Electrostatic repulsion and hydrogen-bonding interactions in a simple N-aryl-L-valinamide organocatalyst control the stereoselectivity in asymmetric aldol reactions

Article abstract of DOI:10.1002/ejoc.201301138

A novel stereocontrol method for asymmetric aldol reactions of aldehydes with ketones is described. The stereoselectivity of the products is controlled by the electrostatic repulsion and hydrogen-bonding interactions of an N-aryl-L-valinamide catalyst. Th

Full text of DOI:10.1002/ejoc.201301138

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301138
Electrostatic Repulsion and Hydrogen-Bonding Interactions in a Simple
N-Aryl-
L
-valinamide Organocatalyst Control the Stereoselectivity in
Asymmetric Aldol Reactions
Yuya Tanimura,[a] Kenji Yasunaga,[a] and Kaori Ishimaru*[a]
Keywords: Synthetic methods / Organocatalysis / Asymmetric catalysis / Aldol reactions / Heterocycles
A novel stereocontrol method for asymmetric aldol reactions
of aldehydes with ketones is described. The stereoselectivity
of the products is controlled by the electrostatic repulsion and
catalyst. The use of this catalyst in a cross-aldol reaction al-
lows easy access to bioactive 3-cyclohexanone-3-hydroxy-2-
oxindole with excellent diastereo- (syn/anti = Ͼ99:1) and
enantioselectivity (Ͼ99% ee).
hydrogen-bonding interactions of an N-aryl-L-valinamide
in l-valine is flexible.[15] In addition, our preliminary experi-
ment showed that the reaction with l-valine itself (see
Table 1) did not proceed. Unlike the organocatalysts re-
ported thus far, catalyst 1e bears a 2,6-difluorophenyl
group; electrostatic repulsion between one fluorine atom on
the aromatic ring and the amide oxygen atom tilts the aro-
matic group,[16,17] and hydrogen bonding of the other fluor-
ine atom with the amide hydrogen atom stabilizes this con-
formation.[18] As a result, the reaction proceeds preferen-
tially from the less-hindered face of the enamine intermedi-
ate in the asymmetric aldol reaction. In addition, electro-
static repulsion between a catalyst fluorine atom and the
aldehyde electrophile oxygen atom may also contribute to
excellent stereoselectivity. Thus, our catalyst should expand
the strategy in asymmetric organocatalysis. Herein, we re-
port the development of an N-aryl-l-valinamide organocat-
alyst derived from l-valine for asymmetric aldol reactions.
Introduction
Organocatalytic asymmetric reactions performed with
the use of chiral amines have received a great deal of atten-
tion in recent decades, and this area of organic chemistry
has been rapidly growing.[1] Since List et al. reported the
direct aldol reaction between acetone and a variety of alde-
hydes catalyzed by l-proline, which formed an enamine sim-
ilar to the mechanism of class I aldolase,[2] asymmetric or-
ganocatalysts including l-proline derivatives have been ex-
tensively investigated.[3] However, most strategies for con-
trolling the stereoselectivity of the products by using the
organocatalysts reported thus far have been quite limited.
Generally, hydrogen-bonding interactions and steric hin-
drance are crucial for achieving high stereoselectivity.[4–8] In
addition, catalysts with more than two chiral centers have
been used in some cases. Other excellent strategies such as
the use of ion-pairing catalysts,[9] carbenes,[10] Lewis
bases,[11,12] and other catalysts have also been reported, but
most of these studies used large molecules to control stereo-
selectivity. New stereocontrol methods with the use of small
molecules should open a new avenue in asymmetric organo-
catalysis.
We have developed a novel strategy for the stereocontrol
of the asymmetric aldol reaction, which is one of the most
important carbon–carbon bond-forming reactions in or-
ganic synthesis for obtaining pharmaceutically useful com-
pounds.[13,14] Our strategy uses N-aryl-l-valinamide 1e,
which is a small, simple, and relatively inexpensive com-
pound, as an organocatalyst (Figure 1). Of the amino acid
derived catalysts, l-valine derivatives are used less often
than proline derivatives, because the primary amine moiety
Figure 1. Stereocontrol strategy in the asymmetric aldol reaction.
Results and Discussion
[a] Department of Chemistry, National Defense Academy,
Hashirimizu 1-10-20, Yokosuka 239-8686, Japan
E-mail: kaoriisi@nda.ac.jp
Initially, we examined the aldol reaction of 4-nitrobenz-
aldehyde (3a) with cyclohexanone (2a) by using N-aryl-l-
valinamides 1a–g (25 mol-%) in brine at room temperature
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301138.
Eur. J. Org. Chem. 0000, 0–0
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Y. Tanimura, K. Yasunaga, K. Ishimaru
SHORT COMMUNICATION
(Table 1). Catalyst 1a with an alkyl amide afforded the substitution patterns and electronic properties were evalu-
product with 51% ee (Table 1, entry 1), whereas 1b–g with ated, and they all afforded the corresponding aldol products
an aryl group gave higher enantioselectivities (Table 1, en- in high stereoselectivities and yields (85–93% yield, 87 to
tries 2–7). Catalyst 1c achieved 83% ee but the yield was Ͼ99% ee; Table 2, entries 1–6). Introducing a sterically de-
low (49%; Table 1, entry 3), because the electron-donating manding 2-nitrophenyl group (as in 3c) or a 2,6-dichloro-
group on the aromatic ring led to undesired side reactions. phenyl group (as in 3d) also led to higher enantioselectivity
Amongst the catalysts bearing an electron-withdrawing (Table 2, entries 2 and 3). Furthermore, separate reactions
substituent (Table 1, entries 4–6), 1e significantly improved with heterocyclic ketones 2b and 2c gave corresponding
the enantioselectivity and yield (syn/anti = 29:71, 96% ee; products 4h (syn/anti = 16:84, 83% ee; Table 2, entry 7) and
Table 1, entry 5). Unexpectedly, 2,6-dimethylphenyl deriva- 4i (syn/anti = 11:89, Ͼ99% ee; Table 2, entry 8), respec-
tive 1g produced lower diastereo- and enantioselectivity tively.
(syn/anti = 50:50, 69% ee; Table 1, entry 7), indicating that
the bulkiness of the aromatic substituent may not be impor-
Table 2. Asymmetric aldol reaction of aldehyde 3 with 2 catalyzed
by l-valinamide 1e.[a]
tant for high stereoselectivity. Furthermore, both 1c, which
has an electron-donating group, and 1d, which has an elec-
tron-withdrawing group, gave higher enantioselectivity than
1b (Table 1, entries 3 and 4 vs. entry 2). This suggests that
catalyst 1 does not control the stereoselectivity through a
hydrogen-bonding interaction between the acidic hydrogen
atom on the amide group in 1 and the oxygen atom of 3a.
Time[b]
[d]
4
Yield[c] syn/anti[d] ee[e]
Table 1. Asymmetric aldol reaction of aldehyde 3a with cyclohex-
anone (2a) catalyzed by l-valinamides 1a–g.[a]
Entry
2
Ar
[%]
[%]
1
2
3
4
5
6
7
8
2a 3-NO2C6H4 (3b)
2a 2-NO2C6H4 (3c)
2a 2,6-Cl2C6H3 (3d)
2a 4-ClC6H4 (3e)
2a Ph (3f)
2a 4-MeOC6H4 (3g)
2b 4-NO2C6H4 (3a)
2c 4-NO2C6H4 (3a)
3
3
3
4b
93
89
92
88
91
85
90
92
16:84
19:81
1:Ͼ99
20:80
29:71
12:88
16:84
11:89
92
Ͼ99
98
90
93
87
83
Ͼ99
4c
4d
4e
4f
4g
4h
4i
7
11
15
3
3
[a] All reactions were carried out with 2 (5 equiv.) and 3 (0.5 mmol)
in H2O (0.5 mL) in the presence of the catalyst (20 mol-%).
[b] Monitored by TLC. [c] Yield of isolated product. [d] Deter-
mined by 1H NMR spectroscopy. [e] Determined by HPLC on a
chiral stationary phase for the anti product.
To elucidate the mechanism of stereoselectivity, our ini-
tial computational analysis focused on three enamine struc-
tures (Figure 2). All structures were fully optimized at the
B3LYP/6-31G(d,p) level with Gaussian 09.[19] The 2,6-di-
methylphenyl group of enamine B and the 2,6-difluoro-
phenyl group of enamine C were inclined at –132.5 and
–145.8° to the amide moiety, respectively, whereas the
phenyl group was in the same plane as that in enamine A.
Thus, the Re faces of enamines B and C were blocked by
the 2,6-dimethylphenylamide and 2,6-difluorophenylamide,
respectively. However, the diastereo- and enantioselectivity
obtained with the use of 1e were higher than those obtained
with the use of 1g (Table 1, entry 5 vs. 7), which suggests
that the fluorine atoms are essential for stereocontrol: the
2,6-difluorophenyl group was inclined towards the amide
group as a result of the electrostatic repulsion between the
amide oxygen atom and a fluorine atom on the aromatic
Entry Catalyst
Time[b]
[h]
Yield[c]
[%]
syn/anti[d]
ee[e]
[%]
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
30
24
12
24
70
48
24
79
72
49
70
81
82
76
48:52
38:62
31:69
27:73
29:71
24:76
50:50
51
64
83
81
96
85
69
1g
[a] All reactions were carried out with 2a (5 equiv.) and 3a
(0.5 mmol) in brine (0.5 mL) in the presence of the catalyst (25 mol-
%). [b] Monitored by TLC. [c] Yield of isolated product. [d] Deter-
mined by 1H NMR spectroscopy. [e] Determined by HPLC on a
chiral stationary phase for the anti product.
After optimizing the reaction conditions (see the Sup- ring, and the hydrogen-bonding interaction between the
porting Information), we investigated the generality of the amide hydrogen atom and the other fluorine atom on the
reaction (Table 2). Aromatic aldehydes 3b–g with different aromatic ring stabilized the conformation.
2
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Controlling Stereoselectivity in Asymmetric Aldol Reactions
vities has not been reported.[25] After optimizing the reac-
tion conditions (see the Supporting Information), the reac-
tions of 2a with isatins 5a–c proceeded smoothly in the
presence of catalyst 1e to afford corresponding aldol prod-
ucts 6a [syn/anti = Ͼ99:1, Ͼ99% ee (syn)], 6b [syn/anti =
99:1, 93% ee (syn)], and 6c [syn/anti = 98:2, 98% ee (syn)],
respectively. The absolute configuration of the products was
unambiguously assigned by single-crystal X-ray analysis of
6b.[26] Generally, the stereochemical courses of both aldol
and cross-aldol reactions were the same with the use of the
same catalyst. However, it is interesting to note that the
aldol reaction with the use of our catalyst occurred on the
less-hindered face of the enamine (Si face of enamine C in
Figure 2), whereas the cross-aldol products were formed by
Re face attack of the enamine. Because isatins bear two ba-
sic oxygen atoms, the hydrogen-bonding interaction be-
tween the oxygen atom in the isatin and the amide hydrogen
atom in the catalyst could give the (2ЈS,3R) isomer in excel-
lent stereoselectivity. We are currently conducting detailed
mechanistic studies.
Figure 2. Enamine structures calculated at the B3LYP/6-31G(d,p)
level.
The transition-state structures were also examined with
DFT calculations (Figure 3, TS1 and TS2).[20] In TS1,
which led to the major experimentally observed product,
the steric hindrance and the electronic repulsion between
the fluorine atom of 1e and the benzaldehyde oxygen atom
would preferentially lead to attack from the Si face of the
enamine. The continuum solvation model was applied to
estimate the barrier height for the aldol reactions, because
water plays an important role in the high stereoselecti-
vity.[21] Single-point energy calculations performed by using
the geometry optimized at the B3LYP/6-31G(d,p) level with
the self-consistent reaction field calculation based on the
polarizable continuum model (ε = 78.39 for water) were
conducted at the same level as that used for the geometry
optimization. We found that the energy of TS1 was lower
than that of TS2 by 4.5 kcalmol–1, which was in good
agreement with the experimental stereoselectivity results.
Scheme 1. Asymmetric cross-aldol reaction of isatins 5 with cyclo-
hexanone (2a) catalyzed by 1e. All reactions were carried out with
2a (10 equiv.) and 5 (0.5 mmol) in tBuOH (1.0 mL) in the presence
of 1e (25 mol-%), H2O (20 mol-%), and pTsOH·H2O (10 mol-%, Ts
= para-toluenesulfonyl).
Conclusions
In conclusion, we have developed a stereocontrol method
by using catalyst 1e, which contains a 2,6-difluorophen-
ylamide group. Catalyst 1e is inexpensive relative to l-pro-
line derivatives and other organocatalysts and is easily pre-
pared from l-valine. Catalytic asymmetric aldol and cross-
aldol reactions by using catalyst 1e gave the corresponding
products in excellent stereoselectivity under mild, environ-
mentally friendly conditions. We are currently conducting
further mechanistic studies and exploring the application of
the catalyst.
Figure 3. Calculated transition-state models for the asymmetric
aldol reaction catalyzed by 1e.
To demonstrate the utility of our catalyst, we prepared a
series of 3-substituted-3-hydroxyindolin-2-ones (6a–c,
Scheme 1), which are desirable targets because many related
structural motifs are found in natural products and phar-
maceutically active compounds.[22] In particular, cross-aldol
product 6a antagonizes maximal electroshock seizures
(anti-MES).[23] Although the organocatalytic reactions of
cyclohexanone with isatin (5a) or substituted isatins have
been described,[24] only a few examples have been reported
for a highly stereoselective reaction.[24b,24e] In addition, the
Experimental Section
General Procedure for the Asymmetric Aldol Reaction of Aromatic
synthesis of the (2ЈS,3R) isomer with excellent stereoselecti- Aldehydes with Cyclic Ketones: To a stirred solution of the catalyst
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Y. Tanimura, K. Yasunaga, K. Ishimaru
SHORT COMMUNICATION
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room temperature in a closed system for an appropriate time until
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on SiO2 (n-hexane/CH3CO2Et = 4:1) to afford the product.
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General Procedure for the Asymmetric Cross-Aldol Reaction of
Cyclohexanone with Isatins: To a stirred solution of the catalyst
(0.125 mmol), H2O (0.1 mmol), and pTsOH·H2O (0.05 mmol) in
tBuOH (1.0 mL) was added cyclohexanone (10.0 mmol) and the
isatin (0.5 mmol) at room temperature under an atmosphere of air.
The reaction mixture was stirred at room temperature in a closed
system for an appropriate time until the reaction was complete, as
monitored by TLC. Then, the mixture was extracted with
CH3CO2Et (3ϫ 10 mL), and the organic layer was dried with anhy-
drous sodium sulfate, filtered, and concentrated. The residue was
purified by flash column chromatography on SiO2 (n-hexane/
CH3CO2Et = 1:4) to afford the product. The diastereomeric ratios
and the enantiomeric excess values of the products were determined
by HPLC on a chiral stationary phase.
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data including 1H
NMR and 13C NMR spectra of the catalysts and products, crystal
structure of 6b, and computational methods.
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4
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Controlling Stereoselectivity in Asymmetric Aldol Reactions
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Received: July 30, 2013
Published Online: ᭿
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5

Job/Unit: O31138
/KAP1
Date: 02-09-13 11:01:56
Pages: 6
Y. Tanimura, K. Yasunaga, K. Ishimaru
SHORT COMMUNICATION
Organocatalysis
Small, simple, and flexible N-(2,6-difluoro-
phenyl)-l-valinamide controls the stereo-
selectivity in asymmetric aldol and cross-
aldol reactions under environmentally
friendly conditions. The use of this catalyst
in a cross-aldol reaction allows easy access
to bioactive 3-hydroxy-3-(2-oxocyclohex-
yl)indolin-2-one with excellent diastereo-
and enantioselectivities.
Y. Tanimura, K. Yasunaga,
K. Ishimaru* ..................................... 1–6
Electrostatic Repulsion and Hydrogen-
Bonding Interactions in a Simple N-Aryl-
l-valinamide Organocatalyst Control the
Stereoselectivity in Asymmetric Aldol Re-
actions
Keywords: Synthetic methods / Organo-
catalysis / Asymmetric catalysis / Aldol
reactions / Heterocycles
6
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Eur. J. Org. Chem. 0000, 0–0