The application of a structurally simple, recyclable, and large-scale l-prolinamide catalyst for asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tetasy.2014.04.009

A highly efficient, bifunctional prolinamide catalyst, which consists of chiral proline and trans-cyclohexanediamine moieties, was prepared and evaluated in the direct asymmetric aldol reactions of various ketones and aldehydes. The catalyst displayed imp

Full text of DOI:10.1016/j.tetasy.2014.04.009

Tetrahedron: Asymmetry 25 (2014) 802–812
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The application of a structurally simple, recyclable, and large-scale
L-prolinamide catalyst for asymmetric aldol reactions
a
a
b
a
Zhi Guan a, , Yuan Luo , Bao-Qiang Zhang , Krystal Heinen , Da-Cheng Yang ,
⇑
Yan-Hong He a,
⇑
a School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
b Department of Chemistry, College of Saint Benedict and Saint John’s University, MN 56374, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient, bifunctional prolinamide catalyst, which consists of chiral proline and trans-cyclohex-
anediamine moieties, was prepared and evaluated in the direct asymmetric aldol reactions of various
ketones and aldehydes. The catalyst displayed impressive catalytic activity toward heterocyclic ketones
containing oxygen, sulfur, or nitrogen, which have not been sufficiently explored. The substrate scope
also covered cyclic and acyclic ketones. With heterocyclic ketones or cyclohexanone, the aldol reactions
gave products in high yields and with respectable enantioselectivities (87–99% ee) and diastereoselectiv-
ities (up to >99:1 anti/syn). The catalyst could be recycled and reused up to seven times resulting in good
yields and with good selectivities. This catalyst is also efficient in large-scale reactions with the enanti-
oselectivities remaining at the same level as in the experimental scale reactions.
Received 18 February 2014
Accepted 7 April 2014
Available online 28 May 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
chain secondary amines, primary amines, diamines, and triamines
in the molecules.4a,6c,7 Some experimental results have demon-
In recent years, chiral organocatalysts have emerged as power-
ful tools for asymmetric synthesis.1 The organocatalytic aldol reac-
tion is an important CAC bond formation reaction with high
enantioselectivity and diastereoselectivity.2 Since List et al.
strated that there are correlations between the acidity of the
NAH bonds and the hydrogen-bonding modes with the catalytic
activities and enantioselectivities of the catalysts.8 More impor-
tantly, the acidity of the NAH, the steric hindrance effect, the elec-
tronic effect, and the strength and number of hydrogen bonds of
the prolinamides are also tunable by changing R1 and R2.9 In addi-
tion, the cyclohexanediamine unit can be replaced by a chiral
1,2-diphenylethylenediamine or an achiral o-phenylenediamine,
which makes the structure of the prolinamides more changeable
in order to catalyze different types of reactions.7a Therefore, the
prolinamides consisting of chiral proline and trans-cyclohexanedi-
amine moieties are expected to be versatile catalysts for asymmet-
ric synthesis.
In an effort to search for new and highly effective prolinamide
catalysts, we have investigated the application of prolinamides in
aldol reactions.10 Although there are numerous reports regarding
organocatalyzed aldol reactions,11 in most reports the use of het-
erocyclic ketones as aldol donors are only listed as one or two
examples. The studies that mainly focus on enantioselective aldol
reactions of heterocyclic ketones are relatively few. Pihko et al.
described asymmetric direct aldol reactions catalyzed by L-proline
in 2000,3 a large number of chemists have directed their efforts
toward identifying new types of chiral enamine catalysts.4 Despite
the variety of aldol acceptors reported, the range of donors has
remained narrow.5 Protocols for enantioselective aldol reactions
of heterocyclic ketones with aldehydes have been especially
limited.6
Both chiral proline and trans-cyclohexanediamine derivatives
have been widely exploited as sources of chirality in many organic
chemistry processes.1b,4b,6c The prolinamides consisting of chiral
proline and trans-cyclohexanediamine moieties are interesting
molecules that can serve as bifunctional organocatalysts
(Scheme 1), and which contain three stereogenic centers with
the structures being reasonably flexible. They can be easily con-
verted into free 1°, 2°, or 3° amines (R1 = R2 = H; R1 or R2 = H; R1,
R2 = alkyl), amides, ureas, sulfonamides, or thioureas, while they
can also contain the structural units of cyclic secondary amines,
reported on the L-proline catalyzed aldol reactions of heterocyclic
ketones, but the desired products were obtained in low yields after
many days (72–216 h).6b Xiao et al. described the prolinamide
catalyzed enantioselective aldol reactions of heterocyclic ketones
⇑
Corresponding authors. Tel./fax: +86 23 68254091.
E-mail addresses: guanzhi@swu.edu.cn (Z. Guan), heyh@swu.edu.cn (Y.-H. He).
http://dx.doi.org/10.1016/j.tetasy.2014.04.009
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
803
O
OCH3
OCH3
OCH3
O
C
1a: R1, R2
=
R
1 = H, R2
=
1e:
(Ref: 10)
R1
N
R2
H
O
N
O
C
H
N
O
O
R1, R2
=
1b:
R
1 = H, R2
=
C
1f:
(Ref: 10)
(Ref: 10)
(Ref: 9)
C
O
(Ref: 9)
O
C
O
R1 = H, R2
=
CF3
O
1g:
R1 = H, R2
=
=
C
1c:
1d:
(Ref: 6a)
(Ref: 6a)
N
H
Ph
O
Ph
N
O
S
R1 = H, R2
N
1h:
H
H
O
NH
Scheme 1. Structures of some prolinamides.
O
O
OH
1f
R
O
OH
O
OH
R
R
R
O
OH
O
O
O
1g
1e
R
+
R
H
X
N
O
N
OH
OH
Boc
R
O
OH
O
O
OH
S
1h
Boc
R
R
S
Xiao's work6a
Scheme 2. The aldol reactions catalyzed by prolinamides.
This work
with excellent yields and enantioselectivities as shown in
Scheme 2.6a However, in consideration of the fact that the range
of aldol donors has remained narrow, the development of highly
efficient catalysts with a broad range of substrates for enantiose-
lective aldol reactions of heterocyclic ketones is still desired.
Herein we report the catalytic behavior of catalyst 1e on the aldol
seen from the summarized results shown in Table 1, all of the cat-
alysts catalyzed the model asymmetric aldol reaction giving the
desired product in moderate to good yields (71–91%) and with
Table 1
The aldol reaction catalyzed by L-prolinamide derivativesa
reactions with
a wide substrate scope covering heterocyclic
CHO
O
OH
O
ketones, cyclic and acyclic ketones (Scheme 2). Catalyst 1e is struc-
turally simple and can be readily prepared from inexpensive start-
ing materials, chiral proline and trans-cyclohexanediamine.
Another notable advantage of this novel catalyst is that it can be
easily recovered and reused, and it is also efficient in large-scale
reactions.
catalyst
+
(20 mol%)
O
NO2
O
THF
NO2
2
3
4c
Entry
Catalyst
Time (h)
Yieldb (%)
drc (anti:syn)
eec (%)
2. Results and discussion
1
2
3
4
1a
1b
1c
1d
1e
1e
58
58
58
50
48
35
84
91
71
90
87
88
50:50
55:45
50:50
72:28
76:24
93:7
50
47
65
62
68
88
All of the catalysts 1a–1e tested (Scheme 1) were easily pre-
pared from available materials by following the literatures in high
yields.10,12 The organocatalyzed aldol reaction was carried out
using 4-nitrobenzaldehyde 2 and tetrahydro-4H-pyran-4-one 3
5
6d
a
The reaction was carried out using 4-nitrobenzaldehyde (0.25 mmol, 1 equiv),
tetrahydro-4H-pyran-4-one (5 equiv), and catalyst (20 mol %) in THF (1.0 mL) at rt.
as
a model reaction in order to investigate the different
parameters, such as the catalysts, the stoichiometry of the reac-
tants, the loading of the catalysts and the temperature. In our
initial investigation, 1a–1e were screened as catalysts. As can be
b
Isolated yield after silica gel chromatography.
Determined by chiral HPLC analysis (AD-H) for the anti-isomer.1b
c
d
1e (20 mol %), HOAc (20 mol %) in THF (1.0 mL) at ꢀ20 °C.

804
Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
47–68% ee for the anti-isomer in THF at 25 °C (Table 1, entries 1–5).
The best enantioselectivity of 68% ee and diastereoselectivity of
76:24 (anti/syn) were achieved using 1e, while 1a and 1b showed
lower enantioselectivities (50% and 47% ee, respectively, Table 1,
entries 1 and 2), thus suggesting that the double hydrogen bonds
on the cyclohexanediamine moiety play an important role in con-
trolling the enantioselectivity. The model reaction could be accel-
erated by adding HOAc. In the presence of HOAc, the reaction at
ꢀ20 °C proceeded faster than the reaction without HOAc at rt
(Table 1, entry 6). Therefore, we chose 1e as a catalyst for the aldol
reaction with HOAc as an additive.
Different solvents were then screened for the model reaction
catalyzed by 1e at ꢀ20 °C (Table 2). When DCM, MeCN, CHCl3,
and toluene were used as solvents, the reaction gave the product
in good yields and with good selectivities (Table 2, entries 1–4).
The reactions in THF, DMF, and EtOH (Table 2, entries 5–7) gave
enantioselectivities slightly less than the results obtained in the
solvents mentioned above. A low yield, with moderate selectivity,
was obtained in water at 10 °C (Table 2, entry 8). The reaction in
dioxane at 25 °C gave the product in high yield but with low selec-
tivity (Table 2, entry 9). In view of both the yield and stereoselec-
tivity, DCM was chosen as the solvent for the aldol reaction. We
next investigated the reaction at 25, 0, ꢀ10, ꢀ20, and ꢀ40 °C in
DCM, respectively (Table 2, entries 1, 10–13). The results indicated
that the enantioselectivity and diastereoselectivity improved from
73% ee (77:23 dr) to 96% ee (97:3 dr) when the reaction tempera-
ture was lowered from 25 to ꢀ40 °C. However, the ee and dr at
ꢀ20 °C were almost the same as those at ꢀ40 °C. Thus, ꢀ20 °C
was selected as the temperature for the aldol reaction.
on the model aldol reaction was then investigated (Table 3, entries
3, 6–10). The reaction could be accelerated by increasing the
amount of ketone from 1 to 6 equiv, but the dr and ee values did
not significantly improve. The aldol product could be obtained in
high yield with excellent stereoselectivity when using 5 equiva-
lents of ketone. Hence the 1:5 molar ratio of 4-nitrobenzaldehyde
to tetrahydro-4H-pyran-4-one was chosen for further investiga-
tion. Moreover, the volume of the solvent also impacted the reac-
tion. The reaction in 0.5 mL of DCM gave an excellent yield of
99% with high stereoselectivity after 12 h (Table 3, entry 11), which
was better than the reaction in 1 mL of DCM (Table 3, entry 3).
Therefore, we used 0.5 mL of DCM for the aldol reaction of 4-nitro-
benzaldehyde (0.25 mmol) and tetrahydro-4H-pyran-4-one
(5 equiv).
Table 3
Effects of the catalyst loading and the molar ratio of the substrates on the aldol
reactiona
CHO
O
O
OH
O
1e (X mol%)
+
HOAc (X mol%)
NO2
O
DCM, -20 o
C
NO2
4c
3
2
Entry Ketone
(equiv)
1e
(mol %)
Time
(h)
Yieldb
(%)
drc
(anti:syn)
eec
(%)
1
2
3
4
5
6
7
8
5
5
5
5
5
1
2
3
4
6
5
2
5
30
30
30
24
20
20
20
20
20
20
12
76
82
96
96
99
72
80
85
90
96
99
96:4
98:2
97:3
96:4
97:3
95:5
95:5
96:4
96:4
96:4
97:3
94
94
95
95
96
93
94
94
94
95
96
10
15
20
10
10
10
10
10
10
Table 2
Solvent screeninga
CHO
O
O
OH
O
O
1e (20 mol%)
+
9
HOAc (20 mol%)
NO2
10
11d
NO2
2
3
4c
a
The reaction was carried out using 4-nitrobenzaldehyde (0.25 mmol, 1 equiv),
tetrahydro-4H-pyran-4-one (1-6 equiv), 1e (X mol %), and HOAc (X mol %) in DCM
(1.0 mL) at ꢀ20 °C.
Entry Solvent
Temp (°C)
Time (h) Yieldb (%)
drc
(anti:syn)
eec (%)
b
Isolated yield after silica gel chromatography.
c
Determined by chiral HPLC analysis (AD-H) for the anti-isomer.
The reaction was carried out in 0.5 mL of DCM.
1
DCM
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
10
30
35
35
35
35
35
35
35
35
40
24
24
12
96
92
90
91
88
91
97
60
98
96
95
98
99
95:5
94:6
95:5
96:4
93:7
95:5
93:7
80:20
73:27
97:3
90:10
84:16
77:23
95
93
92
92
88
87
85
75
60
96
92
86
73
d
2
3
4
5
MeCN
CHCl3
toluene
THF
With the optimized conditions in hand, the reactions of various
aromatic or aliphatic aldehydes with heterocyclic ketones were
studied in order to test the substrate scope and the generality of
the aldol reaction. The results are summarized in Tables 4–6. As
demonstrated, catalyst 1e showed versatile catalytic activity for
the aldol reactions. Different heterocyclic ketones containing oxy-
gen, sulfur, or nitrogen effectively participated in the reaction with
a wide range of aromatic or heteroaromatic aldehydes. The reac-
tions of heterocyclic ketones tetrahydro-4H-pyran-4-one 3, tetra-
6
DMF
7
8
EtOH
H2O
9
Dioxane
DCM
DCM
DCM
DCM
25
10
11
12
13
ꢀ40
ꢀ10
0
25
a
The reaction was carried out using 4-nitrobenzaldehyde (0.25 mmol, 1 equiv),
tetrahydro-4H-pyran-4-one (5 equiv), 1e (20 mol %), and HOAc (20 mol %) in a
solvent (1.0 mL).
hydro-4H-thiopyran-4-one 5, and 1-Boc-4-piperidone
7 with
various aromatic aldehydes provided the corresponding products
in good yields of 70–99% and with excellent enantioselectivities
(87–99% ee for the anti-isomers) and good diastereoselectivities
(anti/syn 87:13–99:1) within 12–35 h (Table 4, entries 1–11;
Table 5, entries 1–10; Table 6, entries 1–8). Aromatic aldehydes
bearing either electro-withdrawing or electron-donating groups
also reacted efficiently. Moreover, the heteroaromatic aldehydes
2-furaldehyde and 2-thiophenecarboxaldehyde could also be used
as acceptors, and gave products in acceptable yields with good
selectivities after 48 h when reacting with tetrahydro-4H-pyran-
4-one 3 (Table 4, entries 12 and 13). It should be noted that in
b
Isolated yield after silica gel chromatography.
Determined by chiral HPLC analysis (AD-H) for the anti-isomer.
c
We next investigated the effects of catalyst loading and the
molar ratio of substrates on the model aldol reaction in DCM at
ꢀ20 °C. The yield and the rate of the aldol reaction were clearly
improved upon when increasing the catalyst loading from 2 to
20 mol %, but no obvious improvement in the enantioselectivity
was observed (Table 3, entries 1–5). We chose 10 mol % as the opti-
mized catalyst loading. The effect of the molar ratio of substrates

Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
805
Table 4
Table 6
Scope of the organocatalyzed direct aldol reactions of various aromatic aldehydes
Scope of the organocatalyzed direct aldol reactions of various aromatic aldehydes
with tetrahydro-4H-pyran-4-onea
with 1-Boc-4-piperidonea
O
O
OH
O
OH
O
O
O
1e
(10 mol%)
1e
R
(10 mol%)
R
+
+
H
R
H
R
HOAc (10 mol%)
DCM, -20 o
HOAc (10 mol%)
DCM, -20 oC
O
O
N
N
Boc
C
Boc
2
4a-m
3
2
7
8a-h
Entry
R
No. Time (h) Yieldb (%) drc (anti:syn) eec (%)
Entry
R
No. Time (h) Yieldb (%) drc (anti:syn) eec (%)
1
2
3
4
5
6
7
8
2-NO2C6H4– 4a
3-NO2C6H4– 4b
4-NO2C6H4– 4c
18
15
12
18
25
30
25
30
25
30
30
48
48
99
92
96
99
83
82
91
88
72
71
83
65
78
91:9
92:8
97:3
94:6
89:11
99:1
92:8
95:5
98:2
97:3
91:9
91:9
87:13
96
96
96
93
92
93
92
94
93
93
87
88
90
1
2
3
4
5
6
7
8
2-NO2C6H4– 8a
3-NO2C6H4– 8b
4-NO2C6H4– 8c
4-FC6H4–
4-ClC6H4–
2-ClC6H4–
4-BrC6H4–
3-BrC6H4–
18
18
18
35
35
35
35
35
87
94
90
99
82
71
90
95
92:8
92:8
92:8
89:11
95:5
>99:1
95:5
93
92
92
4-CNC6H4–
4-ClC6H4–
2-ClC6H4–
4-BrC6H4–
3-BrC6H4–
4-FC6H4–
4-CH3C6H4–
C6H5–
4d
4e
4f
4g
4h
4i
4j
4k
4l
8d
8e
8f
8g
8h
89
>99
>99
93
9
92:8
91
10
11
12
13
a
The reaction was carried out using aldehyde (0.25 mmol, 1 equiv) and 1-Boc-4-
piperidone (5 equiv), 1e (10 mol %), and HOAc (10 mol %) in DCM (0.5 mL) at
ꢀ20 °C.
2-Furyl–
2-Thienyl–
4m
b
Isolated yield after silica gel chromatography.
a
c
The reaction was carried out using aldehyde (0.25 mmol, 1 equiv), tetrahydro-
Determined by chiral HPLC analysis (AD-H, AS-H, OD-H, OJ-H) for the anti-
4H-pyran-4-one (5 equiv), 1e (10 mol %), and HOAc (10 mol %) in DCM (0.5 mL) at
ꢀ20 °C.
isomer.
b
Isolated yield after silica gel chromatography.
c
Determined by chiral HPLC analysis (AD-H, AS-H, OD-H, OJ-H), for the anti-
Under the optimized conditions, all of the reactions of cyclohexa-
none with aromatic aldehydes bearing either electron-withdraw-
ing or electron-donating groups provided the corresponding
products in good to excellent yields of 85–99% with excellent dia-
stereoselectivities (dr from 91:9 to 98:2, anti:syn) and excellent
enantioselectivities (93–96% ee for anti-isomers) (Table 7, entries
1–10). When cyclopentanone was used to react with 4-nitrobenz-
aldehyde, the product was obtained in a high yield of 99% but with
a low dr of 46:54 (anti/syn) and a reversed enantioselectivity (a
good ee of 97% for the syn-isomer; a low ee of 24% for the anti-
isomer) (Table 7, entry 11). In addition, acyclic ketones could also
be used as aldol donors. When reacting with 4-nitrobenzaldehyde,
acetone showed a high reactivity to give the product in an excel-
lent yield of 99% after only 18 h (Table 7, entry 12), while penta-
isomer.
Table 5
Scope of the organocatalyzed direct aldol reactions of various aromatic aldehydes
with tetrahydro-4H-thiopyran-4-onea
O
O
OH
O
1e
R
(10 mol%)
+
H
R
HOAc (10 mol%)
DCM, -20 oC
S
S
5
2
6a-k
Entry
R
No. Time (h) Yieldb (%) drc (anti:syn) eec (%)
1
2
3
4
5
6
7
8
2-NO2C6H4–
3-NO2C6H4–
4-NO2C6H4–
4-CNC6H4–
4-FC6H4–
4-ClC6H4–
2-ClC6H4–
4-BrC6H4–
3-BrC6H4–
6a
6b
6c
6d
6e
6f
6g
6h
6i
18
18
18
18
18
20
30
18
30
35
120
92
99
92
95
70
82
80
92
87
99
48
98:2
98:2
98:2
98:2
93:7
99:1
>99:1
99:1
95:5
89:11
96:4
90
>99
96
>99
92
93
94
95
93
none exhibited low reactivity and gave the product in
a
moderate yield of 70% after 96 h (Table 7, entry 13). Lower selectiv-
ities were obtained with acyclic ketones in comparison with cyclic
ketones.
In order to verify that catalyst 1e could be reused, we performed
a recycling study of 1e in the aldol reaction between tetrahydro-
4H-pyran-4-one and 4-nitrobenzaldehyde (Table 8). Catalyst 1e
could easily be recycled through acid treatment of the reaction
mixture to turn it into a salt that dissolved in the aqueous phase,
and was followed by basification of the aqueous phase to recover
it. In each cycle, the same amounts of substrates were used, and
the recovered 1e retained its catalytic activity without further
purification. By prolonging the reaction time, a good yield of 80%
could be obtained after the seventh cycle while the selectivity
was almost unchanged (Table 8).
Finally, we performed large-scale asymmetric aldol reactions
with 7.5 mmol of aldehydes and 5 equiv of heterocyclic ketones.
The experiments could be easily carried out using the same proce-
dure as for the experimental scale reactions except that a catalyst
loading of 5 mol % was used instead of 10 mol %. As can be seen from
the results summarized in Table 9, delightfully, the yields and selec-
tivities remained at the same level as in the small-scale reactions.
9
10
2,4-Cl2C6H3– 6j
i-Pr 6k
92
90
11d
a
The reaction was carried out using aldehyde (0.25 mmol, 1 equiv), tetrahydro-
4H-thiopyran-4-one (5 equiv), 1e (10 mol %), and HOAc (10 mol %) in DCM (0.5 mL)
at ꢀ20 °C.
b
Isolated yield after silica gel chromatography.
Determined by chiral HPLC analysis (AD-H, AS-H, OD-H, OJ-H), for the anti-
c
isomer.
d
The reaction was carried out using aldehyde (0.5 mmol, 1 equiv), tetrahydro-
4H-thiopyran-4-one (5 equiv), 1e (20 mol %), and HOAc (20 mol %) in DCM (0.5 mL)
at ꢀ20 °C.
addition to aromatic and heteroaromatic aldehydes, the aliphatic
aldehyde isobutyraldehyde could be used in the reaction as well,
and provided the product in a yield of 48% with 96:4 dr and 90%
ee after reaction with tetrahydro-4H-thiopyran-4-one for 120 h
(Table 5, entry 11). In general, catalyst 1e displayed high catalytic
activity and selectivity for the aldol reactions of heterocyclic
ketones with various aldehydes.
3. Conclusion
In addition, we also used other cyclic and acyclic ketones as
aldol donors in order to examine the scope of catalyst 1e (Table 7).
In conclusion, a bifunctional prolinamide catalyst consisting of a
chiral proline and trans-cyclohexanediamine moieties have been

806
Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
Table 7
Scope of the organocatalyzed direct aldol reactions of various aromatic aldehydes with cyclic and acyclic ketonesa
O
OH
O
O
1e
(10 mol%)
HOAc (10 mol%)
DCM, -20 o
R1
R
R1
+
R2
10a-m
H
R
R2
C
9
2
Entry
R1R2
R
No.
Time (h)
Yieldb (%)
drc (anti:syn)
eec (%)
1
2
3
4
5
6
7
8
-(CH2)4–
-(CH2)4–
-(CH2)4–
-(CH2)4–
-(CH2)4–
-(CH2)4–
-(CH2)4–
-(CH2)4–
-(CH2)4–
-(CH2)4–
-(CH2)3–
-CH3, -H
-CH2CH3, -CH3
2-NO2C6H4–
3-NO2C6H4–
4-NO2C6H4–
4-CNC6H4–
2-CH3OC6H4–
3-CH3OC6H4–
4-CH3OC6H4–
4-ClC6H4–
4-BrC6H4–
4-FC6H4–
4-NO2C6H4–
4-NO2C6H4–
4-NO2C6H4–
10a
10b
10c
10d
10e
10f
10g
10h
10i
20
20
18
20
40
40
40
35
35
35
18
18
96
96
97
99
95
85
86
88
94
93
90
99
99
70
98:2
96:4
97:3
95:5
91:9
95:5
96:4
96:4
97:3
93:7
46:54
—
93
96
95
95
94
94
90
94
9
93
94
10
11
12
13
10j
10k
10l
24/97d
78
10m
44:56
87/89e
a
b
c
The reaction was carried out using aldehyde (0.25 mmol, 1 equiv), ketone (5 equiv), 1e (10 mol %), and HOAc (10 mol %) in DCM (0.5 mL) at ꢀ20 °C.
Isolated yield after silica gel chromatography.
Determined by chiral HPLC analysis (AD-H, AS-H, OD-H, OJ-H), for the anti-isomer unless otherwise noted.
24% ee (for the anti-isomer), 97% ee (for the syn-isomer).
d
e
87% ee (for the anti-isomer), 89% ee (for the syn-isomer).
Table 8
Recycling and reuse of catalyst 1ea
selectivities being maintained at the same level as in experimental
scale reactions.
CHO
O
O
O
OH
1e (5 mol%)
4. Experimental
4.1. General
+
HOAc (5 mol%)
DCM, -20 oC
NO2
O
NO2
2
4c
3
NMR data were obtained for 1H at 300 MHz, and for 13C at
75 MHz. Chemical shifts are reported in ppm from tetramethylsil-
ane with the solvent resonance as the internal standard in CDCl3
solution. In each case, the enantiomeric excess was determined
by chiral HPLC analysis on Chiralpak AD-H, AS-H or Chiralcel OD-
Cycle
Time (h)
Yieldb (%)
drc(anti:syn)
eec (%)
1
2
3
4
5
6
7
8
18
20
20
24
32
45
60
96
96
93
90
93
92
88
80
72
93:7
93:7
95:5
95:5
95:5
95:5
93:7
88:12
96
96
95
96
96
95
95
91
H, OJ-H in comparison with authentic racemates. All optical rota-
20
tions [
a
]
were obtained from a polarimeter (WZZ-2S 2SS).
D
High-resolution mass spectra were obtained by using ESI ioniza-
tion sources (Varian 7.0T FTICR-MS).
L
-proline and (1R,2R)-(ꢀ)-
1,2-cyclohexanediamine were obtained from commercial sources
and used directly without further purification. All the reactions
were monitored by thin-layer chromatography (TLC) with Haiyang
GF254 silica gel plates. Flash column chromatography was carried
out using 200–300 mesh silica gel at increased pressure.
a
The reaction was carried out using 4-nitrobenzaldehyde (2 mmol), tetrahydro-
4H-pyran-4-one (5 equiv), 1e (5 mol %), and HOAc (5 mol %) in DCM (4.0 mL) at
ꢀ20 °C.
b
Isolated yield after silica gel chromatography.
c
Determined by chiral HPLC analysis (AD-H) for the anti-isomer.
4.2. Preparation of the catalysts 1a–1d
developed for direct asymmetric aldol reactions. The catalyst is
structurally simple and can be easily prepared from readily avail-
able starting materials. The most notable advantages of this cata-
lyst is its high efficiency for a broad scope of substrates, it is easy
to recover, and that it can be efficiently scaled up. The catalyst dis-
played impressive catalytic activity toward enantioselective aldol
reactions of heterocyclic ketones, which have not been sufficiently
explored. The substrate scope also covered cyclic and acyclic
ketones. When tetrahydro-4H-pyran-4-one, tetrahydro-4H-thiopy-
ran-4-one, 1-Boc-4-piperidone, and cyclohexanone were used as
aldol donors, almost all of the desired products could be obtained
in high yields and with excellent diastereoselectivities (up to >99:1
dr) and enantioselectivities (87–99% ee). The catalyst could easily
be recovered and reused through simple acidification and basifica-
tion. The catalyst was also efficient in large-scale reactions with
Catalysts 1a–1d were prepared according to the literature.9,10
4.3. Preparation of catalyst 1e
Intermediate 11 was prepared according to the literature12 (see
Scheme 3).
4.3.1. Preparation of compound 1212
A solution of Boc-L-proline (2.15 g, 10 mmol) and Et3N (1.15 g,
11 mmol) in dry DCM (50 mL) was stirred at 0 °C under argon.
Ethyl chloroformate (1.3 g, 12 mmol) was then added dropwise
over 15 min. The solution was stirred at 0 °C for 30 min, and solu-
tion of 11 in dry DCM (15 mL) was added dropwise over 15 min.
The mixture was allowed to warm to rt and stirred for 4 h. The

Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
807
Table 9
Large-scale asymmetric aldol reactionsa
O
X
O
X
OH
O
1e (5 mol%)
R
+
HOAc (5 mol%)
DCM, -20 oC
H
R
Entry
1
Product
No.
Timeb (h)
Yield (%)
98
drc (anti:syn)
eec (%)
O
OH
OH
OH
4c
24
91:9
95
O
O
NO2
NO2
2
3
6b
8a
24
30
97
88
94:6
95:5
>99
S
O
NO2
97
N
Boc
a
b
c
The reaction was carried out using aldehyde (7.5 mmol), ketone (5 equiv), 1e (5 mol %), and HOAc (5 mol %) in DCM (15.0 mL) at ꢀ20 °C.
Isolated yield after silica gel chromatography.
Determined by chiral HPLC analysis (AD-H), for the anti-isomer.
OCH3
O
C
OCH3
OCH3
H
N
O
C
NH2
NH2
OCH3
OCH3
DCM
-10 oC - r.t.
Cl
+
NH2
OCH3
11
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
O
C
O
C
H
N
H
N
Boc-L-proline/Et3N
TFA/DCM
ethyl chloroformate/DCM
NH
NH
Boc
N
H
N
O
O
12
Scheme 3. Preparation of catalyst 1e.
1e
mixture was washed with 1 M KHSO4, saturated NaHCO3 and
brine, dried over anhydrous Na2SO4, and concentrated. The residue
was purified by flash chromatography using ethyl acetate/petro-
leum ether (1:2, v/v) as eluent to afford 12 as a white solid. Yield:
3.5 g (90%).
at ꢀ20 °C for 30 min. Next, the aldehyde (0.25 mmol) was added
and the reaction mixture was stirred at ꢀ20 °C. The reaction was
monitored by TLC, then quenched with 3 mL of saturated NH4Cl
solution, extracted with ethyl acetate (3 ꢁ 5 mL), and dried over
Na2SO4. The solvent was evaporated under reduced pressure. Puri-
fication by flash chromatography afforded the corresponding
products.
4.3.2. Preparation of catalyst 1e12
To a solution of 12 (2.5 g, 5 mmol) in DCM (15 mL) at 0 °C was
added TFA (4 mL). The solution was stirred at 0 °C for 2.5 h. Then
the solution was concentrated under vacuum to leave a glutinous
phase. The pH of the mixture was brought to approximately 12
by the addition of 2 M NaOH. The aqueous phase was extracted
with ethyl acetate. The ethyl acetate extracts were combined,
washed with brine, dried over anhydrous Na2SO4, filtered off, and
the solvent was evaporated under reduced pressure to give a crude
residue, which was purified by flash chromatography using ethyl
acetate/methanol (5:1, v/v) as eluent to afford catalyst 1e as a
white solid. Yield: 1.76 g (85%).
4.5. Typical procedure for catalyst recovery
A mixture of catalyst 1e (40 mg, 0.1 mmol), HOAc (6.0 mg,
0.1 mmol) and tetrahydro-4H-pyran-4-one (0.8 mL, 10 mmol) in
DCM (4 mL) was stirred at ꢀ20 °C for 30 min. Then, 4-nitrobenzal-
dehyde (302 mg, 2 mmol) was added and the reaction mixture was
stirred at ꢀ20 °C. The reaction was monitored by TLC. The mixture
was diluted with ethyl acetate (30 mL), 3 M HCl (8 mL) was added,
and the mixture was stirred at ꢀ20 °C for 10 min. The organic
phase was then separated and the aqueous phase was washed with
ethyl acetate (3 ꢁ 15 mL). The combined organic phase was treated
with saturated NaCl solution (3 ꢁ 15 mL), and then the above gen-
eral procedure was applied to obtain the aldol product. The aque-
ous phase was basified with saturated NaOH until pH 12 and
extracted with ethyl acetate (3 ꢁ 30 mL). The organic phase was
4.4. General procedure for the aldol reaction catalyzed by 1e
A mixture of catalyst 1e (10 mg, 0.025 mmol), HOAc (1.5 mg,
0.025 mmol) and ketone (1.25 mmol) in DCM (0.5 mL) was stirred

808
Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
dried over Na2SO4 and filtered, and the solvent was evaporated
under reduced pressure. The resulting residue was used directly
in the next reaction cycle.
4.6.5. 3-[(10-Hydroxy-10-(400-nitrophenyl))methyl]-tetrahydropy-
ran-4-one1b 4c (Table 4, entry 3)
Yield: 96% (60.2 mg), [
a
]
D
20 = ꢀ18.1 (c 1.0, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
80:20, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 21.0 min, tR
(major) = 24.5 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 8.23 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.6 Hz,
2H), 5.01 (dd, J = 2.7, 2.7 Hz, 1H), 4.23–4.17 (m, 1H), 3.90 (d,
J = 3.1 Hz, 1H), 3.81–3.68 (m, 2H), 3.46 (t, J = 10.7 Hz, 1H), 2.94–
2.86 (m, 1H), 2.74–2.63 (m, 1H), 2.58–2.51 (m, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d = 209.2, 147.4, 127.4, 126.3, 123.8,
123.7, 111.4, 71.2, 69.7, 68.3, 57.5, 42.9 ppm.
4.6. General procedure for large-scale aldol reactions
A solution of 1e (150 mg, 0.38 mmol), HOAc (22 mg, 0.38 mmol)
and ketone (38 mmol) in DCM (15 mL) at ꢀ20 °C was stirred for
30 min, after which the aldehyde (7.5 mmol) was added. The reac-
tion was monitored by TLC, and then quenched with 3 M HCl
(25 mL), and extracted with ethyl acetate (3 ꢁ 50 mL). The organic
phase was dried over Na2SO4 and filtered, and the solvent was
evaporated under reduced pressure. Purification by flash chroma-
tography afforded the corresponding product.
4.6.6. 3-[(10-Hydroxy-10-(400-cyanophenyl))methyl]-tetrahydropyran-
4-one13 4d (Table 4, entry 4)
4.6.1. (R)-tert-Butyl2-(((1R,2R)-2-(3,4,5-trimethoxybenzamido)-
cyclohexyl)carbamoyl)pyrrolidine-1-carboxylate 12
Yield: 99% (57.2 mg), [
a
]
D
20 = ꢀ6.2 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
80:20, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 19.3 min, tR
(major) = 22.9 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.67 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 7.8 Hz,
2H), 4.94 (d, J = 7.1 Hz, 1H), 4.20 (br s, 1H), 3.83 (s, 1H), 3.77–
3.67 (m, 2H), 3.43 (t, J = 8.6 Hz, 1H), 2.91–2.83 (m, 1H), 2.73–2.63
(m, 1H), 2.56–2.51 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3):
d = 209.6, 145.7, 132.8, 127.6, 118.8, 112.4, 71.8, 70.0, 68.6, 57.9,
43.1 ppm.
White solid, yield: 3.5 g (90%), mp 104–106 °C. 1H NMR
(300 MHz, CDCl3): d = 7.07 (s, 2H), 6.99 (s, 1H), 6.86–6.43 (m,
1H), 4.21 (br s, 1H), 3.92 (s, 9H), 3.84 (s, 1H), 3.39–3.23 (m, 2H),
2.20–1.98 (m, 7H), 1.84–1.55 (m, 6H), 1.43 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3) d = 167.8, 164.1, 152.9, 129.5, 129.4, 111.3,
104.2(2C), 80.5, 60.8, 56.2(3C), 56.1, 54.6, 52.3, 47.0, 32.3, 32.2,
32.0, 28.3(3C), 24.9, 24.7, 24.4 ppm. HRMS (ESI) calculated for
C
26H39O7N3Na (M+Na+) 528.2684, found 528.2686.
4.6.2. (R)-N-((1R,2R)-2-(3,4,5-Trimethoxybenzamido)cyclohe-
4.6.7. 3-[(10-Hydroxy-10-(400 -chlorophenyl))methyl]-tetrahydropyran-
4-one6c,7c 4e (Table 4, entry 5)
xyl)pyrrolidine-2-carboxamide 1e
White solid, yield: 1.76 g (85%), mp 98–100 °C; [
a]
20 = ꢀ69.1 (c
Yield: 83% (50.0 mg), [
a
]
D
20 = ꢀ7.8 (c 0.5, CHCl3). The ee was
D
0.3, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.89 (s, 1H), 7.22 (br s,
1H), 7.08 (s, 2H), 3.88 (s, 9H), 3.73 (s, 1H), 2.91–2.62 (m, 5H),
2.22 (d, J = 10.1 Hz, 1H), 1.96 (m, 2H), 1.75 (m, 2H), 1.66–1.59 (m,
1H), 1.52–1.44 (m, 2H), 1.39–1.33 (m, 4H) ppm. 13C NMR
(75 MHz, CDCl3): d = 176.2, 175.9, 166.7, 152.8, 140.2, 129.4,
104.2(2C), 60.8, 60.2, 59.9, 56.3, 56.2(3C), 51.7, 47.0, 32.2, 31.8,
30.7, 25.8, 24.9, 24.4 ppm. HRMS (ESI) calculated for C21H32O5N3
(M+H+) 406.2342, found 406.2339.
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 220 nm, tR (minor) = 21.0 min, tR
(major) = 27.0 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.34 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.1 Hz,
2H), 4.86 (d, J = 9.0 Hz, 1H), 4.14 (m, 1H), 3.80–3.63 (m, 3H), 3.38
(t, J = 10.5 Hz, 1H), 2.88–2.80 (m, 1H), 2.68–2.51 (m, 2H) ppm.
13C NMR (75 MHz, CDCl3): d = 209.7, 138.6, 134.1, 128.8, 127.9,
71.4, 69.7, 68.3, 57.9, 42.7 ppm.
4.6.3. 3-[(10-Hydroxy-10-(200-nitrophenyl))methyl]-tetrahydropy-
ran-4-one7d 4a (Table 4, entry 1)
4.6.8. 3-[(10-Hydroxy-10-(200 -chlorophenyl))methyl]-tetrahydropyran-
4-one6a 4f (Table 4, entry 6)
Yield: 99% (62.2 mg), [
a]
20 = ꢀ7.3 (c 0.5, CHCl3). The ee was
Yield: 82% (49.0 mg), [
a
]
D
20 = ꢀ8.4 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (major) = 29.3 min, tR
(minor) = 31.8 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.93 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.8 Hz,
1H), 7.68 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 5.48 (d,
J = 6.6 Hz, 1H), 4.22 (t, J = 8.4 Hz, 1H), 3.96–3.90 (m, 1H), 3.83–
3.74 (m, 2H), 3.10–3.03 (m, 1H), 2.73–2.63 (m, 1H), 2.54–2.48
(m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 209.9, 148.7, 136.4,
133.9, 129.1, 129.1, 124.7, 70.8, 68.7, 67.6, 58.1, 43.6 ppm.
determined by HPLC (Chiralpak AS-H column, hexane/i-PrOH
95:5, flow rate 0.5 mL/min, k = 220 nm, tR (major) = 65.9 min, tR
(minor) = 69.3 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.58 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.2 Hz,
2H), 7.24–7.21 (m, 1H), 5.37–5.33 (dd, J = 3.8, 3.6 Hz, 1H), 4.18–
4.17 (m, 1H), 3.90 (d, J = 3.9 Hz, 1H), 3.84–3.73 (m, 2H), 3.66–
3.59 (t, J = 10.5 Hz, 1H), 3.02–2.94 (m, 1H), 2.72–2.61 (m, 1H),
2.54–2.47 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 209.8,
137.9, 132.2, 129.3, 129.1, 128.1, 127.3, 69.8, 68.3, 68.0, 57.9,
43.1 ppm.
4.6.4. 3-[(10-Hydroxy-10-(300-nitrophenyl))methyl]-tetrahydropy-
ran-4-one6c 4b (Table 4, entry 2)
4.6.9. 3-[(10-Hydroxy-10-(400 -bromophenyl))methyl]-tetrahydropyran-
4-one6a 4g (Table 4, entry 7)
Yield: 92% (57.8 mg), [
a]
20 = ꢀ7.9 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak OD-H column, hexane/i-PrOH
95:5, flow rate 1.0 mL/min, k = 254 nm, tR (major) = 63.9 min, tR
(minor) = 90.1 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 8.20 (d, J = 12.2 Hz, 2H), 7.68 (d, J = 7.5 Hz,
1H), 7.56 (t, J = 7.8 Hz, 1H), 4.98 (dd, J = 2.3, 2.3 Hz, 1H), 4.23 (t,
J = 7.7 Hz, 1H), 3.89 (d, J = 2.8 Hz, 1H), 3.81–3.70 (m, 2H), 3.50–
3.43 (t, J = 10.7 Hz, 1H), 2.97–2.89 (m, 1H), 2.76–2.65 (m, 1H),
2.57–2.51 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 209.4,
148.2, 142.2, 132.6, 129.6, 123.2, 121.6, 71.1, 69.7, 68.3, 57.5,
42.8 ppm.
Yield: 83% (64.8 mg), [
a
]
D
20 = ꢀ7.3 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 220 nm, tR (minor) = 22.6 min, tR
(major) = 29.5 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.47 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz,
2H), 4.82 (d, J = 8.6 Hz, 1H), 4.17–4.10 (m, 1H), 3.78–3.73 (m,
1H), 3.68 (m, 1H), 3.63 (t, J = 5.7 Hz, 1H), 3.34 (t, J = 10.5 Hz, 1H),
2.85–2.77 (m, 1H), 2.68–2.47 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3): d = 209.7, 139.1, 131.8, 128.3, 122.2, 71.4, 69.7, 68.3, 57.8,
42.7 ppm.

Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
809
4.6.10. 3-[(10-Hydroxy-10-(300-bromophenyl))methyl]-tetrahydro-
pyran-4-one6a 4h (Table 4, entry 8)
95:5, flow rate 1.0 mL/min, k = 220 nm, tR (major) = 45.5 min, tR
(minor) = 66.3 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.31–7.24 (m, 1H), 6.97–6.96 (m, 2H), 5.17
(d, J = 8.0 Hz, 1H), 4.21–4.15 (m, 1H), 3.88–3.72 (m, 3H), 3.46–
3.39 (t, J = 10.5 Hz, 1H), 3.01–2.91 (m, 1H), 2.72–2.55 (m, 2H)
ppm. 13C NMR (75 MHz, CDCl3): d = 209.5, 143.6, 126.5, 125.7,
125.2, 69.9, 68.3, 67.9, 58.3, 42.7 ppm.
Yield: 88% (62.7 mg), [
a
]
D
20 = ꢀ8.0 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 220 nm, tR (major) = 22.2 min, tR
(minor) = 27.7 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.50 (s, 1H), 7.47–7.42 (m, 1H), 7.24–7.20
(m, 2H), 4.83 (dd, J = 3.0 Hz, 1H), 4.21–4.16 (m, 1H), 3.74–3.65
(m, 3H) 3.42–3.35 (m, 1H), 2.90–2.82 (m, 1H), 2.72–2.61 (m, 1H),
2.57–2.50 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 209.7,
142.3, 131.4, 130.1, 129.6, 125.2, 122.8, 71.4, 69.7, 68.3, 57.7,
42.7 ppm.
4.6.16. 3-[(10-Hydroxy-10-(200-nitrophenyl))methyl]-tetrahydro-
thiopyran-4-one1b 6a (Table 5, entry 1)
Yield: 92% (61.5 mg), [a]
20 = +35.8 (c 1.0, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 34.6 min, tR
(major) = 42.3 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.92 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 7.5 Hz,
1H), 7.68 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 5.56 (d,
J = 6.6 Hz, 1H), 3.85–3.68 (m, 1H), 3.21–3.14 (m, 1H), 3.08–2.93
(m, 3H), 2.87–2.73 (m, 2H), 2.65–2.61 (m, 1H) ppm. 13C NMR
(300 MHz, CDCl3): d = 211.9, 148.6, 136.2, 133.7 129.3, 128.9,
124.7, 69.3, 60.1, 45.6, 32.9, 30.6 ppm.
4.6.11. 3-[(10-Hydroxy-10-(400 -fluorophenyl))methyl]-tetrahydropyran-
4-one6c 4i (Table 4, entry 9)
Yield: 72% (40.3 mg), [
a]
20 = ꢀ8.5 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
85:15, flow rate 1.0 mL/min, k = 220 nm, tR (major) = 14.5 min, tR
(minor) = 17.1 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.31–7.26 (m, 2H), 7.03 (t, J = 8.6 Hz, 2H),
4.86 (d, J = 8.9 Hz, 1H), 4.17–4.11 (m, 1H), 3.82–3.60 (m, 3H),
3.34 (t, J = 10.4 Hz, 1H), 2.87–2.79 (m, 1H), 2.69–2.49 (m, 2H)
ppm. 13C NMR (75 MHz, CDCl3): d = 209.9, 164.2, 160.9, 135.9,
135.9, 128.2, 115.7, 115.4, 71.3, 69.8, 68.3, 58.0, 42.6 ppm.
4.6.17. 3-[(10-Hydroxy-10-(300-nitrophenyl))methyl]-tetrahydro-
thiopyran-4-one6a 6b (Table 5, entry 2)
Yield: 99% (66.2 mg), [a]
20 = +26.8 (c 0.8, CHCl3). The ee was
D
determined by HPLC (Chiralpak OJ-H column, hexane/i-PrOH
80:20, flow rate 1.0 mL/min, k = 254 nm, tR (major) = 34.4 min, tR
(minor) = 50.3 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 8.20 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.56
(t, J = 7.8 Hz, 1H), 5.05 (d, J = 7.8 Hz, 1H), 3.80–3.68 (m, 1H),
3.08–2.72 (m, 5H), 2.69–2.64 (m, 1H), 2.56–2.49 (m, 1H) ppm.
13C NMR (75 MHz, CDCl3): d = 211.3, 148.3, 142.5, 132.9, 129.5,
123.1, 121.8, 73.1, 59.3, 44.6, 32.7, 30.7 ppm.
0
0
00
4.6.12. 3-[(1 -Hydroxy-1 -(4 -methylphenyl))methyl]-tetrahydropyran-
4-one6a 4j (Table 4, entry 10)
Yield: 71% (39.1 mg), [
a
]
20 = ꢀ6.3 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
95:5, flow rate 1.0 mL/min, k = 220 nm, tR (minor) = 35.5 min, tR
(major) = 38.0 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.18 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.0 Hz,
2H), 4.82 (d, J = 9.0 Hz, 1H), 4.15–4.08 (m, 1H), 3.75 (m, 1H),
3.66–3.62 (m, 2H), 3.37–3.30 (m, 1H), 2.89–2.81 (m, 1H), 2.65–
2.44 (m, 2H), 2.31 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3):
d = 210.4, 155.1, 138.4, 137.4, 129.7, 126.9, 72.2, 70.3, 68.7, 58.4,
43.0, 21.5 ppm.
4.6.18. 3-[(10-Hydroxy-10-(400-nitrophenyl))methyl]-tetrahydro-
thiopyran-4-one1b 6c (Table 5, entry 3)
Yield: 92% (61.5 mg), [a]
20 = +17.6 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
85:15, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 27.5 min, tR
(major) = 48.8 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 8.24 (d, J = 6.5 Hz, 2H), 7.55 (d, J = 6.5 Hz,
2H), 5.04 (d, J = 6.0 Hz, 1H), 3.70 (br s, 1H), 3.05–2.94 (m, 3H),
2.88–2.75 (m, 2H), 2.71–2.65 (m, 1H), 2.54–2.49 (m, 1H) ppm.
13C NMR (75 MHz, CDCl3): d = 211.4, 147.8, 147.6, 127.8, 123.9,
73.2, 59.5, 44.8, 32.87, 30.9 ppm.
4.6.13. 3-[(10-Hydroxy-10-phenyl)methyl]-tetrahydropyran-4-
one14 4k (Table 4, entry 11)
Yield: 83% (42.8 mg), [
a
]
20 = ꢀ9.2 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
85:15, flow rate 1.0 mL/min, k = 220 nm, tR (major) = 16.7 min, tR
(minor) = 18.2 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.39–7.31 (m, 5H), 4.88 (d, J = 8.9 Hz, 1H),
4.17–4.11 (m, 1H), 3.82–3.62 (m, 3H), 3.37 (t, J = 10.4 Hz, 1H),
2.92–2.84 (m, 1H), 2.70–2.51 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3): d = 210.0, 140.0, 128.7, 128.4, 126.6, 72.0, 69.8, 68.4, 58.0,
42.6 ppm.
4.6.19. 3-[(10-Hydroxy-10-(400-cyanophenyl))methyl]-tetrahydro-
thiopyran-4-one1b 6d (Table 5, entry 4,)
Yield: 95% (58.7 mg), [a]
20 = +14.2 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak OD-H column, hexane/i-PrOH
92:8, flow rate 1.0 mL/min, k = 254 nm, tR (major) = 45.6 min). Data
for the major anti isomer: 1H NMR (300 MHz, CDCl3): d = 7.68 (d,
J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 5.00 (dd, J = 3.8, 3.8 Hz,
1H), 3.63 (d, J = 3.9 Hz, 1H), 3.03–2.96 (m, 3H), 2.88–2.75 (m,
2H), 2.68–2.60 (m, 1H), 2.53–2.48 (m, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d = 211.3, 145.7, 132.4, 127.7, 118.5, 112.1,
73.4, 59.4, 44.7, 32.8, 30.8 ppm.
4.6.14. 3-[(10-Hydroxy-10-(200-furyl))methyl]-tetrahydropyran-4-
one6a 4l (Table 4, entry 12)
Yield: 65% (31.9 mg), [
a
]
D
20 = ꢀ10.2 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 220 nm, tR (minor) = 32.5 min, tR
(major) = 38.0 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.38 (m, 1H), 6.33 (m, 2H), 4.91 (d,
J = 10.8 Hz, 1H), 4.24–4.17 (m, 1H), 3.86–3.72 (m, 3H), 3.42 (t,
J = 10.5 Hz, 1H), 3.22–3.14 (m, 1H), 2.73–2.63 (m, 1H), 2.56–2.49
(m, 1H), 13C NMR (75 MHz, CDCl3): d = 209.4, 152.5, 142.6, 110.2,
108.1, 69.7, 68.3, 65.3, 55.5, 42.7 ppm.
4.6.20. 3-[(10-Hydroxy-10-(400-fluorophenyl)methyl]-tetrahydro-
thiopyran-4-one13 6e (Table 5, entry 5)
Yield: 70% (42.1 mg), [a]
20 = +15.7 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 18.4 min, tR
(major) = 30.1 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.35 (m, 2H), 7.06 (t, J = 8.6 Hz, 2H), 4.95
(dd, J = 2.6, 2.6 Hz, 1H), 3.48 (d, J = 3.0 Hz, 1H), 3.00–2.92 (m, 3H),
2.84–2.74 (m, 2H), 2.56–2.47 (m, 2H) ppm. 13C NMR (75 MHz,
4.6.15. 3-[(10-Hydroxy-10-(200-thienyl))methyl]-tetrahydropyran-
4-one6a 4m (Table 4, entry 13)
Yield: 78% (41.4 mg), [
determined by HPLC (Chiralpak AS-H column, hexane/i-PrOH
a
]
20 = ꢀ9.8 (c 0.5, CHCl3). The ee was
D

810
Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
CDCl3): d = 211.7, 164.1, 160.9, 135.9, 128.6, 128.5, 115.7, 115.4,
73.1, 59.7, 44.5, 32.7, 30.8 ppm.
98:2, flow rate 0.7 mL/min, k = 254 nm, tR (major) = 15.6 min, tR
(minor) = 19.6 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 3.57 (br, 1H), 3.00–2.86 (m, 5H), 2.78–2.74
(m, 2H), 1.87–1.79 (m, 1H), 0.98 (d, J = 6.8 Hz, 2H), 0.94 (d,
J = 6.8 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3): d =212.5, 69.9,
55.7, 45.0, 33.6, 30.9, 30.0, 19.9, 16.0 ppm.
4.6.21. 3-[(10-Hydroxy-10-(400-chlorophenyl)methyl]-tetrahydro-
thiopyran-4-one6b 6f (Table 5, entry 6)
Yield: 82% (52.6 mg), [a]
20 = +16.2 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 0.8 mL/min, k = 254 nm, tR (minor) = 23.8 min, tR
(major) = 41.3 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.36–7.27 (m, 4H), 4.94 (dd, J = 3.2, 3.2 Hz,
1H), 3.49 (d, J = 3.4 Hz, 1H), 2.99–2.92 (m, 3H), 2.85–2.73 (m,
2H), 2.57–2.46 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d = 211.7,
145.5, 138.7, 134.0, 128.8, 128.3, 73.2, 59.6, 44.5, 32.8, 30.9 ppm.
4.6.27. 3-[(10-Hydroxy-10-(200-nitrophenyl))methyl]-4-oxo-piperi-
dine-1-caboxylic acid, tert-butyl ester6a 8a (Table 6, entry 1)
Yield: 87% (76.2 mg), [
a
]
D
20 = ꢀ72.2 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
96:4, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 40.3 min, tR
(major) = 51.5 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.92–7.80 (m, 2H), 7.68 (t, J = 7.5 Hz, 1H),
7.46 (t, J = 7.5 Hz, H), 5.50 (s, 1H), 4.26 (br s, 2H), 3.90 (d,
J = 9.0 Hz, 1H), 3.20 (t, J = 12.0 Hz, 2H), 2.91 (br s, 1H), 2.54–2.51
(m, 2H), 1.40 (br s, 9H) ppm. 13C NMR (75 MHz, CDCl3):
d = 210.5, 154.2, 148.2, 136.6, 133.4, 128.8, 128.7, 124.3, 80.7,
67.5, 56.8, 46.8, 43.6, 41.7, 28.1 ppm.
4.6.22. 3-[(10-Hydroxy-10-(200-chlorophenyl)methyl]-tetrahydro-
thiopyran-4-one6a 6g (Table 5, entry 7)
Yield: 80% (51.4 mg), [a]
20 = +18.8 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 16.1 min, tR
(major) = 19.9 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.57 (d, J = 7.9 Hz, 1H), 7.34 (t, J = 7.8 Hz,
2H), 7.24 (m, 1H), 5.43 (dd, J = 4.4, 4.2 Hz, 1H), 3.73 (d, J = 4.5 Hz,
1H), 3.12–3.05 (m, 1H), 3.02–2.94 (m, 2H), 2.87–2.80 (m, 3H),
2.54 (ddd, J = 2.3, 2.3, 2.4, 2.4 Hz, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d = 211.9, 138.1, 132.8, 129.4, 129.1, 128.3, 127.4, 70.0,
59.7, 45.0, 32.7, 30.9 ppm.
4.6.28. 3-[(10-Hydroxy-10-(300-nitrophenyl))methyl]-4-oxo-piperi-
dine-1-caboxylic acid, tert-butyl ester6a 8b (Table 6, entry 2)
Yield: 94% (82.3 mg), [
a
]
D
20 = ꢀ75.1 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
97:3, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 79.2 min, tR
(major) = 95.3 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 8.25 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.71 (d,
J = 9.0 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 4.96 (d, J = 9.0 Hz, 1H), 4.19
(br s, 1H), 4.00–3.95 (m, 1H), 3.73–3.69 (m, 1H), 3.25 (br s, 1H),
2.96–2.81 (m, 2H), 2.59–2.48 (m, 2H), 1.38 (br s, 9H) ppm. 13C
NMR (75 MHz, CDCl3): d = 210.6, 154.1, 148.3, 142.4, 132.8,
129.6, 123.2, 121.8, 80.9, 71.8, 56.2, 45.5, 43.6, 41.3, 27.8 ppm.
4.6.23. 3-[(10-Hydroxy-10-(400-bromophenyl)methyl]-tetrahydro-
thiopyran-4-one6b 6h (Table 5, entry 8)
Yield: 92% (69.5 mg), [a]D
20 = +20.4 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 0.8 mL/min, k = 254 nm, tR (minor) = 25.2 min, tR
(major) = 44.8 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.43 (d, J = 8.4 Hz, 2H), 7.17 (t, J = 7.6 Hz, 2H),
4.85 (d, J = 8.4 Hz, 1H), 3.42 (s, 1H), 2.92–2.84 (m, 3H), 2.78–2.64
(m, 2H), 2.54–2.40 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
d = 212.0, 139.6, 132.1, 128.9, 122.5, 73.6, 59.9, 44.9, 33.1, 31.2 ppm.
4.6.29. 3-[(10-Hydroxy-10-(400-nitrophenyl))methyl]-4-oxo-piperi-
dine-1-caboxylic acid, tert-butyl ester4c 8c (Table 6, entry 3)
Yield: 90% (78.8 mg), [
a
]
D
20 = ꢀ76.4 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
85:15, flow rate 0.5 mL/min, k = 254 nm, tR (major) = 21.2 min, tR
(minor) = 25.7 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 8.25 (d, J = 6.5 Hz, 2H), 7.57–7.54 (m, 2H),
4.96 (d, J = 6.1 Hz, 1H), 4.19 (m, 1H), 3.81–3.71 (m, 2H), 3.25 (br
s, 1H), 2.91 (t, J = 8.7 Hz, 1H), 2.77 (br s, 1H), 2.59–2.52 (m, 2H),
1.41 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): d = 210.4, 154.2,
147.7, 147.6, 127.1, 124.0, 80.8, 72.1, 56.4, 45.4, 43.5, 41.6,
28.0 ppm.
4.6.24. 3-[(10-Hydroxy-10-(300-bromophenyl)methyl]-tetrahydro-
thiopyran-4-one6b 6i (Table 5, entry 9)
Yield: 87% (65.5 mg), [a]
20 = +19.2 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AS-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (major) = 22.8 min, tR
(minor) = 35.2 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.50 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 6.8 Hz,
1H), 7.23–7.19 (m, 2H), 4.90 (d, J = 10.5 Hz, 1H), 3.51 (d,
J = 3.0 Hz, 1H), 3.01–2.91 (m, 3H), 2.83–2.71 (m, 2H), 2.61–2.57
(m, 1H), 2.53–2.48 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3):
d = 212.3, 143.3, 132.1, 130.8, 130.6, 126.3, 123.5, 74.0, 60.2, 45.3,
33.5, 31.5 ppm.
4.6.30. 3-[(10-Hydroxy-10-(400-fluorophenyl))methyl]-4-oxo-piperi-
dine-1-caboxylic acid, tert-butyl ester6a 8d (Table 6, entry 4)
Yield: 99% (80.0 mg), [
a]
20 = ꢀ70.3 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak OD-H column, hexane/i-PrOH
90:10, flow rate 0.5 mL/min, k = 220 nm, tR (major) = 22.5 min, tR
(minor) = 30.8 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.36–7.31 (m, 2H), 7.09–7.03 (t, J = 8.4 Hz,
2H), 4.82 (d, J = 8.4 Hz, 1H), 4.14 (br s, 1H), 3.75–3.69 (m, 2H),
3.27 (br s, 1H), 2.88–2.73 (m, 2H), 2.54–2.50 (m, 2H), 1.39 (br s,
9H), 13C NMR (75 MHz, CDCl3): d = 211.1, 164.2, 160.9, 154.2,
135.9, 128.5, 128.4, 115.7, 115.4, 80.7, 71.8, 56.5, 45.5, 43.5, 41.4,
28.2 ppm.
4.6.25. 3-[(10-Hydroxy-10-(200, 400-dichlorophenyl))methyl]-tetra-
hydrothiopyran-4-one6a 6j (Table 5, entry 10)
Yield: 99% (72.1 mg), [a]
20 = +24.5 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
95:5, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 23.4 min, tR
(major) = 34.0 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.53 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.34–
7.30 (m, 1H), 5.38 (dd, J = 3.5, 3.5 Hz, 1H), 3.86 (d, J = 3.9 Hz, 1H),
3.02–2.74 (m, 7H) ppm. 13C NMR (75 MHz, CDCl3): d = 212.0,
137.3, 134.5, 1336, 129.6, 128.1, 69.9, 59.9, 45.3, 33.0, 31.2 ppm.
4.6.31. 3-[(10-Hydroxy-10-(400-chlorophenyl))methyl]-4-oxo-piperi-
dine-1-caboxylic acid, tert-butyl ester6b 8e (Table 6, entry 5)
Yield: 82% (70.0 mg), [
a
]
20 = ꢀ68.5 (c 0.5, CHCl3). The ee was
D
4.6.26. (S)-3-((S)-1-Hydroxy-2-methylpropyl)dihydro-2H-pyran-
4(3H)-thione 6k (Table 5, entry 11)6b
determined by HPLC (Chiralpak pre-AD+OD-H column, hexane/i-
PrOH 92:8, flow rate 0.7 mL/min, k = 220 nm, tR (major) = 39.5 min,
tR (minor) = 45.4 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.35–7.27 (m, 4H), 4.83–4.79 (dd, J = 2.1,
Yield: 48% (45.1 mg), [
determined by HPLC (Chiralpak OD-H column, hexane/i-PrOH
a
]
20 = ꢀ33.6 (c 0.5, CHCl3). The ee was
D

Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
811
2.1 Hz, 1H), 4.09 (br s, 1H), 3.79–3.68 (m, 2H), 3.28 (br s, 1H), 2.91–
2.83 (t, J = 12.0 Hz, 1H), 2.71 (br s, 1H), 2.52–2.45 (m, 2H), 1.39 (br
s, 9H) ppm. 13C NMR (75 MHz, CDCl3): d = 210.8, 154.2, 138.6,
134.0, 128.7, 128.1, 80.6, 71.8, 56.3, 45.6, 43.4, 41.1, 28.1 ppm.
1.85–1.82 (m, 1H), 1.66–1.55 (m, 3H), 1.45–1.33 (m, 1H) ppm.
13C NMR (75 MHz, CDCl3): d = 214.9, 143.2, 133.2, 129.3, 122.8,
122.0, 73.9, 57.1, 42.7, 30.7, 27.6, 24.6 ppm.
4.6.37. 2-(Hydroxy(4-nitrophenyl)methyl)cyclohexanone1b 10c
(Table 7, entry 3)
4.6.32. 3-[(10-Hydroxy-10-(200-chlorophenyl))methyl]-4-oxo-piperi-
dine-1-caboxylic acid, tert-butyl ester6a 8f (Table 6, entry 6)
Yield: 99% (61.7 mg), [a]
20 = +8.6 (c 0.5, CHCl3).The ee was
D
Yield: 71% (60.3 mg), [
a]
20 = ꢀ79.6 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 27.2 min,
tR (major) = 36.6 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 8.21 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.3 Hz,
2H), 4.91 (d, J = 8.3 Hz, 1H), 4.10 (br s, 1H), 2.60 (m, 1H), 2.53
(m, 2H), 2.32–2.09 (m, 1H), 1.83 (d, J = 10.7 Hz, 1H), 1.65–1.35
(m, 4H) ppm. 13C NMR (75 MHz, CDCl3): d = 214.9, 148.4,
147.5, 147.5, 127.9, 126.6, 123.6, 74.0, 57.2, 42.9, 30.7, 27.6,
24.7 ppm.
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
95:5, flow rate 1.0 mL/min, k = 220 nm, tR (minor) = 20.5 min, tR
(major) = 21.7 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.57 (d, J = 7.8 Hz, 1H), 7.36–7.21 (m, 3H),
5.35 (d, J = 6.3 Hz, 1H), 4.24 (br s, 1H), 3.96 (d, J = 3.0 Hz, 1H),
3.82 (br s, 1H), 3.19 (br s, 1H), 3.04 (t, J = 12.2 Hz, 1H), 2.83 (br s,
1H), 2.58–2.50 (m, 2H), 1.37 (br s, 9H) ppm. 13C NMR (75 MHz,
CDCl3): d = 211.4, 154.5, 138.3, 132.7, 129.7, 129.4, 128.4, 127.7,
81.0, 68.9, 56.8, 46.1, 44.0, 42.0, 28.4 ppm.
4.6.38. 4-(Hydroxy(2-oxocyclohexyl)methyl)benzonitrile3 10d
(Table 7, entry 4)
4.6.33. 3-[(10-Hydroxy-10-(400-bromophenyl))methyl]-4-oxo-piper-
idine-1-caboxylic acid, tert-butyl ester6a 8g (Table 6, entry 7)
Yield: 95% (54.4 mg), [a]
20 = +9.4 (c 0.5, CHCl3). The ee was
D
Yield: 90% (86.2 mg), [
a]
20 = ꢀ74.6 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 29.5 min, tR
(major) = 32.4 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.66–7.63 (m, 2H), 7.46–7.44 (m, 2H), 4.84
(d, J = 8.8 Hz, 1H), 4.10 (s, 1H), 2.62–2.46 (m, 2H), 2.42–2.31 (m,
1H), 2.14–2.08 (m, 1H), 1.84–1.81 (m, 1H), 1.70–1.53 (m, 3H),
1.42–1.28 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 214.8,
146.3, 132.1, 127.7, 118.7, 111.5, 74.0, 57.0, 42.5, 30.6, 27.7,
24.6 ppm.
D
determined by HPLC (Chiralpak OJ-H column, hexane/i-PrOH
96:4, flow rate 1.0 mL/min, k = 220 nm, tR (major) = 36.3 min, tR
(minor) = 61.8 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.49 (d, J = 7.5 Hz, 2H), 7.23 (d, J = 8.4 Hz,
2H), 4.79 (dd, J = 3.0, 3.0 Hz, 1H), 4.09 (br s, 1H), 3.75–3.68 (m,
2H), 3.27 (br s, 1H), 2.86 (t, J = 10.8 Hz, 1H), 2.71 (br s, 1H), 2.52–
2.47 (m, 2H), 1.39 (br s, 9H) ppm. 13C NMR (75 MHz, CDCl3):
d = 210.8, 154.1, 139.1, 131.7, 128.4, 122.1, 80.7, 71.9, 56.5, 45.7,
43.4, 41.1, 27.9 ppm.
4.6.39. 2-(Hydroxy(2-methoxyphenyl)methyl)cyclohexanone3
10e (Table 7, entry 5)
4.6.34. 3-[(10-Hydroxy-10-(300-bromophenyl))methyl]-4-oxo-piper-
idine-1-caboxylic acid, tert-butyl ester6a 8h (Table 6, entry 8)
Yield: 85% (49.8 mg), [a]
20 = +11.4 (c 0.5, CHCl3). The ee was
D
Yield: 95% (91.3 mg), [
a]
20 = ꢀ83.7 (c 0.5, CHCl3). The ee was
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 0.5 mL/min, k = 254 nm, tR (minor) = 37.3 min, tR
(major) = 39.0 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.42–7.39 (m, 1H), 7.28–7.23 (m, 1H),
7.01–6.96 (m, 1H), 6.88–6.85 (m, 1H), 5.29–5.24 (dd, J = 4.3,
4.3 Hz, 1H), 3.86–3.84 (m, 1H), 3.81 (s, 3H), 2.78–2.69 (m, 1H),
2.49–2.31 (m, 2H), 2.08–2.02 (m, 1H), 1.81–1.76 (m, 1H), 1.69–
1.43 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3): d = 215.6, 156.7,
128.6, 127.7, 120.8, 110.4, 68.5, 57.2, 55.3, 42.5, 30.4, 27.9,
24.6 ppm.
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
98:2, flow rate 1.0 mL/min, k = 220 nm, tR (minor) = 66.7 min, tR
(major) = 87.6 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.53 (s, 1H), 7.45 (d, J = 6.9 Hz, 1H), 7.27–
7.21 (m, 2H), 4.80 (d, J = 8.1 Hz, 1H), 4.14 (br s, 1H), 3.80 (s, 1H),
3.73–3.69 (m, 1H), 3.27 (br s, 1H), 2.91–2.73 (m, 2H), 2.59–2.43
(m, 2H), 1.40 (br s, 9H) ppm. 13C NMR (75 MHz, CDCl3):
d = 210.4, 153.8, 142.0, 131.09, 129.7, 129.4, 125.0, 122.3, 80.3,
71.5, 56.1, 43.1, 41.0, 27.7 ppm.
4.6.35. 2-(Hydroxy(2-nitrophenyl)methyl)cyclohexanone1b 10a
(Table 7, entry 1)
4.6.40. 2-(Hydroxy(3-methoxyphenyl)methyl)cyclohexanone3
10f (Table 7, entry 6)
Yield: 96% (59.8 mg), [
a]
20 = +10.4 (c 1.0, CHCl3). The ee was
Yield: 86% (50.4 mg), [a]
20 = +9.4 (c 0.5, CHCl3). The ee was
D
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
92:8, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 24.6 min, tR
(major) = 26.6 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.86–7.83 (m, 1H), 7.78–7.76 (m, 1H),
7.66–7.61 (m, 1H), 7.46–7.41 (m, 1H), 5.46–5.44 (d, J = 7.1 Hz,
1H), 3.99 (br s, 1H), 2.79–2.73 (m, 1H), 2.48–2.29 (m, 2H), 2.12–
2.08 (m, 1H), 1.84–1.61 (m, 5H) ppm. 13C NMR (75 MHz, CDCl3):
d = 214.9, 148.6, 136.5, 133.1, 129.0, 128.4, 124.0, 69.5, 57.2, 42.7,
31.0, 27.7, 24.9 ppm.
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 41.3 min, tR
(major) = 45.0 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.28–7.23 (m, 1H), 6.90–6.82 (m, 3H),
4.77–4.75 (d, J = 8.2 Hz, 1H), 3.98 (s, 1H), 3.81 (s, 3H), 2.65–2.56
(m, 1H), 2.49–2.35 (m, 2H), 2.10–2.05 (m, 1H), 1.81–1.51 (m,
4H), 1.36–1.24 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 215.5,
159.6, 142.5, 129.3, 119.4, 113.3, 112.4, 74.6, 57.3, 55.2, 42.6,
30.8, 27.8, 24.6 ppm.
4.6.36. 2-(Hydroxy(3-nitrophenyl)methyl)cyclohexanon3 10b
(Table 7, entry 2)
4.6.41. 2-(Hydroxy(4-methoxyphenyl)methyl)cyclohexanone3
10g (Table 7, entry 7)
Yield: 97% (60.4 mg), [
a
]
D
20 = +12.6 (c 0.8, CHCl3). The ee was
Yield: 88% (51.6 mg), [a]
20 = +12.1 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (major) = 19.9 min, tR
(minor) = 25.2 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 8.22–8.15 (m, 2H), 7.69–7.67 (m, 1H),
7.56–7.51 (m, 1H), 4.92–4.89 (d, J = 7.4 Hz, 1H), 4.17 (s, 1H),
2.68–2.59 (m, 1H), 2.53–2.32 (m, 2H), 2.15–2.09 (m, 1H),
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 0.8 mL/min, k = 220 nm, tR (minor) = 25.8 min, tR
(major) = 26.8 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.25–7.22 (m, 2H), 6.89–6.86 (m, 2H),
4.75–4.72 (d, J = 8.9 Hz, 1H), 3.90 (s, 1H), 3.80 (s, 1H), 2.59–2.32
(m, 3H), 2.11–2.02 (m, 1H), 1.73–1.52 (m, 4H), 1.28–1.25 (m, 1H)

812
Z. Guan et al. / Tetrahedron: Asymmetry 25 (2014) 802–812
ppm. 13C NMR (75 MHz, CDCl3): d = 215.7, 159.2, 133.0, 128.1,
113.7, 74.2, 57.5, 55.2, 42.6, 30.8, 27.8, 24.7 ppm.
70:30, flow rate 1.0 mL/min, k = 254 nm, tR (major) = 19.4 min, tR
(minor) = 25.9 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 8.21 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.3 Hz,
2H), 5.26 (br s, 1H), 3.62–3.61 (m, 1H), 2.85 (m, 2H), 2.22 (s, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d = 203.1, 152.4, 144.4, 120.9,
118.3, 63.4, 46.0, 25.3 ppm.
4.6.42. 2-((4-Chlorophenyl)(hydroxy)methyl)cyclohexanone3
10h (Table 7, entry 8)
Yield: 94% (56.4 mg), [a]
20 = +15.3 (c 0.5, CHCl3).The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 13.1 min, tR
(major) = 15.2 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.33–7.24 (m, 4H), 4.78–4.74 (d, J = 8.5 Hz,
1H), 4.02 (br s, 1H), 2.57–2.46 (m, 2H), 2.40–2.30 (m, 1H), 2.11–
2.07 (m, 1H), 1.78–1.49 (m, 4H), 1.35–1.26 (m, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d = 215.3, 139.4, 133.5, 128.5, 128.3, 74.1,
57.3, 42.6, 30.7, 27.7, 24.6 ppm.
4.6.47. 1-Hydroxy-2-methyl-1-(4-nitrophenyl)pentan-3-one10
(10m Table 7, entry 13)
Yield: 70% (41.5 mg), [a]
20 = +20.1 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak OJ-H column, hexane/i-PrOH
80:20, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 12.9 min,
tR(major) = 15.5 min). Data for the syn isomer: 1H NMR
(300 MHz, CDCl3): d = 8.20 (d, J = 7.4 Hz, 2H), 7.52 (d, J = 8.3 Hz,
2H), 5.22–4.86 (m, 1H), 3.76–3.62 (m, 1H), 2.99–2.83 (m, 1H),
2.69–2.39 (m, 2H), 1.08–0.98 (m, 6H) ppm. 13C NMR (75 MHz,
CDCl3): d = 216.1, 149.7, 147.3, 127.3, 123.5, 111.4, 75.5, 52.2,
36.4, 14.3, 7.4 ppm.
4.6.43. 2-((4-Bromophenyl)(hydroxy)methyl)cyclohexanone3
10i (Table 7, entry 9)
Yield: 93% (65.8 mg), [a]
20 = +18.2 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 14.5 min, tR
(major) = 17.0 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.49–7.46 (m, 2H), 7.21–7.18 (m, 2H), 4.74
(dd, J = 2.1, 2.1 Hz, 1H), 4.02 (br s, 1H), 2.60–2.46 (m, 2H), 2.40–
2.29 (m, 1H), 2.12–2.06 (m, 1H), 1.78–1.52 (m, 4H), 1.30–1.23
(m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 215.3, 139.9, 131.4,
128.7, 121.6, 74.1, 57.2, 42.6, 30.7, 27.7, 24.6 ppm.
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (No. 21276211).
References
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Asymmetry 2010, 21, 775–779.
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4.6.44. 2-((4-Fluorophenyl)(hydroxy)methyl)cyclohexanone3
10j (Table 7, entry 10)
Yield: 90% (50.0 mg), [a]
20 = +11.5 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
90:10, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 13.2 min, tR
(major) = 14.7 min). Data for the major anti isomer: 1H NMR
(300 MHz, CDCl3): d = 7.32–7.27 (m, 2H), 7.06–7.00 (m, 2H),
4.79–4.76 (d, J = 8.8 Hz, 1H), 4.03 (br s, 1H), 2.61–2.46 (m, 2H),
2.41–2.30 (m, 1H), 2.13–2.06 (m, 1H), 1.82–1.48 (m, 4H), 1.34–
1.22 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 215.5, 160.7,
136.7, 128.6, 115.3, 74.0, 57.4, 42.6, 30.7, 27.7, 24.6 ppm.
4.6.45. 2-(Hydroxy(4-nitrophenyl)methyl)cyclopentanone10 10k
(Table 7, entry 11)
Yield: 99% (58.2 mg), [a]
20 = +15.1 (c 0.5, CHCl3). The ee was
D
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH
95:5, flow rate 1.0 mL/min, k = 254 nm, tR (minor) = 53.5 min, tR
(major) = 55.4 min). Data for the major syn isomer: 1H NMR
(300 MHz, CDCl3): d = 8.22 (d, J = 4.3 Hz, 2H), 7.53 (m, 2H), 5.43
(s, 1H), 4.87–4.79 (m, 1H), 2.52–2.16 (m, 3H), 2.10–1.91 (m, 2H),
1.84–1.68 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d = 222.3,
150.1, 148.6, 127.3, 126.3, 123.7, 123.6, 74.4, 56.0, 51.4, 38.9,
22.2 ppm.
4.6.46. 4-Hydroxy-4-(4-nitrophenyl)butan-2-one10 10l (Table 7,
entry 12)
Yield: 99% (51.8 mg), [
determined by HPLC (Chiralpak AS-H column, hexane/i-PrOH
a]
20 = +18.4 (c 0.5, CHCl3). The ee was
D