Efficient organocatalytic cross-aldol reaction between aliphatic aldehydes through their functional differentiation

Article abstract of DOI:10.1021/ja208873k

A chemo- and stereoselective asymmetric direct cross-aldol reaction between aliphatic aldehydes and α-chloroaldehydes has been developed as a method for the formation of the sole cross-aldol adduct with both enantio- and diastereocontrol, and either anti-

Full text of DOI:10.1021/ja208873k

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Efficient Organocatalytic Cross-Aldol Reaction between Aliphatic
Aldehydes through Their Functional Differentiation
Taichi Kano, Hisashi Sugimoto, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S Supporting Information
b
Scheme 1. Cross-Aldol Reaction between Aliphatic Alde-
hydes through Enamine Catalysis
ABSTRACT: A chemo- and stereoselective asymmetric
direct cross-aldol reaction between aliphatic aldehydes and
α-chloroaldehydes has been developed as a method for the
formation of the sole cross-aldol adduct with both enantio-
and diastereocontrol, and either anti- or syn-aldol adducts
were obtained in good to excellent stereoselectivities by use
of proline or a novel axially chiral amino sulfonamide as
catalyst.
he aldol reaction has long been recognized as one of
T
the most fundamental tools for the construction of new
carbonÀcarbon bonds.1 In this area, the cross-aldol reaction
between two different aldehydes has remained an elusive chal-
lenge because of undesired side reactions including homoaldol
reaction and multiple addition of nucleophilic species such as the
enolate and the enamine to the aldol product.2À14
the formation of the sole cross-aldol product with both enantio-
and diastereocontrol.
In organocatalytic cross-aldol reaction of aldehydes through
the enamine intermediate first reported by MacMillan et al.,13a,15
the cross-aldol adduct could be obtained in a highly stereoselec-
tive fashion without prior formation of activated enolate species.13,14
However, most such reactions required the use of sterically
hindered aliphatic aldehydes, from which the enamine inter-
mediates are rather difficult to be formed, or aromatic aldehydes
as electrophile. In the direct aldol reaction between simple
aliphatic aldehydes, both aldehydes can perform the double role
of nucleophile andelectrophile, and consequently, twocross-aldol
adducts and two homoaldol adducts would be possible major pro-
ducts witheachhavingfourstereoisomers(Scheme1). Accordingly,
the development of chemo- and stereoselective asymmetric direct
cross-aldol reactions between aliphatic aldehydes represents a
highly desirable and challenging goal.
To differentiate the two aldehydes in terms of their role in the
reaction, we introduced a halogen group at the α-position of
acceptor aldehydes as shown in Scheme 1.13d The formation of
the enamine intermediate of the sterically hindered α-haloalde-
hyde and an amine catalyst would be suppressed. Moreover, the
α-haloaldehyde, which is electronically activated by the α-halo
group, would be expected to react predominantly with the enamine
intermediate over the other aliphatic donor aldehyde. Finally, the
halogen group on the cross-aldol adduct can be removed under
reductive conditions.
We first examined the reaction between 3-methylbutanal and
racemic 2-chloro-3-phenylpropanal in the presence of 30 mol %
of L-proline in DMF at 0 °C (Table 1, entry 1). When the
extracted reaction mixture was treated with LiAlH4 in THF,13r
the corresponding anti-diol anti-3 derived from the desired cross-
aldol adduct was obtained in moderate yield with excellent
diastereo- and enantioselectivity. In this reaction, a small amount
of the other diol from the homoaldol adduct of 3-methylbutanal
(7%) was also formed. Use of 2-bromo-3-phenylpropanal re-
sulted in a decrease in yield (entry 2). Improvement of yield was
achieved by use of an excess amount of a donor aldehyde,
3-methylbutanal (entries 5 and 6). In all cases examined, both
enantiomers of α-haloaldehydes were found to be equally
incorporated into the aldol adducts. In addition, almost racemic
α-haloaldehydes remained after the reaction, and hence, the
kinetic resolution of α-haloaldehydes was not observed.
Herein, we wish to report the development of chemo- and
stereoselective asymmetric direct cross-aldol reaction between
aliphatic aldehydes and α-chloroaldehydes13r,16 as a method for
Received: September 20, 2011
Published: October 14, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja208873k J. Am. Chem. Soc. 2011, 133, 18130–18133
|

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Table 1. anti-Selective Cross-Aldol Reaction of 3-Methylbu-
Table 3. Cross-Aldol Reaction of Aliphatic Aldehydes with
tanal with 2-Halo-3-phenylpropanal Catalyzed by L-Prolinea
α-Chloroaldehydes Catalyzed by L-Proline or (S)-2a
R1
R2
yield (%)b
anti/sync
ee (%)d
entry
X
solvent
yield (%)b
anti/sync
ee (%)d
entry
conditions
1
Cl
Br
Cl
Cl
Cl
Cl
DMF
DMF
THF
48
34
46
47
59
65
19/1
>20/1
13/1
16/1
19/1
19/1
97
97
97
98
96
96
1
A
A
A
A
A
A
A
B
B
B
B
B
B
Me
Et
Bn
Bn
Bn
Me
Bn
Me
Bn
Bn
Bn
Bn
Me
Bn
Bn
91
84
72
68
65
55
61
88
82
88
73
90
73
3.5/1
4.3/1
3.3/1
5.7/1
19/1
98
94
94
94
96
94f
94
97
99
98
98
96
98
2
2
3
3
Bu
Bn
i-Pr
i-Pr
Cy
Me
Et
4
MeCN
DMF
DMF
4
5e
6f
5
6e
>20/1
13/1
a The reaction of 3-methylbutanal (0.2 mmol) with 2-halo-3-phenyl-
propanal (0.2 mmol) in a solvent (100 μL) was carried out in the
presence of L-proline (0.06 mmol) at 0 °C. b Isolated yield after reduc-
7
8
1/4.6
1/>20
1/>20
1/3.0
1/>20
1/>20
9
tion of the aldol product with LiAlH4. c Determined by H NMR.
1
d The ee of anti-3 was determined by HPLC using chiral column. e Use
of 6 equiv of 3-methylbutanal (1.2 mmol). f Use of 8 equiv of 3-methyl-
butanal (1.6 mmol).
10
11
12
13
Bu
Bn
i-Pr
Cy
a Conditions A: the reaction of a donor aldehyde (1.6 mmol) with an
acceptor aldehyde (0.2 mmol) in DMF (100 μL) was carried out in the
presence of L-proline (0.06 mmol) at 0 °C for 48 h; Conditions B: the
reaction of a donor aldehyde (0.1 mmol) with an acceptor aldehyde (0.2
mmol) in DMF (100 μL) was carried out in the presence of (S)-2 (0.005
mmol) at room temperature for 6 h. b Isolated yield after reduction of the
aldol product with LiAlH4. c Determined by 1H NMR. d The ee of the
major diastereomer was determined by HPLC using chiral column. e The
reaction was performed at room temperature and the aldol adduct was
isolated as the dimethylacetal. See Supporting Information for details.
f The ee was determined by GC using chiral column.
Table 2. syn-Selective Cross-Aldol Reaction of 3-Methylbu-
tanal with 2-Chloro-3-phenylpropanal Catalyzed by (S)-1 or
(S)-2a
entry
catalyst
temp (°C)
yield (%)b
anti/sync
ee (%)d
1
(S)-1
(S)-2
(S)-2
(S)-2
(S)-2
0
0
13
68
61
90
-
-
97
97
97
96
2
0
1/>20
1/>20
1/>20
1/>20
3
rt
rt
rt
4e
5e,f
a The reaction of 3-methylbutanal (0.1 mmol) with 2-chloro-3-phenyl-
propanal (0.1 mmol) in DMF (100 μL) was carried out in the presence
of a catalyst (0.005 mmol). b Isolated yield after reduction of the aldol
product with LiAlH4. c Determined by 1H NMR. d The ee of syn-3 was
determined by HPLC using chiral column. e The reaction was performed
for 6 h. f Use of 2 equiv of 2-chloro-3-phenylpropanal (0.2 mmol).
Figure 1. Transition state models for the enantioselective cross-aldol
reaction catalyzed by L-proline (left) and (S)-2 (right).
of 5 mol % of (S)-1 in DMF at 0 °C (Table 2, entry 1). We assumed
that the catalyst (S)-1 and the resulting enamine intermediate did
not have sufficient nucleophilicity for the desired cross-aldol
reaction. Accordingly, we have now developed a novel catalyst
(S)-2 with the expectation that it would be more nucleophilic. To
our delight, the reaction with (S)-2 proceeded to give syn-3
exclusively albeit in low yield (entry 2). This promising result
prompted us to undertake optimization studies (entries 3À5).
Use of 2 equiv of α-chloroaldehyde at room temperature was
found to improve the yield without loss of stereoselectivities
(entry 5). It should be noted that the homoaldol adduct was not
obtained even when a large excess of 3-methylbutanal was used.
This result suggested that the enamine intermediate generated
from (S)-2 could distinguish between a simple aliphatic alde-
hyde and an α-chloroaldehyde due to the moderate nucleophi-
licity, and consequently, the desired syn-selective cross-aldol
Most organocatalytic direct cross-aldol reactions of aldehydes
are known to provide anti-aldol adducts predominantly,13 albeit
with a few exceptions giving syn-adducts.14 We previously devel-
oped the syn-selective and enantioselective direct cross-aldol re-
action between aldehydes catalyzed by an axially chiral amino
sulfonamide (S)-1.14a,17 However, this method was applicable
only to the combination of aliphatic aldehydes as nucleophile and
reactive nonenolizable aldehydes, which cannot form enamine
intermediate, as electrophile. In this context, we have been
interested in use of less reactive aliphatic aldehydes as electro-
phile in the syn-selective direct cross-aldol reaction.
Unfortunately, no reaction was observed between 3-methyl-
butanal and racemic 2-chloro-3-phenylpropanal in the presence
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Scheme 2. Synthesis of (Z)-Alkene 5
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedure and
b
spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
maruoka@kuchem.kyoto-u.ac.jp
Scheme 3. Synthesis of (E)-Alkene 8
’ ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan.
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organic synthesis and readily converted to important chiral
building blocks (Scheme 2). Thus, diacetate 4, which was
prepared from the cross-aldol adduct anti-3, could be converted
to the corresponding (Z)-alkene 5 by the photoinduced metala-
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O-acetyl chlorohydrin.19 The resulting (Z)-alkene 5 was hydro-
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selective asymmetric direct cross-aldol reaction between aliphatic
aldehydes and α-chloroaldehydes catalyzed by proline and the
novel axially chiral amino sulfonamide (S)-2. This organocataly-
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between two different aliphatic aldehydes. Further application of
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