Highly diastereo- and enantioselective direct aldol reactions of cycloketones with aldehydes catalyzed by a trans-4-tert-butyldimethylsiloxy-l-proline amide

Article abstract of DOI:10.1016/j.tetasy.2007.01.028

An organocatalyst derived from trans-4-hydroxy-l-proline and (1S,2S)-1,2-diphenyl-2-aminoethanol catalyzes the direct aldol reactions of cycloketones with a wide scope of aldehydes in high yields and with excellent diastereoselectivities of up to >99:1 an

Full text of DOI:10.1016/j.tetasy.2007.01.028

Tetrahedron: Asymmetry 18 (2007) 265–270
Highly diastereo- and enantioselective direct aldol reactions
of cycloketones with aldehydes catalyzed by a
trans-4-tert-butyldimethylsiloxy-L-proline amide
Long He,a,* Jun Jiang,b,c Zhuo Tang,b,c Xin Cui,b,c Ai-Qiao Mi,b,c
Yao-Zhong Jiangb,c and Liu-Zhu Gongb,c,
*
aCollege of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637002, China
bKey Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
cGraduate School of Chinese Academy of Sciences, Beijing, China
Received 14 December 2006; accepted 24 January 2007
Abstract—An organocatalyst derived from trans-4-hydroxy-L-proline and (1S,2S)-1,2-diphenyl-2-aminoethanol catalyzes the direct aldol
reactions of cycloketones with a wide scope of aldehydes in high yields and with excellent diastereoselectivities of up to >99:1 and enantio-
selectivities of up to >99% ee.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
parably low enantioselectivities (<90% ee) given by L-pro-
line amide 1 for aromatic aldehydes substituted with an
electron-donating group9 require significant improvement.
The development of highly efficient and enantioselective
chiral catalysts for the organic transformations that
proceed under mild conditions and tolerate a wide scope
of substrates is an important area of research. Since the
pioneering works of by List and Barbas III et al. in which
L-proline was shown to act as a catalyst in the intermole-
cular direct aldol reaction,1 a great number of organocata-
lysts have been designed for the direct aldol reaction and
other reactions on the basis of so called ‘enamine cataly-
sis’.2–8 Impressive results for the direct aldol reaction of a
wide range of aldehydes with simple ketones, in particular
with acetone have been obtained. However, very few
organocatalysts have given both high diastereo- and
enantioselectivity for the direct aldol reaction of cyclo-
ketones with aldehydes, until very recently, where an L-pro-
line amide 1 derived from a chiral diamine9 and some
acyclic amino acids10 was discovered to catalyze the aldol-
ization of cyclohexanone with high enantioselectivity. Both
cases, however, preclude aliphatic aldehydes as acceptors.
In addition to this, diastereoselectivities ranging from 6:1
to 37:1 were observed with acylic amino acids10 and com-
O
N
O
Ph
O
Ph
OH
NH HN
N
H
N
H
H
1
2
CO2Et
O
CO2Et
N
H
OH
N
H
3
In our continuous efforts toward developing neworganoca-
talysis, we found that L-proline amides derived from chiral
amino alcohols acted as efficient catalysts for direct asym-
metric aldol reactions.5,6 L-Proline amides 2 and 3 catalyze
the direct aldol reactions of both aromatic and aliphatic
aldehydes in neat acetone with high enantioselectivities of
up to >99% ee.5,6 However, neither of them catalyze the
direct aldol reactions between cyclohexanone and aldehydes
with satisfactory stereoselectivity.5b,6 Extensive studies on
*
Corresponding authors. E-mail: helongcwnu@yahoo.com.cn
0957-4166/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.01.028

266
L. He et al. / Tetrahedron: Asymmetry 18 (2007) 265–270
the relationship between the stereogenic centers of the ami-
no alcohol moiety and the stereoselectivity of L-proline
amides have revealed that the chirality of each stereogenic
center has a considerable effect on the stereocontrol.5,6
Thus, we envisioned that organocatalyts 4a–d, which are
structurally similar to 2, but contain an additional stereo-
genic center, might show distinct catalytic performances
from the corresponding L-proline amides. We found that
4d was an efficient organocatalyst for enantioselective
desymmetrizations of the 4-substituted cyclohexanones
using the direct aldol reaction.11 Herein, we report that
trans-4-tert-butyldimethylsiloxy-L-proline-based organo-
catalysts 4a–d catalyze the direct aldol reactions of alde-
hydes with cyclohexanone and its analogues with
excellent enantioselectivities of up to >99% and diastereo-
selectivities of >99:1.
tion temperature decreased (entry 5). More importantly,
4d shows much better enantio- and diastereoselectivity
for the direct aldol reaction of 4-nitrobenzaldehyde with
cyclohexanone than both organocatalysts 2 and 3.5,6 When
the 4d catalyzed reaction of cyclohexanone with 4-nitro-
benzaldehydes was conducted at ꢀ40 °C in dichlorometh-
ane, it gave the aldol adduct in a high yield of 95% and
with an excellent diastereomeric ratio of >99:1 in favor of
the anti-diastereomer, as well as a near perfect enantio-
selectivity of 99% ee (entry 6).
The direct aldol reactions of a variety of aldehydes, includ-
ing aromatic and aliphatic ones, with cyclohexanone were
carried out in the presence of 5 mol % 4d under the optimal
reaction conditions to examine the scope and limitation.
The results are summarized in Table 2. The aldol reactions
of both aromatic and aliphatic aldehydes with cyclohexa-
none proceeded smoothly to give the aldol adducts with
excellent diastereoselectivities (up to >99:1) and enantio-
selectivities (up to >99%). Not only did the aromatic
aldehydes, which had electron-withdrawing groups lead
to the formation of 7aa–ai with very high diastereoselectiv-
ities ranging from 97:3 to >99:1 and enantioselectivities
ranging from 82% to >99% ee (entries 1–9), but also the
one bearing an electron-donating group gave extremely
high diastereoselectivity of >99:1 and enantioselectivity of
99% ee (entry 10). However, neither the acyclic amino acid
nor 1 were able to catalyze the aldol reaction between the
electron-rich aromatic aldehyde and cycloketone with a
similar level of stereoselectivity.9,10 More importantly, 4d
is also catalytically active for the reactions of aliphatic
aldehydes with cyclohexanone, giving anti-7ak and 7al in
excellent diastereoselectivities of up to >99:1 and enantio-
selectivities ranging from 99% to >99%ee (entries 11 and
12). These results demonstrate that organocatalyst 4d is
highly diastereo- and enantioselective for a wider scope
of aldehydes in direct aldol reactions compared with those
reported previously.3b,9,10
Ph
Ph
O
O
TBSO
TBSO
Ph
OH
Ph
OH
N
H
N
H
N
H
N
H
4b
4a
Ph
O
TBSO
Ph
OH
Ph
O
TBSO
Ph
OH
N
H
N
H
N
H
N
H
4c
4d
2. Results and discussion
trans-4-tert-Butyldimethylsiloxy-L-proline amides 4a–d
were readily prepared from TBS-protected trans-4-hydr-
oxy-L-proline and the corresponding enantiomerically pure
1,2-diphenyl-2-aminoethanols. In the presence of 5 mol %
4a–d, the aldol reaction of 4-nitrobenzaldehyde with ace-
tone was first examined to obtain an optimal reaction con-
ditions. As shown in Table 1, these organic molecules
exhibited high catalytic efficiency. The highest enantioselec-
tivity of 65% ee was observed with catalyst 4d (entry 4).
The enantioselectivity increased significantly as the reac-
To investigate further the generality of the current process,
aldol reactions between different cycloketones 5a–d and 4-
nitrobenzaldehyde 6a were examined (Table 3). All the
Table 1. trans-4-tert-Butyldimethylsiloxy-L-proline amides 4a–d catalyzed direct aldol reaction of acetone and cyclohexanone with 4-nitrobenzaldehydea
O
OH
O
O
+
5-20mol% 4a-4d
H
O2N
O2N
Entry
Ketone
Catalyst 4
Amount of 4 (mol %)
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
Acetone
Acetone
Acetone
Acetone
Acetone
Cyclohexanone
4a
4b
4c
4d
4d
4d
20
20
20
20
5
0
0
0
18
18
18
18
60
72
63
61
75
67
57
95
40
61
51
65
91
99d,e
0
ꢀ40
5
ꢀ40
a The reaction was carried out in neat acetone with a concentration of 0.5 M 4-nitrobenzaldehyde.
b Isolated yield.
c Ee values were determined by HPLC analysis.
d The reaction was carried out in CH2Cl2 with a concentration of 0.5 M of 4-nitrobenzaldehyde.
e The diastereomeric ratio of anti/syn is >99:1 on the basis of 1H NMR analysis.

L. He et al. / Tetrahedron: Asymmetry 18 (2007) 265–270
267
Table 2. The 4d catalyzed direct intermolecular aldol reactions of cyclohexanone with different aldehydes
O
O
OH
O
5 mol% 4d
CH2Cl2, -40 oC
+
R
H
R
6a-l
5a
7aa-al
Entry
R
Product
Time (h)
Yielda (%)
drb
eec (%)
1
2
3
4
5
6
7
8
9
4-NO2C6H4 6a
2-NO2C6H4 6b
Ph 6c
4-CN C6H4 6d
4-CF3C6H4 6e
2-FC6H4 6f
2,6-Cl2C6H3 6g
4-ClC6H4 6h
4-BrC6H4 6i
4-MeC6H4 6j
iso-Propyl 6k
Cyclohexyl 6l
7aa
7ab
7ac
7ad
7ae
7af
7ag
7ah
7ai
72
96
96
96
96
96
48
96
96
95
72
49
80
88
92
91
71
60
42
38
40
>99:1
99:1
97:3
>99:1
>99:1
97:3
>99:1
98:2
>99:1
>99:1
>99:1
>99:1
99
99
98
98
97
>99
>99
98
96
99
10
11
12
7aj
120
120
120
7ak
7al
>99
99
a Isolated yield after silica-gel column chromatography.
b The diastereomeric ratios were determined by 1H NMR analyses.
c The enantiomeric excesses were determined by HPLC analysis.
Table 3. Direct aldol reactions of cycloketones with 4-nitrobenzaldehyde
O
O
X
O
OH
5 mol% 4d
CH2Cl2, -40 oC
H
+
X
5a-d
O2N
NO2
6a
7aa-da
Entry
1
Ketone
Product
Yielda (%)
drb (anti:syn)
eec (%)
99
O
OH
O
95
>99:1
(7aa)
(5a)
(5b)
NO2
O
OH
O
2
3
90
82
90
98:2
98:2
96:4
94d
97d
97
(7ba)
NO2
O
O
O
O
O
OH
OH
O
(5c)
(5d)
(7ca)
(7da)
S
NO2
NO2
S
O
O
4
O
O
a Isolated yield.
b The diastereoselectivities were determined by NMR analyses.
c Ee values were determined by HPLC analysis.
d Reactions are carried out at ꢀ15 °C.
reactions took place smoothly and furnished the desired
aldol adducts 7aa–da in high yield, with excellent diastereo-
meric ratios of anti/syn ranging from 96:4 to >99:1 and
very high enantioselectivities of up to 99% ee. The diaste-
reo- and enantioselectivities depend to some degree on
the structure of the cycloketone. The highest enantio- and

268
L. He et al. / Tetrahedron: Asymmetry 18 (2007) 265–270
diastereoselectivity were observed for the reaction of cyclo-
hexanone (entry 1). 1,4-Dioxa-spiro[4.5]decan-8-one 5b
gave a comparably lower enantioselectivity than the other
cycloketones (entry 2). Notably, 5b and 5c seemed less
reactive toward the aldehyde than the other two ketones.
Thus, the reactions of 5b and 5c needed to be conducted
at ꢀ15 °C in order to ensure the high yields. Interestingly,
although 5c and 5d are very similar, 5d is more reactive
than 5c, probably because the sulfur is bulkier than the
oxygen. The asymmetric direct aldol reaction catalyzed
by 4d tolerates a wide scope of donors, which will enhance
its utility in organic synthesis.
CDCl3): d (ppm) 1.32 (m, 1H), 1.50–1.57 (m, 3H), 1.76
(m, 1H), 2.04 (m, 1H), 2.32 (m, 2H), 2.58 (m, 1H), 4.06
(br s, 1H), 4.85 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 8.7 Hz,
2H), 8.16 (d, J = 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d (ppm) 24.606, 27.576, 30.679, 42.601, 57.105, 73.908,
123.488, 126.557, 127.819, 148.345, 214.696; Enantiomeric
excess: 99%, determined by HPLC (Daicel Chiralpak OJ,
i-PrOH/hexane = 35:65), UV 254 nm, flow rate 1.0 mL/
min, tRmajor = 7.099 min; tRminor = 7.919 min.
4.3.2. 2-[Hydroxy-(2-nitro-phenyl)-methyl]-cyclohexanone
1
7ab. Yield: 72%; anti/syn: = 99:1; anti-diastereomer, H
NMR (300 MHz, CDCl3): d (ppm) 1.59–1.74 (m, 5H),
2.03 (m, 1H), 2.31 (m, 2H), 2.72 (m, 1H), 3.75 (br s, 1H),
5.42 (d, J = 7.1 Hz, 1H), 7.41 (m, 1H), 7.62 (m, 1H), 7.74
(m, 1H), 7.81 (m, 1H); 13C NMR (75 MHz, CDCl3): d
(ppm) 24.916, 27.705, 31.050, 42.766, 57.255, 69.692,
124.020, 128.354, 128.962, 133.019, 136.546, 148.692,
214.880; Enantiomeric excess: 99% determined by HPLC
(Daicel Chiralpak OJ, i-PrOH/hexane = 5:95), UV
254 nm, flow rate 1.0 mL/min, tRminor = 19.38 min;
tRmajor = 21.07 min.
3. Conclusion
In conclusion, we have discovered an organocatalyst 4d,
which catalyzes the direct aldol reactions of cycloketones
with a wide range of aldehydes in high yields and with
excellent diastereo- and enantioselectivities. The organo-
catalyst is unique in that it can effectively catalyze the direct
aldol reactions of cycloketones with both aromatic and
aliphatic aldehydes. Catalyst 4d seems more efficient than
those reported previously since as little as 5 mol % 4d is
enough to efficiently catalyze the direct aldol reaction.
4.3.3.
2-[Hydroxy-phenyl-methyl]-cyclohexanone
7ac.
¼
20
Yield: 49%; anti/syn: = 97:3, anti-diastereomer, ½aꢁD
1
ꢀ5:8 (c 0.5, CH3CO2Et); H NMR (300 MHz, CDCl3): d
(ppm) 1.27–1.31 (m, 1H), 1.32–1.61 (m, 4H), 2.16 (m,
1H), 2.45–2.66 (m, 3H), 3.89 (br s, 1H), 4.76 (d,
J = 8.8 Hz, 1H), 7.26–7.37 (m, 5H); 13C NMR (75 MHz,
CDCl3): d (ppm) 24.702, 27.781, 30.822, 42.654, 57.407,
74.731, 127.00, 127.873, 128.353, 140.902, 215.538;
Enantiomeric excess: 98% determined by HPLC (Daicel
Chiralpak OJ, i-PrOH/hexane = 10:90), UV 254 nm, flow
rate 1.0 mL/min, tRmajor = 9.429 min; tRminor = 11.658 min.
4. Experimental
4.1. General
NMR spectra were recorded on a Brucker-300 MHz spec-
trometer. Optical rotations were measured on a Perkin–
Elmer 241 Polarimeter at 589 nm. HPLC analysis was
performed on Waters-Breeze (2487 Dual k Absorbance
Detector and 1525 Binary HPLC Pump). Chiralpak AS,
AD, OD and OJ columns were purchased from Daicel
Chemical Industries, LTD. Chiral GC analysis was
performed on VARIAN CP-3380 with a CP CHIPASIL-
DEX column.
4.3.4. 2-[Hydroxy-(4-cyano-phenyl)-methyl]-cyclohexanone
7ad. Yield: 80%; anti/syn: >99:1, anti-diastereomer,
20
½aꢁD ¼ ꢀ15:2 (c 0.5, CH3CO2Et); 1H NMR (300 MHz,
CDCl3): d (ppm) 1.32–1.63 (m, 5H), 2.08 (m, 1H), 2.34–
2.38 (m, 1H), 2.46–2.61 (m, 2H), 4.03 (d, J = 3.1 Hz,
1H), 4.81 (dd, J = 3.1, 8.4 Hz, 1H); 7.42 (d, J = 8.1 Hz,
2H), 7.62 (d, J = 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d (ppm) 24.65, 27.61, 30.70, 42.63, 57.10, 74.19, 111.67,
118.67, 127.74, 132.15, 146.33, 214.81; Enantiomeric
excess: 98%, determined by HPLC (Daicel Chiralpak
OD, i-PrOH/hexane = 10:90), UV 254 nm, flow rate
1.0 mL/min, tRmajor = 15.975 min; tRminor = 22.525 min.
4.2. Materials
All starting materials were purchased from Acros and used
directly.
4.3. General procedure for aldol reaction
To a solution of the aldehyde (0.5 mmol) and cycloketone
(1.0 mL) in anhydrous CH2Cl2 (2 mL), L-prolinamide 4d
(11 mg, 0.025 mmol) was added. The resulting mixture
was stirred at ꢀ40 °C for 72–96 h. The reaction mixture
was then treated with saturated ammonium chloride solu-
tion, and the layers were separated. The aqueous layer
was extracted with ethyl acetate, and dried over anhydrous
MgSO4. After removal of solvent, the residue was purified
through flash column chromatography on silica gel to give
the corresponding aldol products.
4.3.5. 2-[Hydroxy-(4-trifluoro-phenyl)-methyl]-cyclohexa-
none 7ae. Yield: 88%; anti/syn: >99:1 anti-diastereomer,
20
½aꢁD ¼ ꢀ13:8 (c 0.5, CH3CO2Et); 1H NMR (300 MHz,
CDCl3): d (ppm) 1.30 (m, 1H), 1.36–1.79 (m, 4H), 2.08
(m, 1H), 2.35 (m, 1H), 2.47 (m, 2H), 4.02 (d, J = 2.9 Hz,
1H), 4.82 (dd, J=2.9, 8.6 Hz, 1H), 7.43 (d, J = 8.1 Hz,
2H), 7.59 (d, J = 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d (ppm) 24.70, 27.69, 30.75, 42.67, 57.25, 74.17, 124.1
(J = 270 Hz), 125.28 (J = 3.4 Hz), 127.36, 130.06
(J = 32 Hz), 144.95, 215.12; IR (KBr) 3359, 2946, 2931,
2865, 1690, 1617, 1449, 1416, 1312, 1285, 844 cmꢀ1; Enan-
tiomeric excess: 97% determined by HPLC (Daicel Chir-
alpak OD, i-PrOH/hexane = 10:90), UV 254 nm, flow
rate 1.0 mL/min, tRminor = 8.161 min; tRmajor = 9.770 min.
4.3.1. 2-[Hydroxy-(4-nitro-phenyl)-methyl]-cyclohexanone
7aa. Yield: 95%; anti/syn: >99:1, anti-diastereomer,
20
½aꢁD ¼ ꢀ26:2 (c 0.5, CH3CO2Et); 1H NMR (300 MHz,

L. He et al. / Tetrahedron: Asymmetry 18 (2007) 265–270
269
4.3.6. 2-[Hydroxy-(2-fluoro-phenyl)-methyl]-cyclohexanone
7af. Yield: 92%; anti/syn: = 97:3 anti-diastereomer,
2.38–2.45 (m, 1H), 2.60 (m, 1H), 3.93 (br s, 1H), 4.73 (d,
J = 8.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 4H); 7.19 (d,
J = 8.0 Hz, 4H); 13C NMR (75 MHz, CDCl3): d (ppm)
21.120, 24.68, 27.794, 30.836, 42.635, 57.389, 74.492,
126.887, 129.015, 137.519, 137.903, 215.673; Enantiomeric
excess: 99% determined by HPLC (Daicel Chiralpak AS,
i-PrOH/hexane = 30:70), UV 254 nm, flow rate: 1.0 mL/
min, tRmajor = 6.137 min; tRminor = 7.047 min.
20
½aꢁD ¼ ꢀ14:2 (c 0.5, CH3CO2Et); 1H NMR (300 MHz,
CDCl3): d (ppm) 1.44–1.65 (m, 4H), 1.77 (m, 1H), 2.10
(m, 1H), 2.32 (m, 2H), 2.66 (m, 1H), 3.99 (d, J = 3.2 Hz,
1H), 5.14 (dd, J = 2.9, 8.6 Hz, 1H), 6.96–7.02 (m, 1H),
7.14–7.17 (m, 1H), 7.23–7.26 (m, 1H), 7.46 (m, 1H); 13C
NMR (75 MHz, CDCl3): d (ppm) 24.63, 27.68, 30.21,
42.52, 56.99, 67.94, 114.91 (J = 2.2 Hz), 124.35
(J = 2.9 Hz), 128.22 (J = 3.9 Hz), 129.05 (J = 8.2 Hz),
158.40, 161.65, 215.18; IR (neat) 3512, 2940, 2862, 1698,
1617, 1587, 1492, 1452, 1222, 824, 757; Enantiomeric
excess: >99% determined by HPLC (Daicel Chiralpak
OD, i-PrOH/hexane = 10:90), UV 254 nm, flow rate
1.0 mL/min, tRminor = 6.557 min; tRmajor = 8.106 min.
4.3.11. 2-[Hydroxy-isopropyl-methyl]-cyclohexanone 7ak.
20
Yield: 38%; anti/syn: >99:1; anti-diastereomer, ½aꢁD
¼
1
ꢀ1:2 (c 0.5, CH3CO2Et); H NMR (300 MHz, CDCl3): d
(ppm) 0.85–0.94 (m, 3H), 1.62–2.04 (m, 5H), 2.30 (m,
2H), 2.34–2.42 (m, 3H), 3.14 (br s, 1H), 3.48 (dd, J = 3.9,
7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d (ppm)
15.102, 20.043, 24.870, 26.759, 29.090, 30.570, 42.825,
53.565, 75.571, 216.069; IR (Neat): 3541, 2957, 2953,
2870, 1695, 1616, 1398, 1129, 993 cmꢀ1; Enantiomeric
excess: >99%, determined by chiral GC analysis (CP
CHIRASIL-DEX), Inject Temp 240 °C, Column Temp
100 °C, FID Oven Temp 260 °C, Inlet Pressure 13Psi,
tRmajor = 20.535 min; tRminor = 21.077 min.
4.3.7. 2-[Hydroxy-(2,6-2-chloro-phenyl)-methyl]-cyclohexa-
none 7ag. Yield: 91%; anti/syn: >99:1; anti-diastereomer,
20
½aꢁD ¼ ꢀ80:2 (c 0.5, CH3CO2Et); 1H NMR (300 MHz,
CDCl3): d (ppm) 1.24–1.68 (m, 4H), 1.71 (m, 1H), 2.03
(m, 1H), 2.38–2.49 (m, 2H), 3.47 (m, 1H), 3.65 (d,
J = 4.2 Hz, 1H), 5.80 (dd, J1 = 4.2 Hz, J2 = 9.6 Hz, 1H),
7.11–7.31 (m, 3H), 13C NMR (75 MHz, CDCl3): d (ppm)
24.655, 27.583, 29.822, 42.403, 53.610, 70.541, 129.302,
134.685, 135.650, 214.364; IR (neat): 3564, 3060, 2964,
2937, 2861, 1695, 1560, 1438, 1131, 794, 762 cmꢀ1; Enan-
tiomeric excess: >99%, determined by HPLC (Daicel Chir-
alpak OJ, i-PrOH/hexane = 5:95), UV 254 nm, flow rate:
1.0 mL/min, tRminor = 9.14 min; tRmajor = 10.30 min.
4.3.12. 2-[Hydroxy-cyclohexyl-methyl]-cyclohexanone 7al.
20
Yield: 40%; anti/syn: >99:1; anti-diastereomer, ½aꢁD
¼
1
ꢀ48 (c 0.5, CH3CO2Et); H NMR (300 MHz, CDCl3): d
(ppm) 1.14–1.68 (m, 14H), 1.73 (m, 1H), 1.75 (m, 2H),
2.35 (m, 2H), 2.49 (m, 1H), 3.26 (br s, 1H), 3.45 (dd,
J = 3.6, 7.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d
(ppm) 24.967, 25.892, 26.253, 26.376, 26.549, 27.822,
30.308, 30.814, 39.409, 42.936, 52.823, 75.604, 216.210;
IR (Neat): 3541, 2927, 2853, 1696, 1448, 1129 cmꢀ1; Enan-
tiomeric excess: 99% determined by HPLC (Daicel Chir-
alpak AD, i-PrOH/hexane = 15:85), UV 280 nm, flow
rate 1.0 mL/min, tRmajor = 4.47 min; tRminor = 5.62 min.
4.3.8. 2-[Hydroxy-(4-chloro-phenyl)-methyl]-cyclohexanone
7ah. Yield: 71%; anti/syn: = 98:2 anti-diastereomer,
20
½aꢁD ¼ ꢀ5:0 (c 0.5, CH3CO2Et); 1H NMR (300 MHz,
CDCl3): d (ppm) 1.26–1.31 (m, 1H), 1.31–1.64 (m, 5H),
2.06 (m, 1H), 2.45–2.55 (m, 3H), 3.98 (d, J = 2.7 Hz,
1H), 4.74 (dd, J = 2.7, 8.7 Hz, 1H), 7.23 (d, J = 8.4 Hz,
2H), 7.30 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d (ppm) 24.695, 27.701, 30.738, 42.647, 57.352, 74.122,
128.368, 128.520, 133.569, 139.490, 215.2; Enantiomeric
excess: 98% determined by HPLC (Daicel Chiralpak OJ,
i-PrOH/hexane = 5:95), UV 254 nm, flow rate 1.0 mL/
min, tRmajor = 10.892 min; tRminor = 12.615 min.
4.3.13. 7-[Hydroxy-(4-nitro-phenyl)-methyl]-1,4-dioxa-spiro-
[4.5]decan-8-one 7ba. Yield: 90%; anti/syn: = 98:2; anti-
20
1
diastereomer, ½aꢁD ¼ ꢀ2:8 (c 0.5, CH3CO2Et); H NMR
(300 MHz, CDCl3): d (ppm) 1.48–1.52 (m, 1H), 1.69–1.74
(m, 1H), 1.78–2.04 (m, 2H), 2.47 (m, 1H), 2.71 (m, 1H),
2.98 (m, 1H), 3.86–3.96 (m, 4H), 4.03 (d, J = 3.1 Hz,
1H), 4.90 (dd, J = 3.1, 8.1 Hz, 1H), 7.48 (d, J = 8.4 Hz,
2H), 8.19 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d (ppm) 34.287, 37.750, 38.760, 52.918, 64.627, 73.731,
106.720, 123.552, 126.491, 127.836, 147.853, 213.132;
Enantiomeric excess: 94%, determined by HPLC (Daicel
Chiralpak AS, i-PrOH/hexane = 30:70), UV 254 nm, flow
rate 1.0 mL/min, tRminor = 12.21 min; tRmajor = 17.87 min.
4.3.9. 2-[Hydroxy-(4-bromo-phenyl)-methyl]-cyclohexanone
7ai. Yield: 60%; anti/syn: >99:1, anti-diastereomer,
20
½aꢁD ¼ ꢀ5:0 (c 0.5, CH3CO2Et); 1H NMR (300 MHz,
CDCl3): d (ppm) 1.25–1.64 (m, 4H), 1.78 (m, 1H), 2.04
(m, 1H), 2.33–2.38 (m, 1H), 2.48–2.55 (m, 2H), 3.97 (d,
J = 2.8 Hz, 1H), 4.73 (dd, J = 2.7, 8.6 Hz, 1H), 7.18 (d,
J = 8.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3):
d (ppm) 24.699, 27.698, 30.741,
42.646, 57.314, 74.181, 121.707, 128.724, 131.477,
140.017, 215.223; Enantiomeric excess: 96% determined
by HPLC (Daicel Chiralpak OJ, i-PrOH/hexane = 5:95),
UV 254 nm, flow rate 1.0 mL/min, tRmajor = 11.857 min;
tRminor = 13.832 min.
4.3.14. 3-[Hydroxyl-(4-nitro-phenyl)-methyl]-tetrahydrothio-
pyran-4-one 7ca. Yield: 82%; anti/syn: = 98:2; anti-diaste-
20
reomer, ½aꢁD ¼ ꢀ56 (c 0.5, CH3CO2Et); 1H NMR
(300 MHz, CDCl3): d (ppm) 1.36–1.39 (m, 1H), 1.40–1.57
(m, 1H), 1.81–1.85 (m, 1H), 2.09 (m, 1H), 2.35–2.39 (m,
1H), 2.48–2.59 (m, 2H), 4.06 (d, J = 3.1 Hz, 1H), 4.87
(dd, J = 3.1, 8.3 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 8.19
(d, J = 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3): d
(ppm) 30.807, 32.814, 44.755, 59.450, 73.186, 123.803,
127.775, 147.597, 147.736, 211.256; Enantiomeric excess:
97%, determined by HPLC (Daicel Chiralpak AS,
4.3.10.
2-[Hydroxy-(4-methyl-phenyl)-methyl]-cyclohexa-
none 7aj. Yield: 42%; anti/syn: >99:1; anti-diastereomer,
20
½aꢁD ¼ ꢀ3:8 (c 0.5, CH3CO2Et); 1H NMR (300 MHz,
CDCl3): d (ppm) 1.25–1.30 (m, 1H), 1.51–1.75 (m, 4H),
2.05 (m, 1H), 2.33–2.36 (m, 3H), 2.36–2.38 (m, 1H),

270
L. He et al. / Tetrahedron: Asymmetry 18 (2007) 265–270
Angew. Chem., Int. Ed. 2003, 42, 2785; (j) Northrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 2152; (k) Casas, J.; Engqvist, M.;
i-PrOH/hexane = 30:70), UV 254 nm, flow rate 1.0 mL/
min, tRmajor = 16.012 min, tRminor = 21.637 min.
´
Ibrahem, I.; Kaynak, B.; Cordova, A. Angew. Chem., Int. Ed.
4.3.15. 2-[Hydroxy-(4-nitro-phenyl)-methyl]-tetrahydro-4-
H-pyran-4-one 7da. Yield: 90%; anti/syn: = 96:4; anti-dia-
2005, 44, 1343; (l) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.;
Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2006, 28, 734–735; (m) Hayashi, Y.; Yamaguchi, J.; Hibino,
K.; Sumiya, T.; Urushima, T.; Shoji, M.; Hashizume, D.;
Koshino, H. Adv. Synth. Catal. 2004, 346, 1435; (n) Hayashi,
Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.;
Shoji, M. Angew. Chem., Int. Ed 2006, 45, 958; (o) Rodrıguez,
B.; Rantanen, T.; Bolm, C. Angew. Chem., Int. Ed. 2006, 45,
6924.
20
stereomer, ½aꢁD ¼ ꢀ56:4 (c 0.5, CH3CO2Et); 1H NMR
(300 MHz, CDCl3): d (ppm) 2.50–2.54 (m, 1H), 2.66–2.69
(m, 1H), 2.88–2.90 (m, 1H), 3.42–3.49 (t, J = 9.9 Hz, 1H),
3.70–3.83 (m, 3H), 4.20 (m, 1H), 4.96 (dd, J = 3.3,
8.1 Hz, 1H); 7.50 (d, J = 8.7 Hz, 2H), 8.21 (d, J = 8.7 Hz,
2H); 13C NMR (75 MHz, CDCl3): d (ppm) 42.860,
57.219, 68.342, 69.773, 71.328, 123.848, 127.073, 147.368,
127.448, 209.224; IR (neat): 3529, 3105, 2981, 2879, 2844,
1700, 1516, 1348, 1276, 1215, 1098, 1055, 863 cmꢀ1; Enan-
tiomeric excess: 97%, determined by HPLC (Daicel Chir-
alpak AS, i-PrOH/hexane = 30:70), UV 254 nm, flow rate
1.0 mL/min, tRmajor = 16.134 min; tRminor = 20.919 min.
´
3. (a) Hartikaa, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
2004, 15, 1831; (b) Torii, H.; Nakadai, M.; Ishihara, K.;
Saito, S.; Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43,
1983; (c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37,
570.
4. (a) Martin, H. J.; List, B. Synlett 2003, 1901; (b) Kofoed, J.;
Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003,
13, 2445.
5. (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi,
A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125,
5262; (b) 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, 5755.
Acknowledgment
We are grateful for the financial support from National
Natural Science Foundation of China.
6. 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, 9285.
7. (a) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004,
346, 1141; (b) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D.
A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
8. (a) Saito, S.; Bunya, N.; Inaba, M.; Moriwake, T.; Torii, S.
Tetrahedron Lett. 1985, 26, 5309; (b) Tong, P.-E.; Li, P.;
Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 2301.
9. (a) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.;
Xiao, W.-J. Org. Lett. 2005, 7, 4543–4545; (b) Samanta, S.;
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