Advances towards highly active and stereoselective simple and cheap proline-based organocatalysts

Article abstract of DOI:10.1002/ejoc.201000913

Ten 4-acyloxy-L-prolines were screened as catalysts at loadings of 2-0.1 mol-% for the direct asymmetric aldol reaction in water by using variable amounts of water. Among them, a new catalyst, the L-proline carrying a trans-4-(2,2-diphenylacetoxy) group, and a catalyst previously synthesized by us, the L-proline carrying a trans-4-(4-phenylbutanoyloxy) group, were found to be excellent catalysts for the aldol reaction between cyclohexanone or cyclopentanone and substituted benzaldehydes when employed in only 1 and 0.5 mol-%,respectively, at room temperature without additives. For such catalysts, high turnover numbers were obtained, which are among the highest values obtained for enamine organocatalysis. Finally, these catalysts can be synthesized by direct O-acylation from inexpensive molecules and successfully used in scaled-up reactions. Highest activity and selectivity at minor expense! Simple and cheap 4-acyloxy-L-prolines were easily prepared and successfully employed in the direct asymmetric aldol reaction in water by using a loading of2-0.1 mol-%. Interestingly, high turnover numbers, among the highest values ever reported for enamine organocatalysis, were obtained.

Full text of DOI:10.1002/ejoc.201000913

FULL PAPER
DOI: 10.1002/ejoc.201000913
Advances towards Highly Active and Stereoselective Simple and Cheap
Proline-Based Organocatalysts
Francesco Giacalone,[a] Michelangelo Gruttadauria,*[a] Paola Agrigento,[a] Paolo Lo Meo,[a]
and Renato Noto[a]
Dedicated to Professor Saverio Florio on the occasion of his 70th birthday
Keywords: Aldol reactions / Asymmetric catalysis / Organocatalysis / Water chemistry
Ten 4-acyloxy-L-prolines were screened as catalysts at load- tuted benzaldehydes when employed in only 1 and 0.5 mol-%,
ings of 2–0.1 mol-% for the direct asymmetric aldol reaction
in water by using variable amounts of water. Among them, a
respectively, at room temperature without additives. For such
catalysts, high turnover numbers were obtained, which are
among the highest values obtained for enamine organo-
catalysis. Finally, these catalysts can be synthesized by direct
O-acylation from inexpensive molecules and successfully
used in scaled-up reactions.
new catalyst, the
phenylacetoxy) group, and a catalyst previously synthesized
by us, the -proline carrying a trans-4-(4-phenylbutanoyloxy)
L-proline carrying a trans-4-(2,2-di-
L
group, were found to be excellent catalysts for the aldol reac-
tion between cyclohexanone or cyclopentanone and substi-
Introduction
Organocatalysts are usually used at a loading of 5–
30 mol-%, and in some cases higher catalytic loadings have
been reported.[1] For synthetic purposes, it is of great inter-
est to have highly active organic catalysts that display ac-
tivity at a loading of less than 2 mol-%. Several examples
of organocatalysts employed in low catalytic amount are
present in the literature.[1] In the case of organocatalytic
reactions occurring via an enamine, some catalysts have
also been employed in low catalytic amount.[2] Concerning
the direct asymmetric aldol reaction, several studies have
been carried out where the organocatalysts were used in
low loadings. For example, catalysts 1–6[3–7] (Figure 1) were
synthesized for such a purpose. Although these catalysts
work at a loading of 0.5–2 mol-% to afford aldol products
with high levels of stereoselectivity, they are expensive, syn-
thetically demanding catalysts. These catalysts present ad-
ditional chiral centers to that of proline and are used at low
temperatures (from 0 to –25 °C)[3–6] or at room tempera-
ture.[7]
Figure 1. Catalysts 1–6.
Catalysts 7–9 are simpler because they present only the
chiral centers of hydroxy--proline or -threonine (Fig-
ure 2). Catalysts 7 and 8 were used in 10 or 1 mol-%, al-
though longer reaction times were needed, and 2 mol-%,
respectively.[12] The ionic-tagged cis-4-hydroxy--proline 9
was employed in a lower amount, from 2 to 0.1 mol-%. The
corresponding trans-4-hydroxy--proline was found to be
less reactive. The authors ascribed the better performance
of the former catalyst to the occurrence of a “cis effect”.[13]
Organocatalysts that are even more complex were also
reported for aldol reactions. A spiro diamine catalyst,[8] the
tripeptide H-Pro-Pro-Asp-NH2,[9] a biphenyl-based axially
chiral amino acid,[10] and a very complex dendrimer cata-
lyst[11] were employed in an amount of 1–0.5 mol-%.
[a] Dipartimento Chimica Organica “E. Paternò”,
Università di Palermo,
Viale delle Scienze, Ed. 17, 90128, Palermo, Italy
E-mail: mgrutt@unipa.it
Figure 2. Catalysts 7–9.
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Eur. J. Org. Chem. 2010, 5696–5704

Highly Active and Stereoselective Proline-Based Organocatalysts
Many of the reported reactions were carried out in
water.[14] Indeed, it has been found that water is able to
promote these reactions with high levels of enantio- and
diastereoselectivity and in high yields. Usually, these reac-
tions are carried out with an excess amount of the ketone,
from 2 to 5 equiv. with respect to the aldehyde, and in the
presence of variable amounts of water. Under such condi-
tions the aqueous biphasic environment can simulate the
hydrophobic pocket of class I aldolases. Therefore, hydro-
phobic aldehydes are forced into the hydrophobic region,
resulting in increased activity and stereoselectivity of the
catalyst. The hydrophobic region can be due to a hydro-
phobic substituent or to a hydrophobic support such as a
polystyrene backbone.
Recently, we have been involved in research regarding the
organocatalytic direct asymmetric aldol reaction by using
both supported and nonsupported catalysts.[15] Supported
Figure 3. Catalysts 10a–j and 11 used in this work.
organocatalysts are of great interest because their easy re- 1.2 equiv. (11 µL) of water with the aim to see how the cata-
covery allows the reuse of catalysts that are employed in lyst/water ratio influenced the reactions. We first carried out
high catalyst loading, or in the case of expensive organocat- the reaction by using 2 mol-% of catalyst and an excess
alysts.[16] The use of inexpensive highly active organocata- amount (175 µL) of water (Table 1). The increased hydro-
lysts represents an important alternative approach.
phobicity of 10b compared to that of 10a resulted in a mod-
erate increase in stereoselectivity, whereas the higher rigidity
offered by the fluorenone ring in catalyst 10c afforded the
aldol product in high stereoselectivity (Table 1, Entries 1–
3). In each case, the yield was almost quantitative. When
Results and Discussion
The idea of this study was to find extremely simple and aliphatic chains were examined (10d,e), yields or stereose-
inexpensive organocatalysts that could be used in low load- lectivities were lower. Cyclohexyl-substituted catalyst 10d
ing (1–0.5 mol-%), working at room temperature without (Table 1, Entry 4) gave good stereoselectivity but not quan-
additives, and that could catalyze the aldol reaction be- titative yield, showing an overall decreased efficiency com-
tween cyclic ketones and substituted benzaldehydes with pared to alkyl-substituted catalyst 10j (yield 98%, 95:5dr;
high levels of stereoselectivity. To pursue this aim, we scre- 97%ee).[12a] Note that this compound has been previously
ened five new 4-substituted acyloxyproline derivatives synthesized by the Hansen group although it has never been
10a–e and five known compounds 10f–i[15b] and 10j[12a] employed as a catalyst for the aldol reaction.[17b] Simple
(Figure 3). The new proline derivatives were chosen to have fluorous proline derivative 10e was much less reactive and
very simple hydrophobic substituents. These molecules al- stereoselective (Table 1, Entry 5). With the latter catalyst,
low the set of known compounds to be expanded, which two others solvents (MeOH and iPrOH) were employed,
would make a deeper comparison with them possible. Such but again the results were disappointing (Table 1, Entries 6
a comparison regarded the different hydrophobicities that and 7). This finding could be ascribed to its lower solubility
substituents at the C-4 position give to the molecules. Com- (see the Experimental Section). Catalyst 11 was highly
pound 11 was prepared to investigate the role of the config- active and stereoselective. In comparison to its diastereoiso-
uration at C-4. We show, for the first time, that low catalytic mer 10f,[15b] a slightly lower enantioselectivity was observed
loading (down to 0.1 mol-%) and excellent enantio- and (Table 1, Entry 8).
diastereoselectivities can be reached by using very simple
and inexpensive trans-4-hydroxy--proline derivatives 10b that the best results are achieved when a rigid hydrophobic
and 10f.
group (i.e., 10c) or a long alkyl chain (i.e., 10j)[12a] or, at
A comparison between new and old data[15b] suggests
4-Substituted acyloxyproline derivatives were easily pre- least, a propyl chain bearing an additional hydrophobic
pared as previously reported (see the Experimental Sec- group (i.e., 10f,g, 11) are present as the acyl substituent.
tion).[15b] More recently, a very short synthetic approach
The main factors that play a role in activity and selectiv-
was also reported.[17] This new approach, which does not ity are, in addition to the nature of the acyl group, the
use chromatographic purification and which is easily scal- amount of catalyst and the catalyst/water ratio.
able, makes our simple catalysts more appealing for their
large use in organocatalysis.
After this preliminary test, we carried out further experi-
ments by lowering the catalyst loading (1–0.1 mol-%) and
To find the more active and stereoselective catalyst, we by using an excess amount (175 µL) or 1.2 equiv. (11 µL) of
tested molecules in Figure 3 for the model aldol reaction water (Table 2). Different catalyst loadings and water/cata-
between cyclohexanone and 4-nitrobenzaldehyde. The lyst ratios caused different reaction outcomes in both the
screening was carried out by using 2, 1, or 0.5 mol-% of chemical yields and stereoselectivities. As an example, cata-
catalyst and an excess amount (175 µL, 19 equiv.) or lyst 10a gave excellent enantioselectivity, high diastereo-
Eur. J. Org. Chem. 2010, 5696–5704
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5697

F. Giacalone, M. Gruttadauria, P. Agrigento, P. Lo Meo, R. Noto
FULL PAPER
Table 1. Screening of catalysts 10a–e and 11 (2 mol-%) in the direct asymmetric aldol reaction between cyclohexanone and 4-nitrobenzal-
dehyde in the presence of water.[a]
Entry
Catalyst
Conv. [%]
Yield[b] [%]
anti/syn[c]
ee[d] [%]
TON
1
2
3
4
10a
10b
10c
10d
10e
10e
10e
11
Ͼ99
Ͼ99
Ͼ99
73
18
98
99
98
Ͼ99
72
16
95
87:13
91:9
97:3
86
91
Ͼ98
93
11
28
50
49
50
36
8
47
23
49
92:8
5
83:17
62:38
78:22
96:4
6[e]
7[f]
8
48
Ͼ99
45
98
94
87
[a] Reaction conditions: cyclohexanone (260 µL, 2.5 mmol), aldehyde (0.5 mmol), catalyst (0.01 mmol), H2O (175 µL), room temperature,
1
24 h. [b] Isolated yield. [c] Determined by H NMR spectroscopic analysis of the crude product. [d] The anti diastereoisomer, determined
by HPLC by using a chiral column. [e] Reaction was carried out in MeOH. [f] Reaction was carried out in iPrOH.
selectivity, and moderate yield when used in 1 mol-%. The similar comparison can be done with the remaining cata-
enantioselectivity decreased when 10a was used in 0.5 mol-%, lysts (for example, see: Table 2, Entries 4–6 and 7–9).
whereas a lower amount of water caused a higher yield but Among the new catalysts, the diphenyl and fluorenyl deriva-
a decreased diastereoselectivity (Table 2, Entries 1–3). A tives 10b,c gave excellent results when employed in 1 mol-%
Table 2. Screening of catalysts 10a–j and 11 in the direct asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde in
the presence of water.[a]
Entry
Catalyst Cat. loading [mol-%]
Water [mL]
Conv. [%]
Yield[b] [%]
anti/syn[c]
ee[d] [%]
TON
1
10a
10a
10a
10b
10b
10b
10c
10c
10c
10d
10d
10d
10e
10f
10f
10f
10g
10h
10h
10j
10j
11
1
175
175
11
175
175
11
175
175
11
175
175
11
175
175
175
11
175
175
11
175
11
175
175
11
57
57
91
Ͼ99
74
Ͼ99
Ͼ99
77
68
29
14
20
54
55
90
99
72
98
Ͼ99
75
65
29
12
19
–
99
98
32
47
20
36
18
40
69
39
93
20
39
5
96.5:3.5
93:7
83.5:16.5
97:3
Ͼ99
93
99
Ͼ99
97
80
99
Ͼ99
97
96
99
93
–
98
98
90
99
Ͼ99
Ͼ99
98
54
110
180
99
144
196
100
150
130
29
24
38
–
99
196
64
94
40
72
36
80
69
78
2[e]
3[e]
4
0.5
0.5
1
0.5
0.5
1
0.5
0.5
1
0.5
0.5
0.5
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
0.5
0.5
0.2
0.2
0.1
5[f]
6[f]
7
8
9
10
11
12
13
96:4
87:13
97.5:2.5
97:3
95:5
93:7
n.d.
91:9
–
96:4
96:4
91:9
96.5:3.5
96:4
96:4
96:4
94:6
96.5:3.5
97.5:2.5
93.5:6.5
96:4
–
14
15
Ͼ99
Ͼ99
34
49
21
39
20
43
70
40
95
21
41
16
17[g]
18
19
20[e]
21[e]
22[e]
23[e]
24[f]
25
92
97
97
80
99
Ͼ99
98
11
11
186
100
195
50
10f
10f
10f
175
11
175
26[e]
27
97:3
97:3
6
[a] Reaction conditions: cyclohexanone (260 µL, 2.5 mmol), aldehyde (0.5 mmol), catalyst (0.1 mmol), H2O, room temperature, 24 h.
1
[b] Isolated yield. [c] Determined by H NMR spectroscopic analysis of the crude product. [d] The anti diastereoisomer, determined by
HPLC by using a chiral column. [e] See ref.[18] [f] Hemiacetal in less than 5% (see ref.[18]). [g] See ref.[15b]
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Eur. J. Org. Chem. 2010, 5696–5704

Highly Active and Stereoselective Proline-Based Organocatalysts
(Table 2, Entries 4 and 7). The latter catalysts were more Experimental Section) than 10f, and probably, the different
active and stereoselective if compared to catalyst 7 when solubility could make the comparison devoid of signifi-
employed for the same reaction.[12a] Poor results were ob- cance.
tained with cyclohexyl derivative 10d (Table 2, Entries 10–
We further tested catalyst 10f by decreasing its loading
12). Fluorinated derivative 10e was inactive (Table 2, En- down to 0.1 mol-% (Table 2, Entries 25–27). In each case,
try 13). Again, very promising results were observed with the stereoselectivity was high. Particularly, an interesting
catalyst 10f when used in 1 or 0.5 mol-% (Table 2, En- turnover number (TON) of 195 was obtained by using only
tries 14 and 15), whereas a lower amount of water caused a 0.2 mol-% of catalyst and 1.2 equiv. of water (11 µL).
lower conversion (Table 2, Entry 16). Other catalysts gave
poorer results.
After this deeper screening of catalysts 10a–f we focused
our attention on two of these compounds: known proline
A comparison of the data obtained by using catalysts 11 derivative 10f, which nicely worked at 0.5 mol-% with an
and 10f clearly indicated that catalyst 10f, having a trans excess amount of water (Table 2, Entry 15), and new cata-
configuration, gave better results under the examined con- lyst 10b, which gave excellent results at 1 mol-% loading
ditions. However, catalyst 11 was much less soluble (see the (Table 2, Entry 4). Under the same conditions, compound
Table 3. Direct asymmetric aldol reaction between cyclohexanone and substituted benzaldehydes in the presence of water catalyzed by
10b.[a]
Entry
R
t [h]
Conv. [%]
Yield[b] [%]
anti/syn[c]
ee[d] [%]
TON
1
2
3
4
5
6
7
8
9
4-NO2
4-CN
2-NO2
4-Br
4-Cl
2,3,4,5,6-F5
H
4-CH3
3-OCH3
4-OCH3
24
24
24
24
24
24
24
72
72
72
Ͼ99
99
95
86
87
Ͼ99
75
26
78
Ͻ5
99
95
94
85
81
Ͼ99
69
25
74
–
97:3
96.5:3.5
99:1
96:4
95:5
Ͼ99:1
93.5:6.5
87:13
92:8
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
98
97
94
95
–
100
95
94
85
81
100
69
25
74
–
10
–
[a] Reaction conditions: cyclohexanone (260 µL, 2.5 mmol), aldehyde (0.5 mmol), catalyst, H2O (175 µL), room temperature. [b] Isolated
yield. [c] Determined by 1H NMR spectroscopic analysis of the crude product. [d] The anti diastereoisomer, determined by HPLC by
using a chiral column.
Table 4. Direct asymmetric aldol reaction between cyclohexanone and substituted benzaldehydes in the presence of water catalyzed by
10f.[a]
Entry Cat. loading [mol-%]
R
t [h]
Conv. [%]
Yield[b] [%]
anti/syn[c]
ee[d] [%]
TON
1
2
3
4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.2
0.1
0.5
0.5
0.5
0.5
0.5
4-NO2
4-Cl
4-Br
4-Br
4-CN
2-NO2
2,3,4,5,6-F5
2,3,4,5,6-F5
2,3,4,5,6-F5
3-NO3
2-naphthyl
2-Cl
24
24
24
48
24
24
24
24
24
24
72
24
72
72
Ͼ99
48
27
50
90
47
99
75
40
53
9
99
46
24
47
87
45
97
75
39
50
8
96:4
96:4
95:5
94:6
96.5:3.5
99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
98:2
92:8
94:6
99
Ͼ99
Ͼ99
99
Ͼ99
Ͼ99
98
97
97
96
97
198
92
48
94
176
90
194
375
390
100
16
140
94
5
6[e]
7[e]
8[e]
9[e]
10[e]
11
12
13
14
73
49
28
70
47
27
90
93
95
H
90.5:9.5
94:6
3-OCH3
54
[a] Reaction conditions: cyclohexanone (260 µL, 2.5 mmol), aldehyde (0.5 mmol), catalyst, H2O (175 µL), room temperature. [b] Isolated
yield. [c] Determined by 1H NMR spectroscopic analysis of the crude product. [d] The anti diastereoisomer, determined by HPLC by
using a chiral column. [e] See ref.[18]
Eur. J. Org. Chem. 2010, 5696–5704
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F. Giacalone, M. Gruttadauria, P. Agrigento, P. Lo Meo, R. Noto
FULL PAPER
10c also furnished excellent results (Table 2, Entry 7). How- from high (90.5:9.5) to excellent (Ͼ99:1). In addition to
ever, we decided to further investigate compound 10b be- these very interesting results concerning the stereochemical
cause this proline derivative is less expensive than 10c.
aspects, catalyst 10f proved to be a very active catalyst,
Then, using catalysts 10b and 10f under the optimized working well at a loading of only 0.5 mol-%. Good TONs
reaction conditions, we carried out several aldol reactions. were obtained, and in some cases, the values were over 190.
The results obtained in the aldol reaction between cyclo- In the case of highly reactive pentafluorobenzaldehyde, cat-
hexanone and several substituted benzaldehydes in the pres- alyst 10f was used in only 0.1 mol-% and reached a TON
ence of catalysts 10b and 10f are reported in Tables 3 and as high as 390 (Table 4, Entry 9) while still maintaining high
4, respectively. The use of catalyst 10b gave aldol products stereoselectivity.
in excellent optical purity (98 to Ͼ99%; Table 3, Entries 1–
Further experiments carried out by employing cyclo-
6), high diastereoselectivities, and high yields. Less-reactive pentanone confirmed the high performances of these cata-
aldehydes furnished products still with high ee values (94– lysts. Catalyst 10b gave aldol products with excellent ee val-
97%; Table 3, Entries 7–9) and good yields. Only 4-tolual- ues (96 to Ͼ99%), high diastereoselectivities (89:11 to 96:4),
dehyde gave a moderate yield, whereas 4-methoxybenzalde- and very high yields (82 to Ͼ99%) even with less-reactive
hyde was unreactive.
aldehydes (Table 5).
Catalyst 10f furnished aldol products with high (90–97%;
Reactions between cyclopentanone and substituted benz-
Table 4, Entries 10–14) to excellent (98 to Ͼ99%; Table 4, aldehydes were also carried out by using catalyst 10f
Entries 1–7) optical purity. Diastereoselectivities ranged (Table 6). Again, compound 10f was employed in 0.5 mol-%.
Table 5. Direct asymmetric aldol reaction between cyclopentanone and substituted benzaldehydes in the presence of water catalyzed by
10b.[a]
Entry
R
t [h]
Conv. [%]
Yield[b] [%]
anti/syn[c]
ee[d] [%]
TON
1
2
3
4
5
7
8
10
4-NO2
4-CN
2-NO2
4-Cl
4-Br
H
24
24
24
24
24
24
72
72
Ͼ99
Ͼ99
Ͼ99
93
96
87
Ͼ99
99
Ͼ99
92
96
86
92:8
91.5:8.5
96:4
92:8
92:8
92.5:7.5
89:11
90:10
Ͼ99
Ͼ99
Ͼ99
99
99
98
100
99
100
92
96
86
4-CH3
4-OCH3
84
96
82
96
96
97
82
96
[a] Reaction conditions: cyclopentanone (220 µL, 2.5 mmol), aldehyde (0.5 mmol), catalyst, H2O (175 µL), room temperature. [b] Isolated
yield. [c] Determined by 1H NMR spectroscopic analysis of the crude product. [d] The anti diastereoisomer, determined by HPLC by
using a chiral column.
Table 6. Direct asymmetric aldol reaction between cyclopentanone and substituted benzaldehydes in the presence of water catalyzed by
10f.[a]
[d]
Entry
Cat. loading [mol-%]
R
t [h]
Conv. [%]
Yield[b] [%]
anti/syn[c]
ee [%]
TON
1
2
3
4
5
6
7
8
0.5
0.2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
4-NO2
4-NO2
4-CN
4-Cl
24
24
24
48
48
24
24
48
72
24
24
63
36
99
86
86
63
87
69
49
81
73
60
35
98
86
84
61
86
67
49
80
72
93:7
95:5
91:9
92:8
91:9
98:2
92:8
88:12
87:13
87:13
89:11
Ͼ99
98
120
175
196
172
168
122
172
134
98
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
96
96
96
96
4-Br
2-NO2
3-NO3
3-MeO
4-CH3
H
9
10
11
160
144
2-Cl
[a] Reaction conditions: cyclopentanone (220 µL, 2.5 mmol), aldehyde (0.5 mmol), catalyst, H2O (175 µL), room temperature. [b] Isolated
yield. [c] Determined by 1H NMR spectroscopic analysis of the crude product. [d] The anti diastereoisomer, determined by HPLC by
using a chiral column.
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Highly Active and Stereoselective Proline-Based Organocatalysts
conia rotors spinning at 15 kHz. FTIR spectra were registered with
a Shimadzu FTIR 8300 infrared spectrophotometer. Carbon and
nitrogen contents were determined by combustion analysis with a
Fisons EA 1108 elemental analyzer. Optical rotations were mea-
sured with a Jasco P1010 polarimeter. Hydrogenation reactions
were carried out by using a Parr apparatus. Flash chromatography
was carried out by using Macherey–Nagel (0.04–0.063 mm) silica
gel. Melting points were determined by using a Kofler hot plate.
Chiral HPLC analyses were performed by using a Shimadzu LC-
10AD apparatus equipped with an SPD-M10 A UV detector and
Daicel columns (OD-H, AD-H, AS-H) by using hexane/2-propanol
as the eluent. The aldol products are known compounds and
showed spectroscopic and analytical data in agreement with their
structures. The configurations of the products were assigned by
comparison with literature data. N-Cbz-trans-4-hydroxy--proline
was commercially available (Aldrich). (2S,4R)-Dibenzyl-4-hydroxy-
pyrrolidine-1,2-dicarboxylate was prepared as reported in the lit-
erature.[20] Catalysts 10f–i[15b] and 10j[12a] are known compounds
and showed spectroscopic and analytical data in agreement with
their structures.
In the case of 4-nitrobenzaldehyde, it was also tested in
0.2 mol-%, giving the aldol product with excellent stereo-
selectivity and enhanced TON (Table 6, Entry 2). Again, al-
dol products were obtained with excellent ee values and
high diastereoselectivities. It is noteworthy that there are
only few reports regarding aldol reactions between cyclo-
pentanone and aromatic aldehydes furnishing aldols with
high levels of enantio- and diastereoselectivity.[5,12a,19] In
addition, as for cyclohexanone, also for these reactions
good TON values were reached.
Finally, because of the excellent results obtained by using
catalyst 10b, we prepared it on a larger scale by using a
slightly modified procedure than that reported by Hansen
and co-workers.[17] Direct O-acylation, starting from trans-
4-hydroxy--proline and diphenylacetic acid, gave catalyst
10b in about 60% yield (not optimized), avoiding column
chromatography purification and consequently large sol-
vent wasting. Because of the very easy availability of the
catalyst, we carried out the aldol reaction between cyclo-
hexanone and 4-nitrobenzaldehyde on a larger scale
(20 mmol) in the presence of 1 mol-% of catalyst 10b. The
aldol product was obtained in Ͼ99% yield and 98:2dr with
an excellent optical purity of 99.8%ee.
General Procedure for the Synthesis of Compounds 10 and 11
Step 1: To a solution of (2S,4R)-dibenzyl-4-hydroxypyrrolidine-1,2-
dicarboxylate (562 mg, 1.58 mmol) in anhydrous dichloromethane
(35 mL) the proper carboxylic acid (2.24 mmol) was added. The
mixture was stirred for 10 min at 0 °C under an atmosphere of
argon. Then, a solution of 1,3-dicyclohexylcarbodiimide (DCC;
2.24 mmol) and 4-(dimethylamino)pyridine (DMAP; 0.224 mmol)
in dichloromethane (10 mL) was added, and the mixture was
stirred at 0 °C for 15 min. The reaction mixture was stirred over-
night at room temperature under an atmosphere of argon. After
this period, the dichloromethane solution was washed with water
(2ϫ30 mL), and the organic phase was dried with MgSO4 and
concentrated under reduced pressure.
Conclusions
In conclusion, the data reported represent an update re-
garding the use of cheap proline-based organocatalysts for
the asymmetric aldol reaction in water. Deeper investi-
gations showed the general and wide applicability of hydro-
phobic 4-acyloxyproline derivatives as catalysts for the di-
rect asymmetric aldol reaction between cyclic ketones and
substituted benzaldehydes. Particularly, here we presented
the outstanding activity and stereoselectivity of trans-4-hy-
Step 2: To a solution of compounds 12a–e or 13 (1.91 mmol) in
methanol (65 mL) was added Pd(10%)/C (308 mg). The reaction
mixture was stirred under an atmosphere of hydrogen in a Parr
apparatus for 3 h. After this time, the reaction mixture was filtered
droxy--prolines bearing a simple 2,2-diphenylacetate (10b) through a short pad of Celite and then through a short pad of
silica, washing with methanol. The organic phase was concentrated
under reduced pressure to give compounds 10a–e and compound
11 (see Scheme 1).
and a 4-phenylbutanoate group (10f), which afforded aldol
products with high to excellent enantio- and diastereoselec-
tivities, even when cyclopentanone was employed, with as
low as 1–0.5 mol-% catalytic loading. It is important to
stress that simple catalysts such as 10b and 10f do not need
the use of low temperature or additives, do not need new
chiral centers in addition to those of inexpensive trans-4-
hydroxy--proline, and can be very easily prepared by direct
O-acylation starting from very inexpensive carboxylic acids.
Finally, the data reported in this work suggest that such
catalytic molecules are organized at the ketone/water inter-
face and their organization depends on the nature of the
acyl group and on the catalyst/water ratio (see Tables 1 and
2). Further studies in this field may disclose new simple
more active and stereoselective proline catalysts.
Experimental Section
Scheme 1. Synthesis of catalysts 10a–e and 11 used in this work.
General Methods: NMR spectra were recorded with a Bruker
300 MHz spectrometer by using CDCl3 or [D6]DMSO as solvent.
Solid-state 13C{H} CP-MAS NMR spectra was recorded with a
Bruker AV 400, 400 MHz spectrometer with samples packed in zir-
(2S,4R)-Dibenzyl 4-(4-Propylbenzoyloxy)pyrrolidine-1,2-dicarboxyl-
ate (12a): The residue was purified by column chromatography (pe-
Eur. J. Org. Chem. 2010, 5696–5704
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5701

F. Giacalone, M. Gruttadauria, P. Agrigento, P. Lo Meo, R. Noto
FULL PAPER
troleum ether/ethyl acetate, 5:1) to give compound 12a as a pale-
1715, 1418, 1167, 1353, 1190, 768, 746 cm–1. C34H29NO6 (547.60):
calcd. C 74.57, H 5.34, N 2.56; found C 74.71. H, 5.30, N 2.61.
1
yellow oil. Yield: 92%. [α]2D9 = –33.0 (c = 0.84, CHCl3). H NMR
3
(300 MHz, CDCl3, 25 °C): δ = 0.87 (t, JH,H = 7.4 Hz, 3 H, CH3),
(2S,4R)-4-(9H-Fluorene-9-carbonyloxy)pyrrolidine-2-carboxylic Acid
(10c): White solid; m.p. 129–131 °C. Yield: 90%. [α]2D6 = –17.8 (c =
3
1.57 (s, JH,H = 7.4 Hz, 2 H, CH2), 2.25 (m, 1 H), 2.48 (m, 1 H),
3
2.56 (t, JH,H = 7.4 Hz, 2 H, CH2), 3.80 (m, 2 H), 4.53 (m, 1 H),
1
0.40, MeOH). H NMR (300 MHz, CD3OD, 25 °C): δ = 2.36 (m,
4.93–5.20 (m, 4 H), 5.44 (br. s, 1 H), 7.14–7.28 (m, 12 H), 7.81 (d,
3JH,H = 7.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C; two
rotamers): δ = 172.0, 171.8, 165.9, 154.8, 154.2, 148.9, 148.8, 136.2,
136.2, 135.4, 135.6, 129.7, 128.6, 128.4, 128.4, 128.3, 128.2, 128.1,
28.0, 127.9, 127.8, 126.9, 126.9, 72.9, 72.2, 67.3, 67.1, 67.0, 58.1,
57.8, 52.7, 52.4, 38.0, 36.8, 35.7, 30.9, 24.2, 13.7 ppm. IR (nujol):
1 H), 2.55 (m, 1 H), 3.48 (m, 1 H), 3.74 (m, 1 H), 4.27 (m, 1 H),
5.49 (m, 1 H), 7.37–7.48 (m, 4 H), 7.71–7.83 (m, 4 H) ppm. 13C
NMR (75 MHz, CD3OD, 25 °C; two rotamers): δ = 171.5, 170.2;
141.2, 140.1, 127.9, 127.0, 125.1, 119.6, 74.2, 60.1, 50.2, 35.1 ppm.
IR (nujol): ν = 1734, 1460, 1377, 1193, 721 cm–1. C H NO
˜
19 17
4
(323.34): calcd. C 70.58, H 5.30, N 4.33; found C 70.68, H 5.35, N
4.28.
ν = 2959, 2931, 1749, 1715, 1609, 1353, 755, 698 cm–1. C H NO
˜
30 31
6
(501.57): calcd. C 71.84, H 6.23, N 2.79; found C 71.54, H 6.43, N
2.86.
(2S,4R)-Dibenzyl
4-(Cyclohexanecarbonyloxy)pyrrolidine-1,2-di-
carboxylate (12d): The residue was purified by column chromatog-
raphy (petroleum ether/ethyl acetate, 5:1) to give compound 12d as
(2S,4R)-4-(4-Propylbenzoyloxy)pyrrolidine-2-carboxylic Acid (10a):
Pale-yellow, viscous liquid. Yield: 85%. [α]2D5 = –15.1 (c = 0.47,
DMSO). 1H NMR ([D6]DMSO, 25 °C): δ = 0.79 (t, 3JH,H = 7.3 Hz,
3 H, CH3), 1.50 (m, 3JH,H = 7.3 Hz, 2 H, CH2), 2.05 (m, 1 H), 2.42
(m, 1 H), 2.52 (t, 3JH,H = 7.3 Hz, 2 H, CH2), 3.28 (br. s, 1 H), 3.49
(br. s, 1 H), 3.73 (br. s, 1 H), 5.28 (m, 1 H), 7.24 (d, 3JH,H = 7.5 Hz,
a pale-yellow oil. Yield: 97%. [α]2D6 = –39.9 (c = 0.90, CHCl3). H
1
NMR (300 MHz, CDCl3, 25 °C): δ = 1.17–1.88 (m, 10 H), 2.16 (m,
2 H), 2.39 (m, 1 H), 3.62–3.79 (m, 2 H), 4.50 (dt, 1 H), 5.00 (s, 1
H), 5.06 (s, 1 H), 5.18 (m, 2 H), 5.28 (m, 1 H), 7.20 (s, 1 H),
7.28–7.34 (m, 9 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C; two
rotamers): δ = 175.3, 175.3, 172.0, 171.8, 154.7, 154.1, 136.3, 136.2,
135.4, 135.2, 128.5, 128.4, 128.4, 128.3, 128.2, 128.1, 128.0, 127.8,
72.1, 71.3, 67.3, 67.0, 66.9, 58.0, 57.7, 52.6, 52.2, 42.9, 36.7, 35.6,
3
2 H), 7.82 (d, JH,H = 7.5 Hz, 2 H) ppm. 13C NMR (75 MHz, [D6]
DMSO, 25 °C): δ = 172.2, 165.0, 147.9, 129.2, 128.33 127.2, 127.0,
36.9, 35.9, 28.8, 24.2, 23.7, 23.5113, 13.2 ppm. C15H19NO4
(277.32): calcd. C 64.97, H 6.91, N 5.05; found C 65.10, H 6.96, N
5.12.
32.7, 31.1, 29.9, 28.8, 28.8, 28.7, 25.6, 25.2 ppm. IR (neat): ν =
˜
1709, 1418, 1167, 1130, 768, 754 cm–1. C27H31NO6 (465.54): calcd.
C 69.66, H 6.71, N 3.01; found C 69.72, H 6.77, N 3.10.
(2S,4R)-Dibenzyl
4-(2,2-Diphenylacetoxy)pyrrolidine-1,2-dicarb-
oxylate (12b): The residue was purified by column chromatography
(petroleum ether/ethyl acetate, 4:1) to give compound 12b as a pale-
(2S,4R)-4-(Cyclohexanecarbonyloxy)pyrrolidine-2-carboxylic Acid
(10d): Analytical and spectroscopic data agree with those reported
in the literature.[17b]
1
yellow oil. Yield: 98%. [α]2D9 = –29.8 (c = 0.64, CHCl3). H NMR
(300 MHz, CDCl3, 25 °C): δ = 2.20 (m, 1 H), 2.44 (m,1 H), 3.84
(m, 2 H), 4.47 (dt, 1 H), 5.05 (s, 2 H), 5.11 (s, 1 H), 5.23 (m, 2 H),
5.40 (br. s, 1 H), 7.36 (m, 20 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C; two rotamers): δ = 171.8, 171.7, 171.6, 154.5, 153.9, 137.9,
137.9, 137.8, 136.1, 136.0, 135.2, 135.0, 128.5,128.5, 128.4, 128.3,
128.3, 128.2, 128.2, 128.0, 128.0, 127.9, 127.7, 127.7, 127.3, 127.3,
73.1, 72.4, 69.3, 67.2, 67.1, 66.9, 66.8, 57.7, 56.6, 53.3, 52.2, 51.8,
(2S,4R)-Dibenzyl 4-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononanoyl-
oxy)pyrrolidine-1,2-dicarboxylate (12e): The residue was purified by
column chromatography (petroleum ether/ethyl acetate, 8:1) to give
compound 12e as a pale-yellow oil. Yield: 64%. [α]2D7 = –23.7 (c =
1
0.90, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 2.20 (m,1
H), 2.35 (m, 3 H), 2.54 (m,2 H), 3.55–3.75 (m, 3 H), 4.44 (dt, 1 H),
5.03 (m, 4 H), 5.25 (m, 1 H), 7.19 (m,10 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 171.9, 171.6, 170.4, 170.4, 154.6,
154.1, 136.2, 136.1, 135.3, 135.1, 128.6, 128.5, 128.4, 128.3, 128.2,
128.1, 128.1, 128.0, 127.9, 120.4–103.8 (22 CF signals), 73.4, 72.7,
67.4, 67.4, 67.1, 67.0, 57.9, 57.6, 52.4, 52.0, 36.4, 35.4, 26.6, 26.3,
36.2, 35.2, 31.6, 29.1 ppm. IR: ν = 1715, 1738, 1418, 1186, 1150,
˜
768, 746 cm–1. C34H31NO6 (549.61): calcd. C 74.30, H 5.69, N 2.55;
found C 74.55, H 5.88, N 2.60.
(2S,4R)-4-(2,2-Diphenylacetoxy)pyrrolidine-2-carboxylic Acid (10b):
Pale-yellow solid; m.p. 102–105 °C. Yield: 93%. [α]2D9 = –2.5 (c =
0.62, methanol). 1H NMR (300 MHz, CD3OD, 25 °C): δ = 1.98
26.0, 25.5, 25.4, 25.4037 ppm. IR (nujol): ν = 1746, 1713, 1418,
˜
1354, 1146, 1123, 737, 700 cm–1. C29H24F13NO6 (729.48): calcd. C
47.75, H 3.32, N 1.92; found C 47.86, H 3.43, N 2.00.
3
(br. s, 2 H), 2.95 (d, JH,H = 11.9 Hz, 1 H), 3.26 (m, 1 H), 3.37 (d,
3JH,H = 11.9 Hz, 1 H), 3.58 (br. s, 1 H), 5.17 (s, 1 H), 7.24 (m, 10
H) ppm. 13C NMR (75 MHz, CD3OD, 25 °C): δ = 172.4, 139.6,
129.5, 129.2, 128.0, 75.6, 73.5, 60.6, 56.5, 50.8, 36.3 ppm. IR (nu-
(2S,4R)-4-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononanoyloxy)pyr-
rolidine-2-carboxylic Acid (10e): White-gray powder; m.p. 130–
135 °C. Yield: 92%. Because this compound is very poorly soluble,
it was characterized in the solid state 13C NMR (400 MHz, 25 °C;
Figure 4): δ = 173.5, 170.8, 130–110 (CF signals), 73.7, 62.7, 51.9,
jol): ν = 2853, 2922, 1726, 1456, 1377, 1146 cm–1. C H NO
˜
19 19
4
(325.36): calcd. C 70.14, H 5.89, N 4.31; found C 70.23, H 5.93, N
4.40.
36.4, 25.8, 24.9 ppm. IR (nujol): ν = 2853, 1742, 1460, 1377 cm–1.
˜
(2S,4R)-Dibenzyl 4-(9H-Fluorene-9-carbonyloxy)pyrrolidine-1,2-di-
carboxylate (12c): The residue was purified by column chromatog-
raphy (petroleum ether/ethyl acetate, 5:1) to give compound 12c as
C14H12F13NO4 (505.23): calcd. C 33.28, H 2.39, N 2.77; found C
33.36, H 2.29, N 2.81.
1
a pale-yellow oil. Yield: 85%. [α]2D6 = –39.3 (c = 0.72, CHCl3). H
(2S,4S)-Dibenzyl
4-(4-Phenylbutanoyloxy)pyrrolidine-1,2-dicarb-
NMR (300 MHz, CDCl3, 25 °C): δ = 2.32 (m, 1 H), 2.51 (m, 1 H),
oxylate (13): The residue was purified by column chromatography
3.88 (m, 2 H), 4.63 (dt, 1 H), 4.90 (s, 1 H), 5.11 (s, 1 H), 5.18–5.31 (petroleum ether/ethyl acetate, 3:1) to give compound 13 as a pale-
yellow oil. Yield: 70%. [α]2D8 = –41.5 (c = 0.73, CHCl3). H NMR
3
1
(m, 3 H), 5.44 (br. s, 1 H), 7.32–7.49 (m, 14 H), 7.60 (d, JH,H
=
7.4 Hz, 2 H), 7.80 (d, JH,H = 7.4 Hz, 2 H) ppm. 13C NMR (300 MHz, CD3OD, 25 °C): δ = 1.17 (t, JH,H = 5.5 Hz, 1 H), 1.69
3
3
(75 MHz, CDCl3, 25 °C; two rotamers): δ = 171.6, 171.4, 169.8,
169.8, 154.46, 153.8, 141.1, 141.1, 139.8, 139.8, 136.0, 135.2, 135.0,
128.3, 128.2, 128.2, 128.0, 127.9, 127.8, 127.6, 127.6, 127.2, 127.1,
125.2, 125.1, 125.0, 119.9, 73.3, 72.5, 67.1, 67.0, 66.8, 66.7, 57.7,
(m, 2 H), 1.96 (m, 2 H), 2.20 (dd, 1 H), 2.37 (m, 3 H), 3.45 (dd,
3
3JH,H = 5.0 Hz, 1 H), 3.64 (dd, JH,H = 5.0 MHz, 1 H), 4.45 (dd,
3JH,H = 9.4 MHz, 1 H), 5.02 (m, 5 H), 7.13 (m, 15 H) ppm. 13C
NMR (75 MHz, CD3OD, 25 °C): δ = 173.1, 171.81, 171.6, 155.3,
155.0, 141.6, 136.6, 136.0, 128.4, 128.3, 128.0, 127.7, 125.9, 73.3,
57.4, 52.8, 52.2, 51.9, 36.1, 35.1, 30.6 ppm. IR (neat): ν = 1748,
˜
5702
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5696–5704

Highly Active and Stereoselective Proline-Based Organocatalysts
0.106 mol). The mixture was stirred for 30 min at room tempera-
ture and then at 50 °C for 1 h until a clear light-yellow solution
was obtained. The excess amount of SOCl2 was removed under
reduced pressure to afford the diphenylacetic acid chloride as a
light-yellow solid. In a 25-mL round-bottomed flask, trans-4-hy-
droxy--proline (1.31 g, 0.01 mol) was dissolved in trifluoroacetic
acid (6.4 mL). This solution was added to the flask containing di-
phenylacetic acid chloride and additional TFA (4.6 mL) was added.
A white precipitate was present, and the suspension was stirred at
room temperature for 18 h. After this period, the solution was co-
oled and diethyl ether was carefully added whilst stirring. A white
precipitate was present. The solution was decanted, and the liquid
was removed. Another portion of diethyl ether was added, and the
mixture was filtered under reduced pressure washing with diethyl
ether several times. The white solid was poured in water and treated
with an aqueous solution of NaHCO3 (2 equiv.) until ca. pH 7 was
reached. The solid was filtered under reduced pressure and dried
(Yield: 1.92 g, ca. 60%).
Figure 4. Solid-state 13C NMR spectrum of compound 10e.
72.3, 67.3, 66.8, 58.3, 58.1, 52.8, 52.5, 36.0, 35.1, 34.8, 33.1,
Acknowledgments
26.4 ppm. IR: ν = 3030, 2949, 1711, 1496, 1415, 1165, 1070,
˜
1005 cm–1. C30H29NO5 (483.55): calcd. C 74.52, H 6.04, N 2.90;
found C 74.66, H 6.20, N 2.99.
Financial support from the University of Palermo (Funds for se-
lected topics) and the Italian Ministero dellЈUniversità e della
Ricerca (MIUR) within the national project “Catalizzatori, meto-
dologie e processi innovativi per il regio e stereocontrollo delle sin-
(2S,4S)-4-(4-Phenylbutanoyloxy)pyrrolidine-2-carboxylic Acid (11):
White-gray powder; m.p. 163–167 °C. Yield: 95%. Because this
compound is very poorly soluble, it was characterized in the solid
tesi organiche” and the “Centro Grandi Apparecchiature
–
state 13C NMR: see Figure 5. IR (nujol): ν = 2924, 2852, 17430,
UniNetLab – Università di Palermo funded by P. O. R. Sicilia
2000–2006, Misura 3.15 Quota Regionale” (13C{1H} CP-MAS
spectra) are gratefully acknowledged.
˜
1597, 1460, 1377 cm–1. C15H19NO4 (277.32): calcd. C 64.97, H 6.91,
N 5.05; found C 65.09, H 6.96, N 5.11.
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Figure 5. Solid-state 13C NMR spectrum of compound 11.
Typical Procedure for the Aldol Reactions: Catalysts were added to
a mixture of the corresponding aldehyde (0.5 mmol) and ketone
(2.5 mmol) in distilled water (0.175 mL), and the reaction mixture
was stirred at room temperature. The reaction was quenched by
adding ethyl acetate, and the organic phase was washed with water.
The organic layer was dried (MgSO4) and concentrated under re-
duced pressure. The crude product was checked by 1H NMR spec-
troscopy and HPLC and was then purified by chromatography (pe-
troleum ether/ethyl acetate). Enantiomeric excess values were deter-
mined by HPLC by using chiral columns (OD-H, AD-H, AS-H)
and hexane/2-propanol as eluent.[2]
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Direct Synthesis of (2S,4R)-4-(2,2-Diphenylacetoxy)pyrrolidine-2-
carboxylic Acid (10b): A 25-mL round-bottomed flask was charged
with diphenylacetic acid (4.29 g, 0.02 mol) and SOCl2 (7.7 mL,
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Eur. J. Org. Chem. 2010, 5696–5704
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5703

F. Giacalone, M. Gruttadauria, P. Agrigento, P. Lo Meo, R. Noto
FULL PAPER
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Received: June 25, 2010
Published Online: August 24, 2010
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5696–5704