Chiral 1,2-diaminocyclohexane as organocatalyst for enantioselective aldol reaction

Article abstract of DOI:10.1016/j.tetlet.2011.04.116

A simple and commercially available chiral 1,2-diaminocyclohexane as catalyst, hexanedioic acid as co-catalyst could efficiently catalyze the asymmetric aldol reaction in MeOH-H₂O. Cyclic ketones as aldol substrates gave the anti-β-hydroxyketon

Full text of DOI:10.1016/j.tetlet.2011.04.116

Tetrahedron Letters 52 (2011) 3584–3587
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Tetrahedron Letters
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Chiral 1,2-diaminocyclohexane as organocatalyst for enantioselective
aldol reaction
⇑
⇑
Yi Liu, Junfeng Wang, Qi Sun , Runtao Li
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and commercially available chiral 1,2-diaminocyclohexane as catalyst, hexanedioic acid as co-
catalyst could efficiently catalyze the asymmetric aldol reaction in MeOH–H2O. Cyclic ketones as aldol
substrates gave the anti-b-hydroxyketone products with moderate to good yields, diastereoselectivity
and enantioselectivity (up to 78% yield, >20:1 anti/syn, 94% ee). Hydroxyacetone as aldol substrate affor-
Received 7 March 2011
Revised 16 April 2011
Accepted 29 April 2011
Available online 13 May 2011
ded the syn-
a, b-dihydroxyketones as major products in up to 85% yield with good enantioselectivity (up
to >20:1 syn/anti, 93% ee).
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Asymmetric aldol reaction
Diaminocyclohexane
Organocatalyst
Hydroxyketone
Aldol reaction, which generated many biologically active b-hy-
droxy products, is regarded as one of the most important carbon–
carbon formation reactions.1 Since the pioneering work was re-
catalyze the direct aldol reaction. Herein, we present the primary
results of catalytic efficiency of 11 for asymmetric aldol reaction.
As shown in Table 1, with hexanedioic acid (20 mol %) as co-cat-
alyst and methanol as solvents, the aldol products 14 was formed
in 40% isolated yield with 4:1 anti/syn ratio. The major diastereo-
mer, anti-14a, had 89% ee. Further studies showed that the yield
of 14a could be dramatically increased to 75% when a 1:1
MeOH–H2O mixture was used as solvent.
Subsequently, the effects of different additives, temperature,
and catalyst loading on the reaction were tested. It is worthy to
note that the acid as an additive played an important role in this
reaction. Replacing hexanedioic acid with AcOH or TFA, the yield
and the enantioselectivity significantly decreased (entries 9 and
10, Table 1). The catalyst 11 lost completely the catalytic capability
in the absence of acid (entry 11, Table 1). Lowering the tempera-
ture (0 °C, entry 12, Table 1) and reducing the catalyst loading
(10 mol %, 5 mol %, entries 13 and 14, Table 1) were detrimental
to the results.
With the optimized conditions in hand, the scope of the reac-
tion was then explored and the results were showed in Table 2.
It appears that aromatic aldehydes with electron-withdrawing
groups could react with cyclohexanone 12a affording the corre-
sponding products in good yields (40–78%) with moderate to high
diastereoselectivity and good enantioselectivity (13a–13e, entries
1–5, Table 2). Among them, the reaction with 2-nitrobenzaldehyde
13c and 2-trifluoromethylbenzaldehyde 13e gave exceptional high
anti/syn ratio (>20:1). These results indicated that the ortho sub-
stituents were critical for the diastereoselectivity of the reaction.
Reaction of aldehydes 13f–13g with cyclohexanone 12a gave the
moderate ee values (entries 6 and 7, Table 2). While reaction of
ported by List that L-proline 1 could catalyze the intermolecular al-
dol reaction,2 the organocatalytic asymmetric aldol reaction has
been at the center of research in asymmetric catalysis fields.3 Many
kinds of efficient organic catalysts have been developed for asym-
metric aldol reaction with high yield and excellent enantioselectiv-
ity, such as 2,4 3,5 4,6 5,7 6,8 and 79 (Fig. 1).
Similar to the proline and non-proline-derivated secondary
amine catalysts, primary amine organocatalysts 810 and
9
11(Fig. 2) from natural acyclic amino acids also showed good
asymmetric catalytic action for aldol reaction. Recently, Luo et al.
reported a new kind of primary amine catalyst 10 (Fig. 2) derived
from chiral 1,2-diaminocyclohexane, which catalyzed the aldol
reaction affording the aldol products in excellent yields (up to
95%) and enantioslectivity (up to 96% ee).12 These wonderful re-
sults attracted more organic chemists turning their attention on
the primary amine-based organocatalysts.13
To our best known, most of the primary amine-typed catalysts,
such as catalysts 8–10, suffered from the inconvenient synthesis
from natural amino acid or diaminocyclohexane 11 (Fig. 2). In pre-
vious study, we disclosed that simple and commercially available
chiral 1,2-diaminocyclohexane 11 could act as an effective organo-
catalyst in the Micheal addition reactions of c
-butenolides14 and
cyclopentanone15 with chalcones to give products with up to 99%
ee. These findings encouraged us to explore a possibility of 11 to
⇑
Corresponding authors. Tel.: +86 10 8280 1504; fax: +86 10 8271 6956 (R.L.).
E-mail addresses: sunqi@bjmu.edu.cn (Q. Sun), lirt@mail.bjmu.edu.cn (R. Li).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.116

Y. Liu et al. / Tetrahedron Letters 52 (2011) 3584–3587
3585
Ph
Ph
O
HN
O
O
R
R
N
H
N
H
HN
O
H
COOH
COOH
N
H
NH
HN
N
H
R
N
H
HO
4
1
2: R = Ph, CO2C2H5
3: R = Ph, 3-indolyl
COOH
NH
H
N
H
N
Ar
OPh
S
P
N
N
OPh
O
O
H
H
O
O
O
5
6
7
Figure 1. Secondary amine-typed organocatalysts.
O
NH2
NH2
NH2
N
H
N
OH
H2N
OH
TfOH
NH2
O
TBSO
O
8
9
10
11
Figure 2. Primary amine-typed organocatalysts.
Table 1
Reaction condition screening for the reaction of cyclohexanone and 4-nitrobenzaldehydea
O
OH
O
OH
O
catalyst 11 (20mol%)
+
NO2
CHO
+
additive, r.t., 48h
NO2
NO2
syn-14a
13a
anti-14a
12a
Entry
Additive
Solvent
Yieldb (%)
anti/sync
eed (%)
1
2
3
4
5
6
7
8
HDA (20 mol %)
HDA (20 mol %)
HDA (20 mol %)
HDA (20 mol %)
HDA (20 mol %)
HDA (20 mol %)
HDA (20 mol %)
HDA (20 mol %)
AcOH (40 mol%)
TFA (40 mol%)
—
MeOH
H2O
THF
DMSO
DMF
PhMe
MeOH/CHCl3
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
40
20
—
—
—
4:1
2:1
—
—
—
—
—
4:1
3:1
—
89
92
—
—
—
—
—
93
75
—
—
Trace
75
20
Trace
0
9
10
11
12
13
14
—
—
2:1
—
—
—
90
89
HDA (20 mol %)
HDA (10 mol %)
HDA (5 mol %)
5e
30f
10g
a
b
c
d
e
f
The reaction was performed with aldehyde (0.2 mmol), cyclohexanone (0.6 mmol) for 48 h.
Isolated combined yields of anti-14a and syn-14a.
Determined by 1H NMR.
ee% of anti-14a, determined by chiral HPLC.
The reaction was carried out at 0 °C.
Using 10 mol % catalyst 11.
Using 5 mol % catalyst 11.
g
4-nitrobenzaldehyde 13a with cyclopentanone 12b provided low
ee value (40% yield, 26% ee, entry 8, Table 2). It showed that de-
crease of ring size of cyclohexanone was unfavorable for the yield
and enantioselectivity.
Hydroxyacetone-based aldol reaction is of considerable impor-
tance to provide expedient access to both natural carbohydrates
and unnatural polyhydroxylated molecules.16 Many kinds of
organocatalysts have been developed for this reaction. Gong’s

3586
Y. Liu et al. / Tetrahedron Letters 52 (2011) 3584–3587
Table 2
Reaction of different ketones with aldehydesa
O
OH
O
OH
O
R
R
11(20%),hexanedioicacid (20%)
+
R1
R2
+
R1
R2
syn-14
R
CHO
R1
R2
MeOH-H2O, r.t., 48h
anti-14
12
13
Entry
R1, R2
R
Yield of productsb (%)
anti/sync
eed (%)
1
2
3
4
5
6
7
8
–(CH2)3– (12a)
–(CH2)3– (12a)
–(CH2)3– (12a)
–(CH2)3– (12a)
–(CH2)3– (12a)
–(CH2)3– (12a)
–(CH2)3– (12a)
–(CH2)2– (12b)
H, OH (12c)
12c
4-NO2-phenyl (13a)
3-NO2-phenyl (13b)
2-NO2-phenyl (13c)
4-CF3-phenyl (13d)
2-CF3-phenyl (13e)
4-Pyridinyl (13f)
3-Pyridinyl (13g)
13a
13a
13b
13c
13d
75 (14a)
78 (14b)
40 (14c)
74 (14d)
70 (14e)
50 (14f)
70 (14g)
40 (14h)
80 (14i)
85 (14j)
85 (14k)
50 (14l)
68 (14m)
65 (14n)e
4:1
5:1
>20:1
3:1
>20:1
1:1
2:1
1:2
2:3
3:7
93
90
94
84
90
81
62
26
63
85
89
50
93
89
9
10
11
12
13
14
12c
12c
12c
12c
<1:20
2:3
<1:20
<1:20
13e
2-Cl-phenyl (13h)
a
b
c
The reaction was performed with aldehyde (0.2 mmol), cyclohexanone (0.6 mmol) for 48 h.
Isolated combined yields of anti-14 and syn-14.
Determined by 1H NMR.
Determined by chiral HPLC of major isomer.
Reaction for 72 h.
d
e
H
H
H
H
H
H
H
H
H
H
N
H
H
N
N
N
N
N
N
N
H
H
H
H
H
H
O
O
O
O
O
O
H
Ar
H
Ar
Ar
H
Ar
H
TS1
Sterically unf avorable
TS2
TS1
Thermodynamic instability Thermodynamic stability
TS2
More favorable
O
OH
Ar
O
OH
Ar
O
OH
Ar
O
OH
Ar
OH
anti-product (minor)
OH
syn-product (major)
anti-product (major)
syn-product (minor)
B
A
Scheme 1. Proposed di-iminium activation of both substrates in the aldol reactions of hydroxyacetone with aromatic aldehydes.
group reported that proline derivatives 2 could effectively catalyze
products in good yields (50–85%) and good to excellent enantiose-
lectivity (50–93% ee).1e,21,22 Such as, 2-cholo-benzyl-aldehyde
(13h) gave product 14n in 65% with >20:1 syn/anti and 89% ee (en-
try 14, Table 2), which is much better than the Paradowska’s re-
sult(1:1 anti/syn, 23% ee).23 Likewise, ortho-substituted aromatic
aldehydes also achieved higher diastereoselectivity (up to >20:1
syn/anti, entries 11, 13, and 14, Table 2) than para- or meta-substi-
tuted aromatic aldehydes (entries 9, 10, and 12, Table 2). The abso-
lute configuration of compounds syn-14k and syn-14n was
determined by comparing our chiral HPLC result with Gong’s
results.1e
this reaction affording the linear isomer with excellent enantiose-
lectivity.17 Zhao18 and Luo19 found that using
L-threonine and
diaminocyclohexane derivatives as catalysts in this reaction could
selectively give the branched isomer syn-14 with excellent enanti-
oselectivity. Even though, it still remained a challenge to find more
simple and efficient catalyst.20 Thus, we further explored the
asymmetric reaction of hydroxyacetone 12c with various alde-
hydes under our reaction conditions.
As showed in Table 2, in all the cases of hydroxyacetone as the
aldol substrate, the branched syn-isomer 14 was obtained as major

Y. Liu et al. / Tetrahedron Letters 52 (2011) 3584–3587
3587
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To account for the formation of predominant syn-products in
the cases of hydroxyacetone 12c as a substrate, we proposed a pos-
sible transition states TS1 and TS2 as shown in B, Scheme 1, in
which both substrates could be activated simultaneously by pro-
tonated primary amino-groups of 1,2-diaminocyclohexane. It
could be seen clearly that TS1 is sterically unfavorable and TS2 is
more favorable leading to the formation of the major syn-stereo-
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Scheme 1).
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In conclusion, we have developed an efficient asymmetric aldol
reactions of ketones and aromatic aldehydes using a simple and
commercially available chiral 1,2-diaminocyclohexane as catalyst,
hexanedioic acid as co-catalyst in MeOH–H2O. It was found the
aromatic aldehydes with electron-withdrawing groups could react
with cyclic ketone affording the corresponding product in good
yields (40–78%), with high diastereoselectivity (up to >20:1 anti/
syn) and enantioselectivity (up to 94% ee). While for acyclic
hydroxyacetone, syn-dihydroxyketones as the major products
were obtained in good yields with enantioselectivity(up to 85%
yield, >20:1 syn/anti, 93% ee). The proposed transition state model
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Acknowledgment
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (No. 20972005).
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.116.
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