A highly asymmetric direct aldol reaction catalyzed by chiral proline amide-thiourea bifunctional catalysts

Article abstract of DOI:10.1139/v11-029

A series of chiral proline amide-thiourea bifunctional catalysts derived from l-proline and chiral diamine were prepared and successfully applied to highly enantioselective direct aldol reactions of cyclohexanone with various aldehydes in excellent yields

Full text of DOI:10.1139/v11-029

1312
A highly asymmetric direct aldol reaction
catalyzed by chiral proline amide – thiourea
bifunctional catalysts
Yun Li, Qing-chuan Yang, Xiao-Ying Xu, Yong Zhou, Jian-fei Bai, Fei-ying Wang,
and Li-xin Wang
Abstract: A series of chiral proline amide – thiourea bifunctional catalysts derived from L-proline and chiral diamine were
prepared and successfully applied to highly enantioselective direct aldol reactions of cyclohexanone with various aldehydes
in excellent yields (85%–97%), diastereoselectivities (anti/syn > 20:1) and enantioselectivities (up to 91% ee).
Key words: aldol reaction, bifunctional catalyst, proline, amide–thiourea.
Résumé : On a préparé une série de catalyseurs chiraux bifonctionnels amide de la proline – thiourée dérivés de la L-proline
et d’une diamine chirale et on l’a appliquée avec succès à la réaction d’aldolisation directe hautement énantiosélective de la
cyclohexanone avec divers aldéhydes, avec d’excellents rendements (85 %–97 %), et des diastéréosélectivités (anti/syn >
20 : 1) et énantiosélectivités (allant jusqu’à 91 % ee) élevées.
Mots‐clés : réaction aldolique, catalyseur bifonctionnel, proline, amide–thiourée.
[Traduit par la Rédaction]
Recently, chiral thiourea organocatalysts have been widely
used in asymmetric catalysis because of their effective activa-
tion of carbonyl and nitro groups through double-hydrogen-
bonding interactions.17 Among them, secondary amines, es-
pecially L-proline and its structural analogues, are powerful
tools for the activation of aldehydes and ketones via an en-
amine or imine transition state.2,18 However, the chiral pro-
line amide – thiourea catalysts 4a–4d with two catalytic sites
of chiral thiourea and L-prolic amide skeleton have not drawn
enough attention.19 Based on this background, we expected
to expand the scope of the application for these bifunctional
catalysts and wanted to see if these catalysts may catalyze the
asymmetric direct aldol reaction of cyclohexanone with alde-
hydes.
Aldol reactions are typically performed in organic solvents
such as DMSO, DMF, or chloroform. In recent years, water
has been widely used as a substitute for conventional organic
solvents in asymmetric reactions because it is safe, economi-
cal, and environment friendly.20 Therefore, asymmetric aldol
reactions using an organocatalyst in water have received con-
siderable attention21 since Barbas and co-workers21a and Hay-
ashi et al.9 reported the first example of a small molecule
catalyzed by direct an asymmetric Aldol reaction in pure
water.
Introduction
The aldol reaction is considered one of the most important
carbon–carbon bond-forming reactions that creates the b-
hydroxy ketones frequently found in many biologically active
compounds and drugs.1,2 Since pioneering work discovered
that L-proline is a highly efficient catalyst for asymmetric di-
rect aldol reactions,3 great advances have been made for this
reaction.2–4 The direct aldol reaction involving cyclohexanone
principally generates b-hydroxyketone as a mixture of regio-,
diastereo-, and enantio-isomers, and it is quite difficult to ob-
tain a single isomer. As a result, many efforts have been
made on this conversion. Xiao and co-workers5a developed a
kind of L-prolinamide derived from L-proline and chiral dia-
mine to catalyze this reaction and provide high entioselectiv-
ities, anti-disastereoselectivities, and yields. Since then, a
series of L-prolinamides5 have been prepared and applied to
this transformation, and impressive results have been made.
As well, L-proline6 and L-prolinamides,5 tetrazole,7 3-pyrroli-
dinecarboxylic acid,8 4-substituted L-proline,9 cinchona-derived
primary amines,10 chiral phosphinyl oxide pyrrolidines,11 pro-
linethioamides,12 sulfonamide,13 6-APA,14 cis-diamine deriva-
tives,15 and acyclic amino acids16 have also been evaluated for
this reaction. To the best of our knowledge, L-proline amide –
thiourea bifunctional catalysts have not been reported for the
catalysis of the aldol reaction of cyclohexanone with alde-
hydes.
As a part of our continuing interest in asymmetric synthe-
sis,22,23 herein, we wish to report examples of chiral proline
Received 4 May 2010. Accepted 28 January 2011. Published at www.nrcresearchpress.com/cjc on 15 September 2011.
Y. Li. Department of Chemistry, Sichuan University, Chengdu 610041, China.
Q. Yang, X.Y. Xu, Y. Zhou, J. Bai, F. Wang, and L. Wang. Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan
Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China.
Correspondence author: L.X. Wang (e-mail: wlxioc@cioc.ac.cn).
Can. J. Chem. 89: 1312–1318 (2011)
doi:10.1139/V11-029
Published by NRC Research Press

Li et al.
1313
amide – thiourea bifunctional catalyst promoted enantioselective
direct aldol reaction of cyclohexanone with various aldehydes
in DMSO with water as a co-solvent in excellent yields, as
well as high anti-diastereoselectivities (dr > 20:1) and enan-
tioselectivities (up to 91%). These catalysts are illustrated in
Fig. 1.
Fig. 1. Chiral proline amide – thiourea bifunctional catalysts.
O
(S)
O
(R)
(S)
N
H
(R)
N
H
(S)
N
H
(S)
HN
HN
N
H
HN
HN
S
S
Ar
Ar
4b
4a
Results and discussion
Ph
O
Ph
(S)
O
Chiral catalysts 4a–4d may be similarly prepared as the re-
ported procedures19 and the catalytic activities of 4a–4d were
investigated in the model reaction of cyclohexanone with p-
nitrobenzaldehyde, and the results are summarized in Table 1,
which shows that chiral catalysts with different stereocompat-
ibility and chiral centers have great effects on reactivities and
selectivities. Comparatively, catalysts 4a and 4c gave better
yields and enantioselectivities (Table 1, entries 1 and 3 ver-
sus 2 and 4). This is probably due to the compatibility of the
two catalytic chiral centers. The less compatible chiral centers
in 4b and 4d probably exert no synergic or negative effects
on enantioselectivity. Catalyst 4a, bearing a R,R linker, af-
forded the desired products in excellent yield (97%) and
good enantioselectivity (75% ee) and was chosen for further
optimization. Next, a range of solvents was screened for the
model reaction catalyzed by 4a at room temperature. As
shown in Table 1, the enantioselectivities and yields were
highly variable with different solvents. All the solvents deliv-
ered good yields (60%–94%), moderate to good enantioselec-
tivities (15%–78% ee), and anti-diastereoselectivities (1:1 to
24:1). Less polar aprotic solvents such as hexane, toluene,
and DCM gave good yields and moderate enantioselectivities
(Table 1, entries 5–10). Protic solvents such as i-PrOH and
water separately seemed to have an adverse influence on
enantioselectivities (Table 1, entries 14 and 15). Relatively,
DMSO gave an excellent yield (92%) and a good enantiose-
lectivity (78%) and was chosen for further investigation (Ta-
ble 1, entry 12).
To further improve the results, a series of additives were
studied and the results are listed in Table 2. Additives have
remarkable effects on catalytic activity and enantioselectivity,
and the reaction time was reduced to 7 h (entries 1–8). When
AcOH was used, the yield increased to 92% and the enantio-
selectivity was 86% ee (Table 2, entry 8). Interestingly, when
water was used as a co-solvent, the reaction rate was dramat-
ically accelerated and the reaction was completed within half
an hour with increases in diastereoselectivity (Table 2, entries
9 and 10) and 81% and 87% ee were obtained. Particularly,
when the volume ratio of DMSO to water reached 1:2, excel-
lent yield (97%), good enantioselectivity (87% ee), and dia-
stereoselectivity (96:4) were achieved (Table 2, entry 10).
Through extensive screening, the optimized reaction condi-
tions were found to be 20 mol% of catalyst 4a and 10 equiv
(R)
(S) Ph
N
H
(R) Ph
N
H
(S)
N
H
(S)
HN
N
H
HN
S
S
HN
HN
Ar
Ar
4c
4d
Ar = 3,5-bis(trifluoromethyl)benzene
(Table 3, entries 1–4) gave excellent yields, diastereoselectiv-
ities, and enantioselectivities. Particularly, the strong elec-
tron-withdrawing substituents at the ortho position in the
benzene ring afforded the best enantioselectivities (up to
91% ee; Table 3, entries 6 and 7). The para position also
gave high yields and excellent diastereoselectivities and enan-
tioselectivities (up to 90% ee; Table 3, entries 2 and 3). Cy-
clopentanone was also investigated under these optimized
conditions and gave 94% yield and 71% ee.
Conclusion
In conclusion, we have successfully applied the chiral pro-
line amide – thiourea bifunctional catalysts 4a–4d for the
catalysis of the direct asymmetric aldol reaction of cyclohex-
anone with various aldehydes in the presence of water in ex-
cellent yields (85%–97%) and high anti-diastereoselectivities
(dr > 20:1) and enantioselectivities (up to 91% ee). Further
studies of the newly developed catalyst model and related
catalysts in other organocatalyses are currently underway.
Experimental section
General
All reagents were purchased from a commercial supplier
without further purification. Commercial grade solvent was
dried and purified by standard procedures as specified in the
Purification of Laboratory Chemicals;24 NMR spectra were
recorded with tetramethylsilane as the internal standard (d =
1
0.0 ppm). H NMR spectra were recorded at 300 MHz, and
13C NMR spectra were recorded at 75 MHz (Bruker Avance).
Chemical shifts (d) are reported in ppm downfield from
1
CDCl3 (d = 7.26 ppm) for H NMR and relative to the cen-
cyclohexanone in DMSO and water (VDMSO:VH O ¼ 1:2) at
2
tral CDCl3 resonance (d = 77.0 ppm) for 13C NMR spectro-
scopy. Flash column chromatography was carried out using
silica gel eluting with ethyl acetate and petroleum ether. Re-
actions were monitored by TLC and visualized with UV
light. Melting points were measured on a Büchi B-545 melt-
ing point apparatus. Enantioselectivities (ee) were determined
by HPLC using Daicel Chiralpak AD, OD, WHELK, or AS
25 °C (Table 2, entry 10).
Having established optimized conditions for the model re-
action, the scope and the limitations of the reaction with dif-
ferent aldehydes were examined, and the results are
summarized in Table 3. All the aldehydes bearing electron-
withdrawing groups in the aromatic ring either at ortho (Ta-
ble 3, entries 6–8), meta (Table 3, entry 5), or para positions
Published by NRC Research Press

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Can. J. Chem. Vol. 89, 2011
Table 1. Screening of catalysts 4a–4d and solvents.
O
O
OH
OHC
cat 4. (20 mol%),
solvent
rt , 24 h
NO2
NO2
1a
2a
3a
Entry
1
2
3
4
5
6
7
8
Catalyst
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
Solvent
Neat
Neat
Neat
Neat
Toluene
hexane
DCM
CHCl3
Et2O
Yield (%)a
Anti / synb
ee (%)c
75
41
55
41
41
54
44
62
48
37
39
78
64
15
57
97
85
87
35
94
66
70
87
86
94
88
92
60
91
80
14:1
11:1
32:1
4:1
2:1
2:1
2:1
9:1
2:1
2:1
2:1
3:1
24:1
1:1
4:1
9
10
11
12
13
14
15
THF
4a
4a
4a
4a
CH3CN
DMSO
DMF
i-PrOH
H2O
4a
Note: Unless otherwise specified, all reactions were carried out with catalysts 4 (0.02 mmol), 1a (2 mmol), and
2a (0.1 mmol) in the specified solvent (0.2 mL) at room temperature.
aIsolated yield.
1
bDetermined by H NMR.
cee values were determined via HPLC with a Chiralpak-AD column.
Table 2. The effect of additives.
O
OH
O
OHC
cat 4a. (20 mol%),
rt
DMSO,
NO2
NO2
1a
3a
2a
Time
(h)
7
7
7
7
7
7
7
Entry
1
2
3
4
5
6
7
Additive (20 mol%)
4-OHC6H4CO2H
Phenol
Yield (%)a
Anti/synb
65:35
85:15
76:24
87:13
60:40
79:21
80:20
74:26
91:9
ee (%)c
75
75
72
71
68
66
78
86
84
80
97
94
93
99
80
92
92
97
PhCO2H
4-NO2C6H4CO2H
PhCH2CO2H
H2O
C6H4(CO2H)2
AcOH
8
7
0.5
0.5
9d
10e
AcOH
AcOH
81
87
96:4
Note: Unless otherwise specified, all reactions were carried out with catalysts 4a (0.02 mmol), 1a
(2 mmol), and 2a (0.1 mmol) in DMSO (0.2 mL) at room temperature.
aIsolated yield.
1
bDetermined by H NMR.
cee values were determined via HPLC with a Chiralpak-AD column.
dThe solvent was DMSO–H2O (2:1).
eThe solvent was DMSO–H2O (1:2).
(S)-N-((1R,2R)-2-(3-(3,5-Bis(trifluoromethyl)phenyl)
thioureido)cyclohexyl)pyrrolidine-2-carboxamide (4a)19
Enantiomerically pure 4a was obtained after a single re-
crystallization from petroleum ether – EtOAc (v/v 1:100).
columns with i-PrOH–hexane as the eluent. All compounds
in this manuscript are known compounds. All physical and
spectral data were found to be consistent with those re-
ported.19,22
Published by NRC Research Press

Li et al.
1315
Table 3. The reaction of cyclohexanone with various aldehydes under optimized conditions.
O
O
OH
OHC
AcOH (20 mol%)
DMSO:H2O=1:2
Cat 4a. (20 mol%),
R
R
rt,
2
3
1a
Time
(h)
0.5
2
2
2
2
2
2
2
Entry
R
4-NO2
4-Br
4-CN
4-F
3-NO2
2-Br
Product
3a
3b
3c
3d
3e
3f
3g
3h
Yield (%)a
ee (%)b
87
71
90
63
90
91
91
87
Anti/sync
>20:1
15:85
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
1
2
3
4
5
6
7
8
97
88
97
90
93
97
94
85
2-NO2
2-CN
Note: Unless otherwise specified, all reactions were carried out with catalysts 4a (0.02 mmol), 1a
(2 mmol), and 2 (0.1 mmol) in a mixture of DMSO and water (v/v = 1:2).
aIsolated yield.
bee values were determined by HPLC using a chiral stationary phase.
1
cDetermined by H NMR.
Colorless solid, mp 176–177 °C. Rf (10% MeOH – EtOAc)
10 H), 6.40 (m, 1H), 5.45–5.38 (t, 1H), 3.74–3.69 (m, 1H),
3.14–3.10 (m, 1H), 3.10–2.98 (m, 1H), 2.05–1.64 (m, 6H).
1
0.23. H NMR (300 MHz CDCl3) d (ppm): 9.89–9.84 (m,
13C NMR (75 MHz, CDCl3) d (ppm): 181.5, 176.5, 141.0,
138.0, 131.7, 123.2, 129.0, 128.6, 128.4, 127.9, 127.7,
122.9, 122.1, 117.7, 61.9, 60.5, 58.6, 47.2, 31.1, 26.1.
HRMS (ESI-TOF) calcd for C28H27F6N4OS ([M + H]+):
581.1804; found: 581.1823. All physical and spectral data
were found to be consistent with those reported.19,22
1H), 8.21 (d, J = 10.0 Hz, 1H), 8.15 (d, J = 10.8 Hz, 2H),
7.79 (d, J = 9.5 Hz, 1H), 7.55 (s, 1H), 4.63–4.60 (m, 1H),
3.74–3.67 (m, 2H), 3.01–2.96 (m, 2H), 1.99–1.94 (m, 1H),
1.68–1.22 (m, 12H). 13C NMR (75 MHz, CDCl3) d: 180.9,
176.6, 141.3, 132.1, 128.6, 124.9, 122.1, 121.3, 117.7, 60.3,
56.8, 53.7, 47.1, 32.9, 32.2, 30.9, 25.8, 25.3, 24.7. HRMS
(ESI-TOF) calcd for C20H25F6N4OS ([M + H]+): 483.1648;
found: 483.1660. All physical and spectral data were found
to be consistent with those reported.19,22
(S)-N-((1S,2S)-2-(3-(3,5-Bis(trifluoromethyl)phenyl)
thioureido)-1,2-diphenylethl)pyrrolidine-2-carboxamide
(4d)19
Enantiomerically pure 4d was obtained after a single re-
crystallization from petroleum ether – EtOAc (v/v 1:80). Col-
orless solid, mp 147–148 °C. Rf (10% MeOH – EtOAc) 0.30.
(S)-N-((1S,2S)-2-(3-(3,5-Bis(trifluoromethyl)phenyl)
thioureido)cyclohexyl)pyrrolidine-2-carboxamide (4b)19
Enantiomerically pure 4b was obtained after a single re-
crystallization from petroleum ether – EtOAc (v/v 1:100).
Colorless solid, mp 149–151 °C. Rf (10% MeOH – EtOAc)
1H NMR (300 MHz, CDCl3) d (ppm): 1.25–1.63 (m, 2H),
1.83–1.85 (m, 1H), 2.09–2.13 (m, 2H), 2.74–2.78 (m, 1H),
2.98–3.02 (m, 1H), 3.83–3.88 (m, 1H), 5.23–5.29 (t, J =
8.4 Hz, 9.8 Hz, 1H), 6.53–6.55 (d, J = 6 Hz, 1H), 7.08–
7.19 (m, 12H), 7.43 (s, 1H), 8.65–8.68 (d, J = 9 Hz, 1H).
1
0.26. H NMR (300 MHz, CDCl3) d (ppm): 1.03–1.35 (m,
2H), 1.47–1.57 (m, 3H), 1.63–1.70 (m, 2H), 1.89–2.01 (m,
7H), 2.97–3.03 (m,2H), 3.69–3.73 (m, 2H), 4.59–4.62 (d,
J = 9 Hz, 1H), 7.55 (s, 1H), 7.77–7.80 (d, J = 9 Hz, 1H),
8.13 (s, 2H), 8.19–8.22 (d, J = 9 Hz, 1H), 9.88–9.89 (br,
1H). 13C NMR (75 MHz, CDCl3) d: 180.9, 176.7, 141.4,
132.2, 128.6, 125.0, 122.1, 121.4, 117.0, 60.3, 56.9, 53.7,
47.1, 32.9, 30.9, 25.8, 25.9, 24.7. HRMS (ESI-TOF) calcd
for C20H25F6N4OS ([M + H]+): 483.1648; found: 483.1658.
All physical and spectral data were found to be consistent
with those reported.19,22
13C NMR (75 MHz, CDCl3) d (ppm): 181.6, 176.4, 140.8,
137.8, 131.8, 129.0, 128.6, 128.2, 127.9, 127.7, 127.5,
123.1, 123.4, 122.1, 118.0, 62.9, 60.6, 59.4, 46.9, 30.4,
25.7. HRMS (ESI-TOF) calcd for C28H27F6N4OS ([M + H]+):
581.1804; found: 581.1812. All physical and spectral data
were found to be consistent with those reported.19,22
(S)-N-((1R,2R)-2-(3-(3,5-Bis(trifluoromethyl)phenyl)
thioureido)-1,2-diphenylethyl)pyrrolidine-2-carboxamide
(4c)19
Asymmetric direct aldol reactions of cyclohexanone with
various aldehydes
Enantiomerically pure 4c was obtained after a single re-
crystallization from petroleum ether – EtOAc (v/v 1:80). Col-
orless solid, mp 166–168 °C. Rf (10% MeOH – EtOAc) 0.28.
1H NMR (300 MHz CDCl3) d (ppm): 8.92–8.89 (m, 1H),
8.50–8.48 (m, 1H), 8.07 (s, 2H), 7.60 (s, 1H), 7.28–7.12 (m,
Published by NRC Research Press

1316
Can. J. Chem. Vol. 89, 2011
General procedure for direct aldol reaction of
2.58 (br, 1H), 4.81–4.84 (d, J = 9 Hz, 1H), 7.40–7.45 (m,
2H), 7.63–7.65 (d, J = 6 Hz, 2H). All physical and spectral
data were found to be consistent with those reported.5a,21a
cyclohexanone with various aldehydes (Table 3)
A mixture of 2 (0.1 mmol, 1 equiv), 1a (2 mmol,
20 equiv), 4a (0.02 mmol, 0.2 equiv), and water–DMSO
(0.2 mL, v/v 2:1) was stirred for 0.5–2 h. Then the crude
product was directly purified by silica gel chromatography
without workup using a mixture of EtOAc–hexanes (from
1:5 to 1:6) as the eluent and fractions were collected and
concentrated in vacuo to provide the desired product.
2-[Hydroxy(4-fluorophenyl)methyl]cyclohexanone (3d)
The title compound was prepared according to the general
procedure, as described previously, in 90% yield. HPLC
(Chiralpak WHELK, i-PrOH–hexane = 20:80, flow rate =
1.0 mL/min, l = 220 nm): tminor = 9.08 min, tmajor
=
7.48 min, ee = 63%, dr > 20:1. Pure anti-product was ob-
tained by silica gel chromatography (eluent: Vhexane/Vethyl acetate
=
Spectroscopic data of final products 3
6:1). Furthermore, enantiomerically pure anti-product was
obtained after single recrystallization from petroleum ether –
EtOAc (v/v 1:2). Colorless solid, mp 84–85 °C. (lit.25 mp 84–
2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (3a)
The title compound was prepared according to the general
procedure, as described previously, in 97% yield. HPLC
(Chiralcel AD-H, i-PrOH–hexane = 20:80, flow rate =
1
85 °C). Rf (25% EtOAc – petroleum ether) 0.39. H NMR
(300 MHz, CDCl3) d (ppm): 1.26–1.30 (m, 1H), 1.52–1.68
(m, 4H), 2.07 (m, 1H), 2.34–2.57 (m, 3H), 3.99 (s, 1H),
4.76–4.78 (d, J = 6 Hz, 1H), 6.99–7.06 (m, 2H), 7.26–7.31
(m, 2H). All physical and spectral data were found to be con-
sistent with those reported.21a,26,25
1.0 mL/min, l = 254 nm): tminor = 11.25 min, tmajor
=
14.19 min, ee = 87%, dr > 20:1. Pure anti-product was ob-
tained by silica gel chromatography (eluent: Vhexane/Vethyl acetate
=
6:1). Furthermore, enantiomerically pure anti-product was
obtained after a single recrystallization from petroleum
ether – EtOAc (v/v 1.5:2). Colorless solid, mp 149–150 °C.
(lit.25 mp 149–151 °C). Rf (50% EtOAc – petroleum ether)
2-[Hydroxy(3-nitrophenyl)methyl]cyclohexanone (3e)
The title compound was prepared according to the general
procedure, as described previously, in 93% yield. HPLC
(Chiralcel OD-H, i-PrOH–hexane = 10:90, flow rate =
1
0.40. H NMR (300 MHz, CDCl3) d (ppm): 1.24–1.39 (m,
1H), 1.53–1.65 (m, 3H), 1.81–1.85 (m, 1H), 2.08–2.09 (m,
1H), 2.35–2.39 (m, 1H), 2.47–2.59 (m, 2H), 4.09 (br, 1H),
4.87–4.90 (d, J = 9 Hz, 1H), 7.49–7.52 (d, J = 9 Hz, 2H),
8.19–8.22 (d, J = 9 Hz, 2H). All physical and spectral data
were found to be consistent with those reported.5a,9,21a,25
0.8 mL/min, l = 220 nm): tminor = 18.77 min, tmajor
14.69 min, ee = 90%, dr >20:1. Pure anti-product was ob-
tained by silica gel chromatography (eluent: Vhexane/Vethyl acetate
=
=
6:1). Furthermore, enantiomerically pure anti-product was
obtained after single recrystallization from petroleum ether –
EtOAc (v/v 1:3). Yellow solid, mp 102–104 °C (no literature
2-[(4-Bromophenyl)hydroxy-methyl]cyclohexanone (3b)
The title compound was prepared according to the general
procedure, as described previously, in 88% yield. HPLC (Chir-
alpak AD-H, i-PrOH–hexane = 10:90, flow rate = 1.0 mL/min,
l = 220 nm): tminor = 12.98 min, tmajor = 14.96min, ee =
71%, dr > 85:15. Pure anti-product was obtained by silica
gel chromatography (eluent: Vhexane/Vethyl acetate = 6:1). Fur-
thermore, enantiomerically pure anti-product was obtained
after a single recrystallization from petroleum ether – EtOAc
(v/v 1.8:2). Yellow solid, mp 126–128 °C. (lit.25 mp 126–
1
data reported). Rf (50% EtOAc – petroleum ether) 0.50. H
NMR (300 MHz, CDCl3) d (ppm): 1.39–1.41 (m, 1H), 1.54–
1.65 (m, 3H), 1.81–1.84 (m, 1H), 2.09 (m, 1H), 2.36–2.62
(m, 3H), 4.10–4.11 (s, J = 3 Hz, 1H), 4.87–4.91 (m, 1H),
7.49–7.54 (t, J = 7.89 Hz, 7.92 Hz, 1H), 7.65–7.68 (m, 1H),
8.13–8.20 (m, 2H). All physical and spectral data were found
to be consistent with those reported.5a,9,21a
2-[(2-Bromophenyl)hydroxy-methyl]cyclohexanone (3f)
The title compound was prepared according to the general
procedure, as described previously, in 91% yield. HPLC
(Chiralpak AD-H, i-PrOH–hexane = 10:90, flow rate =
1
127 °C). Rf (25% EtOAc – petroleum ether) 0.27. H NMR
(300 MHz, CDCl3) d (ppm): 1.25–1.31 (m, 1H), 1.51–1.69
(m, 4H), 2.07–2.08 (m, 1H), 2.34–2.38 (m, 3H), 2.45–2.58
(m, 1H), 4.73–4.76 (d, J = 9 Hz, 1H), 7.17–7.26 (q, J =
15.39 Hz, 8.28 Hz, 5.4 Hz, 2H), 7.44–7.48 (m, 2H). All
physical and spectral data were found to be consistent with
those reported.5a,9,21a,25
1.0 mL/min, l = 220 nm): tminor = 11.86 min, tmajor
=
10.28 min, ee = 87%, dr > 20:1. Pure anti-product was ob-
tained by silica gel chromatography (eluent: Vhexane/Vethyl acetate
=
6:1). Furthermore, enantiomerically pure anti-product was
obtained after single recrystallization from petroleum ether –
EtOAc (v/v 1.5:2). Brown solid, mp 105–106 °C (no litera-
ture data reported). Rf (50% EtOAc – petroleum ether) 0.39.
2-[Hydroxy(4-oxo-cyclohexyl)methyl]benzonitrile (3c)
The title compound was prepared according to the general
procedure, as described previously, in 97% yield. HPLC
(Chiralcel AD-H, i-PrOH–hexane = 10:90, flow rate =
1H NMR (300 MHz, CDCl3) d (ppm): 1.57–1.72 (m, 6H),
2.33–2.45 (m, 2H), 2.70 (m, 1H), 4.03–4.05 (d, J = 6 Hz,
1H), 5.28–5.32 (m, 1H), 7.13–7.16 (m, 1H), 7.35–7.37 (m,
1H), 7.51–7.54 (m, 2H). All physical and spectral data were
found to be consistent with those reported.27
1.0 mL/min, l = 220 nm): tminor = 20.48 min, tmajor
=
25.34 min, ee = 90%, dr >20:1. Pure anti-product was ob-
tained by silica gel chromatography (eluent: Vhexane/VDCM
=
1:1). Furthermore, enantiomerically pure anti-product was
obtained after a single recrystallization from petroleum
ether – EtOAc (v/v 1.6:2). Yellow solid, mp 72–74 °C. Rf
2-[Hydroxy(2-nitrophenyl)methyl]cyclohexanone (3g)
The title compound was prepared according to the general
procedure, as described previously, in 94% yield. HPLC
(Chiralcel AD-H, i-PrOH–hexane = 10:90, flow rate =
1
(50% EtOAc – petroleum ether) 0.33. H NMR (300 MHz,
CDCl3) d (ppm): 1.24–1.37 (m, 1H), 1.52–1.64 (m, 3H),
2.08–2.09 (m, 2H), 2.34 (m, 1H), 2.46–2.52 (m, 2H), 2.56–
1.0 mL/min, l = 220 nm): tminor = 18.44 min, tmajor
=
Published by NRC Research Press

Li et al.
1317
(2), 237. doi:10.1016/j.tetasy.2007.01.021; (k) Tang, Z.; Yang,
Z. H.; Chen, X. H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong,
L. Z. J. Am. Chem. Soc. 2005 127 (25), 9285. doi:10.1021/
ja0510156; (l) Guo, H. M.; Cheng, L.; Cun, L. F.; Gong, L. Z.;
Mi, A. Q.; Jiang, Y. Z. Chem. Commun. (Camb.) 2006 (4),
429. doi:10.1039/b514194j; (m) Tang, Z.; Jiang, F.; Cui, X.;
Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. Proc. Natl.
Acad. Sci. U.S.A. 2004 101 (16), 5755. doi:10.1073/pnas.
0307176101.
17.34 min, ee = 91%, dr >20:1. Pure anti-product was ob-
tained by silica gel chromatography (eluent: Vhexane/Vethyl acetate
=
6:1). Furthermore, enantiomerically pure anti-product was
obtained after single recrystallization from petroleum ether –
EtOAc (v/v 1.3:2). Gray solid, mp 111–113 °C. (lit.28 mp
126–127 °C). Rf (50% EtOAc – petroleum ether) 0.21. 1H
NMR (300 MHz, CDCl3) d (ppm): 1.60–1.76 (m, 4H), 2.32–
2.44(m, 4H), 2.73–2.76 (m, 1H), 3.68–3.75 (br, 1H), 5.43–
5.46 (d, J = 9 Hz, 1H), 7.42–7.45 (m, 1H), 7.629–7.63 (m,
1H), 7.75–7.78 (m, 1H), 7.83–7.86 (m, 1H). All physical and
spectral data were found to be consistent with those reporte-
d.5a,21a,28
(5) (a) Chen, J. R.; Lu, H. H.; Li, X. Y.; Cheng, L.; Wan, J.; Xiao,
W. J. Org. Lett. 2005 7 (20), 4543. doi:10.1021/ol0520323;
(b) Chen, J. R.; Li, X. Y.; Xing, X. N.; Xiao, W. J. J. Org.
Chem. 2006 71 (21), 8198. doi:10.1021/jo0615089; (c)
Gandhi, S.; Singh, V. K. J. Org. Chem. 2008 73 (23), 9411.
doi:10.1021/jo8019863; (d) Tzeng, Z. H.; Chen, H. Y.;
Huang, C. T.; Chen, K. Tetrahedron Lett. 2008 49 (26), 4134.
doi:10.1016/j.tetlet.2008.04.122; (e) Zhao, J. F.; He, L.; Jiang,
J.; Tang, Z.; Cun, L. F.; Gong, L. Z. Tetrahedron Lett. 2008 49
(21), 3372. doi:10.1016/j.tetlet.2008.03.131; (f) Chen, F.;
Huang, S.; Zhang, H.; Liu, F. Y.; Peng, Y. G. Tetrahedron
2008 64 (40), 9585. doi:10.1016/j.tet.2008.07.051; (g)
Moorthy, G. N.; Saha, S. Eur. J. Org. Chem. 2009 739; (h)
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Tang, M. S. Tetrahedron Asymmetry 2006 17 (24), 3351.
doi:10.1016/j.tetasy.2006.12.008; (b) Puleo, G. L.; Iuliano, A.
Tetrahedron Asymmetry 2007 18 (24), 2894. doi:10.1016/j.
tetasy.2007.11.023; (c) Wang, C.; Jiang, Y.; Zhang, X. X.;
Huang, Y.; Li, B. G.; Zhang, G. L. Tetrahedron Lett. 2007 48
(24), 4281. doi:10.1016/j.tetlet.2007.04.037; (d) Guizzetti, S.;
Benaglia, M.; Raimondi, L.; Celentano, G. Org. Lett. 2007 9
(7), 1247. doi:10.1021/ol070002p; (e) Maya, V.; Raj, M.;
Singh, V. K. Org. Lett. 2007 9 (13), 2593. doi:10.1021/
ol071013l; (f) Sathapornvajana, S.; Vilaivan, T. Tetrahedron
2007 63 (41), 10253. doi:10.1016/j.tet.2007.07.086; (g)
Doherty, S.; Knight, J. G.; McRae, A.; Harrington, R. W.;
Clegg, W. Eur. J. Org. Chem. 2008, 1759; (h) Yang, H.;
Carter, R. G. Org. Lett. 2008 10 (20), 4649. doi:10.1021/
ol801941j; (i) Guillena, G.; Hita, M. C.; Nájera, C.; Viózquez,
S. F. J. Org. Chem. 2008 73 (15), 5933. doi:10.1021/
jo800773q; (j) Nyberg, A. I.; Usanp, A.; Pihko, P. M. Synlett
2004, 1891.
2-[Hydroxy(2-oxo-cyclohexyl)methyl]benzonitrile (3h)
The title compound was prepared according to the general
procedure, as described previously, in 85% yield. HPLC
(Chiralcel AS-H, i-PrOH–hexane = 5:95, flow rate =
1.0 mL/min, l = 220 nm): tminor = 41.79 min, tmajor
=
44.53 min, ee = 87%, dr >20:1. Pure anti-product was ob-
tained by silica gel chromatography (eluent: Vhexane/Vethyl acetate
=
6:1). Furthermore, enantiomerically pure anti-product was
obtained after single recrystallization from petroleum ether –
EtOAc (v/v 1:2). Yellow solid, mp: 185–186 °C (no literature
1
data reported). Rf (50% EtOAc – petroleum ether) 0.50. H
NMR (300 MHz, CDCl3) d (ppm): 1.52–1.58 (m, 4H), 1.83–
1.85 (m, 2H), 2.34–2.38 (m, 1H), 2.47–2.53 (m, 1H), 2.67–
2.70 (m, 1H), 4.22–4.23 (d, J = 3 Hz, 1H), 5.21–5.23 (d, J =
3.18 Hz, 8.55 Hz, 1H), 7.37–7.43 (m, 1H), 7.59–7.65 (m,
3H). All physical and spectral data were found to be consis-
tent with those reported.29
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