96, 26.22, 24.88; HPLC analysis
Chiralcel AD-H (i-PrOH/hexanes¼5:95, 1 mL/min, 254 nm) tR
19.0 min and tR 22.3 min.
J¼8.4 Hz, 2H), 7.18 (d, J¼8.4 Hz, 2H), 5.33 (s, 1H), 3.10 (d, J¼3.2 Hz,
1H), 2.55 (td, J¼9.7 and 1.2 Hz, 1H), 2.49–2.41 (m, 1H), 2.36 (td,
J¼13.2 and 5.8 Hz, 1H), 2.14–2.04 (m, 1H), 1.88–1.80 (m, 1H), 1.74–
1.40 (m, 4H); 13C NMR (100 MHz, CDCl3):
d 214.49, 140.61, 131.27,
4.3.8. (2R,10S)-2-(Hydroxy-1-naphthylmethyl)cyclohexanone
127.58,120.78, 70.16, 57.01, 42.65, 27.92, 25.98, 24.86; HPLC analysis
Chiralcel OD-H (i-PrOH/hexanes¼5:95, 1 mL/min, 254 nm) tR
10.9 min and tR 11.3 min.
anti-Diastereomer: 1H NMR (400 MHz, CDCl3):
d 8.26 (d,
J¼9.0 Hz, 1H), 7.89–7.77 (m, 2H), 7.55 (d, J¼6.8 Hz, 1H), 7.53–7.43
(m, 3H), 5.82 (dd, J¼8.7 and 3.1 Hz, 1H), 4.13 (d, J¼3.1 Hz, 1H), 3.03–
2.93 (m, 1H), 2.54–2.47 (m, 1H), 2.38 (td, J¼13.1 and 6.1 Hz, 1H),
2.12–2.02 (m, 1H), 1.74–1.58 (m, 1H), 1.55–1.30 (m, 4H); 13C NMR
4.3.12. (2R,10S)-2-(Hydroxy(4-nitrophenyl)methyl)cyclopentanone
anti-Diastereomer:5i 1H NMR (400 MHz, CDCl3):
d
8.22 (d,
(100 MHz, CDCl3):
d 215.71, 136.83, 133.95, 131.39, 128.92, 128.45,
J¼8.6 Hz, 2H), 7.54 (d, J¼8.6 Hz, 2H), 4.85 (d, J¼9.2 Hz, 1H), 4.76 (s,

2888
Z.-H. Tzeng et al. / Tetrahedron 65 (2009) 2879–2888
1H), 2.53–2.34 (m, 2H), 2.33–1.90 (m, 3H), 1.85–1.50 (m, 2H); 13C
NMR (100 MHz, CDCl3): 219.33, 150.05, 148.62, 126.36, 123.64,
70.53, 56.04, 38.88, 22.44, 20.30; HPLC analysis Chiralcel AS-H
(i-PrOH/hexanes¼15:85, 0.6 mL/min, 254 nm) tR 35.6 min and tR
47.4 min.
2006, 45, 8103–8104; (d) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751–2772; (e)
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Commun. 2007, 957–959.
d
4.3.13. (2R,10S)-4-Hydroxy-3-methyl-4-(4-nitrophenyl)-
butan-2-one
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anti-Diastereomer:5j 1H NMR (400 MHz, CDCl3):
d 8.20 (d,
J¼8.7 Hz, 2H), 7.52 (d, J¼8.7 Hz, 2H), 4.86 (d, J¼8.0 Hz, 1H), 3.21 (br
s, 1H), 2.96–2.87 (m, 1H), 2.22 (s, 3H), 1.00 (d, J¼7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3):
d 212.78, 149.32, 147.45, 127.44, 123.57,
75.32, 53.22, 30.00, 13.95; HPLC analysis Chiralcel AS-H (i-PrOH/
hexanes¼15:85, 0.6 mL/min, 254 nm) tR 32.5 min and tR 41.9 min.
Acknowledgements
We thank the National Science Council of the Republic of China
(NSC 96-2113-M-003-005-MY3) for financial support for this work.
We are grateful to the Academic Paper Editing Clinic at NTNU, and
the National Center for High-Performance Computing for providing
computer time and facilities.
References and notes
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