Efficient ball-mill procedure in the 'green' asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides in the presence of water

Article abstract of DOI:10.1016/j.tet.2011.06.042

The organocatalytic activity of (S)-proline-based dipeptides 1a-c has been evaluated in the asymmetric aldol reaction between representative ketones with various aromatic aldehydes under solvent-free conditions in a ball mill. In particular, the methyl ester of (S)-proline-(S)-tryptophan, (S,S)-1c, proved to be an efficient organocatalyst, and the aldol reaction proceeded with good chemical yields and excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 98% ee), in the presence of water, and 5 mol % of benzoic acid as additive.

Full text of DOI:10.1016/j.tet.2011.06.042

Tetrahedron 67 (2011) 6953e6959
Contents lists available at ScienceDirect
Tetrahedron
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Efficient ball-mill procedure in the ‘green’ asymmetric aldol reaction
organocatalyzed by (S)-proline-containing dipeptides in the presence of water
*
ꢀ
ꢀ
Jose G. Hernandez, Eusebio Juaristi
ꢀ
ꢀ
ꢀ
Departamento de Química, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apartado Postal 14e740, 07000 Mexico D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2011
Received in revised form 9 June 2011
Accepted 16 June 2011
Available online 22 June 2011
The organocatalytic activity of (S)-proline-based dipeptides 1aec has been evaluated in the asymmetric
aldol reaction between representative ketones with various aromatic aldehydes under solvent-free
conditions in a ball mill. In particular, the methyl ester of (S)-proline-(S)-tryptophan, (S,S)-1c, proved
to be an efficient organocatalyst, and the aldol reaction proceeded with good chemical yields and ex-
cellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 98% ee), in the presence of
water, and 5 mol % of benzoic acid as additive.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Chiral dipeptides
Organocatalysis
Ball-milling
Green chemistry
Asymmetric aldol reaction
1. Introduction
L-prolinamides and L-prolinethioamides (5 mol %) as organo-
catalysts in solvent-free aldol reaction (2:1 ketone/aldehyde) with
traditional magnetic stirring. The anti-aldol adducts were obtained
in high yields and with excellent diastereo- and enantioselectivities
(up to 99:1 dr, up to 98% ee).7
On the other hand, Bolm and Worch performed the enantiose-
lective aldol reaction of cyclohexanone and aromatic aldehydes in
Organocatalysis is essentially the acceleration of a chemical step
by a non metal-containing relatively small organic molecule. This
simple new concept has totally captured the attention of much of
the organic chemistry community in the last decade.1 For instance,
the fact that organocatalysis prevents the use of a metal means that
organocatalytic processes fulfill one of the guidelines of green
chemistry, where the design of safe chemical process is a key
concept.2a Furthermore, a relevant strategy followed by some re-
searchers in the organocatalysis area to make it ‘greener’ involves
the use of friendly reaction media, avoiding, for example, the use of
toxic, volatile, and/or corrosive solvents.2b,c For example, the use of
ionic liquids,3 heterogeneous catalysts anchored on resins or in-
organic solid supports,4 water as a reaction media5 or application of
solvent-free processes6 have all contributed to the development of
more sustainable chemical processes.
In the field of organocatalysis, the asymmetric aldol reaction has
been extensively studied in view of the fact that this reaction is one
of the most powerful strategies for the formation of new CeC
bonds; that is, facilitates the construction of larger molecules from
smaller ones. Among the many reaction conditions that have been
examined, an attractive advancement corresponds to asymmetric
aldol reactions carried out under solvent-free conditions. For
solvent-free conditions (5:1 ketone/aldehyde), using
L-prolyl-
substituted sulfonimidamides as catalysts (10 mol %), observing
moderate to verygood yields and good to excellent stereoselectivities
(up to 96:4 dr, up to 98% ee) after 2e4 days of stirring at 30 ꢀC.8 In
related work, Bolm and co-workers reported the asymmetric aldol
reaction under solvent-free conditions catalyzed by (S)-proline
(10 mol %) in a ball mill, using nearly stoichiometric amounts of ke-
tone and aldehyde (1.1:1). The anti-aldol products were obtained in
high yields with up to 99% ee. In this study, Bolm and co-workers
demonstrated that the efficiency of the process using High Speed
Ball-Milling (HSBM) was superior relative to traditional magnetic
stirring: reaction times were shorter and in general chemical yields,
diastereo- and enantioselectivities were higher.9 The above men-
tioned High Speed Ball-Milling technique has been increasingly used
in synthetic organic chemistry to promote several solvent-free re-
actions. Reported applications include: Heck-type cross-couplings,10
Knoevenagel condensation reactions,11 BayliseHillman reactions,12
Michael additions,11 functionalization of fullerenes,13 synthesis of
nitrones,14 synthesis of peptides,15 and others.
ꢀ
example, Najera and co-workers have reported the use of
Recently, as part of our continuing interest in HSBM,15a we ex-
amined the asymmetric aldol reaction between ketones and
* Corresponding author. Tel.: þ52 55 5747 3722; fax: þ52 55 5747 3389; e-mail
address: juaristi@relaq.mx (E. Juaristi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.042

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J.G. Hernandez, E. Juaristi / Tetrahedron 67 (2011) 6953e6959
6954
various aromatic aldehydes under solvent-free conditions in a ball
mill using almost stoichiometric amounts of ketone and aldehyde
(1.1:1). The reaction was catalyzed by the methyl ester of (S)-pro-
line-(S)-phenylalanine, (S,S)-1a (7 mol %) and proceed efficiently
affording the anti-aldol products in high yields and with good
diastereo- and enantioselectivities (up to 91:9 dr, up to 95% ee).16,17
We could demonstrate that dipeptide (S,S)-1a was more efficient
organocatalyst in the asymmetric aldol reaction under solvent-free
conditions, relative to the same reaction in solution. In addition we
found that reaction times were shortened compared with the same
reaction employing 10 mol % of amino acid (S)-proline, also in a ball
mill under solvent-free conditions.9 To explain the success of di-
peptide (S,S)-1a as an organocatalyst under solvent-free conditions,
methyl ester hydrochloride, followed by deprotection with hydro-
gen and palladium on carbon, according to the reported method for
the preparation of dipeptide (S,S)-1c (Scheme 1).17o
we suggested that non-covalent
pep interactions between the
aromatic rings of the catalyst and the substrate were maximized in
the absence of solvent, which could be responsible for the high
stereoselectivity in aldol product formation. With the aim of eval-
uating this hypothesis, we decided to prepare two additional
Scheme 1. Synthesis of dipeptides (S,S)-1aec.
Initially, we examined the aldol reaction between cyclohexa-
none and 4-nitrobenzaldehyde in the presence of organocatalyst
(S,S)-1a, (S,S)-1b, and (S,S)-1c. The reaction was carried out at
ꢁ20 ꢀC in a ball mill at 2760 rpm, using 7 mol % of catalyst (Table 1).
After4hofmilling, thedipeptides(S,S)-1band (S,S)-1c afforded the
aldol product in good yield, high diastereo- and enantioselectivity. In
particular, with dipeptide (S,S)-1c as organocatalyst the aldol adduct
was obtained with up to 84:16 anti/syn dr and 85% ee in favor of the
(2S,10R)-enantiomer (entry 3 in Table 1). The absolute configuration of
the products was assigned by comparisonwith literature data.5a,7c,9,17d
(S)-proline-containing
a,a-dipeptides, where the second amino
acid presents a lipophilic residue, in order to compare their orga-
nocatalytic activity in the asymmetric aldol reaction of interest.
Dipeptides (S,S)-1b and (S,S)-1c, derived from (S)-proline and (S)-
phenylglycine or (S)-tryptophan, respectively (Fig. 1) were deemed
most useful to test the mechanistic proposal.
Table 1
Direct asymmetric aldol reaction of 4-nitrobenzaldehyde with cyclohexanone cat-
alyzed by (S,S)-dipeptides 1aeca
O
O
OH
O
1a-c
Fig. 1. Structure of dipeptides (S,S)-1aec.
H
+
+
syn isomer
Ball-milling
2760 rpm
NO
NO
2
2
anti isomer
Dipeptide (S,S)-1c has been previously studied as catalyst in
2a
3a
4a
€ }
asymmetric aldol reactions. Szollosi and co-workers reported the
use of (S,S)-1c (10 mol %) in the aldol reaction between acetone and
2-ethylbutanal, in an excess of acetone (68:1). After 24 h of re-
action, the expected (R)-b-hydroxyketone was obtained in moder-
Entry
Cat.
Yield (%)b
dr (anti/syn)c
eed (%)
95e
82
1
2
3
1a
1b
1c
92
80
86
90:10
89:11
86:14
ate yield and 86% ee.17o Furthermore, the unprotected dipeptide (S)-
NHPro-(S)-TrpOH (1c-OH) has been also evaluated as organo-
catalyst in aldol reactions and proved to be a privileged structure. In
particular, List and Martin studied the asymmetric aldol reaction
between acetone and 4-nitrobenzaldehyde in DMSO using 30 mol %
of (1c-OH) and 18 h of reaction time. The expected aldol product
was isolated in moderate yield and with 65% ee of the (R)-enan-
tiomer.17e Furthermore, in 2007 Li and co-workers reported the use
of dipeptide (1c-OH) in the aldol reaction of representative ketones
with various aromatic, heteroaromatic, aliphatic, and unsaturated
aldehydes in the presence of water. The desired aldol products were
obtained in high yields (up to 94%) and good enantioselectivities
(up to 97% ee).17a In addition, Li and co-workers examined di-
peptide (1c-OH) in the asymmetric aldol reaction of different ke-
tones and aldehydes in solid phase media (Al2O3), using 1,4-
diazabicyclo[2.2.2]octane as additive, observing moderate to high
reaction yields (35e95%), good diastereoselectivities (up to 99:1 dr)
and excellent enantioselectivities (anti-aldol, 98% ee).17d Never-
theless, before the present work dipeptides (S,S)-1b and (S,S)-1c
had not been studied as potential organocatalysts in aldol reactions
under solvent-free reaction conditions.
85
a
Reaction conditions: ketone 2a (0.22 mmol), aldehyde 3a (0.20 mmol), catalyst
1aec (7 mol %), ꢁ20 ꢀC, 4.0 h.
b
Isolated yield.
c
Determined by 1H NMR of the crude product.
d
Determined by chiral HPLC.
Ref. 16.
e
To improve the ee of the products obtained with (S,S)-1c as
organocatalyst, we decided to evaluate the effect of water on the
aldol reaction. Indeed, in aldol reaction catalyzed by proline resi-
dues embedded in a hydrophobic environment, water has dem-
onstrated to play an important role in organocatalytic reactions
inducing significant reaction rate acceleration and/or increasing the
stereoselectivity.5d,9,18
Thus, the effect of different amounts of water in the model re-
action of cyclohexanone and 4-nitrobenzaldehyde at ꢁ20 ꢀC cata-
lyzed by 7 mol % of dipeptide (S,S)-1c was examined (Table 2). The
addition of 0.5 equiv of water to the reaction mixture did not result in
an increase of the yield; however, a small improvement in the ster-
eoselectivity of the product may be observed (entry 2 in Table 2).
Higher conversion was observed when adding 1.1 equiv of water to
the reaction mixture. Furthermore, the diastereo- and enantiose-
lectivity were also superior (up to 91:9 dr, anti-aldol, 92% ee. Entry 3
in Table 2). Nevertheless, excess of water or the use of brine did not
improve the yield nor the stereoinduction (entries 4 and 5 inTable 2).
These results are consistent with the idea that in the presence of
2. Results and discussion
Methyl ester dipeptides (S,S)-1a, (S,S)-1b and (S,S)-1c (Fig. 1)
were prepared by condensation of Cbz-N-protected (S)-proline
with (S)-phenylalanine, (S)-phenylglycine and (S)-tryptophan

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J.G. Hernandez, E. Juaristi / Tetrahedron 67 (2011) 6953e6959
6955
Table 2
the effect of benzoic acid as additive, using a range between 3 mol %
and 30 mol % of PhCO2H (entries 3e7 in Table 3). The most efficient
amount of acid was 5 mol %, which afforded the aldol product with
high diastereo- and enantioselectivity (up to 92:8 dr, anti-aldol, 95%
ee) in favor of the (2S,10R)-enantiomer (entry 6 in Table 3). Finally,
the reaction was performed using 20 mol % of PhCO2H in the ab-
sence of water in order to determine whether the increase in
enantioinduction is due exclusively to the acid present. The ob-
servation that both the diastereo- and enantioselectivity of the
product was lower than those found in the same reaction in the
presence of water (compare entries 4 and 8 in Table 3) suggests that
water does play a significant role in the observed improvements.
We also examined theeffectof the amountofcatalyst(S,S)-1c. This
analysis revealed that best results are obtained when using 3 mol % of
catalyst. The anti-product was obtained in 93% ee in favor of the
(2S,10R)-enantiomer (entry 3 inTable 4). Nevertheless, it is interesting
that even with 1 mol % of the catalyst, the ee of the major anti-aldol
product is remarkably high (up to 90% ee, entry 5 in Table 4).
The effect of water on the direct aldol reaction of 4-nitrobenzaldehyde with cyclo-
hexanone catalyzed by (S,S)-dipeptide 1ca
O
O
OH
O
1c
H
+
+
syn isomer
Ball-milling
2760 rpm
NO
NO
2
2
anti isomer
2a
3a
4a
Entry
H2O (equiv)
Yield (%)b
dr (anti/syn)c
eed (%)
1
2
3
4
5
0.0
0.5
1.1
1.6
86
85
90
88
85
86:14
88:12
91:9
90:10
89:11
85
86
92
90
90
Brinee
Best results are highlighted in bold.
a
Reaction conditions: ketone 2a (0.22 mmol), aldehyde 3a (0.20 mmol), catalyst
1c (7 mol %), ꢁ20 ꢀC, 4.0 h.
b
Isolated yield.
c
Determined by 1H NMR of the crude product.
d
Determined by chiral HPLC.
Saturated brine (4.0 mg).
e
Table 4
The effect of the amount of catalyst on the direct aldol reaction of 4-
nitrobenzaldehyde with cyclohexanone catalyzed by (S,S)-dipeptide 1ca
water, hydrophobic groups on the organocatalyst create a hydro-
phobic ‘cavity’ that facilitates the required proximity between the
hydrophobic organocatalyst and the aromatic region of the aldehyde.
On the other hand, thelimited molar range of water, that is, beneficial
is in line with the observed behavior of reactions catalyzed by en-
zymes, where variations in the amount of water present in the re-
action medium influences drastically activity and stereoselectivity.19
The effect of acidic additives in the direct aldol reaction was then
explored. It has been documented that the presence of Bronsted
acids may affect the outcome of organocatalyzed process.20
O
O
OH
O
1c
H
+
+
sy n isomer
Ball-milling
2760 rpm
NO
NO
2
2
anti isomer
2a
3a
4a
Entry
1c (mol %)
Yield (%)b
dr (anti/syn)c
eed (%)
1
2
3
4
5
14
7
5
94
90
80
78
68
90:10
91:9
91:9
92:8
91:9
91
92
92
93
90
In particular, Pihko21 and Gryko22 have investigated the in-
fluence of acid additives on organocatalyzed aldol reactions and
found that an appropriate proton donor can in fact enhance the
acidity of the catalyst improving its activity. This was clearly
demonstrated for pyrrolidine-based organocatalysts, where the
reaction presumably proceeds via an enamine intermediate. In or-
der to evaluate the effect of Bronsted acids, we carried out the re-
action between cyclohexanone and 4-nitrobenzaldehyde at ꢁ20 ꢀC,
catalyzed by 7 mol % of dipeptide (S,S)-1c and in the presence of
1.1 equiv of water and 30 mol % of acetic acid. The reaction afforded
the aldol adduct with better diastereoselectivity although the yield
was low (compare entries 1 and 2 in Table 3). Then we evaluated
3
1
Best results are highlighted in bold.
a
Reaction conditions: ketone 2a (0.22 mmol), aldehyde 3a (0.20 mmol), catalyst
1c (1e14 mol %), 1.1 equiv of water, ꢁ20 ꢀC, 4.0 h.
b
Isolated yield.
c
Determined by 1H NMR of the crude product.
d
Determined by chiral HPLC.
Finally, dipeptides (S,S)-1a, (S,S)-1b, and (S,S)-1c were reex-
amined in the direct aldol reaction between cyclohexanone and
4-nitrobenzaldehyde under the optimized reaction conditions:
3 mol % of catalyst, 1.1 equiv of water, 5 mol % of benzoic acid,
ꢁ20 ꢀC at 2760 rpm in a ball mill (Table 5). Employing the opti-
mized conditions, catalyst (S,S)-1a afforded the aldol product in
89% of yield and 94% ee, only slightly lower than our previously
Table 3
The effect of acidic additives on the direct aldol reaction of 4-nitrobenzaldehyde
with cyclohexanone catalyzed by (S,S)-dipeptide 1ca
O
O
OH
O
1c
H
+
Table 5
+
syn isomer
Ball-milling
2760 rpm
Direct asymmetric aldol reaction of 4-nitrobenzaldehyde with cyclohexanone cat-
NO
NO
alyzed by (S,S)-dipeptides 1aec under optimum reaction conditionsa
2
2
anti isomer
2a
3a
4a
O
O
OH
O
1a-c
H
+
Entry Additive (mol %) H2O (equiv) Yield (%)b dr (anti/syn)c eed (%)
+
sy n isomer
Ball-milling
2760 rpm
NO
NO
1
2
3
4
5
6
7
8
None
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.0
90
40
90
88
84
82
82
85
91:9
92:8
91:9
89:11
92:8
92:8
92:8
87:13
92
92
88
93
93
95
92
86
2
2
anti isomer
AcOH (30)
PhCO2H (30)
PhCO2H (20)
PhCO2H (10)
PhCO2H (5)
PhCO2H (3)
PhCO2H (20)
2a
3a
4a
Entry
Cat.
Yield (%)b
dr (anti/syn)c
eed (%)
1
2
3
1a
1b
1c
89
79
88
93:7
91:9
92:8
94
85
>98
Best results are highlighted in bold.
Best results are highlighted in bold.
a
a
Reaction conditions: ketone 2a (0.22 mmol), aldehyde 3a (0.20 mmol), catalyst
Reaction conditions: ketone 3a (0.22 mmol), aldehyde 4a (0.20 mmol), catalyst
1c (7 mol %), ꢁ20 ꢀC, 4.0 h.
1aec (3 mol %), ꢁ20 ꢀC, 1.1 equiv H2O, PhCO2H (5 mol %), 6.0 h.
b
b
Isolated yield.
Isolated yield.
c
c
Determined by 1H NMR of the crude product.
Determined by 1H NMR of the crude product.
d
d
Determined by chiral HPLC.
Determined by chiral HPLC.

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6956
J.G. Hernandez, E. Juaristi / Tetrahedron 67 (2011) 6953e6959
reported results.16 Nevertheless the diastereoselectivity in favor of
the anti-diastereomer was significantly improved under the new
reaction conditions, affording the major anti-product in 93:7 dr,
relative to the 90:10 dr that was previously reported (compare
entries 1 in Tables 1 and 5). In the case of the methyl ester (S,S)-1b,
the aldol adduct was also obtained with better diastereo- and
enantioselectivity; however, the ee was only 85% (compare entries
2 in Tables 1 and 5). Best results were generated with dipeptide
(S,S)-1c as catalyst, providing the aldol in 88% yield, a di-
astereomeric ratio of 92:8 in favor of the anti-product and with up
to 98% ee of aldol (2S,10R)-4a, which corresponds to the highest
stereoselectivity so far reported for the preparation of aldol product
4a under HSBM conditions.9,16
Table 6 (continued)
Entry
Product
Yield (%)b
80
dr (anti/syn)c
eed (%)
88
O
OH
7
94:6
4g
Br
Br
O
OH
8
84
94:6
83
4h
O
OH
9
81
62
94:6
96:4
87
90
Following the thorough evaluation of the essential parameters,
e.g., catalyst, amount of catalyst, equivalents of water and additives,
we proceeded to employ (S)-proline-(S)-tryptophan methyl ester,
(S,S)-1c, as organocatalyst in the direct asymmetric aldol reaction
between cyclohexanone 2a and cyclopentanone 2b with several
benzaldehyde derivatives containing different acceptor and donor
substituents 3ael. The nitro, chloro, bromo, cyano, and tri-
fluoromethyl substituents were chosen as electron-withdrawing
groups, and the methoxy substituent as a representative electron-
donating group. The collected data are summarized in Table 6. It
can be appreciated that benzaldehydes substituted by electron-
withdrawing groups are converted to the corresponding anti-al-
dol products in good yields (entries 1e10 in Table 6). The exception
is aldol 4j where the low yield can be explained by the large size of
the o-trifluoromethyl group in the aldehyde substrate, which may
4i
CN
O
O
OH CF3
10
4j
OH
11
12
71
64
95:5
96:4
86
55
4k
O
OH
4l
OH
OMe
NO2
O
13
73
40:60
80
4m
Table 6
Scope of the direct asymmetric aldol reaction of cyclic ketones with various alde-
a
hydes catalyzed by dipeptide 1c under ball-milling conditionsa
Reaction conditions: ketone 2a and b (0.22 mmol), aldehyde 3ael (0.20 mmol),
catalyst 1c (3 mol %), ꢁ20 ꢀC, 1.1 equiv H2O, PhCO2H (5 mol %), 6.0 h.
O
O
OH
O
b
3 mol % (1c)
Isolated yield.
Determined by 1H NMR of the crude product.
c
H2O, PhCO2H
H
+
d
+
R
syn isomer
Determined by chiral HPLC.
R
Ball-milling
2760 rpm
anti isomer
2
3
4
sterically hinder the required approach of the reactive enamine to
form the product. By contrast, the reaction of less reactive benzal-
dehyde with cyclohexanone afforded product 4k in 71% yield (entry
11 in Table 6). In this context, the reaction of p-anisaldehyde with
cyclohexanone afforded the aldol adduct 4l in moderate yield (64%)
(entry 12 in Table 6). Finally, the reaction of cyclopentanone with
4-nitrobenzaldehyde generated a 60:40 mixture of syn- and anti-
isomers in good yield (73%) (entry 13 in Table 6).
Regarding the observed diastereoselectivity, the aldol reaction
using 3 mol % of dipeptide (S,S)-1c as catalyst, exceeded in all cases
the results previously obtained with 7 mol % of catalyst (S,S)-1a.16
The diastereomeric ratio increased significantly and the major
anti-isomer was obtained in a range of 92:8 to 98:2 (entries 1e12 in
Table 6).
With respect to the observed enantioinduction, aldol reactions
using 3 mol % of catalyst (S,S)-1c in the presence of water, showed an
increase in the ee of the aldol products derived from nitro-
containing benzaldehydes and cyclohexanone; 88e98% ee (entries
1e3 in Table 6), relative to the same reaction catalyzed by 7 mol % of
(S,S)-1a. Alsothe eein anti-aldol product 4mwas improvedfrom55%
ee when using (S,S)-1a16 to 80% ee when employing (S,S)-1c
(this work). On the other hand, the aldol reaction of 4-cyano-
benzaldehyde and 2-trifluoromethylbenzaldehyde with cyclohex-
anone afforded the aldol adducts in 87% and 90% ee, respectively
(entries 9 and 10 in Table 6). The use of benzaldehyde derivatives
containing chloro and bromo as electron-withdrawing groups with
cyclohexanone generated the anti-aldol products with ees in the
range of 80%e90% ee (entries 4e8 in Table 6), which is quite similar
to that observed previously with (S,S)-1a as catalyst.16 By contrast,
Entry
1
Product
Yield (%)b
89
dr (anti/syn)c
eed (%)
O
OH
92:8
>98
4a
NO2
NO2
O
OH
2
3
4
90
86
88
93:7
98:2
96:4
88
94
80
4b
O
OH
NO2
4c
O
OH
4d
Cl
Cl
O
OH
5
6
82
77
96:4
94:6
86
90
4e
O
OH
Cl
4f

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J.G. Hernandez, E. Juaristi / Tetrahedron 67 (2011) 6953e6959
6957
the reaction of less reactive benzaldehyde with cyclohexanone
afforded product 4k with 86% ee (entry 11 in Table 6). Finally the
aldol reaction of p-anisaldehyde with cyclohexanone generated the
aldol adduct 4l in 55% ee (entry 12 in Table 6).
a hydrophobic environment with the use of water. Under these
conditions, non-covalent interactions between aromatic rings
pep
of the catalyst and the aldehydes are enhanced, and thus the hy-
drophobic organocatalyst and the aromatic region of the aldehyde
may engage in a more rigid transition state that induces higher
stereoselectivity.24 In addition, present water molecules may be
involved in the formation of hydrogen bonds with the carbonyl
amide group in dipeptide (S,S)-1c. This interaction may enhance the
acidity of the NeH amide bond and provide stronger hydrogen
bond with the aldehyde substrate, which fixes it and promotes
higher stereoselectivity in the process (Fig. 2).5d,9,25,26
In our previous work, we also evaluated dipeptide (S,S)-1a as
catalyst in the asymmetric aldol reaction between acetone and 4-
nitrobenzaldehyde under HSBM conditions. It was found that
organocatalyst (S,S)-1a performs better under solvent-free condi-
tions, as compared with the same reaction in solution.16 For this
reason it was decided to examine the aldol reaction between ace-
tone and nitrobenzaldehydes using dipeptide (S,S)-1c as catalyst in
the presence of water, and using benzoic acid as additive. It can be
appreciated in Table 7 that 3 mol % of (S,S)-1c afforded the corre-
sponding aldol products in acceptable yields and with better
enantioselectivities, relative to the same reaction catalyzed by
7 mol % of dipeptide (S,S)-1a.
3. Conclusion
In summary, (S)-proline-based dipeptides 1aec were prepared
and evaluated as organocatalysts in the asymmetric aldol reaction
under solvent-free condition in a ball mill. It was found that di-
peptide (S,S)-proline-tryptophan-CO2Me 1c is the most efficient
catalyst. This result is in agreement with expectation that di-
peptides of proline and a second hydrophobic residue should be
efficient catalysts in aldol reaction due to the possible formation of
a hydrophobic core. The catalytic activity of (S,S)-1c was improved
by the use of an equimolar amount of water and a catalytic amount
of benzoic acid. In particular, it is shown that the aldol reaction
proceeds efficiently affording the anti-aldol products in good yields
with high diastereo- and enantioselectivities. It is worth mention-
ing that aldol products 4aec, 4m, 4k, and 5b and c were obtained
with higher stereoselectivity by the use of 3 mol % of dipeptide
(S,S)-1c, relative to the same reaction employing 7 mol % of (S,S)-
1a.16 Furthermore, aldol products 4a, 4d, 4k, and 5a were obtained
with higher enantioselectivity, relative to reactions employing
10 mol % of (S)-proline, also in a ball mill under solvent-free
conditions.9
Table 7
Relative catalytic activity of dipeptides (S,S)-1a and (S,S)-1c in asymmetric aldol
reaction of acetone with nitrobenzaldehydes under ball-milling conditionsa
O
O
OH
O
Catalyst
H
+
Ball-milling
2760 rpm
R
R
2c
3a-c
5a-c
Entry
1
Product
Catalyst
Yield (%)b
ee (%)c
O
OH
(S,S)-1a
(S,S)-1c
80
65
69d
58
5a
OH
NO2
NO2
O
(S,S)-1a
(S,S)-1c
85
72
28
54
2
5b
Further work seeking the optimization of the catalyst structure
for asymmetric aldol reactions27 under HSBM conditions is already
in progress in our laboratory.
O
OH
NO2
(S,S)-1a
(S,S)-1c
75
68
67
69
3
5c
Using 1c: ketone 2c (0.60 mmol), aldehyde 3aec (0.20 mmol), catalyst 1c (3 mol %),
ꢁ20 ꢀC, 1.1 equiv H2O, PhCO2H (5 mol %), 6 h.
4. Experimental section
a
Reaction conditions using 1a: ketone 2c (0.40 mmol), aldehyde 3aec
4.1. General remarks
(0.20 mmol), catalyst 1a (7 mol %), ꢁ20 ꢀC, 4 h.
b
Isolated yield.
Determined by chiral HPLC.
Ref. 16.
1H and 13C NMR spectra were recorded on a 500 MHz spec-
trometer. Chemical shift (d) are given in parts per million downfield
c
d
from tetramethylsilane as an internal reference, coupling constants
J are given in hertz. Molecular weights were determined by means
of High-resolution mass spectrometry (HRMS). Infrared spectra (IR)
were reported in reciprocal centimeters. ee was measured by chiral
HPLC at room temperature using a Waters 600 E equipment fitted
with a UVevis Waters 2487 detector at 220 or 254 nm with Chir-
alpak AD-H and Chiralcel OD-H columns. Reactions carried out
under ball-milling conditions were performed in a digital Amal-
gamator, fitted with a reactor (cylinder, 25 mm long and with
a diameter 10 mm) containing one stainless steel ball of 5 mm
diameter.
To account for the stereochemical outcome of the current study,
we propose a transition state similar to those that have been sug-
gested in other cases where catalysis by dipeptides17m and proli-
namides is operative (Fig. 2).23 The increased diastereoselectivity
observed in the aldol products obtained when using catalyst (S,S)-
1c relative to that afforded by (S,S)-1a and (S,S)-1b may be the re-
sult of the large aromatic area present in the lipophilic residue of
tryptophan, which is further reinforced by the creation of
4.2. Preparation of methyl ester (S)-proline-containing
dipeptides 1aec
To a solution of N-Cbz-L-proline (3.0 g, 12.03 mmol) and NMM
(1.45 mL, 13.19 mmol) in dry THF under nitrogen at ꢁ10 ꢀC was
added a solution of isobutyl chloroformate (1.75 mL, 13.41 mmol) in
5 mL of CH2Cl2 dropwise over 20 min. The resulting solution was
stirred at ꢁ10 ꢀC for 20 min before a solution of the corresponding
a-amino ester hydrochlorides (2.6 g, 12.05 mmol for L-phenylala-
nine) and NMM (1.60 mL, 14.55 mmol) in dry CH2Cl2 was added
Fig. 2. Proposed transition state model of the aldol reaction catalyzed by (S,S)-1c.
dropwise over 20 min. After 2 h at ꢁ10 ꢀC the mixture was allowed

ꢀ
J.G. Hernandez, E. Juaristi / Tetrahedron 67 (2011) 6953e6959
6958
to warm to room temperature and further stirred overnight. The
mixture was concentrated and extracted with EtOAc. The organic
phase was washed with satd 1 N HCl, satd NaHCO3 and brine, dried
over anhydrous Na2SO4, and concentrated. The residue was purified
by column chromatographic using CH2Cl2/MeOH (95:5 v/v) as
Supplementary data
Supplementary data associated with this article (copies of NMR
spectra and HPLC chromatograms) are available. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tet.2011.06.042.
eluent to afford the respective N(Cbz)-
To each of the solution of N(Cbz)-
L
-Pro-
L
-aa-CO2Me dipeptide.
L
-Pro-
L-aa-CO2Me dipeptide
(500 mg) in 20 mL AcOEt/MeOH (4:1), 10% Pd/C (50 mg) was added,
followed by stirring for 5 h under hydrogen balloon. The reaction
mixture was filtered and washed with methanol, and the filtrate
was concentrated. The crude product was purified by column
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chromatographic to afford the desired NH-L-Pro-L-aa-CO2Me 1aec
dipeptide.
4.2.1. (S,S)-Proline-phenylalanine methyl ester, 1a. Rf¼0.35 [silica
gel, DCM/MeOH 95:5], ½a D22
ꢂ
ꢁ4.7 (c 1.0, CH3Cl), (FT-IR/ATR cmꢁ1
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nmax 3324, 2951, 1740, 1667. 1H NMR (500 MHz, CDCl3)
d 8.06 (1H, br
d, J¼8.3 Hz), 7.29e7.18 (3H, m), 7.13e7.08 (2H, m), 4.83 (1H, m), 3.71
(3H, s), 3.67 (1H, m), 3.16 (1H, dd, J¼5.6, 13.9 Hz), 3.02 (1H, dd,
J¼7.3, 13.9 Hz), 2.91 (1H, m), 2.72 (1H, m), 2.24 (1H, br s), 2.03 (1H,
m), 1.72 (1H, m), 1.64e1.45 (2H, m) ppm. 13C NMR (125 MHz, CDCl3)
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174.9, 172.0, 136.1, 129.2, 128.3, 126.9, 60.2, 52.4, 52.2, 47.1, 38.0,
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30.6, 26.0 ppm. HR-ESI-TOF: calculated for C15H21N2O3 [MþH]þ:
277.1546; found: 277.1551 (1.5 ppm error).
4.2.2. (S,S)-Proline-phenylglycine methyl ester 1b. Rf¼0.32 [silica
gel, DCM/MeOH 95:5], ½a D22
ꢂ
ꢁ13.0 (c 1.0, CH3Cl), (FT-IR/ATR cmꢁ1
)
nmax 3327, 2952,1742, 1661. 1H NMR (500 MHz, CDCl3)
d 8.45 (1H, br
d, J¼5.5 Hz), 7.37e7.27 (5H, m), 5.56 (1H, d, J¼8.0 Hz), 3.75 (1H, m),
3.70 (3H, s), 2.95 (2H, m), 2.16 (1H, br s) 2.09 (1H, m), 2.02e1.84
ꢀ
ꢀ
7. (a) Guillena, G.; Hita, M. C.; Najera, C.; Viozquez, S. F. Tetrahedron: Asymmetry
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(1H, m), 1.80e1.64 (2H, m) ppm. 13C NMR (125 MHz, CDCl3)
d 174.8,
ꢀ
ꢀ
ꢀ
ꢀ
171.5, 137.0, 129.0, 128.5, 127.3, 60.7, 56.1, 52.6, 47.4, 30.7, 26.2 ppm.
HR-ESI-TOF: calculated for C14H19N2O3 [MþH]þ: 263.1390; found:
263.1393 (1.1 ppm error).
ꢀ
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Synlett 2008, 3031e3035; (e) Almas¸ i, D.; Alonso, D. A.; Balaguer, A. N.; Najera, C.
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DCM/MeOH 95:5], ½a D22
ꢂ
þ2.2 (c 2.1, CH3Cl), (FT-IR/ATR cmꢁ1
) nmax
3297, 2951, 1737, 1650. 1H NMR (500 MHz, DMSO-d6)
d 10.57 (1H, br
s), 7.99 (1H, br s), 7.50 (1H, d, J¼8.1 Hz), 7.36 (1H, d, J¼8.1 Hz), 7.09
(2H, t, J¼7.7 Hz), 7.00 (1H, t, J¼7.6 Hz), 4.68 (1H, q, J¼6.7 Hz), 3.64
(3H, s), 3.56 (1H, dd, J¼8.6, 9.1 Hz), 3.21 (2H, dq, J¼5.8,14.6 Hz), 2.82
(1H, m), 2.64 (1H, m), 1.90 (1H, m), 1.66 (1H, m), 1.51 (2H, m) ppm.
14. Colacino, E.; Nun, P.; Colacino, F.-M.; Martinez, J.; Lamaty, F. Tetrahedron 2008,
64, 5569e5576.
ꢀ
15. (a) Hernandez, J. G.; Juaristi, E. J. Org. Chem. 2010, 75, 7107e7111; (b) Lamaty, F.;
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d 174.5, 172.3, 136.2, 127.3, 123.8,
ꢀ
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4.3. Typical procedure for the intermolecular aldol reaction;
ball-mill method
A mixture of catalyst 1c (3 mol %), ketone 2 (0.22 mmol), alde-
hyde 3 (0.2 mmol), water (0.22 mmol), and benzoic acid (5 mol %)
was vigorously milled for 4.0e6.0 h at 2760 rpm at ꢁ20 ꢀC in
a digital Mixer/Amalgamator fitted with a reactor made of Nylamid
(cylinder, 25 mm long and with a diameter 10 mm) containing one
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The authors are indebted to Conacyt, Mexico for financial sup-
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port via grant 60366-Q. J.G.H. thanks Conacyt, Mexico for a doctoral
fellowship (No 22211).

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