Solvent-effects tuning the catalytic reactivity of prolinamides in asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tetasy.2014.10.019

Novel prolinamides were prepared and applied as organocatalysts in the asymmetric aldol reaction. Stable imidazolidinones were formed between prolinamides and aromatic aldehydes in organic solvents. It was found that aqueous conditions can significantly suppress the formation of the unwanted imidazolidinone intermediate and improve the catalytic activity of the prolinamides. As a consequence, high chemical yields (up to 99%) and good diastereoselectivity (up to >20:1 dr) and enantioselectivity (up to 95% ee) were achieved in 2-Me-THF or brine. This strategy could serve as a general solution to enhance the performance of prolinamides as organocatalysts.

Full text of DOI:10.1016/j.tetasy.2014.10.019

Tetrahedron: Asymmetry 25 (2014) 1590–1598
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Solvent-effects tuning the catalytic reactivity of prolinamides in
asymmetric aldol reactions
⇑
Xiang-Rong Huang, Qi Liu, Jing Wang, Jun-An Xiao, Hua Yang
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2014
Accepted 31 October 2014
Novel prolinamides were prepared and applied as organocatalysts in the asymmetric aldol reaction. Sta-
ble imidazolidinones were formed between prolinamides and aromatic aldehydes in organic solvents. It
was found that aqueous conditions can significantly suppress the formation of the unwanted imidazolid-
inone intermediate and improve the catalytic activity of the prolinamides. As a consequence, high chem-
ical yields (up to 99%) and good diastereoselectivity (up to >20:1 dr) and enantioselectivity (up to 95% ee)
were achieved in 2-Me-THF or brine. This strategy could serve as a general solution to enhance the per-
formance of prolinamides as organocatalysts.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
them have shown excellent stereoselectivities toward various
direct aldol reactions.7
The asymmetric aldol reaction is one of the most commonly
used CAC bond-forming pathways in the synthesis of complex nat-
ural products or biologically active molecules.1 The corresponding
Despite these achievements in the development of prolinamide
organocatalysts for asymmetric aldol reactions, an intrinsic hurdle
has been set up due to the structural features of the prolinamides.
It has been found that prolinamides can readily react with carbonyl
compounds to form imidazolidinones, especially with aldehydes.
Unfortunately, this specific reactivity usually has a negative effect
on the catalytic performance of prolinamides in aldol reactions.
Gryco et al. observed the generation of imidazolidinones between
aldol products, b-hydroxy carbonyl compounds or a,b-unsaturated
carbonyl compounds, are very important and versatile building
blocks in synthetic chemistry.2 In all of the developed asymmetric
aldol methodologies, the organocatalytic asymmetric aldol reac-
tion has received extra attention over the last decade, and has
evolved to be one of the major methods to prepare enantiomeri-
cally enriched compounds, besides metal-catalysis or enzymes.3
Additionally, from the perspective of environmental friendliness,
organocatalytic asymmetric aldol reactions would be the premium
choice for making enantiomerically pure organic compounds.4
Since the first asymmetric direct intermolecular aldol reaction,
L-prolinethioamide and both acetone and aldehydes, which was
found to diminish the chemical yield and enantioselectivity in
the direct aldol reaction.8 Subsequently, Morán et al. also identified
aldol imidazolidinone intermediates.9 Similarly, the formation of
an imidazolidinone was detrimental to the chemical yield and
enantioselectivity. The addition of TFA slowed down the accumula-
tion of this intermediate and improved the catalytic performance
of the prolinamide to some degree (Scheme 1, Eq. a).10 In 2011,
Andreu et al. proposed an interesting solution to inhibit the forma-
tion of the unwanted imidazolidinone intermediate by employing
zinc complexation with prolinamides, leading to faster reactions
with higher enantioselectivity (Scheme 1, Eq. b).11 Apparently,
the unwanted imidazolidinone changed the reaction pathway
and undermined the catalytic activity of the prolinamide, which
would hamper the development of prolinamides as organocata-
lysts in aldol reactions. Undoubtedly, a deeper insight into the
formation of imidazolidinones and facile pathways to inhibit
their formation would be highly demanding and necessary to
overcome this essential drawback for the use of prolinamides as
organocatalysts.
catalyzed by L
-proline, was reported by List et al. in 2000,5 numer-
ous efforts have been made to design more effective organocata-
lysts based on proline to improve their performance in aldol
reactions. In particular, prolinamides have attracted a great deal
of research interest due to their easy preparation and modification,
beneficial chemical structural features, and upgraded physical pro-
files over proline. In 2003, Gong et al. first applied L-proline-
derived amides to catalyze direct aldol reactions of aldehydes with
acetone.6 Subsequently, a wide range of functionalized prolina-
mides have been successfully designed and synthesized to secure
their superior performance in direct aldol reactions and many of
⇑
Corresponding author. Tel.: +86 731 88830833.
E-mail address: hyangchem@csu.edu.cn (H. Yang).
http://dx.doi.org/10.1016/j.tetasy.2014.10.019
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

X.-R. Huang et al. / Tetrahedron: Asymmetry 25 (2014) 1590–1598
1591
O
N
O
easily adjustable motif
improved stereoselectivity
modified physical properties
N
H
N
H
OH
H
prolinamide
proline
Moran et al.
O
N
O
N
H
Ph
O
OH
O
O
H
H
Eq a
N
N
+
Ph
NO2
NO2
formed imidazolidinone intermediate
reduced reaction rate
no additive
TFA
70 h, 21% yield, 10% ee
5 h, 21% yield, 61% ee
decreased enantioselectivity
Andreu et al.
O
O
O
O
O
OH
N
H
N
N
NH2
NH2
NH2
Zn2+
H
H
H
Eq b
+
Zn2+
NO2
NO2
O
no additive
Zn2+
12 h, 100% yield, 14% ee
24 h, 90% yield, 44% ee
formed zinc complex
prevented imidazolidinone formation
improved enantioselectivity
O
OH
Current work:
X = NO2
NO2
96% yield, 91% ee, dr 94:6
prolinamide
4-nitrobenzoic acid
Ph
O
N
HN
X = Br
organic solvent
O
O
N
Br
H
+
Eq c
only formed stable intermediate
no aldol product obtained
X
prolinamide
O
OH
4-nitrobenzoic acid
X = Br
brine
Br
99% yield, 88% ee, dr 91:9
O
NH HN
prolinamide:
.
significantly suppressed the unexpected imidazolidine
formation
. effectively tuned the catalytic activity of prolinamide
NH
Scheme 1. Formation of imidazolidinones via asymmetric aldol reactions catalyzed by prolinamides.
Driven by preparing highly effective prolinamides as organocat-
alysts, we designed and synthesized four prolinamides based on
the o-phenylenediamine moiety, with the aim of providing double
hydrogen-bonding formation with the corresponding substrates. It
should be noted that Saha et al. employed tosyl-functionalized pro-
linamides to catalyze the direct aldol reaction in DMF, and
obtained good enantioselectivity and diastereoselectivity.7n
Herein, one rationale of our design was to improve the solubilities
of tosyl- or acyl-functionalized prolinamides in regular organic
solvents via the introduction of long lipophilic alkyl chains onto
the sulphonamide or amide, in order to provide broader options
for solvents. On the other hand, the N-(phenylmethyl)-1,2-benzen-
ediamine motif, which could effectively provide multi-hydrogen
bonding sites, was incorporated into the prolinamides to facilitate
the direct aldol reaction. The catalytic activities were evaluated on
the asymmetric direct aldol reactions. A stable imidazolidinone
intermediate was isolated and confirmed by X-ray analysis. More
importantly, it was found that the use of brine as a solvent could
considerably suppress the production of this intermediate and
facilitate the catalytic performance of the prolinamides, which
could provide an effective solution to circumvent the problems of
prolinamides in asymmetric aldol reactions (Scheme 1, Eq. c).
2. Results and discussion
Initially, four prolinamides 1–4 were designed and prepared in
good yields, starting from the direct coupling between Cbz or Boc-
protected L-proline with o-phenylenediamine derivatives followed
by deprotection of the Cbz or Boc protecting group. The corre-
sponding synthetic routes for 1–4 are presented in Scheme 2. It

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X.-R. Huang et al. / Tetrahedron: Asymmetry 25 (2014) 1590–1598
1)
O
1)
COOH
N
COOH
N
NH
O
Boc
Boc
N
H
DMAP, EDCI
DCM
O
DMAP, EDCI
DCM
H2N
NH
HN
S
O2S
O
NH
O
N
H
ClO2S
81%
C12H25
C
11H23COOH
2) TFA, DCM
0oC-rt, 4 h
2) TFA, DCM
0oC-rt, 4 h
H2N
HN
DMAP, EDCI
HN
Et3N, DCM
C11H23
DCM, 0oC-rt,
20 h
72%
0oC-rt,
3 h
O
79%
C12H25
C11H23
73%
C12H25
2
5
6
1
H2N
NH2
BnCl, K2CO3
COOH
N
Cbz
1)
MeOH
O
COOH
0oC-rt, 4 h
EDCI, THF
rt, 12h
N
Boc
73%
NH
67%
DMAP, EDCI
DCM
O
N
H
Pd/C, H2
HN
NH2
NCbz
NH
HN
N
H
H2N
N Bn
O
MeOH, 12 h
95%
2) TFA, DCM
H
0oC-rt, 4 h
85%
H2N
3
7
8
4
Scheme 2. Synthetic routes to prolinamides 1–4.
can be rationalized that acidities of the N-Hs on the benzene moi-
ety in prolinamide 1 and 2 would be significantly increased by
introducing a sulfonamide or amide. In sharp contrast, the benzyl
group was combined with the o-phenylenediamine scaffold in
prolinamide 3. Therefore, the basicity of the corresponding NAH
was increased, which could be readily protonated by an acid to
enable hydrogen-bonding formation with substrates. A compara-
tive study of 1, 2, and 3 with the parent compound 4 would help
us to gain insight into the effect of functional groups on catalytic
performance.
between the catalyst and substrate, leading to an improved
stereocontrol.
With the optimum conditions in hand, the scope of this reaction
was investigated by employing a variety of benzaldehydes with
different substitution patterns and various ketones (Table 2). As
can be seen, when using aldehydes bearing a strong electron-with-
drawing group (ANO2) to react with cyclohexanone, no matter
with the substitution pattern, excellent dr and yields as well as
good ee for the corresponding anti-aldol product were obtained
uniformly (entries 1–4). Various ketone partners were tested for
this reaction with 4-nitrobenzaldehyde. As for acetone and cyclo-
pentanone, the enantioselectivities sharply decreased. Good ee
and dr were obtained for 4-methylcyclohexanone with slightly
lower chemical yields (entries 5–7). When benzaldehyde or a
species substituted by mild electron-withdrawing or electron-
donating groups were employed in this reaction, the desired aldol
product was not obtained (entries 8–12).
We were interested in the abnormal catalytic reactivity of cata-
lyst 3. Accordingly, extra caution and further attempts were made
to gain an insight into this unexpected situation. The reaction
between 4-bromobenzaldehyde with cyclohexanone was moni-
tored closely. It was observed that catalyst 3 was completely con-
sumed in several hours to generate an unknown compound with
less polarity. After being purified via silica gel column chromatog-
raphy and characterized by analytical methods, a stable imidazo-
lidinone was found to be formed between 4-bromobenzaldehyde
and prolinamide 3 (Scheme 3). The structure of this compound
was unequivocally confirmed by X-ray analysis of a single crystal
(Fig. 1).12 Morán et al. observed that the imidazolidinone interme-
diate was formed slowly in the reaction of acetone with 4-nitro-
benzaldehyde catalyzed by a prolinamide after nine days.10 These
observed results could help us to explain the different reactivities
of various benzaldehydes. Presumably, the formation of the imi-
dazolidinone intermediate between 4-nitrobenzaldehyde and pro-
linamide 3 was extremely sluggish, which would have a negligible
effect on the progress of the aldol reaction. As a result, the desired
Subsequently, the catalytic activities were evaluated in the
direct asymmetric aldol reaction between 4-nitrobenzaldehyde
and cyclohexanone at room temperature (Table 1). Encouragingly,
all four prolinamides smoothly catalyzed this aldol reaction to pro-
vide the corresponding product in CH2Cl2 (entries 1–4). The use of
catalyst 3 afforded the best ee and dr, while catalyst 4 which had
the least steric effects, afforded the best chemical yield. Therefore,
prolinamide 3 was considered to be the superior catalyst to be
used in the following tests. A series of solvents with varied polar-
ities were screened and it was found that the more polar solvents
usually gave better yields. Using 2-Me-THF as an industry-friendly
and green solvent, afforded excellent yield and good enantioselec-
tivity, albeit with a slightly decreased dr (entries 5–12). Ultimately,
efforts were focused on screening additives to further improve the
enantioselectivity and diastereoselectivity in 2-Me-THF. The addi-
tion of water can significantly accelerate the reaction, while lower-
ing the ee (entry 13). Basic additives such as NaHCO3, had a minor
effect on the catalytic performance (entry 14). When acidic addi-
tives were employed, the diastereoselectivity was generally
improved (entries 15–18). The use of 4-nitrobenzoic acid facili-
tated the reaction and provided excellent yield and moderate ee
in a much shorter reaction time (entry 19). Finally, the reaction
was carried out at 0 °C to furnish the corresponding anti- product
in excellent yield and dr and with good ee (entry 20). Presumably,
the basic nitrogen atom on the benzene ring in catalyst 3 is suscep-
tible by an acid, which could strengthen the hydrogen-bonding

X.-R. Huang et al. / Tetrahedron: Asymmetry 25 (2014) 1590–1598
1593
Table 1
Optimization of the direct asymmetric aldol reaction of 4-nitrobenzaldehyde and cyclohexanone catalyzed by prolinamides 1–4a
O
OH
O
O
catalyst
additive
H
+
solvent
NO2
NO2
O
O
O
O
NH
O
NH
NH
NH
N
H
N
H
N
H
N
H
HN
S
HN
HN
H2N
catalyst:
O
O
C11H23
1
2
3
4
C12H25
Entry
Catalyst
Solvent
T (°C)
Additive
(0.2 equiv)
Time
(h)
Yieldb
(%)
eec
(%, anti/syn)
drd
(anti/syn)
1
2
3
4
5
6
7
8
1
2
3
4
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
CH3OH
DMSO
THF
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
0
—
—
—
—
—
—
—
—
—
—
—
—
48
68
63
77
87
99
95
89
95
98
91
98
98
91
84
97
94
74
90
99
96
76
31/47
61/62
69/38
50/48
65/3
52/31
63/51
68/32
66/16
56/6
74/26
72/28
74/26
62/38
68/32
69/31
78/22
77/23
72/28
69/31
62/38
66/34
79/21
83/17
91/9
48
48
48
48
48
48
48
48
48
48
48
24
48
24
24
48
24
12
24
66
9
Brine
10
11
12
13
14
15
16
17
18
19
20
21
TFTe
2-Me-THF
2-Methyl-tert-butanol
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
88/4
71/21
62/46
74/48
81/10
75/51
88/29
76/40
78/45
91/53
91/22
H2Of
NaHCO3
Trifluoroacetic acid
Acetic acid
Toluenesulfonic acid
Benzoic acid
4-Nitrobenzoic acid
4-Nitrobenzoic acid
Trifluoroacetic acid
74/26
95/5
74/26
82/18
94/6
2-Me-THF
2-Me-THF
0
97/3
a
b
Reaction conditions: 4-nitrobenzaldehyde (0.5 mmol) and cyclohexanone (5.0 mmol), catalyst 1–4 (0.1 mmol), solvent (0.5 mL).
Isolated yield after column chromatography.
Determined by chiral HPLC analysis.
c,d
e
TFT =
a,
a,a
-trifluorotoluene.
f
One drop of H2O was added.
aldol product was obtained in good yield and stereoselectivity.
However, it would be facile for other benzaldehydes with different
electronic features, such as 4-bromobenzaldehyde, to react with
prolinamide 3 to completely furnish the unwanted imidazolidi-
none. As a result, the progress of the aldol reaction was terminated
due to the loss of active catalyst and the corresponding aldol prod-
uct could therefore not be obtained.
As mentioned above, we were faced with the dilemma that this
developed catalytic system was unexpectedly restricted to nitro-
substituted benzaldehydes. We next expected to tune the catalytic
reactivity of the catalyst and broaden the tolerance of substrates. In
principle, the existence of excess amounts of water in this reaction
should be deleterious to the generation of the unwanted imidazo-
lidinone, releasing the active catalyst to the catalytic cycle of the
aldol reaction. Furthermore, the use of water as the solvent would
cut down the consumption of organic solvents, offering an environ-
mentally benign process for this catalytic system. Hence, the most
effective and direct solution for this unexpected problem would be
the use of water as the solvent. Further efforts were applied to con-
duct this aldol reaction under aqueous conditions. The reaction of
4-bromobenzaldehyde with cyclohexanone was chosen as the
model reaction to test the feasibility of our strategy (Table 3).
The corresponding aldol products were successfully obtained in
good yield for catalysts 1–4 in water (entries 1–4). Again, catalyst
3 showed superior catalytic activity. Running this reaction in brine
afforded excellent chemical yield and good ee and dr (entry 5).
Acidic additives were also screened in brine. Similarly, the employ-
ment of trifluoroacetic acid provided relatively higher ee and dr
with a sizeable decrease in the chemical yield (entry 7). Extremely
slow reactions were observed when using toluenesulfonic acid and
NaHCO3 (entries 12 and 13). Among all the acidic additives studied,
4-nitrobenzoic acid was still the optimal choice for this reaction
system.
The effectiveness of this strategy using brine as the solvent was
next tested on various benzaldehydes with different electronic fea-
tures of the substituting groups. Benzaldehyde or benzaldehydes
substituted by electron-withdrawing groups all gave good yields
with slightly decreased ee and dr (Table 4, entries 1–4). In the pres-
ence of an electron-donating substituting group, the reaction rate
and enantioselectivity were significantly decreased. On the con-
trary, the diastereoselectivity was slightly improved (entry 5).
Nitro-substituted benzaldehydes were also evaluated under these
conditions. Compared with the catalytic results in 2-Me-THF,
excellent chemical yields were also obtained although ee and dr
were all slightly decreased (entries 6–8). Only trace amounts of
the desired aldol product were obtained when using acetone to

1594
X.-R. Huang et al. / Tetrahedron: Asymmetry 25 (2014) 1590–1598
Table 2
Scope of direct asymmetric aldol reaction catalyzed by 3 in 2-Me-THFa
O
O
O
OH
3 (20 mol%)
additive (20 mol%)
H
+
R1
R1
2-Me-THF, 0oC
R2
R3
R2
R3
X
X
Entry
Aldehyde
Ketone
(R2, R3)
Time
(h)
Yieldb
(%)
eec
(%, anti/syn)
drd
(anti/syn)
R1
X
1
2
3
4
5
6
7
8
2-NO2
3-NO2
2,4-NO2
2-NO2-4-Br
4-NO2
4-NO2
4-NO2
H
H
4-Br
4-CF3
2-OH
C
C
C
C
C
C
C
C
N
C
C
C
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
H, H
–(CH2)2–
–CH2CH(CH3)CH2–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
48
88
90
99
83
66
99
79
NR
NR
NR
NR
NR
92/55
91/26
92/35
95/11
59
34/83
91/2
—
—
—
—
—
94/6
97/3
93/7
96/4
—
68/32
91/9
—
—
—
—
—
48
36
48
48
48
48
48
48
48
48
48
9
10
11
12
a
Reaction conditions: substituted benzaldehyde (0.5 mmol) and ketones (5.0 mmol), catalyst (3, 0.1 mmol), additive (4-nitrobenzoic acid, 0.1 mmol), solvent (2-Me-THF,
0.5 mL), reaction temperature (0 °C).
b
Isolated yield after column chromatography.
Determined by chiral HPLC analysis.
c,d
Table 3
Screening of direct asymmetric aldol reactions under aqueous conditionsa
O
O
OH
O
O
NH HN
catalyst (20 mol%)
additive (20 mol%)
Ph
O
O
O
Ph
H
3
N
HN
+
NH
solvent, rt
H
Br
Br
+
N
2-Me-THF, rt
Br
Br
Entry Catalyst Solvent Additive
(0.2 equiv)
Yieldb eec
(%) (%, anti/
syn)
drd
(anti/
syn)
9
Scheme 3. Formation of an imidazolidinone intermediate.
1
2
3
4
5
6
7
8
1
2
3
4
3
3
3
3
3
3
3
Water 4-Nitrobenzoic acid
80
90
94
80
99
96
63
93
80
85
89
46/7
68/16
79/6
35/15
88/13
87/19
89/47
86/47
85/24
79/5
70/30
71/29
84/16
72/28
91/9
89/11
98/2
88/12
97/3
Water 4-Nitrobenzoic acid
Water 4-Nitrobenzoic acid
Water 4-Nitrobenzoic acid
Brine 4-Nitrobenzoic acid
Brinee 4-Nitrobenzoic acid
Brine Trifluoroacetic acid
Brine Acetic acid
9
10
11
Brine Benzoic acid
Brine 2-Fluorobenzoic acid
Brine 3,5-Dinitrobenzoic
acid
91/9
86/14
85/16
12
13
3
3
Brine Toluenesulfonic acid Trace
Brine NaHCO3 Trace
ND
ND
ND
ND
a
Reaction conditions: benzaldehyde (0.5 mmol) and cyclohexanone (5.0 mmol),
catalyst 1–4 (0.1 mmol), additive (0.1 mmol), solvent (0.5 mL), reaction tempera-
ture (room temperature), and time (48 h).
b
Isolated yield after column chromatography.
Determined by chiral HPLC analysis.
Half-saturated brine was used.
c,d
Figure 1. ORTEP diagram of imidazolidinone intermediate.
e
react with 4-bromobenzaldehyde, due to the ready dehydration
that occurred in this reaction (entry 9). The aldol reaction of 4-bro-
mobenzaldehyde with cyclopentanone under these conditions
afforded comparatively lower stereoselectivities (entry 10).
unwanted imidazolidinone intermediate was formed and con-
firmed by X-ray analysis. A straightforward and concise strategy
employing brine as the solvent was proven to effectively suppress
the generation of the imidazolidinone. As a consequence, excellent
yields as well as good ee and dr values were achieved while toler-
ating different functional groups. More importantly, this strategy
could serve as an effective and general solution to overcome the
intrinsic drawback of prolinamides and facilitate the development
of prolinamides as organocatalysts.
3. Conclusion
In conclusion, three novel prolinamides have been designed and
prepared to act as organocatalysts in the direct aldol reactions of
cyclohexanone and benzaldehydes. It was found that the electronic
features of the benzaldehydes severely affected the reaction path-
way. Due to the inherent chemical features of the prolinamide, the

X.-R. Huang et al. / Tetrahedron: Asymmetry 25 (2014) 1590–1598
1595
Table 4
(m, 4H), 0.97–1.26 (m, 14H), 0.77–0.84 (m, 5H), 0.68 (t, J = 7.2 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) d 152.9, 151.5, 151.2, 145.1,
137.9, 128.4, 127.6, 127.3, 121.3, 116.1, 45.5, 36.4, 36.2, 31.7,
29.7, 29.4, 29.1, 27.4, 22.5, 14.3, 12.3; HRMS (TOF-ES+) m/z:
[M+H]+ calcd for C24H37N2O2S 417.2576, found 417.2561.
Scope of the direct asymmetric aldol reaction in brine.a
O
O
OH
O
catalyst (20 mol%)
additive (20 mol%)
+
H
R1
R1
R2
R3
brine, rt
R2
R3
4.2.2. (S)-N-(2-(p-Dodecylsulfonamido)phenyl)prolinamide 1
Entry
Aldehyde
R1
Ketone
(R2, R3)
Yieldb
(%)
eec
(%, anti/syn)
drd
(anti/syn)
Sulphonamide 5 (3.37 g, 8.1 mmol) and Boc-L-proline (2.58 g,
12.0 mmol, 1.5 equiv) were dissolved in CH2Cl2 (20 mL) and cooled
to 0 °C immediately. A solution of DMAP (0.78 g, 6.4 mmol,
0.8 equiv) and EDCI (1.84 g, 9.6 mmol, 1.2 equiv) in CH2Cl2
(20 mL) was then added dropwise. The resulting reaction mixture
was stirred at rt and monitored by TLC. After completion of the
reaction, the mixture was partitioned between EtOAc and 1 M
HCl. The organic layer was washed with half-saturated brine. The
dried (Na2SO4) extract was concentrated in vacuo. The crude prod-
uct was then dissolved in CH2Cl2 (20 mL) and cooled to 0 °C. Triflu-
oroacetic acid (4.6 mL, 10.0 equiv) was added dropwise to this
chilled solution and the reaction mixture was stirred at room
temperature for 4 h. At the end of the reaction, the mixture was
basified with NH4OH, extracted with EtOAc, washed with brine,
and dried over Na2SO4. The solvent was removed in vacuo, and
the resulting crude product was purified via flash chromatography
(MeOH:CH2Cl2 = 3–7%) to provide the corresponding catalyst 1 as a
1
2
3
4
5
6
7
8
9
10
H
4-CF3
4-Cl
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
H, H
83
94
91
89
64
99
99
99
Trace
97
63/24
88/20
71/14
80/17
54/67
85/30
87/41
83/39
ND
75/25
79/21
75/25
88/12
98/2
89/19
81/19
77/23
ND
4-F
4-Me
2-NO2
3-NO2
4-NO2
4-Br
4-Br
–(CH2)2–
46/64
64/36
a
Reaction conditions: benzaldehyde (0.5 mmol), cyclohexanone (5.0 mmol),
catalyst 3 (0.1 mmol), additive: 4-nitrobenzoic acid (0.1 mmol), solvent: saturated
brine (0.5 mL), reaction temperature (room temperature), and reaction time (48 h).
b
Isolated yield after silica gel column chromatography.
Determined by chiral HPLC analysis.
c,d
yellow oil (2.98 g, yield 58%). [
a]
25 = ꢀ18.0 (c 0.5, CHCl3); IR (KBr)
m
4. Experimental
4.1. General
D
3241, 2926, 1663, 1596, 1524, 1454, 1161, 832, 756 cmꢀ1; 1H NMR
(400 MHz, CDCl3) d 9.95 (br s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.39 (d,
J = 8.0 Hz, 1H), 7.16–7.22 (m, 3H), 7.05–7.11 (m, 2H), 3.82–3.85 (m,
1H), 3.03–3.07 (m, 1H), 2.95–2.98 (m, 1H), 2.42–2.59 (m, 1H),
2.20–2.25 (m, 1H), 1.98–2.03 (m, 1H), 1.71–1.78 (m, 2H), 1.60–
1.66 (m, 2H), 1.48–1.51 (m, 2H), 1.21–1.23 (m, 9H), 1.02–1.14
(m, 4H), 0.81–0.88 (m, 6H), 0.74 (t, J = 7.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 174.8, 152.1, 137.2, 133.0, 128.4, 128.1,
127.8, 127.5, 127.2, 125.8, 122.9, 60.7, 47.3, 45.9, 36.7, 31.8, 30.9,
29.6, 29.3, 27.6, 27.2, 26.3, 22.6, 20.7, 14.1, 12.1; HRMS (TOF-ES+)
m/z: [M+H]+ calcd for C29H44N3O3S 514.3103, found 514.3096.
Unless noted otherwise, all the reagents were purchased from
commercial suppliers and used without further purification. The
reactions were monitored by TLC (thin layer chromatography).
The purification of products was carried out by flash column chro-
matography on silica gel (200–300 mesh). Chemical yields refer to
pure isolated substances. Melting points were measured on a XR-4
apparatus (thermometer uncorrected). Optical rotations were
recorded with a Jasco-P-2000 digital polarimeter. Nuclear mag-
netic resonance (NMR) spectra were measured by Bruker Avance
400 spectrometer. 1H NMR spectra were recorded at 400 MHz.
Data were reported as follows: chemical shift, multiplicity (s = sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constants (Hz), integration. 13C NMR data were recorded at
100 MHz with complete proton decoupling. Infrared spectra (IR)
were measured by FT-IR apparatus using KBr disks in the 400–
4000 cmꢀ1 region. High resolution mass spectroscopy (HRMS)
was recorded on TOF MS ES+ mass spectrometer. HPLC analyses
were performed on Waters (2996 photodiode array detector and
binary HPLC Pump). Chiralcel AD-H, AS-H, OD-H, and OJ-H col-
umns were purchased from Daicel Chemical Industries, Ltd.
4.2.3. N-(2-Aminophenyl)-dodecanamide 613
To a flask containing o-phenylenediamine (2.16 g, 20.0 mmol,
2.0 equiv) dissolved in CH2Cl2 (30 mL) cooled to 0 °C was added
dropwise a solution of lauric acid (2.00 g, 10.0 mmol, 1.0 equiv),
DMAP (0.98 g, 8.0 mmol, 0.8 equiv), and EDCI (2.30 g, 12.0 mmol,
1.2 equiv) in CH2Cl2 (20 mL). The reaction mixture was then stirred
at rt for 20 h. At the end of the reaction as judged by TLC analysis,
the reaction mixture was concentrated to give the crude product,
which was further purified via silica gel column chromatography
(EtOAc:PE = 20–30%) to afford compound 6 as a white solid
(2.12 g, yield 73%). mp: 111–113 °C; IR (KBr)
m 3264, 2920, 2849,
1643, 1534, 864, 766, 716 cmꢀ1 1H NMR (400 MHz, DMSO-d6) d
;
4.2. Preparation of catalysts 1–4
9.08 (br s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H),
6.71 (d, J = 8.0 Hz, 1H), 6.54 (t, J = 7.6 Hz, 1H), 4.80 (s, 2H), 2.30
(t, J = 7.6 Hz, 2H), 1.59 (t, J = 6.4 Hz, 2H), 1.26–1.29 (m, 16H),
0.85–0.88 (m, 3H); 13C NMR (100 MHz, DMSO-d6) d 171.6, 142.3,
126.1, 125.7, 124.0, 116.6, 116.4, 36.2, 31.8, 29.49, 29.48, 29.4,
29.3, 29.2, 29.1, 25.8, 22.6, 14.4; HRMS (TOF-ES+) m/z: [M+Na]+
calcd for C18H30N2ONa 313.2256, found 313.2252.
4.2.1. N-(2-Aminophenyl)-4-dodecyl-benzenesulfonamide 5
To a flask containing o-phenylenediamine (1.19 g, 11.0 mmol,
1.1 equiv) dissolved in CH2Cl2 (20 mL) was added Et3N (1.01 g,
10.0 mmol, 1.0 equiv) at 0 °C. Next,
a solution of p-dod-
ecylbenzenesulfonyl chloride (3.44 g, 10.0 mmol) in CH2Cl2
(10 mL) was added dropwise to it. The resulting reaction mixture
was stirred at room temperature for 3 h. After quenching with
water, the organic phase was extracted with CH2Cl2, dried over
Na2SO4, and concentrated in vacuo. The crude product was purified
via flash column chromatography on silica gel (EtOAc:PE = 5–15%)
4.2.4. (S)-N-(2-Dodecylamidophenyl)prolinamide 2
The coupling of 6 with Boc-L-proline and the following depro-
tection were conducted according to the experimental procedure
for 1. The crude product was further purified through silica gel col-
umn (MeOH:CH2Cl2 = 1–5%) to provide compound 2 as a white
to afford compound 5 as a yellow oil (3.37 g, yield 81%). IR (KBr)
m
3253, 2924, 1620, 1318, 1158, 746, 672 cmꢀ1 1H NMR (400 MHz,
;
solid (2.25 g, yield 58%). mp: 117–121 °C; [
CHCl3); IR (KBr)
750 cmꢀ1
1H), 7.74 (d, J = 8.0 Hz, 1H), 7.19–7.26 (m, 2H), 7.12–7.15 (m,
a
]
25 = ꢀ34.5 (c 0.5,
D
DMSO-d6) d 8.32 (br s, 1H), 7.60–7.64 (m, 2H), 7.31–7.36 (m, 2H),
6.86 (t, J = 7.6 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.43–6.49 (m, 1H),
6.25–6.34 (m, 1H), 4.96 (br s, 2H), 2.56–2.59 (m, 1H), 1.51–1.63
m
3254, 2921, 2851, 1655, 1596, 1549, 879,
;
1H NMR (400 MHz, CDCl3) d 9.90 (br s, 1H), 8.74 (s,

1596
X.-R. Huang et al. / Tetrahedron: Asymmetry 25 (2014) 1590–1598
1H), 3.91–3.95 (m, 1H), 3.08–3.14 (m, 1H), 2.98–3.03 (m, 1H), 2.34
(t, J = 8.0 Hz, 2H), 2.22–2.29 (m, 1H), 1.98–2.06 (m, 1H), 1.75–1.82
(m, 2H), 1.67–1.74 (m, 2H), 1.26–1.34 (m, 16H), 0.88 (t, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 174.9, 171.9, 131.0, 129.3, 126.4,
126.1, 125.5, 123.7, 60.7, 47.4, 37.7, 31.9, 31.2, 29.6, 29.5, 29.4,
29.3, 26.3, 25.8, 22.7, 14.1; HRMS (TOF-ES+) m/z: [M+H]+ calcd
for C23H38N3O2 388.2964, found 388.2960.
DMSO-d6) d 171.5, 171.3, 154.8, 143.3, 137.4, 128.9, 128.3, 128.1,
127.6, 126.9, 126.6, 126.0, 123.1, 116.4, 66.4, 60.8, 47.1, 30.7,
24.6; HRMS (TOF-ES+) m/z: [M+Na]+ calcd for C19H21N3O3Na
362.1481, found 362.1468.
4.2.8. (S)-N-(2-Aminephenyl)prolinamide 4
To a solution of 8 (2.27 g, 6.7 mmol) in MeOH (50 mL) was
added 10% Pd–C (0.23 g). The resulting mixture was stirred under
hydrogen for 12 h before it was filtered and washed with MeOH.
The filtrate was evaporated and the crude product was further
purified via silica gel column chromatography (MeOH:CH2Cl2 = 4–
8%) to give compound 4 as a white solid (1.31 g, yield 64%). mp:
4.2.5. N1-(Phenylmethyl)-1,2-benzenediamine 714
o-Phenylenediamine (3.24 g, 30.0 mmol, 1.5 equiv) and K2CO3
(4.15 g, 30.0 mmol, 1.5 equiv) were suspended in methanol
(30 mL) and cooled to 0 °C. To this solution was added benzyl chlo-
ride (2.3 mL, 20.0 mmol, 1.0 equiv) very slowly. The reaction mix-
ture was stirred at rt for 4 h. The suspension was filtered and the
cake was washed twice with methanol. The filtrate was evaporated
under reduced pressure. The residue was dissolved in EtOAc,
washed with water and brine, and dried over anhydrous over Na2-
SO4. The solvent was removed under reduced pressure and the
crude product was further purified through silica gel column chro-
matography (EtOAc:PE = 5–15%) to afford compound 7 as a color-
118–121 °C; [
a]
D
25 = ꢀ55.5 (c 0.5, CHCl3); IR (KBr)
m
3432, 3329,
3221, 2859, 1663, 1631, 1512, 1483, 1305, 750, 609 cmꢀ1
;
1H
NMR (400 MHz, DMSO-d6) d 9.50 (s, 1H), 7.36 (dd, J = 8.0, 1.2 Hz,
1H), 6.90 (td, J = 8.0, 1.6 Hz, 1H), 6.79 (dd, J = 8.0, 1.2 Hz, 1H),
6.60 (td, J = 8.0, 1.2 Hz, 1H), 4.73 (s, 2H), 3.72–3.74 (m, 1H), 2.91
(t, J = 6.4 Hz, 2H), 2.01–2.10 (m, 1H), 1.78–1.85 (m, 1H), 1.67–
1.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) d 173.6, 141.5,
125.8, 124.6, 124.2, 117.4, 116.9, 61.2, 47.2, 31.0, 26.4; HRMS
(TOF-ES+) m/z: [M+H]+ calcd for C11H16N3O 206.1293, found
206.1284.
less solid (2.89 g, yield 73%). mp: 60–63 °C; IR (KBr)
m
3281,
3039, 2811, 1604, 1507, 1452, 1260, 909, 743 cmꢀ1
;
1H NMR
(400 MHz, DMSO-d6) d 7.39 (m, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.24
(t, J = 7.2 Hz, 1H), 6.59–6.61 (m, 1H), 6.41–6.46 (m, 2H), 6.36–
6.39 (m, 1H), 5.12 (t, J = 5.6 Hz, 1H), 4.58 (s, 2H), 4.32 (d,
J = 5.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) d 140.9, 136.1,
135.7, 128.7, 127.7, 127.0, 118.0, 117.5, 114.8, 110.9, 47.5; HRMS
(TOF-ES+) m/z: [M+H]+ calcd for C13H15N2 199.1235, found
199.1234.
4.2.9. (3R,7aS)-Hexahydro-2-(2-benylaminophenyl)-3-(4-bromo-
phenyl)-1H-Pyrrolo[1,2-c]imidazol-1-one 9
Colorless solid, mp: 173–175 °C; [
a]
25 = +39.5 (c 0.4, CH2Cl2); IR
D
(KBr) ;
m
3421, 2924, 1682, 1417, 1293, 845, 747 cmꢀ1 1H NMR
(400 MHz, DMSO-d6) d 7.45 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz,
2H), 7.25–7.28 (m, 2H), 7.17–7.21 (m, 1H), 7.13 (d, J = 7.2 Hz,
2H), 7.03 (d, J = 7.6 Hz, 1H), 6.90–6.94 (m, 1H), 6.49 (td, J = 8.2,
1.2 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 5.59 (s, 1H), 5.45 (t, J = 5.6 Hz,
1H), 4.22–4.33 (m, 2H), 4.16–4.19 (m, 1H), 2.98–3.12 (m, 2H),
1.97–2.14 (m, 2H), 1.66–1.92 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) d 173.4, 144.4, 140.6, 140.3, 131.4, 130.2, 128.8, 128.6,
128.2, 127.2, 126.9, 122.0, 121.9, 116.1, 112.2, 84.3, 64.9, 55.6,
46.4, 28.6, 25.1; HRMS (TOF-ES+) m/z: [M+Na]+ calcd for C25H24N3-
OBrNa 484.1000, found 484.0989.
4.2.6. (S)-N-(2-Benylaminephenyl)prolinamide 3
The coupling of 7 with Boc-L-proline and the following depro-
tection were conducted according to the experimental procedure
for 1. The crude product was further purified through silica gel col-
umn chromatography (MeOH:CH2Cl2 = 1–5%) to provide com-
pound 3 as a colorless solid (3.67 g, yield 62%). mp: 135–139 °C;
[
a
]
25 = ꢀ57.0 (c 0.5, CHCl3); IR (KBr)
m 3348, 3148, 2834, 1662,
D
1593, 1529, 1494, 1297, 750, 734 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 9.59 (br s, 1H), 7.39–7.41 (m, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.24–
7.29 (m, 2H), 7.08 (td, J = 8.0, 0.8 Hz, 1H), 6.72–6.78 (m, 2H),
4.55–4.57 (m, 1H), 4.35 (d, J = 6.0 Hz, 2H), 3.90 (q, J = 5.2 Hz, 1H),
3.04–3.10 (m, 1H), 2.94–2.99 (m, 1H), 2.16–2.24 (m, 1H), 2.00–
2.10 (m, 2H), 1.71–1.78 (m, 2H); 13C NMR (100 MHz, CDCl3) d
174.2, 141.9, 139.4, 128.6, 127.3, 127.1, 126.9, 124.4, 124.2,
118.2, 113.3, 60.9, 48.2, 47.4, 31.1, 26.4; HRMS (TOF-ES+) m/z:
[M+H]+ calcd for C18H22N3O 296.1763, found 296.1755.
4.3. General procedure for the aldol reaction and
characterization of the products
Method A: To a stirred solution of benzaldehyde (0.5 mmol) and
ketone (5 mmol) in 2-Me-THF (0.5 mL) were added catalyst 3
(295 mg, 0.1 mmol) and 4-nitrobenzoic acid (167 mg, 0.1 mmol).
The reaction was stirred at 0 °C. After the reaction was complete
as monitored by TLC analysis, the mixture was purified via silica
gel column chromatography to give the corresponding aldol
product.
4.2.7. (2S)-1-Pyrrolidinecarboxylic acid-2-[[(2-aminophenyl)
amino]carbonyl]-phenylmethyl ester 815
Method B: To a stirred solution of benzaldehyde (0.5 mmol) and
cyclohexanone (0.52 mL, 5 mmol) were added catalyst 3 (295 mg,
0.1 mmol) and 4-nitrobenzoic acid (167 mg, 0.1 mmol), after
which the aqueous solvent (0.5 mL) was added. The reaction was
stirred at rt for 48 h. After the reaction was finished as monitored
by TLC analysis, the mixture was purified via silica gel column
chromatography to give the corresponding aldol product.
To a solution of Cbz-L-proline (2.49 g, 10.0 mmol) in THF
(10 mL) was added EDCI (2.00 g, 10.0 mmol). After stirring for
1 h, o-phenylenediamine (2.16 g, 20.0 mmol, 2.0 equiv) was then
added to it. The reaction mixture was stirred overnight and the
solvent was removed in vacuo. The residue was taken up in CH2Cl2
and washed with NaHCO3, 1 M HCl, and water two times. The
organic layer was dried over anhydrous Na2SO4, and the solvent
was removed under reduced pressure. The crude product was
further purified through silica gel column chromatography (EtOAc:
PE = 20–40%) to afford compound 8 as a white solid (2.27 g, yield
4.3.1. (2S,10R)-2-(Hydroxy-(4-nitrophenyl)methyl)cyclohexan-1-
one (Table 1)16
25 = +20.4 (c 0.5, CHCl3); 1H NMR
67%). mp: 188–190 °C; [
a
]
25 = ꢀ88.8 (c 0.5, CHCl3); IR (KBr)
m
(119 mg, yield 96%); [a]
D
D
(400 MHz, CDCl3) d 8.22 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H),
4.90 (dd, J = 8.4, 2.8 Hz, 1H), 4.08 (d, J = 3.2 Hz, 1H), 2.36–2.63
(m, 3H), 1.36–2.14 (m, 6H); HPLC analysis: (Chiralpak AD-H
column, hexane/2-propanol = 85:15, flow rate = 1.0 mL/min, k =
254 nm): tR = 14.28 min (syn, minor), 16.31 min (syn, major),
17.75 min (anti, minor), 23.34 min (anti, major).
3430, 3355, 3200, 3034, 2878, 1697, 1651, 1545, 1501, 1452,
1422, 1112, 750, 700 cmꢀ1 1H NMR (400 MHz, DMSO-d6) d 9.33
;
(s, 1H), 7.29–7.40 (m, 5H), 7.07–7.09 (m, 1H), 6.91–6.92 (m, 1H),
6.74 (t, J = 6.8 Hz, 1H), 6.55 (t, J = 7.2 Hz, 1H), 5.07–5.15 (m, 2H),
4.85 (s, 1H), 4.73 (s, 1H), 4.34–4.45 (m, 1H), 3.36–3.55 (m, 2H),
2.19–2.31 (m, 1H), 1.85–2.02 (m, 3H); 13C NMR (100 MHz,

X.-R. Huang et al. / Tetrahedron: Asymmetry 25 (2014) 1590–1598
1597
4.3.2. (2S,10R)-2-(Hydroxy-(2-nitrophenyl)methyl)cyclohexan-1-
4.3.8. (2S,4S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)-4-methyl-
one (Table 2, entry 1)16
cyclohexan-1-one (Table 2, entry 7)16
(110 mg, yield 88%); [
a]
25 = +21.7 (c 0.5, CHCl3); 1H NMR
(104 mg, yield 79%); [
a]
25 = ꢀ29.7 (c 0.5, CHCl3); 1H NMR
D
D
(400 MHz, CDCl3) d 8.22 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H),
4.90 (d, J = 8.4 Hz, 1H), 4.10 (br s, 1H), 2.56–2.63 (m, 1H), 2.33–
2.52 (m, 2H), 1.25–2.15 (m, 6H); HPLC (Chiralpak AD-H column,
hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, k = 254 nm):
tR = 19.57 min (syn, minor), 23.39 min (syn, major), 25.75 min (anti,
minor), 34.47 min (anti, major).
(400 MHz, DMSO-d6) d 8.22 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz,
2H), 5.73 (d, J = 4.8 Hz, 1H), 5.19 (dd, J = 9.2, 4.8 Hz, 1H),
2.19–2.69 (m, 3H), 1.29–1.97 (m, 5H), 0.88 (d, J = 6.8 Hz, 3H); HPLC
(Chiralpak AD-H column, hexane/2-propanol = 90:10, flow
rate = 1.0 mL/min, k = 254 nm): tR = 16.65 min (syn, minor),
19.14 min (syn, major), 30.51 min (anti, major), 33.47 min (anti,
minor).
4.3.3. (2S,10R)-2-(Hydroxy-(3-nitrophenyl)methyl)cyclohexan-1-
4.3.9. (2S,10R)-2-(Hydroxy-(4-bromophenyl)methyl)cyclohexan-
one (Table 2, entry 2)16
1-one (Table 3)16
(112 mg, yield 90%); [a]
25 = +16.8 (c 0.5, CHCl3); 1H NMR
(140 mg, yield 99%); [a]
25 = +15.3 (c 0.5, CHCl3); 1H NMR
D
D
(400 MHz, CDCl3) d 8.21 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.67 (d,
J = 7.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.14
(s, 1H), 2.59–2.66 (m, 1H), 2.38 (td, J = 12.8, 5.6 Hz, 1H), 2.10–
2.16 (m, 1H), 1.37–1.86 (m, 6H); HPLC (Chiralpak AD-H column,
hexane/2-propanol = 85:15, flow rate = 1.0 mL/min, k = 254 nm):
tR = 12.35 min (syn, minor), 12.95 min (syn, major), 14.35 min (anti,
major), 17.77 min (anti, minor).
(400 MHz, DMSO-d6) d 7.51 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz,
2H), 5.30 (d, J = 4.0 Hz, 1H), 4.94 (dd, J = 7.6, 4.4 Hz, 1H),
2.58–2.62 (m, 1H), 2.33–2.37 (m, 2H), 1.15–1.83 (m, 6H); HPLC
(Chiralpak AD-H column, hexane/2-propanol = 90:10, flow rate =
1.0 mL/min, k = 230 nm): tR = 9.68 min (syn, minor), 11.63 min
(syn, major), 15.31 min (anti, minor), 18.19 min (anti, major).
4.3.10. (2S,10R)-2-(Hydroxy-(phenyl)-methyl)cyclohexan-1-one
4.3.4. (2S,10R)-2-(Hydroxy-(2,4-dinitrophenyl)methyl)cyclohex-
(Table 4, entry 1)16
an-1-one (Table 2, entry 3)16
(84.3 mg, yield 83%); [
(400 MHz, DMSO-d6) 7.31–7.33 (m, 4H), 7.25 (dd, J = 8.4,
a]
25 = +14.1 (c 0.4, CHCl3); 1H NMR
D
(145 mg, yield 99%); [a]
25 = +16.8 (c 0.5, CHCl3); 1H NMR
D
d
(400 MHz, CDCl3) d 8.76 (d, J = 2.0 Hz, 1H), 8.48 (dd, J = 8.4,
1.6 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 5.52 (d, J = 6.0 Hz, 1H), 4.32
(s, 1H), 2.75 (m, 1H), 2.30–2.48 (m, 2H), 1.58–2.15 (m, 6H); HPLC
(Chiralpak AD-H column, hexane/2-propanol = 85:15, flow
rate = 1.0 mL/min, k = 254 nm): tR = 14.40 min (syn, major), 16.41
(syn, minor), 20.19 min (anti, minor), 22.55 min (anti, major).
4.4 Hz, 1H), 5.30 (d, J = 4.4 Hz, 1H), 4.94 (q, J = 4.0 Hz, 1H), 2.57–
2.62 (m, 1H), 2.38–2.44 (m, 1H), 2.29–2.36 (m, 1H), 1.13–1.81
(m, 6H); HPLC (Chiralpak OD-H column, hexane/2-propa-
nol = 90:10, flow rate = 1.0 mL/min, k = 220 nm): tR = 7.23 min
(syn, major), 8.05 min (syn, minor), 8.63 min (anti, major),
10.33 min (anti, minor).
4.3.11. (2S,10R)-2-(Hydroxy-(4-(trifluoromethyl)phenyl)methyl)-
4.3.5. (2S,10R)-2-(Hydroxy-(2-nitro4-bromophenyl)methyl)
cyclohexan-1-one (Table 4, entry 2)16
cyclohexan-1-one (Table 2, entry 4)
(128 mg, yield 94%); [a]
25 = +19.1 (c 0.5, CHCl3); 1H NMR
(135 mg, yield 83%); [
3098, 2952, 2932, 1690, 1530, 1334, 1040, 874, 842, 799, 714,
556 cmꢀ1 1H NMR (400 MHz, DMSO-d6) d 8.08 (d, J = 1.6 Hz, 1H),
a] m 3428,
25 = +23.4 (c 0.4, CHCl3); IR (KBr)
D
D
(400 MHz, DMSO-d6) d 7.66 (m, 4H), 5.42 (m, 1H), 5.05 (m, 1H),
2.62 (m, 1H), 2.36 (t, J = 6.4 Hz, 2H), 1.57–1.84 (m, 6H); HPLC (Chir-
alpak AD-H column, hexane/2-propanol = 98:2, flow rate = 1.0 mL/
min, k = 220 nm): tR = 16.48 min (syn, major), 21.45 min (syn,
minor), 30.84 min (anti, minor), 44.25 min (anti, major).
;
7.90 (dd, J = 8.4, 1.6 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 5.69 (d,
J = 4.4 Hz, 1H), 5.27 (dd, J = 7.6, 4.8 Hz, 1H) 2.77–2.83 (m, 1H),
2.22–2.46 (m, 2H), 1.24–1.91 (m, 6H); 13C NMR (100 MHz,
DMSO-d6) d 210.5, 149.8, 137.6, 136.1, 132.4, 126.3, 120.6, 67.1,
57.3, 56.7, 31.1, 28.3, 24.5, 19.3; HRMS (TOF-ES+) m/z: [M+Na]+
calcd for C13H14NO4BrNa 350.0004, found 350.0003; HPLC (Chir-
alpak OD-H column, hexane/2-propanol = 75:25, flow rate =
1.0 mL/min, k = 254 nm): tR = 10.75 min (syn, major), 14.12 min
(syn, minor), 15.20 min (anti, minor), 20.12 min (anti, major).
4.3.12. (2S,10R)-2-(Hydroxy-(4-chlorophenyl)methyl)cyclohex-
an-1-one (Table 4, entry 3)16
(109 mg, yield 91%); [a]
25 = +10.9 (c 0.5, CHCl3); 1H NMR
D
(400 MHz, DMSO-d6) d 7.36 (m, 4H), 5.29 (d, J = 4.4 Hz, 1H), 4.95
(m, 1H), 2.51–2.53 (m, 2H), 2.33–2.37 (m, 1H), 1.63–1.81 (m,
6H); HPLC (Chiralpak AD-H column, hexane/2-propanol = 90:10,
flow rate = 1.0 mL/min, k = 230 nm): tR = 9.18 min (syn, major),
10.90 min (syn, minor), 14.22 min (anti, minor), 16.48 min (anti,
major).
4.3.6. (S)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one (Table 2,
entry 5)16
(74.3 mg, yield 66%); [a]
25 = +28.2 (c 0.4, CHCl3); 1H NMR
D
(400 MHz, CDCl3) d 8.21 (m, 2H), 7.55 (m, 2H), 5.27 (dd, J = 8.0,
4.0 Hz, 1H), 3.61 (s, 1H), 2.85–2.87 (m, 2H), 2.23 (s, 3H); HPLC
(Chiralpak AS-H column, hexane/2-propanol = 85:15, flow
rate = 1.0 mL/min, k = 254 nm): tR = 27.65 min (major), 39.69 min
(minor).
4.3.13. (2S,10R)-2-(Hydroxy-(4-fluorophenyl)methyl)cyclohex-
an-1-one (Table 4, entry 4)16
(99.4 mg, yield 89%); [a]
25 = +13.3 (c 0.5, CHCl3); 1H NMR
D
(400 MHz, DMSO-d6) d 7.36 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 5.23
(d, J = 4.0 Hz, 1H), 4.95 (m, 1H), 2.41–2.52 (m, 1H), 2.32–2.39 (m,
2H), 1.25–1.82 (m, 6H); HPLC (Chiralpak AD-H column, hexane/
2-propanol = 95:5, flow rate = 1.0 mL/min, k = 210 nm): tR = 12.86 -
min (syn, minor), 15.64 min (syn, major), 21.68 min (anti, minor),
24.64 min (anti, major).
4.3.7. (2S,10R)-2-(Hydroxy-(4-nitrophenyl)methyl)cyclopentan-
1-one (Table 2, entry 6)16
(116 mg, yield 99%); [
(400 MHz, DMSO-d6) 8.20 (m, 2H), 7.63 (m, 2H), 5.72
a]
25 = +26.8 (c 0.5, CHCl3); 1H NMR
D
d
4.3.14. (2S,10R)-2-(Hydroxy-(4-methylphenyl)methyl)cyclohex-
(d, J = 4.4 Hz, 1H), 5.19 (t, J = 3.2 Hz, 1H), 1.86–2.47 (m, 4H),
1.66–1.71 (m, 3H); HPLC (Chiralpak AD-H column, hexane/2-pro-
panol = 90:10, flow rate = 1.0 mL/min, k = 254 nm): tR = 26.73 min
(anti, major), 37.41 min (anti, minor), 48.04 min (syn, minor),
49.99 min (syn, major).
an-1-one (Table 4, entry 5)16
(70.1 mg, yield 64%); [a]
25 = +52.8 (c 0.4, CHCl3); 1H NMR
D
(400 MHz, DMSO-d6) d 7.21 (m, 2H), 7.13 (m, 2H), 5.10 (d,
J = 4.4 Hz, 1H), 4.89 (dd, J = 8.4, 4.4 Hz, 1H), 2.53–2.59 (m, 1H),

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2.37–2.44 (m, 1H), 2.37–2.42 (m, 1H), 2.27–2.34 (m, 3H),
1.66–1.79 (m, 4H), 1.17–1.53 (m, 2H); HPLC (Chiralpak AD-H
column, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min,
k = 210 nm): tR = 3.29 min (syn, major), 4.35 min (syn, minor),
6.76 min (anti, major), 8.39 min (anti, minor).
4.3.15. (2S,10R)-2-(Hydroxy-(4-bromophenyl)methyl)cyclopen-
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tan-1-one (Table 4, entry 10)16
(130 mg, yield 97%); [a]
25 = +28.8 (c 0.5, CHCl3); 1H NMR
D
(500 MHz, DMSO-d6) d 7.50 (m, 2H), 7.30 (m, 2H), 5.47 (d,
J = 3.6 Hz, 1H), 5.04 (t, J = 2.4 Hz, 1H), 2.03–2.51 (m, 3H), 1.55–
1.93 (m, 4H); HPLC (Chiralpak AD-H column, hexane/2-propanol =
90:10, flow rate = 1.0 mL/min, k = 220 nm): tR = 8.73 min (anti,
major), 10.81 min (anti, minor), 13.38 min (syn, major), 14.35 min
(syn, minor).
7. For selected examples of prolinamides as organocatalysts, see: (a) Tanimori,
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Acknowledgements
We gratefully acknowledge the financial support from National
Natural Science Foundation of China (21276282 and 21376270),
Hunan Provincial Science
& Technology Department (2012W
K2007), and Central South University.
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