Direct asymmetric aldol reactions catalysed by trans-4-hydroxy-(S)-prolinamide in solvent-free conditions

Article abstract of DOI:10.1016/j.tetasy.2015.09.003

Direct asymmetric aldol reactions between 4-nitrobenzaldehyde and cyclohexanone were catalysed by trans-4-hydroxy-(S)-prolinamide (10 mol %) in the presence of CH₃COOH (10 mol %) as the co-catalyst under solvent-free conditions at 15 °C. (2S,4R)-4-Hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide 2 efficiently catalysed the asymmetric aldol reaction to afford the product in >99% yield and with 95% ee with an anti/syn ratio of 88:12 after 18 h. The additional trans-hydroxyl group on (S)-prolinamide and (S)-1-phenylethylamine both influenced the ee of the predominant anti aldol product. Different benzaldehyde derivatives with cyclohexanone gave the corresponding aldol products in 38-89% yields and with 56-94% ee with anti/syn (100:0-71:29). Catalyst 2 can be used up to 5 continuous cycles for asymmetric aldol reactions between 4-nitrobenzaldehyde and cyclohexanone with overall 91% yield and 86% yield of anti-product with anti/syn (98:2).

Full text of DOI:10.1016/j.tetasy.2015.09.003

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Direct asymmetric aldol reactions catalysed by trans-4-hydroxy-(S)-
prolinamide in solvent-free conditions
⇑
Geeta Devi Yadav, Surendra Singh
Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct asymmetric aldol reactions between 4-nitrobenzaldehyde and cyclohexanone were catalysed by
trans-4-hydroxy-(S)-prolinamide (10 mol %) in the presence of CH3COOH (10 mol %) as the co-catalyst
under solvent-free conditions at 15 °C. (2S,4R)-4-Hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-carbox-
amide 2 efficiently catalysed the asymmetric aldol reaction to afford the product in >99% yield and with
95% ee with an anti/syn ratio of 88:12 after 18 h. The additional trans-hydroxyl group on (S)-prolinamide
and (S)-1-phenylethylamine both influenced the ee of the predominant anti aldol product. Different ben-
zaldehyde derivatives with cyclohexanone gave the corresponding aldol products in 38–89% yields and
with 56–94% ee with anti/syn (100:0–71:29). Catalyst 2 can be used up to 5 continuous cycles for asym-
metric aldol reactions between 4-nitrobenzaldehyde and cyclohexanone with overall 91% yield and 86%
yield of anti-product with anti/syn (98:2).
Received 9 July 2015
Accepted 1 September 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
to the practise of green chemistry, it is beneficial to develop
organocatalysts, which can catalyse the reaction using low catalyst
The aldol reaction is one of the most powerful methods for car-
bon–carbon bond formation. The products (b-hydroxycarbonyls) of
direct asymmetric aldol reactions are privileged molecular seg-
ments in biologically important molecules required by the phar-
maceutical industry. Therefore, the development of suitable
organocatalysts for enantioselective aldol reactions is important.1
Direct asymmetric aldol reactions are highly atom economical
compared with other well-established processes using enol or eno-
late derivatives as the aldol donor.2 Hajos and Parrish have
loading under solvent-free conditions. Kelleher et al. reported a
series of simple 4-hydroxyprolinamides for asymmetric Michael
addition reactions for aldehydes to nitroolefins.22 Herein we report
the synthesis of trans-4-hydroxy-(S)-prolinamides and cis-4-
hydroxy-(R)-prolinamide shown in Figure 1 and their evaluation
HO
O
O
N
H
N
H
HN
HN
described organocatalysed aldol reactions using L-proline as the
catalyst3 while the pioneering work by List et al. was published
in 2000.4 After these reports numerous proline-derived organocat-
alysts such as proline analogues,5 acyclic amino acids,6 different
types of prolinamides,7–15 prolinethioamides,16 sulfonamides,17
chiral amines,18 organic salts19 and recoverable organocatalysts20
have been designed for direct asymmetric aldol reactions. Chimni
et al. used protonated (S)-prolinamides derived from proline and
different amines such as (S)-1-phenylethylamine, (R)-phenylethy-
lamine, aniline derivatives.21 Most methodologies for direct asym-
metric aldol reactions use a large excess of nucleophile, high
catalyst loading (up to 30 mol %) and non-biodegradable solvents
such as DMF and DMSO. To overcome these issues and contribute
2
1
HO
HO
O
O
N
N
H
HN
HN
H
3
4
HO
O
N
H
HN
5
⇑
Corresponding author. Tel.: +91 11 276 66694; fax: +91 11 276 66605.
E-mail address: ssingh1@chemistry.du.ac.in (S. Singh).
Figure 1. Structure of the organocatalysts (prolinamides) 1–5.
http://dx.doi.org/10.1016/j.tetasy.2015.09.003
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Yadav, G. D.; Singh, S. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.09.003

2
G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
in the catalysis of direct asymmetric aldol reactions in solvent-free
conditions at room temperature.
Asymmetric aldol reactions in polar solvents such as methanol,
DMF, water and brine showed diastereomeric ratios of anti/syn;
90:10–81:19 and 70–90% conversions to aldol products 18 with
58–90% enantiomeric excesses of the major product anti-18 (90–
58%) (Table 1, entries 1–4). Aldol reaction in less polar solvents,
such as THF, CHCl3, CH2Cl2 and toluene gave 85–91% conversions
and anti/syn ratios of 87:13–86:14 with 70–90% ee of anti-products
(Table 1, entries 5–8). The ee’s of diastereomer syn-18 were found
to be better with less polar solvents than polar solvents. Reaction
under neat conditions were found to be better than reactions in
solvents, conversion of product was >99% and anti/syn was 84:16
with 97% ee of product (Table 1, entry 9).
2. Results and discussion
Organocatalysts 1–4 were synthesized by the reaction of trans-
4-hydroxy-(S)-proline or (S)-proline with (S)-1-phenylethylamine,
(R)-1-phenylethylamine and benzyl amine (Scheme 1). (S)-Proline
6 and trans-4-hydroxy-(S)-proline 7 were protected as N-boc
derivatives in quantitative yields. N-Boc-trans-4-hydroxy-(S)-
proline
9 was treated with (S)-1-phenylethylamine, (R)-1-
phenylethylamine and benzyl amine in the presence of
triethylamine and ethylchloroformate, to give the corresponding
N-boc-prolinamides 11–13 in 74–90% yields. Similarly the reaction
of N-boc-proline 8 was carried out with (S)-1-phenylethylamine to
obtain N-boc-prolinamide 10. Deprotection of the N-boc group by
TFA in dichloromethane at room temperature gave prolinamides
1–4.
After screening different solvents for direct asymmetric aldol
reactions, we also screened different additives, catalysts, loadings
of the catalyst and reaction temperatures (Table 2). The aldol reac-
tion of 4-nitrobenzaldehyde 17 and cyclohexanone (3 equiv) was
carried out using catalyst 2 (10 mol %) with different acids as
additives (10 mol %) such as benzoic acid, 4-nitrobenzoic acid,
4-methoxybenzoic acid, triflic acid, trifluoroacetic acid and acetic
acid. Acetic acid and benzoic acid were found to be better additives
compared to other acids but acetic acid gave better dr (anti/syn;
88:12) with 95% ee of the product anti-18 (Table 2, entries 1 and
6). We also increased the catalyst loading up to 20 mol % and the
product anti-18 was obtained in excellent yield with 92% ee but
dr (anti/syn; 78:22) was poor (Table 2, entry 8). Using less additive
(5 mol %) slightly improved the dr, but led to a decrease in the ee
(Table 2, entry 9).
We also synthesized cis-4-hydroxy-(R)-prolinamide 5 from cis-
4-hydroxy-(R)-proline 14 using the similar procedures used for
the prolinamide 2 (Scheme 2). cis-4-Hydroxy-L-proline was synthe-
sized according to the literature.23
2.1. Optimization of the reaction conditions
In our initial investigation, we screened different solvents for
the direct asymmetric aldol reaction between 4-nitrobenzaldehyde
17 and cyclohexanone using organocatalyst 2 (10 mol %) and ben-
zoic acid (10 mol %) as additives at room temperature (Table 1).
The aldol reaction was also carried out at different tempera-
tures; lowering the temperature from 15 °C to 0 °C, improved the
dr up to (anti/syn; 94:6) but decreased the conversion to 57%
R
R
O
R
O
O
(Boc)2O
R'NH2, DCM
HN R'
N
H
OH
N
N
Et3N, ClCO2Et,
r.t. 6 h, 74-90%
THF/H2O, r.t.,12 h
quantitative
OH
Boc
Boc
6; R = H
R = OH
8; R = H
10; R= H
11-13;
7;
9;
R = OH
R = OH
TFA : DCM (1:1)
r.t., 2 h, 95-97%
R
R' =
O
N
H
HN R'
2;
3;
4;
R = OH
R = OH
R = OH
1; R = H
1-4
Scheme 1. Synthesis of (S)-prolinamide and trans-4-hydroxy-(S)-prolinamides 1–4.
HO
O
HO
(S)-1-phenyl
HO
(Boc)2O
ethylamine
CO2H
.HCl
CO2H
N
HN
DCM, Et3N,
ClCO2Et, r. t., 6h
N
H
N
THF/H2O
r.t. 12 h
Boc
Boc
16
15
14
HO
O
TFA : DCM
98 %
N
H
HN
5
Scheme 2. Synthesis of (2R,4R)-4-hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide 5.
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G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Table 1
Screening of different solvents for direct asymmetric aldol reactiona
CHO
O
OH
O
OH
O
(
S
)
catalyst 2 (10 mol%)
(
S
)
(
)
R
+
(S)
+
PhCOOH
solvent, 15 °C, 18 h
O2N
O2N
NO2
18
18
(1'S,2S)-syn-
(1'S,2R)-anti-
17
Entry
Solvent
Conversionb (%)
dr (anti/syn)c
ee (%) (anti/syn)c,d
1
2
3
4
5
6
7
8
9
Water
DMF
MeOH
Brine
THF
CHCl3
DCM
Toluene
Neat
70
71
90
72
91
85
92
85
>99
89:11
81:19
90:10
85:15
86:14
86:14
86:14
87:13
84:16
90:18
58:32
86:68
83:55
70:54
90:79
82:78
84:78
97:32
a
b
c
Catalyst 2 (0.1 mmol, 10 mol %), solvent (1 mL), PhCOOH (0.1 mmol, 10 mol %), cyclohexanone (3 mmol) and 4-nitrobenzaldehyde (1 mmol) were stirred at 15 °C for 18 h.
Conversion was determined by HPLC using response factor for 4-nitrobenzaldehyde 17 and product 18.
Diastereomeric ratio (anti/syn) and ee were determined by HPLC using chiralpak AD-H column.
The absolute configuration was determined by comparing the specific rotation of product anti-18 with literature values and found to be (10S, 2R).
d
Table 2
Optimization of reaction conditions for asymmetric direct aldol reactiona
CHO
O
OH
O
catalyst
additive,
neat, 18 h
O2N
NO2
17
anti-18
Entry
Catalyst
Catalyst loading (mol %)
Additive
Conversionb (%)
dr (anti/syn)c
ee (%) (anti)c
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
2
2
1
3
4
5
10
10
10
10
10
10
5
20
10
10
10
10
10
10
10
10
PhCOOH
>99
>99
>99
>99
80
>99
97
>99
83
57
97
>99
72
100
97
84:16
77:23
77:23
73:27
48:52
88:12
85:15
78:22
89:11
94:6
89:11
79:21
84:16
88:12
86:14
86:14
97
75
81
84
72
95
86
92
83
90
80
69
68
79
75
74
p-NO2 PhCOOH
p-OMe PhCOOH
Triflic acid
Trifluoroacetic acid
CH3COOH
CH3COOH
CH3COOH
9
CH3COOHd
CH3COOHe
CH3COOHf
CH3COOHg
CH3COOH
10
11
12
13
14
15
16
CH3COOH
CH3COOH
CH3COOHh
>99
a
b
c
Catalyst 2 (0.1 mmol, 10 mol %), additive (0.1 mmol, 10 mol %), cyclohexanone (3 mmol) and 4-nitrobenzaldehyde (1 mmol) were stirred at 15 °C for 18 h.
Conversion was determined by HPLC using response factor for 4-nitrobenzaldehyde 17 and product 18.
Diastereomeric ratio (anti/syn) and ee were determined by HPLC using chiralpak AD-H column.
Additive (5 mol %) was used.
Reaction conducted at 0 °C.
Reaction conducted at 40 °C for 6 h.
d
e
f
g
h
Reaction conducted at 60 °C for 6 h.
The opposite enantiomer of product anti-18 was obtained.
(Table 2, entry 10). Increasing the temperature from 15 °C to 40 °C
and 60 °C took less time to complete the reaction but the ee’s
decreased (Table 2, entries 11 and 12). We also screened different
organocatalysts 1–5 and organocatalyst 2 was found to be the best
catalyst. The ee’s of product anti-18 with organocatalysts 1–2
indicated that the trans-4-hydroxyl group of (S)-prolinamide
influenced the ee of product anti-18, which may be due to
intermolecular hydrogen bonding in organocatalyst 2.
trans-4-Hydroxy-(S)-prolinamides 2 containing (S)-1-phenylethy-
lamine were found to be better catalysts compared to
(R)-1-phenylethylamine and benzyl amine (Table 2, entries 6, 14
and 15). cis-4-Hydroxy-(R)-prolinamide 5 was also found to be poor
compared to catalyst 2 and gave the opposite enantiomer of the
product anti-18. These results show that the absolute configuration
is governed by the stereogenic centre of pyrrolidine ring with an
amide bond.
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4
G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 3
2.2. Transition state for asymmetric aldol reaction
Aldol reaction of cyclohexanones with substituted benzaldehydes in the presence of
organocatalyst 2a
In Figure 2, we proposed a transition state between cyclohex-
anone, organocatalyst 2 and 4-nitrobenzaldehyde 17. According
to the well-known mechanism of the aldol reaction, cyclohexanone
first forms an iminium bond with organocatalyst 2, then the hydro-
gen bonding occurs between the hydrogen of the amide of
organocatalyst 2 and the oxygen of 4-nitrobenzaldehyde. In this
transition state, the two phenyl rings (phenyl ring of organocata-
O
O
O
OH
2
catalyst (10 mol%)
Ar
Ar
H
neat, r.t.
CH3COOH,
Entry
Ar
Time (h) Yieldb (%)
24 50
36 89
dr (anti/syn)c
ee (%) (anti)d
lyst 2 and phenyl ring of 4-nitrobenzaldehyde) show p–p interac-
1
2
3
4
5
6
7
8
Phenyl
91:9
88:12
91:9
76
80
93
94
72
93
86
80
84
87
56
93
75
tions (Fig. 2). The double bond of cyclohexene attacks the Si-face of
4-nitrobenzaldehyde and gives anti-(10S)-2((R)-hydroxy(4-nitro-
phenyl)methyl)cyclohexanone as the major product with 95% ee.
Diastereomeric ratios and ee’s of the aldol product anti-18 catal-
ysed by organocatalyst 2 (trans-4-hydroxy-prolinamide) were
found to be better compared to prolinamide 1 in solvent free con-
ditions. These results indicate that the additional effect of the
hydroxyl group of prolinamide 2 may take part in intermolecular
hydrogen bonding with the two OH groups of the 4-hydroxy pro-
line, which could improve the ee and dr of the product 18 (Fig. 3).
1-Naphthyl
2-NO2C6H4
2-FC6H4
12
33
30
28
26
28
21
30
30
36
36
82
88
63
65
50
66
78
46
38
63
74
90:10
86:14
87:13
82:18
85:15
88:12
88:12
79:21
100:0
85:15
4-FC6H4
2-ClC6H4
4-ClC6H4
2-BrC6H4
4-BrC6H4
2-OMeC6H4
4-OMeC6H4
2-CF3C6H4
4-CF3C6H4
9
10
11
12
13
a
Catalyst 2 (0.1 mmol, 10 mol %), CH3COOH (0.1 mmol, 10 mol %), cyclohexanone
2.3. Scope and limitation of the asymmetric aldol reaction
(3 mmol) and 4-nitrobenzaldehyde (1 mmol) were stirred at 15 °C for specified
time.
b
We also investigated the asymmetric direct aldol reaction of
substituted benzaldehydes with cyclohexanone and cyclopen-
tanone catalysed by prolinamide 2 (10 mol %) and co-catalyst
CH3COOH (10 mol %) at 15 °C. Benzaldehyde gave the product in
a 50% yield with 76% ee and an anti/syn ratio of 91:9, while the
bulkier naphthaldehyde slightly reduced the anti/syn ratio, but
the ee was slightly improved. An electron withdrawing group such
as a nitro on the benzaldehyde improved the reactivity and 2-ni-
trobenzaldehyde gave 93% ee with a slightly improved anti/syn
ratio compared to 4-nitrobenzaldehyde (Table 2, entry 6 and
Table 3, entry 3). Halogenated benzaldehydes required longer reac-
tion times and 2-halogenated benzaldehydes afforded products in
better ee compared to 4-halogenated benzaldehydes (Table 3,
entries 4–6). Furthermore, the size of halogens affected the ee of
the product; when the size increases (F < Cl < Br) the ee’s of the
corresponding product decreases (F > Cl > Br). Electron donating
groups such as methoxy on the benzaldehyde, were found to be
less reactive compared to derivatives of electron withdrawing
groups. This can be explained by the fact that electron withdraw-
ing groups enhance the electrophilicity of carbonyl carbons in
aldehydes, which facilitate the reaction, while electron donating
groups lessen the electrophilicity of carbonyl carbons. In the case
of 2-(trifluoromethyl)benzaldehyde, it exclusively afforded the
anti-product with 93% ee (Table 3, entry 12). The ee’s of anti-aldol
products with 2-susbstituted benzaldehydes were found to be
better compared to 4-substituted benzaldehydes.
Isolated yield after purification by column chromatography.
c
The diastereomeric ratios were determined by 1H NMR.
d
The ee was determined by HPLC using chiralpak AD-H and OD-H columns.
NO2
H
O
N
H
N
O
H
O
O
H
O
H
O
N
O
N
H
O
H
H
N
O
H
N
NO2
NO2
Figure 3. Intermolecular hydrogen bonding in 4-hydroxyprolinamide in the
catalytic transition state.
OH
N
O
OH
O
We also studied the direct asymmetric aldol reaction between
2- and 4-substituted benzaldehydes with cyclopentanone catal-
ysed by organocatalyst 2 at 15 °C (Table 4). The reactivity of ben-
zaldehydes with electron withdrawing groups was faster than
with electron donating groups. In the case of 4-substituted ben-
zaldehydes, the anti/syn ratios of the aldol products were poor
and the ee of anti-products were 51–25%. In the case of 2-halo-ben-
zaldehydes the major products were syn with 61–54% ee (Table 4,
entries 1, 3, 5 and 7). The diastereomeric ratio and the ee of the
syn-aldol product of 2-fluorobenzaldehyde were found to be better
compared to other benzaldehydes (Table 4, entries 3 and 5).
H
N
( )
S
O
(
)
R
H
O2N
N
O-
O
Figure 2. Transition state for the direct asymmetric aldol reaction between
cyclohexanone and 4-nitrobenzaldehyde 17 catalysed by prolinamide 2.
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G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
Table 4
Aldol reaction of cyclopentanone and acetone with substituted benzaldehydes in the presence of organocatalyst 2a
O
O
O
OH
catalyst 2 (10 mol%)
Ar
H
Ar
neat, CH3COOH
Entry
Ar
Time (h)
Yieldb (%)
dr (anti/syn)c
ee (%) (anti/syn)d
1
2
3
4
5
6
7
8
2-NO2C6H4
4-NO2C6H4
2-FC6H4
4-FC6H4
2-ClC6H4
4-ClC6H4
2-OMeC6H4
4-OMeC6H4
10
10
33
33
26
28
36
36
83
68
89
87
83
71
87
82
46:54
49:51
9:91
61:39
14:86
51:49
30:70
44:56
76:54
61:45
76:61
54:26
85:54
56:33
nd:50
25:0
a
Catalyst 2 (0.1 mmol, 10 mol %), CH3COOH (0.1 mmol, 10 mol %), cyclopentanone (3 mmol) and 4-nitrobenzaldehyde (1 mmol)
were stirred at 15 °C for specified time.
b
Isolated yield after purification by column chromatography.
c
The diastereomeric ratios were determined by 1H NMR.
d
The ee was determined by HPLC using chiralpak AD-H and OD-H columns.
2.4. Desymmetrization of prochiral ketone
repeating this procedure for another 5 catalytic cycles, the product
was obtained in 91% overall yields with a 98:2 dr and 86% ee for
the product anti-18. We also conducted direct asymmetric aldol
reactions using large quantities of substrates (substrate/cata-
lyst = 60, catalyst loading is 1.67 mol %) to afford product anti-18
in 79% yield with 87% ee and 93:7 dr. A comparison of the two sys-
tems shows the ee values of anti-18 product to be comparable but
the diastereomeric ratio was found to better with continuous use
of catalyst 2. The improvement in the dr of anti-18 product may
be due to use of excess cyclohexanone (see Table 5).
4-Substituted cyclohexanones are common prochiral ketones;
the asymmetric desymmetrization of these compounds may lead
to the formation of chiral products with the creation of multiple
stereogenic centres. We used 4-tert-butylcyclohexanone as the
prochiral ketone in the aldol reaction with aromatic aldehydes to
provide aldol products with three new stereogenic centres. It is
worth mentioning that the prochiral centre C-4 is distant from
C-2 of the cyclic ketones where the aldolization takes place. Hence
the catalyst should have the ability to control the diastereoselectiv-
ity and enantioselectivity and more importantly to distinguish the
stereochemistry of C-4 distant from the reactive site at C-2. The
reaction of 4-tert-butylcyclohexanone was performed in dichloro-
methane with 3 equiv of ketone, and we observed that the confir-
mation of cyclohexanone in the anti-aldol products was found to
be equatorial while the ee was better with 2-nitrobenzaldehyde
(Scheme 3). Direct asymmetric aldol reaction between 4-tert-
butylcyclohexanone as the prochiral substrate and 2-nitro and
4-nitrobenzaldehyde was studied.
Table 5
Continuous use of organocatalyst 2 for aldol reactions between cyclohexanone and
4-nitrobenzaldehyde 17a
Cycle
Time (h)
Conversionb (%)
ee (%) antic
1
2
3
4
5
6
18
18
20
20
20
20
>99
96
96
95
94
97
93
87
86
86
86
86
2.5. Continuous use of the catalyst
94
After purification
91d
We carried out 6 successive catalytic cycles for the direct asym-
metric aldol reactions between cyclohexanone (1.2 mmol) with
p-nitrobenzaldehyde 17 (0.4 mmol) using prolinamide 2 as the cat-
alyst (10 mol %) and acetic acid (10 mol %) as the additive at 15 °C.
After complete consumption of 17 (TLC and HPLC analysis),
cyclohexanone (1.2 mmol) and 17 (0.4 mmol) were added to the
reaction mixture without any additional catalyst or additives. After
a
Catalyst 2 (0.04 mmol, 10 mol %), CH3COOH (0.04 mmol, 10 mol %), cyclohex-
anone (1.2 mmol) and 4-nitrobenzaldehyde (0.4 mmol) were stirred at 15 °C for
specified time.
b
Conversion was determined by HPLC using response factor for 4-nitroben-
zaldehyde 17 and product 18.
c
The ee was determined by HPLC using chiralpak AD-H columns.
Isolated yield after purification by column chromatography.
d
O
R1
OH
O
O
2
catalyst (10 mol%)
H
+
CH3COOH (10 mol%)
neat, rt
R2
R1
R2
17, R2 = NO2
19, R1 = NO2
, R1 = NO2, yield 90%, ee 90%
, R2 = NO2, yield 80%, ee 85%
20
21
Scheme 3. Asymmetric aldol reactions between prochiral ketone (4-tert-butylcyclohexanone) and nitrobenzaldehyde.
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6
G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
residue was adjusted to pH 2 by the addition of 10% aqueous
3. Conclusions
KHSO4. The acidic solution was extracted several times with ethyl
acetate. The combined organic extracts were washed with H2O and
brine, and dried over anhydrous Na2SO4. The solvent was removed
by rotavapor to afford compound 9 as a syrup (4.40 g, 100%), which
In conclusion we have developed direct asymmetric aldol reac-
tions between benzaldehydes and cycloalkanones catalysed by
trans-4-hydroxyprolinamide. The reaction between cyclohexanone
and 4-nitrobenzaldehyde afforded the anti-aldol product as the
major product with 95% ee. Benzaldehydes with electron with-
drawing groups are more reactive than electron donating groups.
The syn-aldol was obtained as the major product by the reaction
of 2-susbtituted benzaldehydes and cyclopentanone but 4-susbsti-
tuted benzaldehydes gave approximately equal distributions of
syn/anti with moderate ee’s. Catalyst 2 can be used for 5 continu-
ous cycles for asymmetric aldol reactions between 4-nitroben-
zaldehyde and cyclohexanone with a slight loss in ee but an
improved dr.
was used without purification for the next step. [
a
]
D
25 = ꢀ68.1 (c
1.3, MeOH). IR (film):
m
= 3462, 2976, 2934, 1740, 1639 cmꢀ1
.
1H
NMR (400 MHz, CDCl3): d 7.52 (br s, 1H), 4.44–4.12 (m, 1H),
3.50–3.32 (m, 2H), 2.10–1.80 (m, 4H), 1.47 (s, 9H) ppm. 13C NMR
(100 MHz, CDCl3): d 174.90, 153.68, 79.51, 68.81, 57.51, 53.14,
30.52, 27.73 ppm.
4.1.3. (S)-tert-Butyl 2-((S)-1-phenylethylcarbamoyl)pyrrolidine-
1-carboxylate 107
At first, (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic
acid 8 (4.50 g, 20.9 mmol) was dissolved in dry dichloromethane
(56 mL), after which triethylamine (3.47 g, 24.9 mmol) and ethyl
chloroformate [2.36 g, 24.9 mmol, in dichloromethane (11 mL)]
were added dropwise at 0 °C. The solution was stirred at the same
temperature for 15 min after which a solution of (S)-1-phenylethyl
amine (2.50 g, 20.9 mmol) in dichloromethane (11 mL) was added
slowly. The resulting mixture was warmed to room temperature
and stirred for 5 h. The reaction mixture was washed with 10%
HCl solution, a saturated NaHCO3 solution, brine and dried over
anhydrous Na2SO4. The solvent was evaporated under vacuum
and the residue was recrystallized from ethyl acetate to afford 10
4. Experimental
4.1. General
Benzaldehyde derivatives, cyclohexanone and cyclopentanone
were purchased from commercial source and used as such. Proton
and carbon nuclear magnetic resonance spectra (1H and 13C NMR,
respectively) were recorded on 400 MHz (operating frequencies:
1H, 400.13 MHz; 13C, 100.61 MHz) Jeol-FT-NMR spectrometers at
ambient temperature. The chemical shifts (d) for all compounds
are listed in parts per million (ppm) downfield from tetramethylsi-
lane using the NMR solvent as an internal reference. The reference
values used for deuterated chloroform (CDCl3) were 7.26 and
77.00 ppm for 1H and 13C NMR spectra, respectively. HRMS analy-
sis was carried out using QSTAR XL Pro system microTOF-Q-II.
Infrared spectra were recorded on a Perkin–Elmer FT-IR spectrom-
eter. Thin layer chromatography was carried out using Merck
Kieselgel 60 F254 silica gel plates. Column chromatography separa-
tions were performed using silica gel 230–400 mesh. The enan-
tiomeric excess was determined on Shimadzu LC-2010HT using
chiralcel OD-H and chiralpak AD-H columns. Optical rotations
were taken using Rudolph digipol polarimeter. All of the new syn-
thesized compounds were characterized by 1H, 13C NMR and HRMS
and known compounds were characterized by 1H and 13C NMR.
as a white solid (5.78 g, 87%). Mp 81–84 °C. [
MeOH). IR (KBr):
a]
25 = ꢀ48.0 (c 1.06,
D
m
= 3287, 2978, 1684, 1656 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d 7.27–7.26 (m, 5H), 5.51–4.96 (m, 1H), 4.26–
4.12 (m, 1H), 3.45–3.26 (m, 1H), 2.11 (d, J = 8.39 Hz, 3H), 1.88–
1.71 (m, 2H), 1.41 (s, 9H), 1.32–1.21 (m, 3H) ppm. 13C NMR
(100 MHz, CDCl3): d 170.87, 154.80, 143.48, 128.46 (2C), 127.29,
125.99 (2C), 80.44, 61.23, 59.79, 48.16, 30.93, 28.12, 23.55,
21.38 ppm.
4.1.4. (2S,4R)-tert-Butyl-4-hydroxy-2-((S)-1-phenylethylcar-
bamoyl)pyrrolidine-1-carboxylate 1122
Compound 9 (2.14 g, 9.3 mmol) was dissolved in dry dichloro-
methane (25 mL), after which triethylamine (1.54 mL, 11.1 mmol)
and ethyl chloroformate (1.05 mL, 11.1 mmol, in dichloromethane
(5 mL)) were added slowly at 0 °C and stirred for 15 min. (S)-1-
Phenylethylamine (1.19 mL, 9.3 mmol) in 5 mL of dichloromethane
was added to the above solution and the reaction mixture was
allowed to return to room temperature and stirred for 5 h. The
reaction mixture was concentrated by a rotary evaporator. The
resulting oil was purified on silica gel using 30% ethyl acetate in
4.1.1. (S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid
825
To a stirred solution of L-proline 6 (4.76 g, 40 mmol) in dry DCM
(60 mL), triethyl amine (7.60 g, 56 mmol) and di-tert-butyldicar-
bonate (12.39 mL, 54 mmol) were added dropwise at 0 °C. The
resulting reaction mixture was stirred for 5 h. The reaction mixture
was acidified with a saturated solution of citric acid to pH 5–4 and
extracted with CH2Cl2. The extract was washed with brine and
water and dried over anhydrous sodium sulfate. The solvent was
evaporated and dissolved in the minimum amount of ethyl acetate,
after which hexane and ethyl acetate (6:1) were added and kept at
0 °C for 24 h to give a white solid (7.2 g, 85%). Mp = 136 °C.
hexane to give a colourless oil 11 (2.5 g, 81%). [
2.0, MeOH). IR (film):
a]
25 = ꢀ97.3 (c
D
m
= 3302, 2976, 1666, 1547 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d 7.51 (br s, 1H), 7.24–7.16 (m, 5H), 5.04–4.95
(m, 1H), 4.53–4.21 (m, 2H), 3.51–3.28 (m, 2H), 2.32–2.19 (m,
1H), 1.93–1.91 (m, 1H), 1.39 (s, 9H), 1.29–1.17 (m, 3H) ppm. 13C
NMR (100 MHz, CDCl3): d 171.77, 155.57, 143.00, 128.12 (2C),
126.61, 125.81 (2C), 80.14, 69.09, 59.39, 54.08, 48.37, 36.36,
27.86, 21.43 ppm.
[
a
]
27 = ꢀ121.8 (c 1, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 10.0 (br
D
s, 1H), 4.36–4.18 (m, 1H), 3.57–3.29 (m, 2H), 2.31–1.81 (m, 4H),
1.42 (s, 4.5H), 1.39 (s, 4.5H) ppm. 13C NMR (100 MHz, CDCl3): d
178.75, 175.86, 155.92, 153.89, 81.03, 80.29, 58.90, 46.84, 46.27,
30.77, 28.86, 28.33, 28.21, 24.24, 23.55 ppm.
4.1.5. (2S,4R)-tert-Butyl 2-(benzylcarbamoyl)-4-hydroxypyrro-
lidine-1-carboxylate 1322
Compound 9 (2.14 g, 9.3 mmol) was dissolved in dry dichloro-
methane (25 mL), after which triethylamine (1.54 mL, 11.1 mmol)
and ethyl chloroformate (1.05 mL, 11.1 mmol) were added and
then benzyl amine (1.01 mL, 9.3 mmol) was added. The rest of
the procedure was followed as the synthesis of compound 10. Yield
4.1.2. (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-
carboxylic acid 924
trans-4-Hydroxy-L-proline 7 (2.50 g, 19 mmol) was dissolved in
25 = ꢀ40.25 (c 0.82, MeOH), IR (film):
m = 3300,
38 mL of THF/H2O (2:1) and then treated with 10% aqueous NaOH
(8 mL) followed by the addition of di-tert-butyldicarbonate (6.00 g,
28 mmol). The reaction mixture was stirred at room temperature
overnight and then THF was removed by a rotary evaporator. The
(2.67 g, 90%). [
a]
D
2976, 1685, 1664 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 7.24 (br s,
1H), 6.75–6.69 (m, 5H), 4.25 (s, 1H), 3.93–3.69 (m, 2H), 3.58–
3.54 (m, 1H), 3.06–2.92 (m,1H), 2.73–2.50 (m, 1H), 1.71–1.49 (m,
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G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
2H), 0.91–0.69 (m, 9H), ppm. 13C NMR (100 MHz, CDCl3): d 172.03,
153.54, 138.55, 127.43 (2C), 126.88, 126.37 (2C), 78.79, 67.66,
58.87, 54.04, 43.56, 37.12, 29.97 ppm.
4.1.10. cis-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-
butyl ester 15
cis-4-Hydroxy-L-proline hydrochloride 14 (0.50 g, 3.0 mmol)
was dissolved in 6 mL of THF/H2O (2:1) and then treated with
10% aqueous NaOH (1.25 mL) followed by the addition of di-tert-
butyldicarbonate (0.95 g, 4.42 mmol). The reaction mixture was
stirred at room temperature overnight and then THF was removed
by rotavapor. The residue was adjusted to pH 2 by the addition of
10% aqueous KHSO4. The acidic solution was extracted several
times with ethyl acetate. The combined organic extracts were
washed with H2O and brine, and dried over anhydrous Na2SO4.
The solvent was removed by a rotary evaporator to afford com-
pound 15 as a syrup (542 mg, 78%), which was used without purifi-
4.1.6. (S)-N-((S)-1-Phenylethyl)pyrrolidine-2-carboxamide 122
Compound 10 (2.0 g, 6.2 mmol) was dissolved in dry dichloro-
methane (2.8 mL) after which trifluoroacetic acid (2.8 mL) was
added, then stirred at room temperature for 6 h. Reaction mixture
was concentrated in vacuo, dissolved in H2O (10 mL), and the pH
was adjusted to ꢁ8 by adding Et3N dropwise at 0 °C. The product
was then extracted with dichloromethane (3 ꢂ 10 mL), dried over
MgSO4 and concentrated in vacuo to yield an oil, which was puri-
fied by column chromatography using methanol/dichloromethane
(10:90), to afford product 1 in 98% yield (1.34 g). [
a
]
D
25 = ꢀ71.1 (c
cation for the next step. [
a]
25 = 15.3 (c 1.02, MeOH). IR (film):
D
1.10, MeOH). IR (film):
m
= 3288, 3087, 1778, 1672, 1666 cmꢀ1
.
1H
m
= 3462, 2976, 2934, 1740, 1639 cmꢀ1 1H NMR (400 MHz, CDCl3)
.
NMR (400 MHz, CDCl3): d 7.82 (br s, 1H), 7.32–7.19 (m, 5H), 4.91
(d, J = 6.9 Hz, 1H), 4.54–4.54 (m, 1H), 3.27–3.26 (m, 2H), 2.40–
2.36 (m, 1H), 1.97–1.87 (m, 3H), 1.42 (d, J = 6.9 Hz, 3H) ppm. 13C
NMR (100 MHz, CDCl3): d 167.73, 142.94, 128.66 (2C), 127.35,
125.29 (2C) 59.84, 50.45, 46.68, 29.87, 24.05, 21.72 ppm. HRMS
(ESI): m/z [M+H]+ calcd for C13H19N2O: 219.1492; found: 219.1498.
d 7.22 (br s, 1H), 5.11–5.09 (m, 2H), 4.94–4.93 (m, 1H), 4.40 (s, 1H),
3.64–3.62 (m, 1H), 3.49–3.44 (m, 2H), 2.27–1.90 (s, 9H). 13C NMR
(100 MHz, CDCl3): d 172.47, 151.74, 75.81, 67.15, 55.24, 52.27,
35.97, 25.63 ppm. HRMS (ESI): m/z [M+H]+ calcd for C10H18NO5:
232.1185; found: 232.1171.
4.1.11. (2R,4R)-tert-Butyl 4-hydroxy-2-((S)-1-phenylethylcar-
bamoyl)pyrrolidine-1-carboxylate 16
4.1.7. (2S,4R)-4-Hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-
carboxamide 222
Compound 15 (0.542 g, 2.34 mmol) was dissolved in dry
dichloromethane (6 mL), after which triethylamine (0.39 mL,
2.79 mmol) and ethyl chloroformate (20.26 mL, 2.79 mmol, in
1 mL dry dichloromethane) were added dropwise at 0 °C. The solu-
tion was stirred at the same temperature for 15 min and then (S)-
1-phenylethyl amine (0.30 mL, 2.34 mmol) was added slowly. The
resulting mixture was warmed to room temperature and stirred for
5 h. The reaction mixture was washed with 10% HCl solution, sat-
urated NaHCO3 solution, brine and dried over anhydrous Na2SO4.
The solvent was evaporated under vacuum and the residue was
recrystallized from ethyl acetate to afford 16 as a colourless oil
The compound 11 (2.0 g, 5.98 mmol) was dissolved in dry
dichloromethane (2.8 mL), after which trifluoroacetic acid
(2.80 mL) was added, then stirred at room temperature for 6 h.
The reaction mixture was concentrated in vacuo, dissolved in
H2O (10 mL), and the pH was adjusted to ꢁ8 by adding Et3N drop-
wise at 0 °C. The product was then extracted with dichloromethane
(3 ꢂ 10 mL), dried over MgSO4 and concentrated in vacuo to yield
an oil, which was purified by column chromatography using
methanol/dichloromethane (10:90), to afford product 2 (1.37 g,
98%). [
a
]
25 = ꢀ78.7 (c 1.7, MeOH). IR (film):
m = 3298, 3078, 1674,
D
1660 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 8.56 (br s, 1H), 6.90–
(450 mg, 58%). [
a
]
D
25 = ꢀ53.8 (c 0.51, MeOH). IR (film):
m = 3298,
6.78 (m, 5H), 4.6–4.53 (m, 1H), 4.20–4.05 (m, 2H), 2.96–2.91 (m,
2H), 2.10–2.05 (m, 1H), 1.43–1.41 (m, 1H), 1.08–1.01 (m, 3H). 13C
NMR (100 MHz, CDCl3): d 166.37, 142.87, 127.60 (2C), 126.15,
124.97 (2C), 69.12, 57.53, 53.02, 48.53, 38.18, 21.40 ppm. HRMS
(ESI): m/z [M+H]+ calcd for C13H19N2O2: 235.1441; found:
235.1452.
3078, 1674, 1660 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 7.53 (br s,
1H) 7.28–7.19 (m, 5H), 5.00 (t, J = 12.97 Hz, 1H), 4.43–4.30 (m,
1H), 3.41–3.38 (m, 1H), 2.32–2.28 (m, 1H), 2.15–2.07 (m, 1H),
2.00–1.93 (m, 1H), 1.44 (d, J = 6.87 Hz, 3H), 1.41 (s, 9H), 1.30–
1.26 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): d 172.04, 155.59,
142.87, 128.59 (2C), 126.99, 125.71 (2C), 80.67, 70.65, 59.67,
56.92, 49.34, 35.54, 28.23, 22.62 ppm. HRMS (ESI): m/z [M+H]+
calcd for C18H27N2O4: 335.1971; found: 335.1974.
4.1.8. (2S,4R)-4-Hydroxy-N-((R)-1-phenylethyl)pyrrolidine-2-
carboxamide 322
A similar procedure was followed to that of compound 2, to give
4.1.12. (2R,4R)-4-Hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-
carboxamide 5
a colourless oil 3 (1.37 g, 98%). [
a]
25 = +25.9 (c 1, MeOH). IR (film):
D
m
= 3298, 3078, 1674, 1660 cmꢀ1. 1H NMR (400 MHz, CDCl3): d 8.68
Compound 13 (400 mg, 1.19 mmol) was taken in dry dichloro-
methane (0.57 mL) with TFA (0.57 mL) using the method as previ-
ously described for 2, to give an oil. The oil was purified on silica
gel using methanol/dichloromethane (10:90), yielding product 5
(br s, 1H) 6.96–6.08 (m, 5H), 5.10–5.08 (m, 1H), 4.76–4.71 (m, 1H),
4.41–4.27 (m, 2H), 3.13–3.13 (m, 2H), 2.30–2.28 (m, 1H), 1.77–1.75
(m, 1H), 1.22–1.01 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3): d
167.52, 143.58, 129.92 (2C), 127.27, 126.40 (2C), 70.18, 58.65,
54.10, 49.72, 39.22, 22.22 ppm. HRMS (ESI): m/z [M+H]+ calcd for
as an oil (273 mg 98%). [
a
]
D
25 = ꢀ24.8 (c 0.58, MeOH). IR (film):
3298, 3078, 1674, 1660 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 8.61
C
13H19N2O2: 235.1441; found: 235.1443.
(br s, 1H) 7.10–7.03 (m, 5H), 4.78–4.73 (m, 1H), 4.23–4.19 (m,
2H), 3.19–3.16 (m, 1H), 3.05–3.01 (m, 1H), 2.34–2.26 (m, 1H),
1.96–1.93 (m, 1H), 1.23–1.20 (m, 3H) ppm. 13C NMR (100 MHz,
CDCl3): d 167.49, 142.77, 128 (2C), 126.65, 125.73 (2C), 68.80,
57.89, 50.04, 49.29, 38.05, 21.42 ppm. HRMS (ESI): m/z [M+H]+
calcd for C13H19N2O2: 235.1441; found: 235.1443.
4.1.9. (2S,4R)-N-Benzyl-4-hydroxypyrrolidine-2-carboxamide 422
Compound 13 (2.00 g, 6.25 mmol) was taken in dry dichloro-
methane (2.80 mL) with TFA (2.80 mL) using the method as previ-
ously described for 2, to give an oil. The oil was purified on silica
gel using methanol/dichloromethane (10:90), yielding the product
4 as an oil (1.35 g, 98%). [
m
a]
25 = ꢀ25.7 (c 1.29 in MeOH), IR (film):
4.2. General experimental procedure for the aldol reaction
D
= 3300, 2976, 1685, 1664 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d
8.52 (br s, 1H), 6.69–6.66 (m, 5H), 3.93–3.79 (m, 4H), 2.82–2.68
(m, 2H), 1.90–1.87 (m, 1H), 1.41–1.37 (m, 1H) ppm. 13C NMR
(100 MHz, CDCl3): d 163.03, 137.08, 127.32 (2C), 126.37 (2C),
126.08, 68.60, 57.26, 52.67, 42.02, 39.96 ppm. HRMS (ESI): m/z
[M+H]+ calcd for C12H16N2O2: 221.1290; found: 221.1286.
4.2.1. Reaction in solvent
Organocatalyst 2 (23.4 mg, 0.10 mmol) was dissolved in a sol-
vent (1 mL), as described in Table 1, cyclohexanone (0.310 mL,
3 mmol) and acetic acid (6
20 min at 15 °C after which 4-nitrobenzaldehyde (151 mg,
lL, 0.10 mmol) and was stirred for
Please cite this article in press as: Yadav, G. D.; Singh, S. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.09.003

8
G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
1 mmol) was added. The reaction mixture was stirred for a speci-
fied reaction time period at the same temperature. The solvent
was removed by a rotary evaporator under reduced pressure to
give a crude aldol adduct, which was purified by flash column
chromatography on silica gel (hexane/ethyl acetate (3:1)). The ee
and dr of the aldol product were determined by HPLC using chiral
column (chiralpak AD-H) using hexane/2-propanol as the mobile
phase.
4.2.8. (S)-2-((R)-Hydroxy(4-fluoro-phenyl)methyl)cyclohexanone
(Table 3, entry 5)8b
1H NMR (400 MHz, CDCl3): d 7.28–7.24 (m, 2H), 7.02–6.97 (m,
2H), 4.75 (d, J = 8.54 Hz, 1H), 2.58–2.51 (m, 1H), 2.44–2.30 (m,
2H), 2.09–2.02 (m, 1H), 1.83–1.54 (m, 3H), 1.30–1.19 (m, 2H)
ppm. HPLC analysis: Chiralcel OD–H (Hexane/i-PrOH = 95:5,
1.0 mL/min, 254 nm, 25 °C): tmajor = 11.4 min, tminor = 18.1 min,
ee: 72%.
4.2.2. Reaction in solvent free conditions
4.2.9. (S)-2-((R)-Hydroxy(2-chloro-phenyl)methyl)cyclohexanone
(Table 3, entry 6)8b
Organocatalyst
(0.310 mL, 3 mmol) and acetic acid (6
2
(23.4 mg, 0.10 mmol), cyclohexanone
L, 0.10 mmol) were stirred
1H NMR (400 MHz, CDCl3): d 7.45 (dd, J = 7.93, 1.83 Hz, 1H),
7.24–7.19 (m, 2H), 7.13–7.09 (m, 1H), 5.26 (d, J = 7.93 Hz, 1H),
2.62–2.56 (m, 1H), 2.39–2.21 (m, 2H), 1.98–1.96 (m, 1H),
1.73–1.70 (m, 1H), 1.65–1.43 (m, 3H), 1.21–1.17 (m, 1H)
ppm. HPLC analysis: Chiralcel OD-H (Hexane/i-PrOH = 92:8,
0.5 mL/min, 220 nm, 25 °C): tmajor = 14.2 min, tminor = 16.6 min,
ee: 93%.
l
for 20 min at 15 °C, then 4-nitrobenzaldehyde (151 mg, 1 mmol)
was added. The reaction mixture was stirred for a specified reac-
tion time period at the same temperature. The crude aldol product
was then purified by flash column chromatography on silica gel
(hexane/ethyl acetate (3:1)). The diastereomeric ratio was deter-
mined by 1H NMR of the crude product. The ee of the aldol product
was determined by HPLC using chiral column (chiralpak AD-H and
OD-H) using hexane/2-propanol as the mobile phase.
4.2.10. (S)-2-((R)-Hydroxy(4-chloro-phenyl)methyl)cyclohexanone
(Table 3, entry 7)8b
4.2.3. (S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexanone
(Table 2, entry 6)8b
1H NMR (400 MHz, CDCl3): d 7.26–7.16 (m, 4H), 4.70 (d,
J = 12.82 Hz, 1H), 4.15 (br s, 1H), 2.53–2.46 (m, 1H), 2.40–1.34
(m, 2H), 2.00–1.97 (m, 1H), 1.72–1.41 (m, 3H), 1.25–1.16 (m, 2H)
ppm. HPLC analysis: Chiralpak AD-H (Hexane/i-PrOH = 90:10,
1.0 mL/min, 224 nm, 25 °C): tminor = 13.1 min, tmajor = 15.6 min,
ee: 86%.
1H NMR (400 MHz, CDCl3): d 8.14 (d, J = 8.39 Hz, 2H), 7.44 (d,
J = 7.93 Hz, 2H), 4.85 (d, J = 7.63 Hz, 1H), 2.60–2.53 (m, 1H), 2.43–
2.27 (m, 2H), 2.06–2.01 (m, 1H), 1.80–1.74 (m, 1H), 1.69–1.45
(m, 3H), 1.36–1.29 (m, 1H) ppm. HPLC analysis: Chiralpak AD-H
(Hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm, 25 °C): tminor = 22.6
min, tmajor = 30.9 min, ee: 95%.
4.2.11. (S)-2-((R)-Hydroxy(2-bromo-phenyl)methyl)cyclohexanone
(Table 3, entry 8)8b
4.2.4. (S)-2-((R)-Hydroxy(phenyl)methyl)cyclohexanone (Table 3,
entry 1)8b
1H NMR (400 MHz, CDCl3): d 7.45–7.41 (m, 2H), 7.25 (t,
J = 7.32 Hz, 1H), 7.06–7.02 (m, 1H), 5.22 (d, J = 7.93 Hz, 1H), 2.64–
2.57 (m, 1H), 2.36–2.24 (m, 2H), 2.02–1.97 (m, 1H), 1.75–1.47
(m, 4H), 1.20–1.17 (m, 1H) ppm. HPLC analysis: Chiralpak AD-H
1H NMR (400 MHz, CDCl3): d 7.33–7.24 (m, 5H), 4.75 (d,
J = 8.54 Hz, 1H), 2.63–2.56 (m, 1H), 2.46–2.42 (m, 1H), 2.36–2.28
(m, 1H), 2.05–2.02 (m, 1H), 1.75–1.48 (m, 4H), 1.28–1.23 (m,1H)
ppm. HPLC analysis: Chiralpak AD-H (Hexane/i-PrOH = 80:20,
1.0 mL/min, 254 nm, 25 °C): tmajor = 15.7 min, tminor = 20.3 min,
ee: 76%.
(Hexane/i-PrOH = 90:10, 1.0 mL/min, 220 nm, 25 °C): tmajor
6.6 min, tminor = 7.2 min, ee: 80%.
=
4.2.12. (S)-2-((R)-Hydroxy(4-bromo-phenyl)methyl)cyclohexanone
(Table 3, entry 9)8b
4.2.5. (S)-2-((R)-Hydroxy(naphthyl)methyl)cyclohexanone (Table 3,
entry 2)8b
1H NMR (400 MHz, CDCl3): d 7.42 (d, J = 8.39 Hz, 2H), 7.14 (d,
J = 8.39 Hz, 2H), 4.71 (d, J = 8.39 Hz, 1H), 2.55–2.38 (m, 2H), 2.34–
2.26 (m, 1H), 2.06–2.01 (m, 1H), 1.76–1.73 (m, 1H), 1.65–1.44
(m, 3H), 1.29–1.22 (m, 1H) ppm. HPLC analysis: Chiralpak AD-H
1H NMR (400 MHz, CDCl3): d 8.23 (d, J = 7.63 Hz, 1H), 7.89–7.74
(m, 2H), 7.55–7.43 (m, 4H), 5.57 (d, J = 9.16 Hz, 1H), 3.01–3.94 (m,
1H), 2.51–2.32 (m, 2H), 2.04–2.02 (m, 1H), 1.69–1.63 (m, 2H),
1.44–1.24 (m, 3H) ppm. HPLC analysis: Chiralcel OD-H (Hexane/i-
PrOH = 90:10, .5 mL/min, 280 nm, 25 °C): tminor = 26.8 min,
tmajor = 30.7 min, ee: 80%.
(Hexane/i-PrOH = 90:10, 0.3 mL/min, 222 nm, 25 °C): tminor
45.3 min, tmajor = 53.6 min, ee: 84%.
=
4.2.13. (S)-2-((R)-Hydroxy(2-methoxy-phenyl)methyl)cyclohex-
anone (Table 3, entry 10)8b
4.2.6. (S)-2-((R)-Hydroxy(2-nitro-phenyl)methyl)cyclohexanone
(Table 3, entry 3)8b
1H NMR (400 MHz, CDCl3): d 7.31 (d, J = 7.63 Hz, 1H), 7.18 (d,
J = 8.01 Hz, 1H), 6.89 (d, J = 7.63 Hz, 1H), 6.77 (d, J = 7.63 Hz, 1H),
5.18 (d, J = 8.39 Hz, 1H), 3.72 (s, 3H), 3.33 (br s, 1H), 2.68–2.61
(m, 1H), 2.39–2.25 (m, 2H), 1.97–1.93 (m, 1H), 1.71–1.34 (m, 4H)
1.18–1.16 (m, 1H) ppm. HPLC analysis: Chiralpak OD-H (Hexane/
i-PrOH = 92:8, 0.5 mL/min, 222 nm, 25 °C): tmajor = 33.8 min,
tminor = 36.1 min, ee: 87%.
1H NMR (400 MHz, CDCl3): d 7.76 (d, J = 8.39 Hz, 1H), 7.67 (d,
J = 7.25 Hz, 1H), 7.57 (t, J = 7.63 Hz, 1H), 7.37 (t, J = 7.63 Hz, 1H),
5.38 (d, J = 7.63 Hz, 1H), 2.87–2.82 (m, 1H), 2.43–2.30 (m, 2H),
2.10–2.04 (m, 1H), 1.93–1.86 (m, 1H), 1.79–1.73 (m, 1H), 1.67–
1.64 (m, 1H), 1.45–1.34 (m, 1H), 1.01–.97 (m, 1H) ppm. HPLC
analysis: Chiralcel OD-H (Hexane/i-PrOH = 90:10, 1.0 mL/min,
254 nm, 25 °C): tmajor = 16.0 min, tminor = 18.4 min, ee: 93%.
4.2.14. (S)-2-((R)-Hydroxy(4-methoxy-phenyl)methyl)cyclohex-
anone (Table 3, entry 11)8b
4.2.7. (S)-2-((R)-Hydroxy(2-fluoro-phenyl)methyl)cyclohexanone
(Table 3, entry 4)
1H NMR (400 MHz, CDCl3): d 7.24–7.20 (m, 2H), 6.87–6.85 (m,
2H), 4.73 (d, J = 8.54 Hz, 1H), 3.81 (s, 3H), 2.62–2.55 (m, 1H),
2.45–2.33 (m, 2H), 2.07–2.04 (m, 1H), 1.78–1.54 (m, 3H), 1.30–
1.23 (m, 2H) ppm. HPLC analysis: Chiralpak AD-H (Hexane/i-
PrOH = 90:10, 1.0 mL/min, 254 nm, 25 °C): tminor = 20.0 min,
tmajor = 20.9 min, ee: 56%.
1H NMR (400 MHz, CDCl3): d 7.48–7.39 (m, 1H), 7.19–7.06 (m,
2H), 6.96–6.89 (m, 1H), 5.11 (d, J = 9.16 Hz, 1H), 4.14 (br s, 1H),
2.64–2.57 (m, 1H), 2.45–2.26 (m, 2H), 2.09–1.98 (m, 1H), 1.72–
1.37 (m, 4H), 1.20–1.16 (m, 1H) ppm. HPLC analysis: Chiralcel
OD-H (Hexane/i-PrOH = 90:10, 1.0 mL/min, 220 nm, 25 °C):
tmajor = 11.5 min, tminor = 12.0 min, ee: 94%.
Please cite this article in press as: Yadav, G. D.; Singh, S. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.09.003

G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
9
4.2.15. (S)-2-((R)-Hydroxy(2-trifluoromethyl-phenyl)methyl)-
cyclohexanone (Table 3, entry 12)
220.36, 158.80 (d, J = 245.80 Hz), 129.90 (d, J = 13.42 Hz), 128.39
(d, J = 8.63 Hz), 127.25 (d, J = 3.83 Hz), 123.91 (d, J = 3.83 Hz),
114.73 (d, J = 21.09 Hz), 65.12, 54.43, 38.94, 22.63 20.22; anti
222.99, 159.67 (d, J = 252.08 Hz), 130.83 (d, J = 8.63 Hz), 129.12
(d, J = 8.63 Hz), 127.99 (d, J = 3.83 Hz), 124.35 (d, J = 2.88 Hz),
115.02 (d, J = 22.04 Hz), 67.91, 54.86, 38.44, 26.27, 20.22 ppm.
HPLC analysis Chiralpak AD-H (Hexane/i-PrOH = 95:5, .5 mL/min,
220 nm, 25 °C): syn: tminor 11.5 min, tmajor 14.7 min, ee: 61%; anti:
tmajor 20.8 (S, R) min, tminor 22.4 min (R, S), ee: 76%.
1H NMR (400 MHz, CDCl3): d 7.58 (d, J = 7.32 Hz, 1H), 7.51–7.44
(m, 2H), 7.25 (t, J = 7.93 Hz, 1H), 5.17 (d, J = 8.54 Hz, 1H), 2.66–2.59
(m, 1H), 2.39–2.20 (m, 2H), 1.97–1.91 (m, 1H), 1.64–1.13 (m, 5H)
ppm. HPLC analysis: Chiralcel AD–H (Hexane/i-PrOH = 95:5,
0.5 mL/min, 254 nm, 25 °C): tmajor = 30.7 min, tminor = 33.5 min,
ee: 93%.
4.2.16. (S)-2-((R)-Hydroxy(4-trifluoromethyl-phenyl)methyl)-
cyclohexanone (Table 3, entry 13)
4.2.22. 2-[Hydroxy-(4-fluoro-phenyl)methyl]-cyclopentanone
(Table 4, entry 4)8b
1H NMR (400 MHz, CDCl3): d 7.60 (d, J = 8.39 Hz, 2H), 7.43 (d,
J = 9.16 Hz, 2H), 4.85 (d, J = 8.39 Hz, 1H), 4.09 (br s, 1H), 2.63–
2.34 (m, 3H), 2.12–2.06 (m, 1H), 1.82–1.52 (m, 4H), 1.37–1.25
(m, 1H) ppm. HPLC analysis: Chiralpak AD–H (Hexane/i-PrOH =
1H NMR (400 MHz, CDCl3): d 7.24–7.18 (m, 4H), 6.95–6.90 (m,
3.5H), 5.16 (d, J = 2.29 Hz, 1H syn), 4.61 (d, J = 9.16 Hz, 1H anti),
2.36–2.26 (m, 3H), 2.23–1.99 (m, 3H), 1.95–1.84 (m, 2H), 1.73–
1.54 (m, 3H), 1.44–1.35 (m, 1H), 1.20–1.15 (m, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d syn 220.48, 161.82 (d, J = 244.41 Hz),
138.51, 128.10 (d, J = 7.67 Hz, 2C), 115.05 (d, J = 21.09 Hz, 2C),
70.61, 56.11, 39.10, 26.74, 22.53; anti 222.88, 162.28 (d,
J = 245.37 Hz), 137.17, 127.06 (d, J = 7.67 Hz, 2C), 115.15 (d,
J = 21.09 Hz, 2C), 74.37, 55.25, 38.59, 26.74, 20.25 ppm. HPLC anal-
ysis: Chiralpak AD-H (Hexane/i-PrOH = 90:10, 1.0 mL/min, 222 nm,
25 °C): syn: tmajor 8.0 min, tminor 9.5 min, ee: 26%; anti: tmajor
10.8 min (S, R), tminor 11.8 min (R, S), ee: 54%.
90:10, 0.5 mL/min, 230 nm, 25 °C): tminor = 10.3 min, tmajor
=
13.2 min, ee: 75%.
4.2.17. (2S,4S)-4-tert-Butyl-2-((R)-hydroxy-(2-nitrophenyl)me-
thyl)cyclohexanone 208b
1H NMR (400 MHz, CDCl3): d 7.84 (d, J = 8.39 Hz, 1H), 7.71 (d,
J = 8.39 Hz, 1H), 7.61 (d, J = 8.39 Hz, 1H), 7.41 (d, J = 9.16 Hz, 1H),
5.45 (d, J = 7.63 Hz, 1H), 2.84–2.78 (m, 1H), 2.40–2.39 (m, 2H),
1.93–1.89 (m, 1H), 1.64–1.47 (m, 4H), 0.76 (s, 9H) ppm; HPLC anal-
ysis: Chiralpak AD-H (Hexane/i-PrOH = 95:5, .5 mL/min, 254 nm,
25 °C): tminor = 41.0 min, tmajor = 51.8 min, ee: 90%.
4.2.23. 2-[Hydroxy-(2-chloro-phenyl)methyl]-cyclopentanone
(Table 4, entry 5)
4.2.18. (2S,4S)-4-tert-Butyl-2-((R)-hydroxy-(4-nitro-phenyl)me-
thyl)cyclohexanone 218b
1H NMR (400 MHz, CDCl3): d 7.48–7.40 (m, 1H), 7.19–7.00 (m,
3H), 6.93–6.83 (m, 1H), 5.48 (d, J = 3.05 Hz, 1H syn), 4.99 (d,
J = 9.16 Hz, 0.29H anti), 3.41–3.25 (m, 1H), 2.49–2.42 (m, 1H),
2.38–2.14 (m, 1H), 2.07–1.97 (m, 1H), 1.91–1.81 (m, 2H), 1.67–
1.48 (m, 3H), 13C NMR (75 MHz, CDCl3): d syn 220.24, 140.23,
130.75, 129.03, 128.11, 127.38, 126.66, 67.59, 53.36, 38.94, 22.22,
20.23; anti 222.76, 138.94, 132.16, 129.11, 128.75, 128.20,
127.19, 70.15, 55.22, 38.50, 26.29, 20.36 ppm. HPLC analysis Chi-
ralpak AD-H (Hexane/i-PrOH = 95:5, 1.0 mL/min, 222 nm, 25 °C):
syn: tminor 7.4 min, tmajor 8.8 min ee: 54%; anti: tmajor 12.4 min (S,
R), tminor 13.0 min (R, S), ee: 85%.
1H NMR (400 MHz, CDCl3): d 8.18 (d, J = 9.16 Hz, 1H), 7.47 (d,
J = 9.16 Hz, 1H), 4.90 (d, J = 9.92 Hz, 1H), 3.60 (s, 1H), 2.62–2.55
(m, 1H), 2.48–2.30 (m, 2H), 1.93–1.86 (m, 1H), 1.59–1.31 (m,
4H), 0.71 (s, 9H) ppm; HPLC analysis: Chiralpak AD-H (Hexane/i-
PrOH = 90:10, 0.5 mL/min, 254 nm, 25 °C): tmajor = 27.7 min,
tminor = 36.1 min, ee: 85%.
4.2.19. 2-[Hydroxy(2-nitro-phenyl)methyl]-cyclopentanone
(Table 4, entry 1)8b
1H NMR (400 MHz, CDCl3) d = 8.00 (d, J = 8.54 Hz, 0.4H), 7.89 (d,
J = 7.93 Hz, 1H), 7.83 (d, J = 7.93 Hz, 1H), 7.74 (dd, J = 7.93, 4.27 Hz,
1H), 7.60–7.55 (m, 2H), 7.46 (d, J = 7.93 Hz, 1H), 7.37 (dd, J = 7.93,
3.97 Hz, 1H), 5.80 (s, 1H syn), 5.34 (d, J = 7.93 Hz, 1H anti), 4.45
(s, .7H), 2.74–2.71 (m, .8H), 2.63–2.59 (m, 1H), 2.49–2.44 (m,
.7H), 2.38–2.32 (m, 1H), 2.27–2.24 (m, 1H), 2.13–1.87 (m, 4H),
1.72–1.61 (m, 4H), 1.22–1.17 (m, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d syn HPLC analysis Chiralcel OD-H (Hexane/i-PrOH = 95:5,
1.0 mL/min, 254 nm, 25 °C): syn: tminor 11.5 min, tmajor 14.7 min,
ee: 55%; anti: tmajor 20.8 min (S, R), tminor 22.4 min (R, S), ee: 77%.
4.2.24. 2-[Hydroxy-(4-chloro-phenyl)methyl]-cyclopentanone
(Table 4, entry 6)
1H NMR (400 MHz, CDCl3): d 7.24–7.16 (m, 8.93H), 5.18 (d,
J = 2.29 Hz, 1.23H syn), 4.61 (d, J = 9.16 Hz, 1H anti), 2.38–2.27
(m, 3H), 2.25–2.00 (m, 3H), 1.94–1.83 (m, 3H), 1.71–1.58 (m,
5H), 1.42–1.37 (m, 0.66H), 1.17–1.12 (m, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d syn 220.37, 141.26, 132.81, 128.68 (2C),
127.84 (2C), 74.44, 55.17, 38.61, 26.76, 20.35; anti 222.79,
139.85, 132.84, 128.37 (2C), 126.88 (2C), 70.62, 56.04, 39.09,
26.76, 22.52 ppm. HPLC analysis Chiralpak AD-H (Hexane/
i-PrOH = 90:10, 1.0 mL/min, 222 nm, 25 °C): syn: tmajor 7.9 min,
tminor 9.6 min, ee: 33%; anti tmajor 11.3 min (S, R), tminor 12.2 min
(S, R), ee: 56%.
4.2.20. 2-[Hydroxy(4-nitro-phenyl)methyl]-cyclopentanone
(Table 4, entry 2)8b
1H NMR (400 MHz, CDCl3): d 8.16–8.06 (m, 3H), 7.45–7.42 (m,
3.6H), 5.48 (d, J = 2.44 Hz, 0.66H syn), 4.79 (d, J = 9.16 Hz, 1H anti),
3.48–3.32 (m, 1H), 2.99–2.71 (m, 1H), 2.43–2.29 (m, 4H), 2.24–2.01
(m, 1.6H), 1.95–1.84 (m, 2H) 1.65–1.43 (m, 2H) ppm. HPLC analysis
Chiralcel AD-H (Hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm,
25 °C): syn: tmajor 14.7 min, tminor 19.1 min, ee: 45%; anti: tminor
23.3 min (R, S), tmajor 24.6 min (S, R), ee: 61%.
4.2.25. 2-[Hydroxy-(2-methoxy-phenyl)methyl]-cyclopentanone
(Table 4, entry 7)
1H NMR (400 MHz, CDCl3): d 7.45 (t, J = 9.92 Hz, 1H), 7.28–7.21
(m, 1H), 6.99–6.94 (m, 2H), 6.85 (t, J = 8.39 Hz, 2H), 5.56 (d,
J = 2.29 Hz, 1H syn), 5.19 (d, J = 12.21 Hz, 1H anti), 3.80 (s, 4.6H),
2.83–2.77 (m, 1H), 2.64–2.58 (m, 1H), 2.51–2.49 (m, 1H), 2.36–
2.10 (m, 3H), 2.00–1.96 (m, 2H), 1.72–1.69 (m, 3H) ppm. 13C
NMR (75 MHz, CDCl3): d syn 220.80, 155.40, 130.87, 127.90,
126.35, 120.32, 109.75, 66.56, 55.23, 55.01, 39.07, 26.37, 20.34;
anti 123.14, 156.30, 129.64, 128.55, 127.48, 120.80, 110.36,
68.28, 55.20, 56.68, 38.54, 26.37, 22.81 ppm; HPLC analysis Chiral-
pak AD-H (Hexane/i-PrOH = 95:5, .5 mL/min, 222 nm, 25 °C): syn:
tminor 11.5 min, tmajor 14.7 min, ee: 50%.
4.2.21. 2-[Hydroxy(2-fluoro-phenyl)methyl]-cyclopentanone
(Table 4, entry 3)
1H NMR (400 MHz, CDCl3): d 7.48–7.40 (m, 1H), 7.19–7.10 (m,
1H), 7.04 (t, J = 7.63 Hz, 1.9H), 6.88 (t, J = 8.39 Hz, 1H), 5.48 (d,
J = 3.05 Hz, 1H syn), 4.99 (d, J = 9.16 Hz, .23 anti), 2.49–2.40 (m,
1H), 2.38–2.12 (m, 2H), 2.06–1.97 (m, 1H), 1.93–1.82 (m, 2H),
1.67–1.48 (m, 2.6H) ppm. 13C NMR (75 MHz, CDCl3): d syn
Please cite this article in press as: Yadav, G. D.; Singh, S. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.09.003

10
G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
10. Catalysed by prolinamide with b-amino alcohol: (a) Vishnumaya, Raj M.;
Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097; (b) Maya, V.; Raj, M.; Singh, V.
K. Org. Lett. 2007, 9, 2593; (c) Okuyama, Y.; Nakano, H.; Watanabe, Y.; Makabe,
M.; Takeshita, M.; Uwai, K.; Kabuto, C.; Kwon, E. Tetrahedron Lett. 2009, 50,
193; (d) Vishnumaya, R. M.; Singh, V. K. J. Org. Chem. 2009, 74, 4289; (e) Chen,
X. H.; Yu, J.; Gong, L. Z. Chem. Commun. 2010, 6437.
11. Prolinamide of cholic acid methylester: Puleoa, G. L.; Iuliano, A. Tetrahedron:
Asymmetry 2007, 18, 2894.
12. Catalysed by aminoimidazole containing prolinamides: Tang, G. K.; Gun, U.;
Altenbach, H. J. Tetrahedron 2012, 68, 10230.
4.2.26. 2-[Hydroxy-(4-methoxy-phenyl)methyl]-cyclopentanone
(Table 4, entry 8)
1H NMR (400 MHz, CDCl3): d 7.57–7.51 (m, 0.7H), 7.24–7.20 (m,
2H), 6.93 (d, J = 8.54 Hz, 1H), 6.83 (d, J = 8.54 Hz, 2H), 5.19 (d,
J = 3.66 Hz, 1H syn), 4.62 (d, J = 12.82 Hz, 0.4 anti), 3.82 (s, 0.62),
3.76 (s, 3H), 3.05 (m, 1H), 2.45–2.30 (m, 2H), 2.14–2.13 (m, 1H),
2.02–1.88 (m, 2H), 1.86–1.78 (m, 1H), 1.74–1.61 (m, 1H), 1.47–
1.22 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d syn 220.72,
159.19, 134.86, 127.69 (2C), 113.68 (2C), 74.64, 56.06, 55.17,
38.69, 26.89, 20.31; anti 223.20, 158.70, 133.57, 126.71 (2C),
113.61 (2C), 71.18, 56.06, 55.29, 39.19, 22.84, 24.43 ppm. HPLC
analysis Chiralpak AD-H (Hexane/i-PrOH = 90:10, 1.0 mL/min,
222 nm, 25 °C): anti: tmajor 17.0 min (S, R), and tminor 18.6 min (R,
S), ee: 25%.
13. Catalysed by (L)-prolinamides of chiral and achiral diamines: (a) Samanta, S.;
Liu, J.; Dodda, R.; Zhao, C. G. Org. Lett. 2005, 7, 5321; (b) Pedrosa, R.; Andres, J.
M.; Manzano, R.; Rodriguez, P. Eur. J. Org. Chem. 2010, 5310; (c) Delaney, J. P.;
Henderson, L. C. Adv. Synth. Catal. 2012, 354, 197.
14. Catalysed by prolinamide of camphor: Tzeng, Z. H.; Chen, H. Y.; Huang, C. T.;
Chen, K. Tetrahedron Lett. 2008, 49, 4134.
15. Catalysed by dipeptides and pseudopeptides: (a) Lei, M.; Shi, L. X.; Li, G.; Chen,
S. L.; Fang, W. H.; Ge, Z. M.; Cheng, T. M.; Li, R. T. Tetrahedron 2007, 63, 7892; (b)
Chen, F. B.; Huang, S.; Zhang, H.; Liu, F. Y.; Peng, Y. G. Tetrahedron 2008, 64,
9585; (c) Chandrasekhar, S.; Johny, K.; Reddy, C. R. Tetrahedron: Asymmetry
2009, 20, 1742; (d) Pearson, A. J.; Panda, S. Org. Lett. 2011, 13, 5548; (e)
Hernandez, J. G.; Juaristi, E. J. Org. Chem. 2011, 76, 1464; (f) Machuca, E.; Rojas,
Y.; Juaristi, E. Asian J. Org. Chem. 2015, 4, 46; (g) Triandafillidi, I.; Bisticha, A.;
Voutyritsa, E.; Galiatsatou, G.; Kokotos, C. G. Tetrahedron 2015, 71, 932; (h)
Machuca, E.; Juaristi, E. Tetrahedron Lett. 2015, 56, 1144.
16. For recent examples of aldol reactions catalyzed by prolinethioamides, see: (a)
Gryko, D.; Lipinski, R. Adv. Synth. Catal. 2005, 347, 1948; (b) Almasi, D.; Alonso,
D. A.; Najera, C. Adv. Synth. Catal. 2008, 350, 2467; (c) Almasi, D.; Alonso, D. A.;
Balaguer, A. N.; Najera, C. Adv. Synth. Catal. 2009, 351, 1123; (d) Wang, B.; Liu,
X. W.; Liu, L. Y.; Chang, W. X.; Li, J. Eur. J. Org. Chem. 2010, 5951; (e) Fotaras, S.;
Kokotos, C. G.; Tsandi, E.; Kokotos, G. Eur. J. Org. Chem. 2011, 1310; (f) Fotaras,
S.; Kokotos, C. G.; Kokotos, G. Org. Biomol. Chem. 2012, 10, 5613; (g) Revelou, P.;
Kokotos, C. G.; Minakakis, P. M. Tetrahedron 2012, 68, 8732; (h) Maycock, C. D.;
Ventura, M. R. Tetrahedron: Asymmetry 2012, 23, 1262; (i) Kokotos, C. G. J. Org.
Chem. 2012, 77, 1131.
Acknowledgements
S.S. acknowledges the financial assistance from Science and
Engineering Research Board (SERB), Department of Science and
Technology (DST), India, under scheme Fast Track Young Scientist
(SB/FT/CS-020/2012) and University Science Instrumentation Cen-
ter (USIC), University of Delhi, India for analytical data. Authors are
thankful to DU-DST mass facility at USIC. G.D.Y. is thankful to CSIR
for providing SRF.
References
17. For recent examples of aldol reactions catalyzed by sulfonamides, see: (a) Mei,
K.; Zhang, S.; He, S.; Li, P.; Jin, M.; Xue, F.; Luo, G.; Zhang, H.; Song, L.; Duan, W.;
Wang, W. Tetrahedron Lett. 2008, 49, 2681; (b) Tsandi, E.; Kokotos, C. G.;
Kousidou, S.; Ragoussis, V.; Kokotos, G. Tetrahedron 2009, 65, 1444; (c) Zhang,
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Please cite this article in press as: Yadav, G. D.; Singh, S. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.09.003

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