L -t-Leucine-catalyzed direct asymmetric aldol reaction of cyclic ketones

Article abstract of DOI:10.1002/ejoc.201001413

L-t-Leucine-catalyzed direct asymmetric aldol reactions are described. In the aldol reaction of p-nitrobenzaldehyde with a cyclic ketone at room temperature, L-t-leucine exhibits catalytic activity resulting in moderate to high diastereo- and enantioselec

Full text of DOI:10.1002/ejoc.201001413

FULL PAPER
DOI: 10.1002/ejoc.201001413
L
-t-Leucine-Catalyzed Direct Asymmetric Aldol Reaction of Cyclic Ketones
Takuya Kanemitsu,[a] Atsushi Umehara,[a] Michiko Miyazaki,[a] Kazuhiro Nagata,[a] and
Takashi Itoh*[a]
Keywords: Asymmetric synthesis / Aldol reactions / Organocatalysis / Amino acids / Ketones
L
-t-Leucine-catalyzed direct asymmetric aldol reactions are
described. In the aldol reaction of p-nitrobenzaldehyde with
a cyclic ketone at room temperature, -t-leucine exhibits
enantioselectivity. Use of cycloheptanone or cyclooctanone
as a substrate resulted in production of the syn selective
product.
L
catalytic activity resulting in moderate to high diastereo- and
rare.[7a,7c,12] Thus, we focused on finding an efficient
organocatalyst for syn selective asymmetric aldol reactions
of cyclic ketones and found that l-t-leucine has excellent
catalytic activity toward cyclic ketones. To the best of our
knowledge, this is the first report that l-t-leucine can be
used as a catalyst for an asymmetric reaction. In this paper,
we report that l-t-leucine has unique properties distinct
from those of other amino acids, and that l-t-leucine ef-
ficiently catalyzes direct aldol reactions to yield syn selective
adducts using cycloalkanones (C7–C8) as electron donors.
Introduction
Metal-free organocatalysts have been recently developed
for various enantioselective reactions. Organocatalysts have
several advantages over conventional metal catalysts, such
as nontoxicity, stability, and easy manipulation. These im-
portant merits have led to the development of organocata-
lytic asymmetric reactions as a major field in organic chem-
istry.[1] We are interested in the application of organocata-
lysts to the synthesis of nitrogen-containing molecules and
have described several asymmetric reactions of isoquinoline
and carboline derivatives.[2] Since the publication of a
pioneering work by List, Lerner, and Barbas,[3] the asym-
metric aldol reaction catalyzed by l-proline has been a rep-
resentative reaction in the field of organocatalysis, and
many groups have investigated its application and reaction
mechanism.[4] However, there is a drawback to using proline
as a catalyst in this reaction, namely, a high loading of the
catalyst is required for reasonable yields in the direct aldol
reaction of aromatic aldehydes because proline itself reacts
with aromatic aldehydes to form iminium salts, followed by
decarboxylation.[5] Therefore, various new catalysts have
been developed to overcome this problem. Córdova re-
ported primary amine catalyzed direct asymmetric aldol re-
actions with anti selective diastereoselectivities.[6] Sub-
sequently, Lu,[7] Barbas,[8] Gong,[9] Wu et al.,[10] and Luo et
al.[11] reported syn selective aldol reactions catalyzed by chi-
ral primary amines. According to Luo’s report,[11f] a pri-
mary amine and an aliphatic ketone form a (Z)-enamine to
furnish a syn selective product. In the case of a cyclic
ketone, however, a (Z)-enamine cannot be formed. The
study of the organocatalyzed direct asymmetric reaction of
cyclic ketones to afford syn selective products is very
Results and Discussion
Our initial experiment was to test the utility of a series
of amino acids as catalysts (2.5 mol-%) in the reaction of p-
nitrobenzaldehyde with cyclohexanone at room tempera-
ture. We used l-alanine, l-valine, l-leucine, and l-t-leucine
as primary amine catalysts, and l-proline as a secondary
amine catalyst. As shown in Table 1, l-t-leucine exhibited
much higher efficiency than the other catalysts (Table 1, En-
try 4). A small amount (2.5 mol-%) of l-t-leucine catalyzed
the aldol reaction and gave high yield and enantio-
selectivity; however, a large amount (10 mol-%) of the cata-
lyst was required to get satisfactory diastereoselectivity. Ex-
periments aimed at optimizing the conditions for using l-t-
leucine as a catalyst indicated that 50 equiv. of water in
DMSO increased both the diastereo- and enantioselectivity
without causing a loss of reactivity. Thus, the aldol reaction
of cyclohexanone and p-nitrobenzaldehyde in the presence
of l-t-leucine in DMSO with a small amount of water gave
the corresponding β-ketoalcohol in 95% yield, 97%ee, and
1:12 (syn/anti) dr (Table 1, Entry 5).
The aldol reaction of a range of aromatic aldehydes with
cyclohexanone in the presence of l-t-leucine was then inves-
tigated by using these optimized conditions. Except for the
reaction of p-nitrobenzaldehyde, all reactions of aryl alde-
hydes with cyclohexanone required a catalyst loading of
[a] School of Pharmaceutical Sciences, Showa University,
1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax: +81-3-37845982
E-mail: itoh-t@pharm.showa-u.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001413.
Eur. J. Org. Chem. 2011, 993–997
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Kanemitsu, A. Umehara, M. Miyazaki, K. Nagata, T. Itoh
FULL PAPER
Table 1. l-Amino acid catalyzed asymmetric aldol reaction.
Table 2. l-t-Leucine-catalyzed asymmetric aldol reaction of cyclo-
hexanone.
Entry[a]
Catalyst
Yield
[%][b]
dr
ee of anti
(syn/anti)[c]
[%][d]
1
2
3
l-alanine
l-valine
l-leucine
l-t-leucine
l-t-leucine
l-proline
25
7
16
95
95
11
1:3.6
1:2.7
1:3.4
1:2.2
1:12
80
87
82
94
97
69
Entry[a]
Ar
Product
Yield
[%][b]
dr
ee of anti
(syn/anti)[c]
[%][d]
1[e]
2
3
4
5
6
7
8
9
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
3,5-(CF3)2C6H3
4-ClC6H4
4-CF3C6H4
C6H5
2-naphthyl
4-pyridinyl
3-quinolinyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
94
93
90
89
94
70
79
51
58
91
84
1:12
1:8.1
1:13
97
98
98
97
96
98
97
92
97
97
96
4
5[e]
6
1:1.2
1:7.3
1:5.3
1:6.7
1:5.7
1:9.0
1:9.0
1:6.1
1:8.1
[a] Unless otherwise stated, the reaction was performed with p-ni-
trobenzaldehyde (1 equiv.) and cyclohexanone (10 equiv.) for 7 d.
[b] Combined yield of the diastereomers determined by H NMR
spectroscopy. [c] Determined by H NMR spectroscopy. [d] Deter-
mined by HPLC. [e] The reaction was performed with p-nitrobenz-
aldehyde (1 equiv.), cyclohexanone (1.5 equiv.), and l-t-leucine
(0.1 equiv.) in DMSO in the presence of H2O (50 equiv.) for 7 d.
1
1
10
11
3j
3k
[a] Unless otherwise stated, the reaction was performed with alde-
hyde (1 equiv.), cyclohexanone (1.5 equiv.), and l-t-leucine
(0.2 equiv.) in DMSO in the presence of H2O (50 equiv.) for 7 d.
[b] Combined isolated yield of the diastereomers. [c] Determined by
1H NMR spectroscopy. [d] Determined by HPLC. [e] The reaction
was performed in the presence of 0.1 equiv. of l-t-leucine.
20 mol-% to afford the desired aldol product in satisfactory
yields. In all cases, l-t-leucine efficiently controlled anti
selectivity and afforded excellent enantioselectivity. The
yield was slightly dependent on the electronic and steric fea-
tures of the substituent on the aldehyde. For example, high
yields were obtained with benzaldehydes containing an elec-
tron-withdrawing substituent (Table 2, Entries 1–7). Benzal- Initially, the optimized conditions used with cyclohexanone
dehyde and 2-naphthaldehyde were less reactive toward cy- were tested with these substrates, but reactions catalyzed
clohexanone (Table 2, Entries 8 and 9), whereas 4-pyridine- by l-t-leucine in the presence of water in DMSO yielded
carboxaldehyde and 3-quinolinecarboxaldehyde showed undesirable results (Table 3, Entries 5 and 11). In the case of
high reactivity (Table 2, Entries 10 and 11).
cycloheptanone and cyclooctanone, solvent-free conditions
Next, we studied the utility of several amino acids in the without added water were found to be effective. l-Alanine,
aldol reaction of p-nitrobenzaldehyde with cycloheptanone l-leucine, and l-proline showed low reactivity towards cy-
and cyclooctanone; the results are summarized in Table 3. cloheptanone (Table 3, Entries 1, 3, and 6), and l-valine ex-
Table 3. l-Amino acid catalyzed asymmetric aldol reaction of cycloheptanone and cyclooctanone.
Entry[a]
n
Catalyst
(mol-%)
Time
[d]
Product
Yield
[%][b]
dr
ee of syn
(syn/anti)[c]
[%][d]
1
2
3
2
2
2
2
2
2
3
3
3
3
3
3
l-alanine (10)
l-valine (10)
10
8
10
6.5
8
6a
6a
6a
6a
6a
6a
7a
7a
7a
7a
7a
7a
11
trace
7
87
22
2.7:1
nd[e]
2.8:1
6.1:1
1:1
1.3:1
nd[e]
nd[e]
nd[e]
10:1
2.6:1
nd[e]
22
nd[e]
15
l-leucine (10)
l-t-leucine (10)
l-t-leucine (30)
l-proline (10)
l-alanine (30)
l-valine (30)
l-leucine (30)
l-t-leucine (30)
l-t-leucine (30)
l-proline (30)
4
65
5[f]
6
nd[e]
5
7
8
7
8
9
10
11[f]
12
10
10
8
10
10
10
trace
trace
trace
70
10
trace
nd[e]
nd[e]
nd[e]
60
nd[e]
nd[e]
[a] The reaction was performed with p-nitrobenzaldehyde (1 equiv.) and cyclic ketone (10 equiv.). [b] Combined yield of the diastereomers
1
1
determined by H NMR spectroscopy. [c] Determined by H NMR spectroscopy. [d] Determined by HPLC. [e] Not determined. [f] The
reaction was performed in the presence of H2O in DMSO.
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l-t-Leucine-Catalyzed Asymmetric Aldol Reaction of Cyclic Ketones
hibited no catalytic activity in this reaction (Table 3, En- Table 5. l-t-Leucine-catalyzed asymmetric aldol reaction of cyclo-
pentanone.
try 2). In contrast, l-t-leucine afforded high syn selectivity,
high enantioselectivity, and good yield (Table 3, Entry 4).
For cyclooctanone, no amino acid other than l-t-leucine
showed significant reactivity in the aldol reaction (Table 3,
Entries 10 and 11). These results suggest that l-t-leucine has
unique features compared to other amino acids.
The same reaction conditions, employing l-t-leucine as a
catalyst, were used with other aldehydes, and the results are
Entry[a]
Ar
Product Yield
[%][b]
dr
ee of anti
summarized in Table 4. First, cycloheptanone was treated
with various aromatic aldehydes in the presence of l-t-leu-
cine to give the desired product in high yield and syn selec-
tivity (Table 4, Entries 1–5). This is the first report of the
syn selective aldol reaction of cycloheptanone. In the case
of cyclooctanone, reaction with aromatic aldehydes gave
moderate to high yields (Table 4, Entries 6–10). Although
one example of syn selective aldol reaction of cyclooct-
anone with p-nitrobenzaldehyde has been reported by Da
et al., their reported diastereo- and enantioselectivity was
low (syn/anti = 2.5:1, 19%ee).[13]
(syn/anti)[c]
[%][d]
1
2
3
4
5
4-O2NC6H4
3-O2NC6H4
4-NCC6H4
3,5-(F3C)2C6H3
4-F3CC6H4
3a
3b
3d
3e
3g
69
82
71
83
68
1:2.3
1:1.7
1:1.9
1:1.0
1:1.0
89
90
86
91
83
[a] The reaction was performed with aldehyde (1 equiv.), cyclo-
pentanone (10 equiv.), and l-t-leucine (0.1 equiv.). [b] Combined
isolated yield of the diastereomers. [c] Determined by 1H NMR
spectroscopy. [d] Determined by HPLC.
We also examined aldol reactions of cyclopentanone with
substituted benzaldehydes. The reactions were carried out ments, l-alanine, l-valine, and l-leucine reacted slowly with
by using l-t-leucine under solvent-free conditions without p-nitrobenzaldehyde, and complex 1H NMR spectra consis-
added water, as well as the case of cycloheptanone and cy- tent with decomposition of these compounds were obtained
clooctanone (Table 5). Although l-t-leucine gave aldol (see Supporting Information). A proposed decomposition
products with low diastereoselectivities, high enantio- process is shown in Scheme 1. In the case of l-t-leucine with
selectivities were obtained. These results presumably indi- p-nitrobenzaldehyde, however, the corresponding imine,
cate that the aldol reaction of smaller (less than C7) cyclic which is reconverted into l-t-leucine and p-nitrobenzalde-
ketones using l-t-leucine as the catalyst gave anti selectivity. hyde, is formed without decarboxylation. These results sug-
l-t-Leucine provides superior results compared to other gest that l-t-leucine is sufficiently stable to retain its cata-
amino acids due to its stability under the reaction condi- lytic activity under aldol reaction conditions.
tions. According to Orsini’s report,[5a] proline and N-substi-
In addition, anti selective products were obtained in the
tuted primary amino acids react with p-nitrobenzaldehyde aldol reaction of cyclohexanone, whereas the use of cyclo-
to form an immonium salt which undergoes decarboxyl- heptanone or cyclooctanone gave syn products. These re-
ation. The resulting 1-oxapyrrolizidine and 1,3-oxazolidines sults suggest that the cyclohexanone transition state is fun-
have been obtained as stable compounds. In our experi- damentally different from that of cycloheptanone or cyclo-
Table 4. l-Amino acid catalyzed asymmetric aldol reaction of cycloheptanone and cyclooctanone.
Entry[a]
n
Ar
Catalyst
(mol-%)
Time
[d]
Product
Yield
[%][b]
dr
ee of syn
(syn/anti)[c]
[%][d]
1
2
3
4
5
6
7
8
9
2
2
2
2
2
3
3
3
3
3
4-O2NC6H4
3-O2NC6H4
4-NCC6H4
3,5-(F3C)2C6H3
4-pyrydinyl
2,4-(O2N)2C6H3
4-O2NC6H4
4-NCC6H4
3,5-(F3C)2C6H3
4-pyrydinyl
10
20
20
20
20
30
30
30
30
30
7
7
7
7
7
10
10
10
10
10
6a
6b
6d
6e
6j
84
84
89
94
89
82
68
51
79
71
6.1:1
6.7:1
5.7:1
5.9:1
6.7:1
4.0:1
10:1
10:1
13:1
10:1
63
71
62
64
50
58
60
51
31
53
7i
7a
7d
7e
7j
10
[a] The reaction was performed with aldehyde (1 equiv.) and cyclic ketone (10 equiv.). [b] Combined isolated yield of the diastereomers.
1
[c] Determined by H NMR spectroscopy. [d] Determined by HPLC.
Eur. J. Org. Chem. 2011, 993–997
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995

T. Kanemitsu, A. Umehara, M. Miyazaki, K. Nagata, T. Itoh
FULL PAPER
Scheme 1. Reactions between amino acids and aryl aldehyde.
octanone. According to previous reports,[6c,14] the anti rently investigating the possibility of improving the enantio-
product is formed through the s-trans-enamine, but the syn selectivity and understanding the mechanisms controlling
product is formed via the s-cis-enamine in aldol reactions the generation of optically active products.
of cyclic ketones. Plausible transition states are shown in
Scheme 2. Molecular mechanics calculations suggest that l-
t-leucine has a tendency to afford the s-cis-enamine in the Experimental Section
case of cycloheptanone and cyclooctanone, but the s-trans-
General Information: All materials were purchased from commer-
cial suppliers and used without further purification. Progress of
the reactions was monitored by thin-layer chromatography (TLC)
performed on Merck Art. 5715 Kieselgel 60 F254/0.25 mm thickness
plates. Visualization was accomplished with UV light and cerium
enamine for cyclohexanone.[15] That is, the tert-butyl group
of l-t-leucine influences the stability of the enamines to
make one isomeric enamine dominant. The approach of an
aldehyde, and the hydrogen bond formed between the hy-
drogen of the carboxyl group of l-t-leucine and the oxygen sulfate–ammonium molybdate solution followed by heating. Col-
umn chromatography was performed by using forced flow of the
indicated solvent on Sigma H-type silica Gel 60N (100–210 μm).
1H and 13C NMR spectra were recorded with a JEOL JNM AL-
400 instrument (400 MHz for 1H and 100 MHz for 13C) or a JEOL
JMN ECA-500 instrument (500 MHz for 1H and 125 MHz for 13C)
in the aldehyde, apparently results in a rigid transition state.
At this point, the aryl group of the aldehyde is located on
the opposite side of the carboxyl group of l-t-leucine due
to steric effects. Therefore, the s-cis enamine attacks the Re
face of the aldehyde to generate the syn product in the case
of seven- and eight-membered rings.
1
in deuterated solvent, using tetramethylsilane (δ = 0.0 ppm for H
NMR spectra) and CDCl3 (δ = 77.0 ppm for 13C NMR spectra) as
internal standards. Optical rotations were measured with a JASCO
P1020 polarimeter operating at the sodium D line at room tempera-
ture. HPLC analyses were performed with Shimadzu equipment
(254 λ absorbance Detector) using Daicel Chemical Industries, Ltd.
Chiralcel OD, Chiralcel OJ-H, Chiralpak AD-H, or Chiralpak IC
columns with hexane/isopropyl alcohol or hexane/ethyl acetate.
HPLC methods were calibrated with the corresponding racemic
mixtures. High-resolution mass spectra (HRMS) were measured
with a JEOL JMS-MS700V using p-nitrobenzyl alcohol as a ma-
trix. The known compounds have been identified by comparison
of spectroscopic data with those reported. The absolute configura-
tions of the optically active compounds were determined on the
basis of the measured optical rotation compared with literature val-
ues.
Typical Procedure for Organocatalyzed Direct Aldol Reaction of Cy-
clohexanone: To a mixture of aldehyde (0.5 mmol) and l-t-leucine
(0.1 mmol) in DMSO (2.0 mL) was added H2O (25 mmol) and cy-
clohexanone (1.5 mmol), and the mixture was stirred at room tem-
perature. The reaction was monitored by TLC analysis. After 7 d,
brine was added, and the mixture was extracted with CH2Cl2 (3ϫ).
The combined organic extracts were dried with MgSO4 and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate, gradient) to give the de-
sired product.
Scheme 2. Proposed transition states of anti- and syn-aldol reac-
tions.
Conclusions
In summary, we have developed an l-t-leucine-catalyzed
asymmetric direct aldol reaction, which gives access to op-
tically active compounds in moderate to high yield. Com-
pared to reactions with other amino acid catalysts, l-t-leu-
cine gave far better results. In the case of cycloheptanone
or cyclooctanone, the l-t-leucine-catalyzed reaction af-
Typical Procedure for Organocatalyzed Direct Aldol Reaction of Cy-
cloheptanone: To a mixture of aldehyde (0.5 mmol) and l-t-leucine
(0.1 mmol) was added cycloheptanone (5 mmol), and the mixture
forded the product with high syn selectivity. We are cur- was stirred at room temperature. The reaction was monitored by
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Eur. J. Org. Chem. 2011, 993–997

l-t-Leucine-Catalyzed Asymmetric Aldol Reaction of Cyclic Ketones
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TLC analysis. After 7 d, brine was added, and the mixture was
extracted with CH2Cl2 (3ϫ). The combined organic extracts were
dried with MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate, gradient) to give the desired product.
Typical Procedure for Organocatalyzed Direct Aldol Reaction of Cy-
clooctanone: To a mixture of aldehyde (0.25 mmol) and l-t-leucine
(0.075 mmol) was added cyclooctanone (2.5 mmol), and the mix-
ture was stirred at room temperature. The reaction was monitored
by TLC analysis. After 10 d, brine was added, and the mixture was
extracted with CH2Cl2 (3ϫ). The combined organic extracts were
dried with MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate, gradient) to give the desired product.
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aldol products, and HPLC traces for all results in Tables 2, 4, and
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afford s-cis-enamine geometry with cycloheptanone or cyclooc-
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Received: October 16, 2010
Published Online: December 15, 2010
Eur. J. Org. Chem. 2011, 993–997
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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