Proline-based dipeptides with two amide units as organocatalyst for the asymmetric aldol reaction of cyclohexanone with aldehydes

Article abstract of DOI:10.1016/j.tet.2008.07.051

A series of proline-based dipeptide organocatalysts with two amide units (1-16) have been developed and evaluated in the direct catalytic asymmetric aldol reactions of aldehydes with cyclohexanone. These catalysts showed good solubility in organic solvents compared with their corresponding carboxyl terminal dipeptides. The robust amide bond formation allowed structural modifications and fine tuning of catalyst properties by varying the stereo and electronic effects of the terminal amide to affect the ability of hydrogen bonding formation between the catalysts and the substrates. The reactions proceeded smoothly in high yields (up to 99%), enantioselectivities (up to 98% ee) and anti-diastereoselectivities (up to 99:1) in the presence of bifunctional organocatalyst 4 under the optimal reaction conditions.

Full text of DOI:10.1016/j.tet.2008.07.051

Tetrahedron 64 (2008) 9585–9591
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Proline-based dipeptides with two amide units as organocatalyst for the
asymmetric aldol reaction of cyclohexanone with aldehydes
*
Fubin Chen, Shi Huang, Hui Zhang, Fengying Liu, Yungui Peng
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of proline-based dipeptide organocatalysts with two amide units (1–16) have been developed
and evaluated in the direct catalytic asymmetric aldol reactions of aldehydes with cyclohexanone. These
catalysts showed good solubility in organic solvents compared with their corresponding carboxyl ter-
minal dipeptides. The robust amide bond formation allowed structural modifications and fine tuning of
catalyst properties by varying the stereo and electronic effects of the terminal amide to affect the ability
of hydrogen bonding formation between the catalysts and the substrates. The reactions proceeded
smoothly in high yields (up to 99%), enantioselectivities (up to 98% ee) and anti-diastereoselectivities (up
to 99:1) in the presence of bifunctional organocatalyst 4 under the optimal reaction conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 22 December 2007
Received in revised form 13 July 2008
Accepted 15 July 2008
Available online 18 July 2008
Keywords:
Dipeptide
Aldol reaction
Organocatalyst
Enantioselectivity
1. Introduction
the catalysts and the substrate in the transition state. Xiao et al.
have shown that L-prolinamide derivatives are able to efficiently
The aldol reaction is one of the most important carbon–carbon
bond-forming reactions in modern organic synthesis. Direct aldol
reaction does not require pre-formed enolate, and therefore, it is
more convenient to carry out and is highly atomically economic. A
lot of efforts have been devoted to the development of this reaction,
and a great success has been achieved in this field.1 Shibasaki has
reported the first example of a direct asymmetric aldol reaction
catalyzed by heterobimetallic complexes.2 Since List and Barbas
catalyze intermolecular cyclohexanone aldolisation with high
enantioselectivity.5b,g However, those catalysts were prepared from
L-proline and unnatural enantiopure (R,R)- or (S,S)-1,2-di-
aminocyclohexane. Inspired by these observations, we designed
a new series of proline-based dipeptides as chiral organic catalysts
with two amide units. These catalysts may have the following
merits: (1) the solubility of the dipeptides in organic solvents could
be significantly improved by converting carboxyl into the corre-
sponding amide; (2) the robust amide bond formation allowed
structural modifications, therefore, fine tuning of catalyst proper-
ties by varying the stereo and electronic effects of the terminal
amide to affect the ability of hydrogen bonding formation between
the catalysts and substrates. Intrigued by the potential structural
diversity and motivated by our interest in stereoselective organo-
catalysis, herein, we report a series of proline-based dipeptides
1–16 (Fig. 1) with two amide units as tunable and bifunctional
organocatalysts in attaining the direct asymmetric aldol reaction
with high efficiency.
discovered that
enantioselective direct aldol reaction,3,9g many groups have de-
veloped proline,4 proline-derivatives including -prolinamides,5
proline N-sulfonyl amides,6 substituted -prolines,7 diamines,8
-proline-based small peptides,9 and other organocatalysts10 for the
L-proline may be used as the catalyst for the
L
L
L
direct asymmetric aldol reaction. Among them, N-terminal prolyl
dipeptides are effective for the direct catalytic asymmetric aldol
reaction.9c,g However, those dipeptides have low solubility in most
of organic solvents and hence highly polar solvents such as DMSO
and DMF are often used in the organocatalytic reactions. Such high-
boiling point solvents are difficult to remove. Tomasini and Gong
groups had tried to use N-terminal prolyl dipeptides esters to cat-
alyze the aldol reaction.9d,f Those soluble dipeptide esters gave
moderate results due to the decrease of the stereoselectivity control
ability arising from the weak carboxyl hydrogen bonding between
2. Results and discussion
As shown in Figure 1, a variety of proline-based dipeptides 1–16
were prepared from commercially available proline, the corre-
sponding amino acids and amine derivatives. The catalytic activity
of these new catalysts was then evaluated in the direct asymmetric
aldol reaction of 4-nitrobenzaldehyde with cyclohexanone. The
results are summarized in Table 1. Preliminary tests showed that
* Corresponding author. Tel.: þ86 23 68254290; fax: þ86 23 68254000.
E-mail addresses: pengyungui@hotmail.com, pyg@swu.edu.cn (Y. Peng).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.051

9586
F. Chen et al. / Tetrahedron 64 (2008) 9585–9591
O
catalyst is 1:1 (Table 1, entry 6). In addition, when the catalyst load
R1
H
O
was reduced from 20% to 10%, reactivity, enantioselectivity, and
diastereoselectivity all decreased dramatically (Table 1, entries 6, 8).
Then, we used 20 mol % of catalysts and 20 mol % of AcOH to test the
catalytic activity (Table 1, entries 1–3,11–22). We also optimized the
temperature using 4 as the catalyst and found that reaction ran at
ꢀ20 ꢁC afforded the product in high yield and better enantiose-
lectivity (Table 1, entries 6, 9, 10). At ꢀ10 ꢁC, the reaction was
complete quantitatively in >99% yield, but the ee of the major
product was 87% (Table 1, entry 9). When lowering the temperature
further to ꢀ30 ꢁC, 88% ee was obtained, but the yield dropped from
99% to 38.4% (Table 1, entry 10). We then tested other catalysts in the
reaction. The catalytic activities and steroselectivities were signifi-
cantly influenced by both R1 and R2 in catalysts 1–16. When R2 was
phenyl and R1 changed to benzyl from phenyl, the ee of the product
slightly increased from 87% up to 92% (Table 1, entries 1, 2). The best
enantioselectivity (93% ee) was obtained when R1 was methyl (Ta-
ble 1, entry 6). With further changes of R1 into iso-butyl, iso-propyl,
and sec-butyl, respectively, the ee of the products varied from 79% to
90% (Table 1, entries 11–13). Particularly, when R1 was hydrogen, the
catalytic activity was very low. This may be caused by its poor sol-
ubility in the reaction system (Table 1, entry 3). We also investigated
the influence of R2 on the reaction. When R1 was benzyl, R2 was
changed from phenyl to methyl, both yields and ee of the products
decreased and from 99% yield, 92% ee down to 77% yield, 89% ee
(Table 1, entries 2, 14). Electron-withdrawing or electron-donating
substitutes on the phenyl showed slight influence on the reaction
(Table 1, entries 2, 15, 16). When R1 was methyl, the similar elec-
tronic and steric effects of R2 were observed as when R1 was benzyl
(Table 1, entries 6, 17–20). With electron-withdrawing p-nitro on
the phenyl, the reactivity was reduced dramatically to yield only
60% of the product (Table 1, entry 20). With p-methoxyl on the
phenyl, the reactivity was also reduced and the yield was 72% (Table
1, entry 19). The chirality of R2 had slight influence on the reactivity
and enantioselectivity (Table 1, entry 17). Among the catalytic sys-
tems examined, the best catalyst was 4, which gave good selectivity
(anti/syn 91/9; 93% ee) and 98% yield (Table 1, entry 6) under the
same conditions. The product with the opposite configuration was
N
N
H
H
HN
R2
1: R1 = R2 = Ph
H-L-Pro-L-Phg-NPh
H-L-Pro-L-Phe-NPh
H-L-Pro-Glu-NPh
2: R1 = Bn, R2 = Ph
3: R1 = H, R2 = Ph
4: R1 = Me, R2 = Ph
5: R1 = i-Bu, R2 = Ph
6: R1 = i-Pr, R2 = Ph
7: R1 = s-Bu, R2 = Ph
8: R1 = Bn, R2 = Me
H-L-Pro-L-Ala-NPh
H-L-Pro-L-Leu-NPh
H-L-Pro-L-Val-NPh
H-L-Pro-L-Ile-NPh
H-L-Pro-L-Phe-NMe
9: R1 = Bn, R2 = (p-MeO)Ph
H-L-Pro-L-Phe-N(p-MeO)Ph
H-L-Pro-L-Phe-N-3,5-(CF3)2Ph
10: R1 = Bn, R2 = 3, 5-(CF3)2Ph
11: R1 = Me, R2 = (S)-CH(CH3)Ph
12: R1 = Me, R2 = (p-Me)Ph
13: R1 = Me, R2 = (p-MeO)Ph
14: R1 = Me, R2 = (p-NO2)Ph
H-L-Pro-L-Ala-N-(S)-CH(CH3)Ph
H-L-Pro-L-Ala-N(p-Me)Ph
H-L-Pro-L-Ala-N(p-MeO)Ph
H-L-Pro-L-Ala-N(p-NO2)Ph
O
R1
H
O
N
N
H
H
HN
R1
R2
15: R1 = Me, R2 = (p-Me)Ph
H-D-Pro-L-Ala-N(p-Me)Ph
H-L-Pro-D-Ala-NPh
O
H
O
N
H
N
H
HN
R2
16: R1 = Me, R2 = Ph
Figure 1. Proline-based dipeptides 1–16.
the presence of a BrFnsted acid enhanced both reactivity and
selectivity using 4 as the catalyst (Table 1, entries 4–7). The same
phenomenon was also observed in Xiao’s catalytic system.5b
Without the BrFnsted acid additive, both reactivity and selectivity
decreased sharply, only 35% yield and 60% ee were obtained after
24 h (Table 1, entry 4). The ratio of catalyst to additive was then
optimized and we found that the best ratio of acid additive to
Table 1
Direct asymmetric aldol reaction of 4-nitrobenzaldehyde with cyclohexanone cat-
alyzed by prolinamide derivatives 1–16
CHO
O
O
OH
obtained when
-proline (Table 1, entries 18, 21). On the contrary, when
was changed into -alanine, the configuration of the product didn’t
L-proline moiety in the catalyst was replaced by
Cat / Additive
CHCl3
D
L-alanine
+
D
NO2
NO2
vary. Only the ee value decreased slightly from 92% to 89% (Table 1,
entries 6, 22). This indicated that the stereoselectivity was con-
trolled by the proline part of the dipeptide. When proline was used
as catalyst in the same conditions, only 11.2% yield of the product
was obtained with 92% ee (Table 1, entry 23).
A series of solvents were also screened, and the results are
summarized in Table 2. Good yields and enantiomeric excesses
were obtained in moderate polar aprotic solvents such as CH2Cl2,
THF, Et2O, CHCl3, PhCH3 (Table 2, entries 1–3, 7, 8), and the best
result was achieved in CHCl3 (Table 2, entry 7). On the other hand,
Entry Cat.
Additive
T (ꢁC) Time (h) Yielda (%) anti/synb eec (%)
1
2
3
4
5
6
7
8
1 (20%)
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
24
24
24
24
24
24
24
48
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
>99
>99
<10
91/9
85/15
d
87
92
2 (20%)
3 (20%)
4 (20%)
4 (20%)
4 (20%)
4 (20%)
4 (10%)
4 (20%)
4 (20%)
5 (20%)
6 (20%)
7 (20%)
8 (20%)
9 (20%)
10 (20%)
11 (20%)
12 (20%)
13 (20%)
14 (20%)
15 (20%)
16 (20%)
d
None
ꢀ20
35.2
75.2
98
82/18
79/21
98/2
60
85
93
92
88
86
88
83
79
90
89
92
90
90
92
89
89
ꢀ89
89
92
AcOH (10%) ꢀ20
AcOH (20%) ꢀ20
AcOH (40%) ꢀ20
AcOH (10%) ꢀ20
AcOH (20%) ꢀ10
AcOH (20%) ꢀ30
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
AcOH (20%) ꢀ20
>99
64
>99
38.4
88/12
88/12
84/16
89/11
78/22
81/19
92/8
97/3
71/29
93/7
88/12
92/8
87/13
87/13
98/2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
98
77
97
77
82
93
82
96
72
60
99
92
11.2
Table 2
The effect of solvents on the direct aldol reaction of 4-nitrobenzaldehyde with
cyclohexanone by 4 (20 mol %) and AcOH (20 mol %)
Entry
Solvent
Yielda (%)
anti/synb
eec (%)
1
2
3
4
5
6
7
8
CH2Cl2
THF
Et2O
85
77
75
44
38
36
98
87
88/12
90/10
87/13
96/4
79/21
73/27
98/2
90
82
86
70
75
83
93
83
DMF
CH3CN
MeOH
CHCl3
Tol
92/8
93/7
Pro (20%) AcOH (20%) ꢀ20
81/19
a
b
c
a
Isolated yield.
Isolated yield.
Determined by 1H NMR of the crude product.
Determined by chiral HPLC.
Determined by 1H NMR of the crude product.
Determined by chiral HPLC.
b
c

F. Chen et al. / Tetrahedron 64 (2008) 9585–9591
9587
Table 4
reactions in more polar solvents such as DMF, CH3CN, and protic
MeOH led to a decrease both in yields and in enantioselectivities
(Table 2, entries 4–6).
Scope of the aldehydes for the direct aldol reaction with cyclohexanone under
optimal conditions
O
OH
O
Pyrrolidine-based organocatalysts catalyze the aldol reaction is
presumed to proceed via enamine intermediate.4y The overall rate
of the reaction would be improved by any factors, which could
promote the enamine formation.4x,8a,d,e,11 Pihko4x and Gryko10r have
thoroughly studied the influence of additives on the reactions and
found that an appropriate acid could effectively enhance the activity
of the catalysts. This influence is susceptible to subtle changes in the
catalyst structures and reaction conditions. In order to find proper
acid additive to match our catalyst, we have studied the influence of
acid additive on the reactivity (Table 3). When stronger acids were
used, the reaction was almost completely suppressed (Table 3, en-
tries 1, 4, 8). This is somewhat same as what was observed in Gryko’s
4 (20%), additive (20%)
R
+
CHO
R
CHCl3, -20 °C
Entry
R
Additivea
Yieldb (%)
anti/sync
eed (%)
1
2
3
4
5
6
7
8
4-NO2C6H4
4-NO2C6H4
3-NO2C6H4
3-NO2C6H4
2-NO2C6H4
2-NO2C6H4
4-BrC6H4
4-BrC6H4
Ph
A
B
A
B
A
B
A
B
A
B
B
A
B
A
B
A
B
98
87
99
94
60
85
75
75
27
29
98
93
93
61
81
73
86
98/2
93
93
94
96
94
95
93
98
90
52
87
97
96
94
93
94
94
87/13
82/18
87/13
82/18
90/10
91/9
90/10
81/19
94/6
81/19
99/1
99/1
94/6
98/2
9
L-prolinethioamide catalyst system. Benzoic acid, substituted ben-
10
11e
12
13
14
15
16
17
Ph
Ph
zoic acid, and acetic acid gave similar good yields and enantiose-
lectivities (Table 3, entries 3, 5, 11, 12). Acetic acid gave the optimal
performance, where all the yield, chemoselectivity, and enantiose-
lectivity were the most satisfactory (Table 3, entry 12). The same
enantioselectivity was observed when 2-methylbenzoic acid was
used. Use of H2O and AcOH in the ratio of 1:1 as additive only slightly
decreased the yield and selectivity (Table 3, entry 2 vs entry 12).
2,4-Cl2C6H4
2,4-Cl2C6H4
2-ClC6H4
2-ClC6H4
2-BrC6H4
2-BrC6H4
95/5
91/9
a
A¼AcOH, B¼2-MePhCOOH.
b
c
Isolated yield.
Determined by 1H NMR of the crude product.
Determined by chiral HPLC.
The reaction was carried out at ꢀ10 ꢁC.
Table 3
d
e
The effect of additives on the direct aldol reaction of 4-nitrobenzaldehyde with
cyclohexanone by 4 (20 mol %) in chloroform
Entry
Additive (20%)
Yielda (%)
anti/synb
eec (%)
obtained when this reaction was carried out at ꢀ10 ꢁC (Table 4,
entry 11). This is possibly due to its electron-rich character and
hence has showed lower reactivity.
1
2
3
4
5
6
7
8
CF3COOH
AcOH, H2O
PhCOOH
Trace
94
98
<10
95
79
79
<10
39
38
87
d
d
92/8
91/9
d
92
92
88
92
87
90
95
71
67
93
93
PTSA$H2O
The reactions of 4-nitrobenzaldehyde with acetone (I), butanone
(II), and 2-pentanone (III) using 4 as catalyst were also investigated.
As shown in Scheme 1, acetone gave the desired product in 88%
yield with 48% ee. The reaction with butanone also worked well and
preferentially occurred at the C-3 position of butanone to give the
desired product (IIb) (54% yield) in good diastereoselectivity
(90:10) and enantioselectivity (96% ee), and the minor product (IIa)
(36% yield) with only 53% ee. On the contrary, the reaction of
2-heptanone only occurred at its C-1 position gave the correspond-
ing product (IIIa) with low enantioselectivity (20% ee) in 69% yield.
According to the stereochemical outcome in the above direct
aldol reactions catalyzed by 4, we propose that the proline-based
dipeptides could catalyze the direct asymmetric aldol reactions
between ketones and aldehydes via the plausible six-membered
chair-like transition state T1 (Scheme 2).5f,10k The aldehyde could be
activated by hydrogen bonding with the two NH of the catalyst in
a manner such that C–C bond formation could take place from its re
face. When 2-heptanone was used as the substrate, the reaction
only took place at its C-1 position. This may be explained by tran-
sition states T2 and T3. If the reaction took place at its C-3 position,
the strong-nonbonding interaction between R group and ethyl
group would have had been disfavored as shown in transition state
T3. When butanone was used as the substrate, the nonbonding
interaction between R group and methyl group was weaker, so two
products IIa and IIb were obtained.
2-FPhCOOH
n-Octylic acid
ClCH2COOH
2,4,6-Trinitrophenol
4-Nitrophenol
Phenol
91/9
86/14
91/9
d
9
84/16
92/8
87/13
98/2
10
11
12
2-MePhCOOH
AcOH
98
a
Isolated yield.
b
c
Determined by 1H NMR of the crude product.
Determined by chiral HPLC.
With the optimal conditions in hand, we investigated a variety
of aromatic aldehydes and the results are summarized in Table 4.
High yields and enantioselectivities (up to 98% ee) were obtained
for aromatic aldehydes with electron-withdrawing group on the
benzene ring (Table 4, entries 1–8, 12–17). The additive 2-MePh-
COOH (pKa¼4.36) is superior to AcOH (pKa¼4.76) for most sub-
strates and better yield or enantioselectivity (Table 4, entries 5–8,
16–17) was achieved. Besides the slight difference in their pKa
value, the counter ion of BrFnsted acid may also cause steric effect
on the reaction and different enantioselectivity was observed when
they were used independently to co-catalyze the same substrate.
The reaction of benzaldehyde proceeded very slowly at ꢀ20 ꢁC and
only 27% yield was obtained with 90% ee after 24 h (Table 4, entry
9), whereas good yield (98%) and enantioselectivity (84% ee) were
O
OH
O
OH
CHO
O
+
R3
4 (20%), HOAc(20%)
+
R3
R3
O2N
CHCl3, -20 °C
NO2
NO2
I: R3 = H
II: R3 = Me
Ia: 88% yield, 48% ee
IIa:36% yield, 53% ee;
IIb:54% yield, anti/syn
ee
= 90 /10; anti: 96%
III:R3 = Et
IIIa: 69% yield, 39% ee
Scheme 1.

9588
F. Chen et al. / Tetrahedron 64 (2008) 9585–9591
dropwise and the resulting mixture was stirred for 20 min. Aniline
O
O
O
(0.56 g, 6 mmol) was added and the resulting mixture was stirred
for another 1 h, then the reaction mixture was warmed to room
temperature slowly and stirred overnight. NaHCO3 solution (5%,
10 mL) was added and the resulting mixture was stirred for 30 min.
The aqueous solution was extracted with ethyl acetate (3ꢂ50 mL).
The combined organic layers were washed with 1.0 M hydrochloric
acid (20 mL), brine (30 mL), and dried over Na2SO4. The solvent was
evaporated to give a residue (white solid, 1.2 g). The solid was
dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added. The mixture
was stirred overnight at room temperature. Then diluted with ethyl
acetate (100 mL) and washed with 10% sodium hydroxide solution
(20 mL). The organic layer was washed with brine (20 mL) and
N
N
N
R1
R
Me
Me
Me
R
O
H
N
H
H
N
H
H
N
H
O R2
R
O
H
H
H
H
N
N
N
H
H
O
O
O
T2
Scheme 2.
T3
T1
3. Conclusion
dried over Na2SO4. The solvent was evaporated to give
(0.80 g, 4.8 mmol).
L-Ala–NHPh
We have developed a series of new proline-based dipeptides
catalysts with two amide units for asymmetric direct aldol reaction.
High yields (up to 99%), enantioselectivities (up to 98% ee) and anti-
diastereoselectivities (up to 99:1) were obtained using this catalytic
N-Boc-L-proline (0.86 g, 4.0 mmol) and TEA (0.70 mL, 5.0 mmol)
were dissolved in dry THF (30 mL). The solution was cooled down
to ꢀ15 ꢁC. Ethylchloroformate (0.60 mL, 4.8 mmol) was added
dropwise and the reaction mixture was stirred for 20 min, L-Ala–
system. Based on the L-proline catalysis model, we believe that the
NHPh (0.80 g, 4.8 mmol) was added and the reaction mixture was
stirred for another 1 h, then slowly warmed to room temperature
and stirred overnight. NaHCO3 solution (5%, 10 mL) was added and
the mixture was stirred for 30 min. The aqueous layer was extrac-
ted with ethyl acetate (3ꢂ50 mL). The combined organic layers
were washed with 1.0 M hydrochloric acid (20 mL), brine (30 mL),
and dried over Na2SO4. The solvent was evaporated to give a resi-
due and flash column chromatography on silica afforded Boc-4 as
white solid. The solid was dissolved in CH2Cl2 (2 mL) and TFA
(2 mL) was added. The mixture was stirred overnight at room
temperature. Then diluted with ethyl acetate (100 mL), the mixture
was washed with 10% sodium hydroxide solution (20 mL). The or-
ganic layer was washed with brine (20 mL) and dried over Na2SO4.
two amide units play a key role in stabilizing the transition state by
forming hydrogen bonds between the catalysts and the aldehydes,
and these two tunable functionalities not only activate the aldol
acceptor but also favor one-face of the acceptor to the attack of the
enamine. The extension of the catalysts to other organic trans-
formations is currently being investigated in our laboratory and
will be reported in due course.
4. Experimental
4.1. General
Unless otherwise indicated, all reagents were purchased from
commercial suppliers and used without further purification.
Reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm silica gel plates visualized with UV light
and/or by staining with ethanol phosphomolybdic acid (PMA).
Flash column chromatography was performed on silica gel H (10–
The solvent was evaporated to give 4 (1.0 g) as a white solid; yield
rt
(97%). [
n
a
]
D
ꢀ169.2 (c 0.52, CHCl3); mp 172–173 ꢁC; IR (KBr):
¼3309, 3269, 3205, 3142, 3101, 2979, 2871, 1697, 1647, 1613, 1556,
1515, 1447, 1375, 1322, 1251, 1215, 763, 733, 695 cmꢀ1
;
1H NMR
¼9.15 (s, 1H), 8.20 (d, J¼7.41 Hz, 1H), 7.56 (d,
(CDCl3, 300 MHz):
d
J¼7.80 Hz, 2H), 7.28 (t, J¼7.11 Hz, 2H), 7.06 (t, J¼7.35 Hz, 1H), 4.60–
4.67 (m, 1H), 3.75–3.80 (q, 1H), 2.99–3.07 (m, 1H), 2.88–2.96 (m,
1H), 2.12–2.22 (m, 1H), 2.05 (s, 1H), 1.90–1.96 (m, 1H), 1.68–1.78 (m,
2H), 1.46 (d, J¼6.9 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): 176.2, 170.2,
138.2, 128.8, 123.9, 119.7, 60.3, 49.2, 47.2, 30.6, 26.2, 16.9 ppm. MS
(ESI): 261.71 (Mþ).
40
mm). NMR spectra were recorded on 300 MHz instruments.
Chemical shifts (
d) are given in parts per million relative to TMS,
coupling constants (J) in hertz. IR spectra were recorded on a Perkin
Elmer-GX spectrometer. Melting points were determined on an X-6
digital melting-point apparatus and were uncorrected. Optical
rotations were measured on a Perkin Elmer 341 Polarimeter at
l
¼589 nm. Analytical high performance liquid chromatography
4.2.2. H–
L-Pro–L-Phg–NPh (1)
(HPLC) was carried out on WATERS 510 instrument (2487 Dual
Absorbance Detector and 515 HPLC Pump) using chiral column.
l
rt
White solid; [
a]
D þ54.3 (c 0.49, CHCl3); mp 176–177 ꢁC; IR (KBr):
n
¼3283, 3206, 3141, 3092, 2970, 2871, 1693, 1652, 1603, 1551, 1500,
1443, 1369, 1330, 1247, 758, 695 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
4.2. General procedure for the synthesis of catalysts12
d
¼9.35 (s, 1H), 9.06 (d, J¼8.0 Hz, 1H), 7.47–7.58 (m, 4H), 7.22–7.33
(m, 5H), 7.04 (t, J¼7.3 Hz, 1H), 6.01 (d, J¼8.12 Hz, 1H), 3.81–3.85 (q,
1H), 2.94–3.09 (m, 2H), 2.09–2.19 (m, 2H), 1.89–1.99 (m, 1H), 1.67–
1.76 (m, 2H); 13C NMR (CDCl3, 75.5 MHz): 175.5, 168.5, 138.2, 137.9,
128.9, 128.8, 128.1, 127.0, 124.1, 119.7, 60.5, 57.2, 47.3, 30.7, 26.2 ppm.
MS (ESI): 323.85 (Mþ).
O
R1
R1
NHR2
O
NHR2
NH2
O
OH
R2NH2
a
b
NHBoc
R1
R1
NHBoc
COOH
O
R1
O
4.2.3. H–
White solid; [
(KBr):
L-Pro–L-Phe–NPh (2)
N
b
O
O
Boc
rt
a]
ꢀ57.4 (c 1.0, CHCl3); mp 141.7–143.5 ꢁC; IR
N
H
N
H
D
a
N
H
N
n
¼3443, 3315, 3063, 2970,1690,1648,1534,1499,1445, 1368,
HN
HN
Boc
R2
R2
1313, 1204, 1135, 750, 699 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d¼8.90
(a) ClCOOCH2CH(CH3)2, Et3N, THF; (b) F3CCOOH, CH2Cl2
(s, 1H), 8.29 (d, J¼7.83 Hz, 1H), 7.47 (d, J¼7.88 Hz, 1H), 7.21–7.49 (m,
7H), 7.06 (t, J¼7.35 Hz, 1H), 4.75–4.82 (m, 1H), 3.70–3.74 (q, 1H),
3.25–3.32 (m, 1H), 3.02–3.10 (m, 1H), 2.87–2.93 (m, 1H), 2.65–2.69
(m, 1H), 2.16 (s, 1H), 1.97–2.04 (m, 1H), 1.63–1.73 (m, 1H), 1.50–1.60
(m, 1H), 1.27–1.41 (m, 1H); 13C NMR (CDCl3, 75.5 MHz): 176.3, 169.2,
137.8, 136.8, 129.2, 128.8, 128.5, 126.8, 124.1, 119.8, 60.1, 54.7, 47.0,
37.0, 30.5, 25.7 ppm. MS (ESI): 337.87 (Mþ).
4.2.1. H–
L
-Pro–
L-Ala–NPh (4)
N-Boc-
L-alanine (1.1 g, 5.8 mmol) and TEA (1.2 mL, 9.1 mmol)
were dissolved in dry THF (30 mL). The solution was cooled down
to ꢀ15 ꢁC. Ethylchloroformate (0.88 mL, 7.0 mmol) was added

F. Chen et al. / Tetrahedron 64 (2008) 9585–9591
9589
4.2.4. H–
L
-Pro–Glu–NPh (3)
121.5, 113.9, 60.1, 55.4, 54.6, 47.0, 37.1, 30.5, 25.8 ppm. MS (ESI):
367.86 (Mþ).
rt
White solid; [
a]
ꢀ39.8 (c 0.5, MeOH); mp 99–103 ꢁC; IR (KBr):
D
n
¼3348, 3318, 3268, 3075, 2939, 2869, 1693, 1636, 1601, 1560, 1521,
1500, 1444, 1423, 1372, 1310, 1260, 1213, 1100, 750, 689 cmꢀ1
;
1H
¼7.54 (d, J¼7.88 Hz, 2H), 7.30 (t,
4.2.10. H–
White solid; [
(KBr):
L-Pro–L-Phe–N–3,5-(CF3)2Ph (10)
rt
NMR (CD3OD, 300 MHz):
d
a
]
ꢀ63.7 (c 0.52, CHCl3); mp 132–134 ꢁC; IR
D
J¼7.68 Hz, 2H), 7.08 (t, J¼7.37 Hz, 1H), 4.90 (s, 3H), 4.03 (d,
J¼3.57 Hz, 2H), 3.72–3.76 (m, 1H), 2.90–3.04 (m, 2H), 2.09–2.21 (m,
1H), 1.71–1.88 (m, 3H); 13C NMR (CD3OD, 75.5 MHz): 178.0, 169.4,
139.5, 129.8, 125.2, 121.1, 61.5, 47.9, 43.6, 31.9, 27.0 ppm. MS (ESI):
247.68 (Mþ).
n
¼3294, 3190, 3117, 2971, 2877, 1653, 1580, 1525, 1472, 1444,
1385, 1280, 1172, 1133, 886, 741, 700, 682 cmꢀ1
300 MHz):
;
1H NMR (CDCl3,
d
¼9.87 (s, 1H), 8.41 (d, J¼7.34 Hz, 1H), 7.99 (s, 2H), 7.53
(s, 1H), 7.19–7.28 (m, 5H), 4.77–4.84 (m, 1H), 3.74–3.79 (m, 1H),
3.28–3.34 (m, 1H), 3.05–3.10 (m, 1H), 2.91–2.99 (m, 1H), 2.64–2.71
(m, 1H), 2.01–2.08 (m, 1H), 1.56–1.76 (m, 3H), 1.33–1.38 (m, 1H); 13
C
4.2.5. H–
L
-Pro–
L
-Leu–NPh (5)
NMR (CDCl3, 75.5 MHz): 177.0, 169.9, 139.5, 136.3, 132 (q), 129.1,
128.7, 127.1, 124.9, 121.2, 119.4, 117.0, 60.1, 55.0, 47.1, 36.9, 30.6,
25.8 ppm. MS (ESI): 473.87 (Mþ).
rt
White solid; [
a]
ꢀ70.2 (c 1, MeOH); mp 92.0–93.5 ꢁC; IR (KBr):
D
n
¼3279, 3139, 3084, 2960, 2870, 1694, 1648, 1603, 1544, 1523, 1502,
1442, 1313, 1251, 1107, 756, 694 cmꢀ1 1H NMR (CDCl3, 300 MHz):
;
d
¼9.13 (s, 1H), 8.15 (d, J¼7.91 Hz, 1H), 7.53 (d, J¼7.91 Hz, 2H), 7.26 (t,
4.2.11. H–
L-Pro–L-Ala–N–(S)-CH(CH3)Ph (11)
rt
J¼6.88 Hz, 2H), 7.05 (t, J¼7.34 Hz, 1H), 4.57–4.60 (m, 1H), 3.75–3.80
(m, 1H), 2.98–3.06 (m, 1H), 2.86–2.94 (m, 1H), 2.09–2.22 (m, 1H),
2.04 (s, 1H), 1.62–1.96 (m, 6H), 0.97 (d, J¼6.14 Hz, 3H), 0.92 (d,
J¼6.25 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): 176.3, 170.1, 138.1,
128.7, 123.9, 119.7, 60.2, 51.9, 47.2, 39.7, 30.7, 26.2, 24.9, 22.9,
21.9 ppm. MS (ESI): 303.83 (Mþ).
White solid; [
a]
D ꢀ146 (c 0.55, CHCl3); mp 208–209 ꢁC; IR (KBr):
n
¼3297, 2968, 1641, 1554, 1534, 1449, 1380, 1218, 1158, 754,
701 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d
¼8.13 (s, 1H), 7.36–7.22 (m,
5H), 7.16 (s,1H), 5.00–5.09 (m,1H), 4.45–4.49 (m,1H), 3.71–3.76 (m,
1H), 2.97–3.05 (m, 1H), 2.86–2.94 (m, 1H), 2.28 (s, 1H), 2.06–2.16
(m,1H),1.82–1.93 (m,1H),1.65–1.74 (m, 2H),1.44 (d, J¼6.90 Hz, 3H),
1.34 (d, J¼6.93 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): 175.4, 171.2,
143.4, 128.6, 127.1, 126.0, 60.3, 48.8, 48.5, 47.2, 30.6, 26.1, 22.1,
17.9 ppm. MS (ESI): 289.82 (Mþ).
4.2.6. H–
White solid; [
(KBr):
L-Pro–L-Val–NPh (6)
rt
a
]
D
ꢀ64.6 (c 0.5, MeOH); mp 210.9–212.7 ꢁC; IR
n
¼3278, 3140, 2959, 2870, 1694,1648, 1603, 1546, 1523,1503,
1442, 1312, 1251, 1107, 756, 694 cmꢀ1
;
1H NMR (CDCl3, 300 MHz):
4.2.12. H–
White solid; [
(KBr):
L-Pro–L-Ala–N(p-Me)Ph (12)
rt
d
¼8.90 (s, 1H), 8.38 (d, J¼8.85 Hz, 1H), 7.57 (d, J¼7.80 Hz, 2H), 7.28
a
]
ꢀ166.9 (c 0.45, CHCl3); mp 168–169 ꢁC; IR
D
(t, J¼7.65 Hz, 2H), 7.07 (t, J¼7.33 Hz, 1H), 4.39–4.43 (br, 1H), 3.80
(dd, J¼9.15 Hz, 4.89 Hz, 1H), 2.94–3.04 (m, 2H), 2.13–2.29 (m, 3H),
1.95–1.99 (m, 1H), 1.71–1.76 (m, 2H), 0.99–1.04 (m, 6H); 13C NMR
(CDCl3, 75.5 MHz): 175.9, 169.7, 138.0, 128.8, 124.1, 119.9, 60.4, 59.1,
47.3, 30.9, 30.3, 26.1, 19.5, 18.2 ppm. MS (ESI): 289.78 (Mþ).
n
¼3359, 3305, 3268, 3201, 3133, 2972, 2869, 1684, 1645,
1610, 1547, 1511, 1448, 1405, 1315, 1248, 821, 734 cmꢀ1
;
1H NMR
¼9.03 (d, J¼19.8 Hz, 1H), 8.19 (s, 1H), 7.44 (d,
(CDCl3, 300 MHz):
d
J¼7.95 Hz, 2H), 7.08 (d, J¼8.1 Hz, 2H), 4.60–4.67 (m, 1H), 3.72–3.79
(q, 1H), 2.98–3.06 (m, 1H), 2.88–2.95 (m, 1H), 2.29 (s, 3H), 2.11–2.21
(m, 1H), 1.87–1.99 (m, 2H), 1.68–1.77 (m, 2H), 1.45 (d, J¼6.9 Hz, 3H);
13C NMR (CDCl3, 75.5 MHz): 176.0, 170.1, 135.6, 133.5, 129.3,
119.6, 60.2, 49.1, 47.2, 30.6, 26.2, 20.8, 17.3, 17.2 ppm. MS (ESI):
275.75 (Mþ).
4.2.7. H–
White solid; [
(KBr):
750, 716 cmꢀ1
J¼9.12 Hz, 1H), 7.58 (d, J¼7.89 Hz, 2H), 7.26 (t, J¼7.65 Hz, 2H), 7.05
(t, J¼7.35 Hz, 1H), 4.54 (t, J¼8.43 Hz, 1H), 3.75–3.80 (q, 1H),
2.92–3.01 (m, 2H), 2.29 (s, 1H), 2.11–2.18 (m, 1H), 1.90–2.04 (m, 2H),
1.67–1.76 (m, 2H), 1.52–1.63 (m, 1H), 1.07–1.20 (m, 1H), 1.00 (d,
J¼6.7 Hz, 3H), 0.91 (t, J¼7.36 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz):
175.7,170.0,138.1,128.7,123.9,119.9, 60.3, 58.0, 47.2, 36.9, 30.9, 26.1,
24.8, 15.6, 11.1 ppm. MS (ESI): 303.86 (Mþ).
L-Pro–L-Ile–NPh (7)
rt
a]
ꢀ108.8 (c 0.48, CHCl3); mp 154–155 ꢁC; IR
D
n
¼3305, 3216, 2962, 2856, 1645, 1602, 1541, 1445, 1377, 1197,
;
1H NMR (CDCl3, 300 MHz):
d¼9.29 (s, 1H), 8.40 (d,
4.2.13. H–
L-Pro–L-Ala–N(p-MeO)Ph (13)
rt
White solid; [
a]
ꢀ95.8 (c 1, MeOH); mp 184–186 ꢁC; IR (KBr):
D
n
¼3360, 3308, 3267, 3200, 3133, 2970, 1685, 1646, 1611, 1546,
1512, 1446, 1403, 1316, 1247, 1204, 1106, 937, 821, 733 cmꢀ1
;
1H
¼8.99 (s, 1H), 8.20 (d, J¼7.56 Hz, 1H),
NMR (CDCl3, 300 MHz):
d
7.46 (d, J¼8.93 Hz, 2H), 6.82 (d, J¼8.96 Hz, 2H), 4.60–4.64 (m, 1H),
3.74–3.79 (m, 4H), 3.01–3.07 (m, 1H), 2.88–2.99 (m, 1H), 2.04–2.20
(m, 2H), 1.88–1.94 (m, 1H), 1.68–1.77 (m, 2H), 1.44 (d, J¼6.94 Hz,
3H); 13C NMR (CDCl3, 75.5 MHz): 176.1, 169.9, 156.1, 131.3,
121.3, 113.9, 60.3, 55.4, 49.1, 47.2, 30.6, 26.2, 17.1 ppm. MS (ESI):
291.75 (Mþ).
4.2.8. H–
L-Pro–L-Phe–NMe (8)
rt
White solid; [
a
]
D ꢀ77.1 (c 0.55, CHCl3); mp 148–149 ꢁC; IR (KBr):
n
¼3282, 3099, 3028, 2961, 2909, 1643, 1596, 1501, 1414, 1328, 1162,
1099, 747, 713 cmꢀ1
;
1H NMR (CDCl3, 300 MHz):
d¼8.10 (d,
J¼8.04 Hz, 1H), 7.18–7.30 (m, 5H), 6.33 (s, 1H), 4.54–4.57 (m, 1H),
4.2.14. H–
L-Pro–L-Ala–N(p-NO2)Ph (14)
rt
3.64–3.69 (q, 1H), 3.15–3.22 (q, 1H), 2.87–3.04 (m, 2H), 2.65–2.74
Yellow oil; [
a]
ꢀ115.6 (c 0.5, CHCl3); IR (KBr): ¼3287, 3158,
n
D
(m, 4H), 1.91–1.99 (m, 2H), 1.53–1.67 (m, 2H), 1.33–1.40 (m, 1H); 13
C
3094, 2969, 2874, 1705, 1650, 1619, 1597, 1563, 1509, 1451, 1409,
NMR (CDCl3, 75.5 MHz): 175.8, 171.6, 137.0, 129.1, 128.4, 126.8, 60.2,
1340, 1301, 1258, 1198, 1174, 1153, 1111, 855, 751, 690 cmꢀ1; 1H NMR
53.8, 47.1, 37.5, 30.5, 26.1, 25.8 ppm. MS (ESI): 275.74 (Mþ).
(CDCl3, 300 MHz):
d¼10.07 (s, 1H), 8.34 (d, J¼6.93 Hz, 1H), 8.14 (d,
J¼9.03 Hz, 2H), 7.71 (d, J¼9.03 Hz, 2H), 4.64–4.71 (m,1H), 3.82–3.87
(q, 1H), 3.04–3.12 (m, 1H), 2.92–2.99 (m, 1H), 2.16–2.29 (m, 2H),
1.89–1.97 (m, 1H), 1.72–1.81 (m, 2H), 1.48 (d, J¼6.86 Hz, 3H); 13C
NMR (CDCl3, 75.5 MHz): 176.6, 170.9, 144.2, 143.1, 124.8, 119.0, 60.2,
49.6, 47.2, 30.6, 26.2, 17.0 ppm. MS (ESI): 306.8 (Mþ).
4.2.9. H–
White solid; [
(KBr):
L-Pro–L-Phe–N(p-MeO)Ph (9)
rt
a]
ꢀ52.2 (c 0.46, CHCl3); mp 100–101 ꢁC; IR
D
n
¼3286, 3063, 2957, 1659, 1609, 1553, 1511, 1410, 1241, 1174,
1109, 1032, 830, 742, 700, 653 cmꢀ1 1H NMR (CDCl3, 300 MHz):
;
d
¼8.64 (s, 1H), 8.27 (d, J¼7.83 Hz, 1H), 7.36 (d, J¼8.82 Hz, 2H),
7.21–7.29 (m, 5H), 6.80 (d, J¼8.84 Hz, 2H), 4.71–4.78 (q, 1H), 3.77
(s, 3H), 3.68–3.73 (m, 1H), 3.24–3.30 (m, 1H), 3.02–3.10 (m, 1H),
2.87–2.95 (m, 1H), 2.63–2.70 (m, 1H), 1.94–2.04 (m, 2H), 1.62–1.73
(m, 1H), 1.52–1.60 (m, 1H), 1.30–1.39 (m, 1H); 13C NMR (CDCl3,
75.5 MHz): 176.3, 168.9, 156.2, 136.9, 130.9, 129.2, 128.5, 126.8,
4.2.15. H–
White solid; [
(KBr):
D-Pro-L–Ala–N(p-Me)Ph (15)
rt
a
]
ꢀ50.9 (c 1.0, CHCl3); mp 183.8–185.6 ꢁC; IR
D
n
¼3447, 3297, 3071, 2962, 1652, 1602, 1544, 1500, 1444, 1380,
1313, 1243, 1200, 1058, 1031, 935, 900, 746, 691 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz):
d¼8.93 (s, 1H), 8.15 (d, J¼7.29 Hz, 1H), 7.41 (d,

9590
F. Chen et al. / Tetrahedron 64 (2008) 9585–9591
J¼8.31 Hz, 2H), 7.10 (d, J¼8.22 Hz, 2H), 4.57–4.64 (m, 1H), 3.80 (dd,
J¼9.16 Hz, 5.25 Hz, 1H), 2.96–3.02 (m, 1H), 2.86–2.93 (m, 1H), 2.29
(s, 3H), 2.10–2.22 (m, 1H), 1.82–1.93 (m, 2H), 1.63–1.72 (m, 2H), 1.46
(d, J¼6.96 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): 176.4, 170.0, 135.6,
133.5, 129.3, 119.7, 60.3, 49.1, 47.2, 30.9, 26.1, 20.8, 16.7 ppm. MS
(ESI): 275.73 (Mþ).
hexane 10/90), 254 nm, flow rate 0.5 mL/min, tminor¼32.4 and
tmajor¼39.1.
4.3.5. (2S,10R)-2-(Hydroxy-(2,4-dichlorophenyl)methyl)
cyclohexan-1-one6b
rt
Yield: 93%; [
a
]
22.9 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
D
d
¼7.50 (d, J¼8.40 Hz, 1H), 7.35 (d, J¼1.95 Hz, 1H), 7.27–7.31 (m, 1H),
4.2.16. H–
L
-Pro–
D
-Ala–NPh (16)
5.27–5.31 (m, 1H), 4.05 (d, J¼3.96 Hz, 1H), 2.58–2.66 (m, 1H), 2.45–
2.49 (m, 1H), 2.28–2.39 (t, 1H), 2.07–2.13 (m, 1H), 1.83–1.85 (m, 1H),
1.52–1.76 (m, 4H); ee: 97%, determined by HPLC (Daicel Chiralpak
AS-H, i-PrOH/hexane 10/90), 254 nm, flow rate 0.5 mL/min,
tminor¼15.2 and tmajor¼16.8.
rt
White solid; [
a
]
þ56.3 (c 1.0, CHCl3); mp 174–176 ꢁC; IR (KBr):
D
n
¼3311, 3276, 3209, 3148, 3106, 2977, 2935, 2874, 1691, 1645, 1613,
1558,1519,1447,1378,1348,1318,1298,1252,1179,1145, 1081,1062,
997, 941, 759, 735, 693 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
¼9.12 (s,
d
1H), 8.19 (d, J¼5.67 Hz, 1H), 7.54 (d, J¼7.87 Hz, 2H), 7.29 (t,
J¼7.63 Hz, 2H), 7.07 (t, J¼7.33 Hz, 1H), 4.61–4.68 (m, 1H), 3.81 (dd,
J¼9.15 Hz, 5.27 Hz, 1H), 2.97–3.05 (m, 1H), 2.87–2.94 (m, 1H), 2.10–
2.22 (m, 1H), 2.06 (s, 1H), 1.83–1.94 (m, 1H), 1.64–1.73 (m, 2H), 1.47
(d, J¼6.96 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): 176.3, 170.2, 138.2,
128.8, 123.9, 119.7, 60.3, 49.2, 47.2, 30.8, 26.1, 16.8 ppm. MS (ESI):
261.73 (Mþ).
4.3.6. (2S,10R)-2-(Hydroxy-(o-chlorophenyl)methyl)
cyclohexan-1-one5b
rt
Yield: 81%; [
a]
þ4.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
D
d
¼7.54–7.56 (m, 1H), 7.18–7.34 (m, 3H), 5.35 (d, J¼8.10 Hz, 1H), 4.04
(s, 1H), 2.64–2.70 (m, 1H), 2.29–2.49 (m, 2H), 2.06–2.12 (m, 1H),
1.80–1.84 (m, 1H), 1.50–1.75 (m, 4H); ee: 97%, determined by HPLC
(Daicel Chiralpak OD-H, i-PrOH/hexane 5/95), 220 nm, flow rate
1 mL/min, tmajor¼9.4 and tminor¼12.1.
4.3. General procedure for aldol reaction of cyclohexanone
with aldehyde
4.3.7. (2S,10R)-2-(Hydroxy-(o-bromophenyl)methyl)
The catalyst (0.1 mmol) and AcOH (0.1 mmol) were stirred in
2 mL chloroform/cyclohexanone (1:1) for 20 min at ꢀ20 ꢁC. The
corresponding aldehyde (0.5 mmol) was added and the mixture
was stirred for 24–72 h. The reaction mixture give pure aldol
adduct after flash column chromatography on silica gel. The
enantiomeric excess was determined by chiral HPLC with Daicel
Chiralpak AS-H, AD-H, or OD-H.
cyclohexan-1-one
rt
Yield: 86%; [
a
]
D þ20.1 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3):
d
¼7.50–7.54 (m, 2H), 7.33 (t, J¼24.6 Hz, 1H), 7.11–7.16 (m, 1H), 5.30
(d, J¼9.60 Hz, 1H), 4.02 (s, 1H), 2.64–2.73 (m, 1H), 2.29–2.49 (m,
2H), 2.06–2.12 (m, 1H), 1.49–1.84 (m, 5H); ee: 97%, determined by
HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane 5/95), 220 nm, flow
rate 1 mL/min, tmajor¼9.8 and tminor¼12.5.
4.3.1. (2S,10R)-2-(Hydroxy-(p-nitrophenyl)methyl)
4.3.8. (2S,10R)-2-(Hydroxy(phenyl)methyl) cyclohexan-1-one8e
rt
cyclohexan-1-one3d
Yield: 98%; [
a]
D þ22.9 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
rt
Yield: 98%; [
a]
D þ11.3 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
d
¼7.25–7.38 (m, 5H), 4.79 (d, J¼9.3 Hz, 1H), 4.00 (m, 1H), 2.63–2.67
d
¼8.22 (d, J¼9.3 Hz, 2H), 7.52 (d, J¼9.3 Hz, 2H), 4.90 (d, J¼6.2 Hz,
(m, 1H), 2.35–2.47 (m, 2H), 2.07 (m, 1H), 1.52–1.78 (m, 4H), 1.20–
1.22 (m, 1H); ee: 84%, determined by HPLC (Daicel Chiralpak OD-H,
i-PrOH/hexane 5/95), 220 nm, flow rate 1 mL/min, tmajor¼12.3 and
tminor¼19.5.
1H), 4.10 (s, 1H), 2.48–2.60 (m, 2H), 2.32–2.42 (m, 1H), 2.09–2.15
(m, 1H), 1.20–1.85 (m, 5H); ee: 96%, determined by HPLC (Daicel
Chiralpak AD-H, i-PrOH/hexane 5/95), 254 nm, flow rate 1.0 mL/
min, tmajor¼46.6 and tminor¼63.3.
4.3.9. (R)-1-Hydroxy-1-(4-nitrophenyl) pentan-3-one8e
4.3.2. (2S,10R)-2-(Hydroxy-(m-nitrophenyl)methyl)
Yield: 36%; 1H NMR (300 MHz, CDCl3):
d
¼8.20 (d, J¼8.7 Hz, 2H),
cyclohexan-1-one8e
7.55 (d, J¼8.6 Hz, 2H), 5.26–5.29 (q, 1H), 3.69 (s, 1H), 2.81–2.84 (m,
2H), 2.45–2.52 (q, 2H), 1.06–1.11 (t, 3H); ee: 53%, determined by
HPLC (Daicel Chiralpak AS-H, i-PrOH/hexane 30/70), 254 nm, flow
rate 1 mL/min, tmajor¼6.7 and tminor¼8.7.
rt
Yield: 94%; [
a
]
37.6 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3):
D
d
¼8.09–8.20 (m, 2H), 7.66 (d, J¼7.7 Hz, 1H), 7.49–7.55 (m, 1H), 4.89
(d, J¼8.49 Hz, 1H), 4.12–4.15 (m, 1H), 2.58–2.67 (m, 1H), 2.36–2.52
(m, 2H), 2.08–2.14 (m, 1H), 1.70–1.85 (m, 1H), 1.53–1.70 (m, 3H),
1.35–1.44 (m, 1H); ee: 96%, determined by HPLC (Daicel Chiralpak
AD-H, i-PrOH/hexane 5/95), 254 nm, flow rate 1.0 mL/min,
tmajor¼41.5 and tminor¼55.6.
4.3.10. (3S,4R)-4-Hydroxy-3-methyl-4-(4-nitrophenyl)
butan-2-one8e
Yield: 54%; 1H NMR (300 MHz, CDCl3):
d
¼8.22 (d, J¼8.7 Hz, 2H),
7.53 (d, J¼8.7 Hz, 2H), 4.88 (d, J¼8.7 Hz, 1H), 2.86–2.94 (q, 1H), 2.21
(s, 3H), 1.03 (d, J¼7.3 Hz, 3H); ee: 96%, determined by HPLC (Daicel
Chiralpak AS-H, i-PrOH/hexane 30/70), 254 nm, flow rate 1 mL/
min, tmajor¼6.3 and tmino r¼7.1.
4.3.3. (2S,10R)-2-(Hydroxy-(o-nitrophenyl)methyl)
cyclohexan-1-one8e
rt
Yield: 85%; [
a
]
D
18.0 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3):
d
¼7.84 (d, J¼7.62 Hz, 1H), 7.77 (d, J¼7.31 Hz, 1H), 7.63 (t, 1H), 7.42 (t,
1H), 5.44 (d, J¼5.9 Hz,1H), 3.87 (br,1H), 2.75 (d, J¼5.1 Hz,1H), 2.33–
2.47 (m, 2H), 2.07 (s, 1H), 1.25–1.86 (m, 5H); ee: 95%, determined by
HPLC (Daicel Chiralpak AD-H, i-PrOH/hexane 1/9), 254 nm, flow
rate 0.5 mL/min, tmajor¼45.5 and tminor¼49.6.
4.3.11. (4R)-4-Hydroxy-4-(4-nitrophenyl) butan-2-one8e
Yield: 88%; 1H NMR (300 MHz, CDCl3):
d
¼8.21 (d, J¼8.7 Hz, 2H),
7.54 (d, J¼8.7 Hz, 2H), 5.25–5.29 (t, 1H), 3.60 (s, 1H), 2.84–2.87 (t,
2H), 2.23 (s, 3H); ee: 48%, determined by HPLC (Daicel Chiralpak
AS-H, i-PrOH/hexane 30/70), 254 nm, flow rate 1 mL/min,
tmajor¼9.8 and tminor¼12.2.
4.3.4. (2S,10R)-2-(Hydroxy-(p-bromophenyl)methyl)
cyclohexan-1-one8e
rt
Yield: 75%; [
CDCl3):
a
]
þ11.3 (c 1.0, CHCl3); 1H NMR (300 MHz,
4.3.12. (1R)-1-Hydroxy-1-(4-nitrophenyl) hexan-3-one
D
d
¼7.46–7.49 (m, 2H), 7.17–7.21 (m, 2H), 4.75 (d, J¼8.70 Hz,
Yield: 69%; 1H NMR (300 MHz, CDCl3):
2H), 7.54 (d, J¼8.7 Hz, 2H), 5.25–5.29 (m, 1H), 2.80–2.83 (t, 2H),
2.41–2.46 (t, 2H), 1.57–1.69 (m, 2H), 0.85–0.95 (t, J¼7.38 Hz, 3H);
ee: 20%, determined by HPLC (Daicel Chiralpak AS-H, i-PrOH/
d
¼8.21 (d, J¼8.7 Hz,
1H), 4.00 (s, 1H), 2.46–2.57 (m, 2H), 2.34–2.40 (m, 1H), 2.06–2.12
(m, 1H), 1.77–1.82 (m, 1H), 1.51–1.69 (m, 3H), 1.20–1.35 (m, 1H);
ee: 98%, determined by HPLC (Daicel Chiralpak AD-H, i-PrOH/

F. Chen et al. / Tetrahedron 64 (2008) 9585–9591
9591
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hexane 30/70), 254 nm, flow rate 1 mL/min, tmajor¼6.3 and
tminor¼7.5.
Acknowledgements
This work was supported by the Natural Science Foundation of
China (NSFC 20572087), the Ministry of Education, PR China (No.
106141) and the Program for New Century Excellent Talents (NCET-
06-0772) in University.
7. (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M.
Angew. Chem., Int. Ed. 2006, 45, 958; (b) Gu, Q.; Wang, X. F.; Wang, L.; Wu, X. Y.;
Zhou, Q. L. Tetrahedron: Asymmetry 2006, 17, 1537; (c) Font, D.; Jimeno, C.;
Perica`s, M. A. Org. Lett. 2006, 8, 4653; (d) Gu, L. Q.; Yu, M. L.; Wu, X. Y.; Zhang, Y.
Z.; Zhao, G. Adv. Synth. Catal. 2006, 348, 2223; (e) Benaglia, M.; Cinquini, M.;
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.07.051.
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