Chiral Primary Amine Organocatalysts for Syn-selective Asymmetric Cross-Aldol Reactions

Article abstract of DOI:10.1016/S1872-2067(10)60237-9

Based on the "acid-base" interaction strategy, organocatalysts for the asymmetric cross-aldol reaction were synthesized by the in situ combination of chiral primary amines with protonic acids. Unlike general secondary amine catalysts that give anti-selective products, as-prepared primary amine catalysts can give syn-selective cross-aldol products with high yield and high selectivity (up to 90% yield, 90:10 syn/anti ratio, 90% ee). Compared with the complex synthesis of the reported catalysts, the primary amine catalyst that gave the best results was easily prepared using commercial available (1S,2S)-(+)-cyclohexanediamine.

Full text of DOI:10.1016/S1872-2067(10)60237-9

CHINESE JOURNAL OF CATALYSIS
Volume 32, Issue 6, 2011
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2011, 32: 899–903.
SHORT COMMUNICATION
Chiral Primary Amine Organocatalysts for Syn-selective
Asymmetric Cross-Aldol Reactions
GAO Qiang1,2, LIU Yan1, LU Shengmei1, LI Can1,*
1State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
2Graduate University of Chinese Academy of Sciences, Beijing 100049, China
Abstract: Based on the “acid-base” interaction strategy, organocatalysts for the asymmetric cross-aldol reaction were synthesized by the in
situ combination of chiral primary amines with protonic acids. Unlike general secondary amine catalysts that give anti-selective products,
as-prepared primary amine catalysts can give syn-selective cross-aldol products with high yield and high selectivity (up to 90% yield, 90:10
syn/anti ratio, 90% ee). Compared with the complex synthesis of the reported catalysts, the primary amine catalyst that gave the best results
was easily prepared using commercial available (1S,2S)-(+)-cyclohexanediamine.
Key words: chiral primary amine; organocatalysis; asymmetric catalysis; cross-aldol reaction
The aldol reaction is one of the most important car-
bon-carbon bond forming reactions in organic chemistry [1,2].
Since the pioneering work on the L-proline catalyzed asym-
metric direct aldol reaction was reported by List et al. [3] in
2000, organocatalytic aldol reactions have become the most
powerful and versatile tools to synthesize optically active
ȕ-hydroxy compounds [4,5]. Among these aldol reactions,
asymmetric cross-aldol reactions of aldehydes can provide an
attractive strategy for the construction of chiral Į-substituted
ȕ-hydroxy aldehydes, which are important synthons in the
synthesis of polypropionate and polyacetate products.
salts, however, the substrate scope and enantioselectivities
were limited. Excellent syn-selectivities and enantioselectivi-
ties have previously been obtained while these catalysts have
been used to catalyze the aldol reaction between aliphatic
ketones and aromatic aldehydes [11]. Herein, we report the
asymmetric syn-selective cross-aldol reaction of aldehydes (up
to 90% yield, 90:10 syn/anti ratio, 90% ee), using easily pre-
pared primary amine catalysts.
Diastereoselectivity control in these reactions depends on
finding an appropriate catalyst based on a reasonable analysis
of the reaction mechanism. Similar to the previously proposed
mechanism [12], mechanism (I) for the proline catalytic
cross-aldol reaction (Scheme 1) shows that the E-enamine
transition state (TS) is the main factor that determines
anti-selectivity in this reaction, and the carboxylic acid group
of L-proline provides a hydrogen bond to stabilize the TS.
However, the mechanism (II), we proposed for the primary
amines catalyzed cross-aldol reaction, shows that
syn-selectivity could be reasoned by the Z-enamine TS, and the
N-H•O hydrogen bonds are assumed to stabilize the Z-enamine
TS. Based on this model, various primary amines 1–7 were
screened for the syn-selective asymmetric cross-aldol reaction
(Scheme 2).
In 2002, Northrup et al. [6] reported the first asymmetric
cross-aldol reaction of aldehydes using proline as a catalyst.
Since then, a variety of organocatalysts have been designed and
synthesized for this kind of cross-aldol reaction and the prod-
ucts are mainly anti-selective [7]. Recently, Kano et al. [8,9]
reported syn-selective cross-aldol reactions that were catalyzed
by axially chiral amino sulfonamide with high diastereoselec-
tivity and enantioselectivity, however, the synthetic routes to
obtain the catalyst are too convoluted. During our data collec-
tion for this paper, Li et al. [10] reported syn-selective
cross-aldol reactions with good enantioselectivity that were
catalyzed by chiral primary-tertiary diamine-Brönsted acid
Received 29 March 2011. Accepted 21 April 2011.
*Corresponding author. Tel: +86-411-84379070; Fax: +86-411-84694447; E-mail: canli@dicp.ac.cn
This work was supported by the National Natural Science Foundation of China (20921092) and the Program for Strategic Scientific Alliances between China and
Netherlands (2008DFB50130).
Copyright © 2011, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(10)60237-9

GAO Qiang et al. / Chinese Journal of Catalysis, 2011, 32: 899–903
Mechanism (I):
O
Table 1 Chiral primary amine catalysts for the cross-aldol reaction of
propanal and 2-chlorobenzaldehyde
O
OH
O
Cl OH
Cl
O
O
N
Catalyst
0 oC
NaBH4 / MeOH
Ar
H
O
OH
H
H
H
Ar
H
O
O
H
R
8
9
10
C
R
Entry
Primary amine
Yielda (%)
Syn/Antib
82:18
76:24
—
eeb (%)
Ar
H
H
R
Anti
1
1
2
3
4
5
6
7
79
73
—
—
80
83
87
79
E-enamine favored
Mechanism (II):
O
2
–65
—
3c
4c
5
N
OH
R
O
—
—
H
H
Ar
H
NH2
75:25
78:22
74:26
–55
27
Ar
H
H
Ar
R
O
O
6
R
7
29
H
H
Syn
Reaction conditions: in situ prepared catalysts with 0.1 mmol primary
Z-enamine favored
amine and 0.2 mmol trifluoroacetic acid (TFA),
2-chlorobenzaldehyde, 0.36 ml propanal, 0 oC, 72 h.
aIsolated yield. bDetermined by chiral phase HPLC after conversion to
the monobenzoyl ester. cNo obvious aldol product was detected.
1
mmol
Scheme 1. Proposed mechanisms. (I) Anti-aldol transition state (TS)
favored when using proline and its derivatives; (II) Syn-aldol TS favored
when using primary amines.
NH2
NH2
NH2
NH2
NH2
reactions were found by TLC detection. No products were
found when using primary amine 4 and this may be attributed
to the lack of hydrogen bonds that would stabilize the TS as
proposed in mechanism (II). The best diastereoselectivity and
enantioselectivity (82:18 syn/anti ratio, 79% ee) were achieved
in the model reaction when using 1 [(1S,2S)-(+)-cyclohex-
anediamine] as the catalyst (entry 1). The commercially
available (1S,2S)-(+)-cyclohexanediamine was then chosen as
the primary amine to optimize the reaction conditions.
NH2
NH2
1
4
2
3
OMe
N
NH2
N
NH2
NH2
N
N
N
H
H
From the transition state model, the hydrogen-bond between
+
NH3 and the carbonyl group plays an important role in the
5
7
6
syn-selectivity of the cross-aldol reaction of aldehydes. The
strength of the hydrogen bond is dependent on the acidity of the
additives. Therefore, different acid additives such as TFA,
triflic acid (TfOH), acetic acid (HOAc), H3PW12O40, and chiral
camphorsulfonic acid (L-CSA) were screened in our work
(Table 2). Higher yields, diastereoselectivities, and enantiose-
lectivities (80% yield, 85:15 syn/anti, 90% ee) were obtained
when using TfOH (Table 2, entry 2 vs entries 1, 3–5). After
Scheme 2. Chiral primary amines for the asymmetric cross-aldol reac-
tion.
The cross-aldol reaction of propanal and 2-chlorobenzal-
dehyde was selected as a model reaction. The catalysts were
prepared in-situ by stirring 0.1 mmol primary amine and 0.2
mmol trifluoroacetic acid (TFA) in CH2Cl2 for 0.5 h. After
evaporating the solvent under reduced pressure, the residues
obtained were used directly as catalysts for the reaction. All the
aldol reaction products are known compounds [10,13]. The
Table 2 Optimization of the reaction conditions for primary amine 1
with different protonic acid additives
1
reaction results are listed in Table 1. H NMR of the aldol
Yielda (%) Syn/Antib
eeb (%)
79
1
Entry
Additive
0.2 mmol TFA
products 10: H NMR (400 MHz, CDCl3): į 0.84–0.89 (3H,
1
2
3
4
5
6
7
73
80
69
75
60
70
90
82:18
85:15
68:32
69:31
84:16
77:23
90:10
m), 2.09–2.14 (1H, m), 2.58 (2H, brs), 3.68–3.79 (2H, m),
5.31(1H, d, J = 7.2 Hz), 7.20–7.25 (1H, m), 7.30–7.34 (2H, m),
7.56–7.58 (1H, d, J = 7.6 Hz); Enantiomeric excess was de-
0.2 mmol TfOH
0.2 mmol HOAc
0.067 mmol H3PW12O40
0.2 mmol L-CSA
0.1 mmol TfOH
0.15 mmol TfOH
90
38
64
termined by HPLC with
a Chiralpak AS-H column
40
(n-hexane:2-propanol = 99:1, Ȝ = 254 nm, 1.2 mL/min; major
enantiomer tr = 19.0 min, minor enantiomer tr = 28 min, after
conversion to the monobenzoyl ester [13]. Except for the pri-
mary amine catalysts 3 and 4 which gave trace amounts of the
product (entries 3 and 4), all the other primary amine catalysts
gave syn-selective cross-aldol products in accordance with the
proposed mechanism (II). Using primary amine 3, many side
85
90
Reaction conditions: in situ prepared catalysts with 0.1 mmol primary
amine 1 and the corresponding protonic acid additives,
1 mmol
2-chlorobenzaldehyde, 0.36 ml propanal, 0 oC, 72 h.
aIsolated yield. bDetermined by chiral phase HPLC after conversion to the
monobenzoyl ester.

GAO Qiang et al. / Chinese Journal of Catalysis, 2011, 32: 899–903
Table 3 Substrate scope of the cross-aldol reaction
In summary, primary amine organocatalysts based on our
OH
O
O
proposed mechanism for catalyst design efficiently catalyzed
the syn-selective cross-aldol reaction of aldehydes with up to
90% yield, 90:10 syn/anti, and 90% ee. Compared with the
complex synthesis of the reported catalysts, we present primary
amine catalysts prepared from commercially available (1S,2S)-
(+)-cyclohexanediamine. This paper may offer a new method
to design catalysts for different selectivities in various reac-
tions.
R1
Catalyst
0 o
NaBH4/MeOH
OH
H
H
R1
C
R2
R1
R2
Entry
1
R2
Time (h) Yielda (%) Syn/Antib eeb (%)
Me
Me
Me
Me
Me
Et
4-NO2
3-NO2
2-NO2
4-F
36
36
36
80
80
72
72
71
78
67
69
60
—
—
63:37
56:44
64:36
61:39
68:32
—
72
70
76
72
80
—
—
2
3
4c
5c
6d
7d
4-Cl
2-Cl
i-Pr
2-Cl
—
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