New simple hydrophobic proline derivatives as highly active and stereoselective catalysts for the direct asymmetric Aldol reaction in aqueous medium

Article abstract of DOI:10.1002/adsc.200800555

New 4-substituted acyloxyproline derivatives with different hydrophobic properties of the acyl group were easily synthesized and used as catalysts in the direct asymmetric aldol reaction between cyclic ketones (cyclohexanone and cyclopentanone) and severa

Full text of DOI:10.1002/adsc.200800555

FULL PAPERS
DOI: 10.1002/adsc.200800555
New Simple Hydrophobic Proline Derivatives as Highly Active
and Stereoselective Catalysts for the Direct Asymmetric Aldol
Reaction in Aqueous Medium
Francesco Giacalone,a Michelangelo Gruttadauria,a,* Paolo Lo Meo,a
Serena Riela,a and Renato Notoa
a
Dipartimento di Chimica Organica “E. Paternꢀ”, Universitꢁ di Palermo, Viale delle Scienze, Pad. 17, 90128, Palermo,
Italy
Fax : (+39)-091-596-825; e-mail: mgrutt@unipa.it
Received: September 10, 2008; Revised: October 20, 2008; Published online: November 17, 2008
Abstract: New 4-substituted acyloxyproline deriva- mol% at room temperature without additives to give
tives with different hydrophobic properties of the aldol products in excellent stereoselectivities. These
acyl group were easily synthesized and used as cata- results demonstrate that derivatization of the proline
lysts in the direct asymmetric aldol reaction between moiety with the proper simple hydrophobic substitu-
cyclic ketones (cyclohexanone and cyclopentanone) ent in the 4-position can furnish highly active and
and several substituted benzaldehydes. Reactions stereoselective catalysts without the need of addi-
were carried out using water, this being the best re- tional chiral backbones in the molecule. Finally, an
action medium examined. Screening of these cata- explanation of the observed stereoselectivities in the
lysts showed that compounds bearing the most hy- presence of water is provided.
drophobic acyl chains [4-phenylbutanoate and 4-
(pyren-1-yl)butanoate] provided better results. The Keywords: aldehydes; aldol reaction; ketones; or-
latter catalysts were successfully used in only 2 ganic catalysis; proline
Introduction
Several examples are shown in Figure 2. Usually,
these reactions have been carried out in organic sol-
Enantioselective organocatalysis via enamines has re- vents. The proline-catalyzed direct aldol reaction in
ceived much attention in recent years.[1] Since the first water does not work.[5] Recently, the organocatalyzed
reports on the asymmetric direct aldol reaction cata- direct aldol reaction in water has been indipendently
lyzed by proline,[2] many organocatalysts have been reported by Hayashi[6] and Barbas III.[5] Previously,
synthesized with the aim of increasing the reactivity the aqueous aldol reaction between acetone and 4-ni-
and stereoselectivity. Indeed, proline may be used in trobenzaldehyde catalyzed by a nicotine metabolite
up to 30 mol%. Moreover, in several cases, for in- was reported.[7] Barbas III used the TFA salt of a pyr-
stance, in the aldol reaction between ketones and aryl rolidine derivative bearing long alkyl groups as cata-
aldehydes, the enantio- and diastereoselectivities were lyst in the reaction between cyclic ketones and aryl al-
not good.[3] In order to achieve higher stereoselectivi- dehydes while Hayashi used a TBDPS-protected hy-
ties more complex organocatalysts have been de- droxyproline. Interesting results, for the same reac-
signed and reactions at low temperature (down to tions, were previously reported using proline/d-CSA
À408C) have been carried out.[4] However, the in- in water.[8] Since 2006, several papers appeared on
creased complexity is not a synonym of higher stereo- this topic. Simple tryptophan,[9] or other aromatic
selectivity, for instance a Cinchona-derived proline
gave low enantioselectivity in the reaction between
cyclohexanone and 4-nitrobenzaldehyde.[4l] Usually,
these organocatalysts are substituted prolinamides of
the general structure I (Figure 1) in which the intro-
duction of additional hydrogen bonding sites can im-
prove their performances.
Figure 1. Substituted prolinamdies.
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Francesco Giacalone et al.
FULL PAPERS
ecules of general formulae II, III and IV (Figure 3).
In several cases, additives were also employed.[13]
In Figure 4 are reported several examples of orga-
nocatalysts of type II–IV for the asymmetric direct
aldol reaction in water. Also several prolinamides,
which were previously used in organic solvents (see
Figure 2), were subsequently successfully employed in
water.[13c,e,g,l] In addition to these proline-derived orga-
nocatalysts, also simple primary amino acid-derived
organocatalysts[14a] or more expensive amino acid-de-
rived and diamine-substituted organocatalysts[14b,c]
were employed in water. Depending on the nature of
the organocatalyst, different amounts of catalyst can
be used, from 20 mol% in the presence of 20 mol% of
an additive to 0.5 mol% at À108C. Stereoselectivities
ranged from good to high, depending on the complex-
ity of the catalyst. Considering the complexity of the
molecule and the observed stereoselectivities, in our
opinion the best results have been obtained using the
Hayashiꢃs catalyst (10 or 1 mol%).[13k]
Since the substrates are insoluble in water, a topic
of debate has been opened as to whether some of
these reactions really are “all wet”.[15] Hayashi has
proposed that these reactions might be better consid-
ered as carried out “in the presence of water”.[16] On
the other hand, Blackmond has raised doubts about
the greenness of organocatalytic reactions carried out
in the presence of water.[17]
Figure 2. Examples of substituted prolinamides as organoca-
talysts for the asymmetric direct aldol reaction.
We believe that the development of small organic
molecules capable of catalyzing enantioselective reac-
tions using water as reaction medium is still attracting
great interest. In this context, we started a research
project in order to find new organocatalysts, structur-
ally simple, which are able to catalyze the asymmetric
aldol reaction in water in low amounts (<10 mol%)
Figure 3. General structure of substituted proline derivatives
as catalysts for aldol reaction in water.
amino acids,[10] and dipeptides, in aqueous media[11] or without the need of additives. In the last years our ef-
in the presence of water and additives[12] were used. forts have been devoted to the investigation of new
Apart from these molecules, the asymmetric direct recyclable proline-derived organocatalysts[18] and to
aldol reaction in water has been carried out with mol- the elucidation of some mechanistic aspects of pro-
Figure 4. Examples of organocatalysts of types II–IV for the asymmetric direct aldol reaction in water.
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New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts
FULL PAPERS
Table 1. Effect of the solvent on the catalytic aldol reaction
between cyclohexanone and 4-nitro-benzaldehydes cata-
lyzed by 1e.[a]
Entry
Solvent
Conv.[b] [%]
anti/syn[c]
ee[d] [%]
1
2
3
4
5
6
Toluene
CHCl3
DMSO
H2O
47
60
99
99
69/31
69/31
75/25
95/5
92/8
59/41
96
94
93
98
96
87
H2O[f]
none
99
48[e]
[a]
Figure 5. Structure of catalysts 1a–e.
Reaction conditions: cyclohexanone (260 mL, 2.5 mmol),
aldehyde (75.5 mg, 0.5 mmol) catalyst (0.05 mmol), sol-
vent (175 mL).
[b]
[c]
[d]
[e]
[f]
line-catalyzed reactions.[19] From a green chemistry
point of view such studies are interesting because the
direct aldol reaction is atomically economic, a low
amount of an organocatalyst can be employed and
the reaction medium is water.
Yields: ꢀ95% of conversion.
1
Determined by H NMR of the crude product.
Determined by HPLC using a chiral stationary phase.
Yield 38%.
Common tap-water.
phobic one (1e, 10 mol%). Both diastereoselectivity
and conversion were not good when toluene and
chloroform were used. DMSO showed increased con-
Results and Discussion
With the aim to discover new simple organocatalysts version and diastereoselectivity, while water gave the
for the direct asymmetric aldol reaction in water, we highest stereoselectivity. Even undistilled water
prepared five new proline derivatives 1a–e. The R showed a similar behaviour (entry 5). Each solvent
group was varied in such a way to obtain molecules gave a high ee value. When the reaction was carried
with increased hydrophobicity going from a phenyl to out under neat conditions (entry 6) low yield and very
a propylpyrene substituent (Figure 5).
low diastereoselectivity were observed coupled with a
Compounds 1a–e were easily prepared from N- decreased enantioselectivity.
Cbz-4-hydroxyproline 2 by benzylation and subse-
Then, using water as reaction medium, we investi-
quent esterification in the presence of DCC/DMAP gated the above reaction employing different amounts
followed by removal of the protecting groups by cata- of catalyst 1e (Table 2). Using a larger amount
lytic hydrogenolysis (Scheme 1). Products were ob- (10 mol%) of catalyst the reaction was faster but ste-
tained in 83–97% overall yield.
reoselectivity was lower than in the other cases. The
As a first step, we screened several solvents for the amount was decreased up to 0.5 mol%. After 24 h the
reaction between cyclohexanone and 4-nitro-benzal- conversion was not good but dr and ee values were
dehyde (Table 1). As catalyst we used the most hydro- high. Noticeably, using 2 mol% of catalyst after 24 h,
we obtained an almost quantitative conversion and
excellent stereoselectivity. Even with 1 mol% of cata-
lyst results were very good.
Using catalyst 1e (2 mol%) we investigated the
effect of different amount of water (Table 3). When a
stoichiometric amount of water was used (entry 1) the
conversion was not good. However, using 5 or more
equivalents of water (entries 2–4) a complete conver-
sion was observed. In each case stereoselectivities
were high but, when a large amount of water (ca.
20 equiv.) was employed, we obtained excellent dia-
stereo- and enantioselectivity.
We also investigated if a lower amount of cyclohex-
anone can be employed. In Table 4 results of the reac-
Scheme 1. Synthesis of catalysts 1a–e.
tion performed with 1.5, 3 and 5 equivalents of
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Table 2. Effect of the amount of the catalyst in the aldol re-
action between cyclohexanone and 4-nitrobenzaldehyde cat-
alyzed by 1e.[a]
Table 4. Effect of the amount of cyclohexanone in the aldol
reaction between cyclohexanone and 4-nitrobenzaldehyde
catalyzed by 1e.[a]
Entry Cat. (mol%) t [h] Conv.[b] [%] anti/syn[c] ee[d] [%]
Entry Cyclohexanone
[equiv.]
Conv.[b]
[%]
anti/
ee[d]
[%]
syn[c]
1
2
3
4
5
10
5
2
1
0.5
6
99
95/5
97/3
99/1
97/3
98
99
>99
>99
99
6.5 >99
1
2
3
1.5
3
5
97
>99
>99
95/5
95/5
99/1
99
99
>99
24
24
24
>99
96
49
96.5/3.5
[a]
Reaction conditions: cyclohexanone (see Table), alde-
hyde (75.5 mg, 0.5 mmol), water (175 mL), room tempera-
ture.
[a]
Reaction conditions: cyclohexanone (260 mL, 2.5 mmol),
aldehyde (75.5 mg, 0.5 mmol), water (175 mL), room tem-
perature.
[b]
[c]
[d]
Yields: ꢀ95% of conversion.
[b]
[c]
[d]
1
Yields: ꢀ95% of conversion.
Determined by H NMR of the crude product.
1
Determined by H NMR of the crude product.
Determined by HPLC using a chiral stationary phase.
Determined by HPLC using a chiral stationary phase.
Table 3. Effect of the amount of water in the aldol reaction
between cyclohexanone and 4-nitrobenzaldehyde catalyzed
by 1e.[a]
Table 5. Effect of the temperature on the catalytic aldol re-
action between cyclohexanone and 4-nitrobenzaldehydes
catalyzed by 1e.[a]
Conv.[b] [%]
anti/syn[c]
ee[d] [%]
Entry
T [8C]
Conv.[b] [%]
anti/syn[c]
ee[d] [%]
Entry
H2O [mL]
1[e]
2
3
25
35
40
50
90
92
90
60
97/3
96.5/3.5
96/4
>99
>99
>99
>99
1
2
3
4
9
30
90/10
93/7
97/3
99/1
96
97
99
>99
45
90
175
>99
>99
>99
4
93/7
[a]
[a]
Reaction conditions: cyclohexanone (260 mL, 2.5 mmol),
aldehyde (75.5 mg, 0.5 mmol) catalyst (0.01 mmol), sol-
vent (175 mL).
Reaction conditions: cyclohexanone (260 mL, 2.5 mmol),
aldehyde (75.5 mg, 0.5 mmol), water (see Table), room
temperature.
[b]
[c]
[d]
[b]
[c]
[d]
Yields: ꢀ95% of conversion.
Yields: ꢀ95% of conversion.
1
1
Determined by H NMR of the crude product.
Determined by H NMR of the crude product.
Determined by HPLC using a chiral stationary phase.[e]
When the reaction is carried out for 24 h, conversion is
complete.
Determined by HPLC using a chiral stationary phase.
ketone are reported. The data obtained show that the
aldol product can be obtained in high yield and ste-
reoselectivity even with only 1.5 equivalents of catalyst loading at room temperature. We used these
ketone. conditions in the reaction between cyclohexanone and
Finally, we investigated the effect of the reaction two aldehydes (benzaldehyde and 4-nitrobenzalde-
temperature using water as reaction medium and cat- hyde, Table 6).
alyst 1e (2 mol%) (Table 5). No differences were ob-
Going from the less hydrophobic to the most hy-
served in the range 25–408C while at higher tempera- drophobic catalyst, we observed an increased enantio-
ture (508C) a small decrease in diastereoselectivity selectivity in the reaction between cyclohexanone and
coupled with a decrease in conversion was observed. benzaldehyde while the diastereoselectivity was simi-
Noticeably, the enantioselectivity was excellent in lar except when 1a was employed. In this case a lower
each case.
diastereoselectivity was observed. When the reaction
After these preliminary observations we tested cat- between cyclohexanone and 4-nitrobenzaldehyde was
alysts 1a–e using water as reaction medium, 5 equiv. investigated, catalysts 1a–e showed a more marked
of cyclohexanone, ca. 20 equiv. of water, 2 mol% of difference. Indeed, both diastereoselectivity and enan-
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New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts
Table 6. Catalytic aldol reactions between cyclohexanone and benzaldehyde or 4-nitrobenzaldehyde catalyzed by 1a–e.[a]
FULL PAPERS
Entry
Catalyst
Conv.[b] [%]
anti/syn[c]
ee[d] [%]
Conv.[a] [%]
anti/syn[b]
ee[d] [%]
R=H
R=NO2
1
2
32
39
86/14
91/9
91
95
91
96
86.5/13.5
89/11
87
91
3
4
50
55
93/7
94/6
96
96
>99
>99
91.5/8.5
96/4
93
99
5
49
92/8
98
>99
99/1
>99
[a]
Reaction conditions: cyclohexanone (260 mL, 2.5 mmol), aldehyde (0.5 mmol) catalyst (0.01 mmol), water (175 mL), room
temperature.
[b]
[c]
[d]
Yields: ꢀ95% of conversion.
1
Determined by H NMR of the crude product.
Determined by HPLC using a chiral stationary phase.
tioselectivity increased when the hydrophobicity of Table 7. Catalytic aldol reactions between cyclohexanone
and aryl aldehydes catalyzed by 1d.[a]
the catalyst was increased. Finally, higher conversions
were observed with the more hydrophobic catalysts. It
is interesting to note that with 4-acyloxyproline cata-
lysts, in which the acyl group was a linear alkyl chain,
the diastereoselectivity and enantioselectivity de-
creased on going from the less hydrophobic to the
Entry
R
Conv.[b] [%]
anti/syn[c]
ee[d] [%]
most hydrophobic catalyst.[13k]
As can be seen from the results summarized in
Table 6, catalysts 1d and e can efficiently catalyze the
direct asymmetric aldol reaction with a high level of
stereoselectivity. Then, we carried out several aldol
reactions using the above catalysts in order to demon-
strate their catalytic activity. First we checked the
aldol reaction between cyclohexanone and several
aryl aldehydes using 1d as catalyst.
Results are summarized in Table 7. Yields and both
diastereo- and enantioselectivities (94–>99%) were
high. Lower yields were observed only with the less
reactive substrates.
1
2
3
4
H
55
>99
45
>99
>99
82
94/6
96/4
92/8
96/4
97/3
90/10
96/4
99/1
96
99
99
98
98
94
99
>99
4-NO2
2-naphthyl
4-CN
5
2-Cl
6[e]
7
3-OCH3
4-CF3
2-NO2
98
97
8
[a]
Reaction conditions: cyclohexanone (260 mL, 2.5 mmol),
aldehyde (0.5 mmol) catalyst (0.01 mmol), water
(175 mL), room temperature.
[b]
[c]
[d]
[e]
Yields: ꢀ95% of conversion.
1
Determined by H NMR of the crude product.
When cyclopentanone was employed interesting re-
sults were obtained (Table 8). In particular, enantiose-
lectivities were excellent (97–>99%).
Determined by HPLC using a chiral stationary phase.
Reaction time: 72 h.
We further investigated compound 1e as catalyst in
the reaction between aryl aldehydes and cyclohexa-
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Table 8. Catalytic aldol reactions between cyclopentanone
and aryl aldehydes catalyzed by 1d.[a]
Table 10. Catalytic aldol reactions between cyclopentanone
and aryl aldehydes catalyzed by 1e.[a]
Conv.[b] [%]
anti/syn[c]
ee[d] [%]
Entry
R
Conv.[b] [%]
anti/syn[c]
ee[d] [%]
Entry
R
1
2
3
4
H
83
>99
84
>99
>99
95
>99
>99
89/11
87/13
89/11
85/15
90/10
85/15
87/13
92/8
97
98
97
>99
98
97
97
99
1
2
3
4
5
6
7
8
4-NO2
2-NO2
3-NO2
4-CF3
4-CN
4-Cl
2-Cl
H
2-naphthyl
4-Br
4-CH3
4-OCH3
3-OCH3
>99
>99
>99
>99
>99
>99
>99
97
90
98
85
48
88/12
92/8
>99
99
99
98
99
98
98
96
98
98
96
97
93
4-NO2
2-naphthyl
4-CN
87/13
85/15
86/14
88/12
88/12
86/14
88/12
87/13
85/15
82/18
80/20
5
2-Cl
6[e]
7
3-OCH3
4-CF3
2-NO2
8
[a]
9
Reaction conditions: cyclopentanone (220 mL, 2.5 mmol),
aldehyde (0.5 mmol) catalyst (0.01 mmol), water
(175 mL), room temperature.
10
11
12
13
[b]
[c]
[d]
[e]
Yields: ꢀ95% of conversion.
1
97
Determined by H NMR of the crude product.
[a]
Determined by HPLC using a chiral stationary phase.
Reaction time: 72 h.
Reaction conditions: cyclopentanone (220 mL, 2.5 mmol),
aldehyde (0.5 mmol) catalyst (0.01 mmol), water
(175 mL), room temperature.
[b]
[c]
[d]
Yields: ꢀ95% of conversion.
1
Determined by H NMR of the crude product.
Table 9. Catalytic aldol reactions between cyclohexanone
and aryl aldehydes catalyzed by 1e.[a]
Determined by HPLC using a chiral stationary phase.
Again, excellent results were obtained when cata-
lyst 1e was used in the reaction with cyclopentanone
(Table 10). Enantioselectivities ranged from 96 to
>99%, only the 3-methoxy derivative showed a
sligthly lower enantioselectivity (93%).
Entry
X
t [h] Conv.[b] [%] anti/syn[c] ee[d] [%]
1
2
3
4
5
6
7
8
4-NO2
4-Cl
4-CN
2-naphthyl 48
H
3-OCH3
4-CH3
4-CF3
4-Br
2-Cl
24
24
24
>99
79
98
52
66
78
42
95
80
91
97
99/1
94/6
96/4
>99
99
97
Finally, we checked the aldol reaction between
other ketones (acetone, 2-butanone, tetrahydro-4H-
pyran-4-one, 4-methylcyclohexanone, cycloheptanone)
and 4-nitrobenzaldehyde using catalyst 1e (2 mol%)
(Table 11). The reaction with acetone was carried out
both in the presence and in the absence of water. In
the first case we obtained the aldol product in high
yield (84%) and low enantioselectivity (11%)
(entry 1). When we carried out the reaction without
water (entry 2) we obtained the aldol product in low
yield (18%) and good enantioselectivity (76%). How-
ever, it is worth noting that the configuration of aldol
product was reversed. In our opinion the presence of
water increased the activity of the catalyst because
the more hydrophilic medium increased the affinity of
the hydrophobic aldehyde to the hydrophobic cata-
lyst. When water was absent, the aldehyde was well
dissolved in acetone and this caused a lower yield.
91.5/8.5
91/9
91/9
87/13
96/4
93/7
99
98
91
87
>99
>99
97
48
72
72
24
24
24
24
9
10
11
97/3
97/3
2-F
96
[a]
Reaction conditions: cyclohexanone (260 mL, 2.5 mmol),
aldehyde (0.5 mmol) catalyst (0.01 mmol), water
(175 mL), room temperature.
[b]
[c]
[d]
Yields: ꢀ95% of conversion.
1
Determined by H NMR of the crude product.
Determined by HPLC using a chiral stationary phase.
none (Table 9) and cyclopentanone (Table 10). Ste- More difficult to explain is the observed enantioselec-
reoselectivities were high. In particular, in the case of tivity in the presence of water. By contrast, the reac-
cyclohexanone, enantioselectivities ranged from 96 to tion between cyclohexanone and 4-nitrobenzaldehyde
>99%. Only in the cases of 3-methoxy and 4-methyl under neat conditions did not show a reversed enan-
derivatives (Table 9, entries 6 and 7) was the enantio- tioselectivity. This is probably due to the different hy-
selectivity slightly lower (91 and 87%, respectively).
drophilicity between the two ketones.
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New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts
FULL PAPERS
Table 11. Catalytic aldol reactions between several ketones and 4-nitrobenzaldehyde catalyzed by 1e.[a]
Entry
1
Reaction conditions
Product
Conv.[b] [%]
84
anti/syn[c]
ee[d] [%]
A[e]
–
11
2
3
4
5
B[e]
18
nr
nr
35
–
76
–
A
A
A
[e], B[e]
–
–
–
97.5/2.5
95
6
A
C
97
96
94/6
92/8
99
98
7
[a]
Reaction conditions: A, ketone (2.5 mmol), aldehyde (0.5 mmol) catalyst 1e (0.01 mmol), water (175 mL), room tempera-
ture; B, ketone (2.5 mmol), aldehyde (0.5 mmol) catalyst 1e (0.01 mmol), room temperature; C, ketone (2.5 mmol), alde-
hyde (0.5 mmol) catalyst 1d (0.01 mmol) , water (175 mL), room temperature.
[b]
[c]
[d]
[e]
Yields: ꢀ95% of conversion.
1
Determined by H NMR of the crude product.
Determined by HPLC using a chiral stationary phase.
For 48 h.
Using the same conditions for acetone, 2-butanone lent results were obtained using 4-methylcyclohexa-
gave very poor results (entry 3). This can be viewed none both with catalysts 1e and 1d (entries 6 and 7).
as an interesting result because 1e appears to be a From a mechanistic point of view, water plays a
substrate-selective catalyst. The same behaviour was crucial role. In fact, the data of the reactions carried
observed when cycloheptanone was used (entry 4). out with cyclohexanone under aqueous and neat con-
The reaction did not take place. However, it should ditions (Table 1, entries 4, 5 and 6) showed that water
be remembered that cycloheptanone is not a very re- enhances the catalyst activity (yield from 38 to 99%),
active substrate. Indeed, only few papers report aldol diastereoselectivity (from 59/41 to 95/5) and enantio-
reactions with cycloheptanone under aqueous condi- selectivity (from 87 to 98%). We hypothesize that,
tion.[5,13g,18e]
under the reaction conditions employed, a hydropho-
Tetrahydro-4H-pyran-4-one gave high stereoselec- bic region and a hydrophilic region can be formed in
tivities but low conversion (entry 5), whereas excel- the presence of catalyst 1e, as depicted in Figure 6.
Adv. Synth. Catal. 2008, 350, 2747 – 2760
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Francesco Giacalone et al.
FULL PAPERS
Figure 6. Proposed structure of catalyst 1e in the presence of
water.
The enhanced activity of organic catalysis on water
has been recently theoretically investigated. Free OH
groups of interfacial water molecules play a key role
in catalyzing reactions via the formation of hydrogen
bonds.[20]
Quantum mechanical calculations have predicted
the transition state geometries for the reaction of cy-
clohexanone enamine with benzaldehyde.[21] The tran-
sition states involving the re attack on the anti-enam-
ine are lower in energy than the transition states for
Figure 7. Proposed transition state model for the major ste-
reoisomer (A), its enantiomer (B), and the minor diastereo-
isomer (C).
si attack on the syn-enamine.[21] Following this mecha- down to 0.5 mol% with excellent stereoselectivity and
nism, in order to explain the observed enhanced ste- moderate yield after only 24 h. This can be considered
reoselectivities, we hypothesize that transition state A an interesting result since in several cases catalysts
(Figure 7) is highly stabilized because the hydropho- that are used in higher amounts (up to 20 mol%) re-
bic aldehyde attacking the anti-enamine lies in the hy- quired long reaction times.[4c,f,i,k,10,11,12,13e,g] In our case,
drophobic region. The excellent enantioselectivities the reaction conditions are very mild, water is used as
observed can be explained by transition state B. In reaction medium, there is no need to perform the re-
this case the less favoured attack of aldehyde on the actions at low temperature to reach high stereoselec-
syn-enamine is more destabilized because the hydro- tivity, indeed, reactions are carried out at room tem-
phobic aldehyde lies in the hydrophilic region. Finally, perature and even higher temperatures can furnish
the high diastereoselectivities observed can be ex- aldol products in excellent stereoselectivity, no addi-
plained by transition state C. In this case the attack of tives are used and, finally, only 2 mol% of catalyst is
aldehyde on anti-enamine is more destabilized be- employed. Aldol products are obtained from good to
cause the hydrophobic part of the aldehyde is direct- almost quantitative yields in a reasonable time and
ed towards the hydrophilic region. This model can ex- stereoselectivities are excellent in almost all the cases.
plain the lower stereoselectivity observed when water In particular, aldol products from cyclopentanone are
is absent.
obtained in excellent enantioselectivities. This work
demonstrates that derivatization of the proline moiety
with the proper simple hydrophobic substituent in the
4-position can furnish highly active and stereoselec-
tive catalysts without the need of additional expensive
Conclusions
We have synthesized five new organocatalysts for the chiral backbones in the molecule. In addition to Hay-
direct asymmetric aldol reaction. These catalysts are ashiꢃs catalyst,[13k] compounds 1d and e represent the
easily prepared in a few high-yielding steps, so they best compromise between activity and simplicity of
are easily accessible. Screening of these molecules structure. When acetone was employed as donor com-
show that the most hydrophobic compounds 1d and e pound great differences were observed both in yield
are very active catalysts. Catalyst 1e can be used and enantioselectivity when the reaction was carried
2754
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New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts
FULL PAPERS
53.6, 52.6, 52.2, 36.6, 35.5; IR (nujol): nmax =1740, 1700 cmÀ1
;
˜
out in the presence or in the absence of water. This is
probably due to the higher hydrophilicity of the ace-
tone compared to cyclic ketones. Finally, an explana-
tion of the observed stereoselectivities for cyclic ke-
tones in the presence of water was given.
anal. calcd. for C27H25NO6 (459.49): C 70.58, H 5.48, N 3.05;
found: C 70.67, H 5.45, N 3.09.
AHCTUNGTREG(NNUN 2S,4R)-Dibenzyl 4-(2-phenylacetoxy)pyrrolidine-1,2-di-
carboxylate (4b): The residue was purified by column chro-
matography (petroleum ether/ethyl acetate, 4:1), to give
compound 4b as a yellow oil; yield: 92%; [a]2D6: À41.6 (c
0.89, CHCl3). 1H NMR (CDCl3): d=2.03–2.14 (m, 1H),
2.24–2.32 (m, 1H), 3.48 (d, J=2.1 Hz, 2H), 3.53–3.70 (m,
2H), 4.39 (ddd, J=8.0, 8.0 and 29.8 Hz, 1H), 4.93 (d, J=
19 Hz, 2H), 5.03–5.11 (m, 2H), 5.13–5.20 (m, 1H), 7.10–7.30
(m, 15H); 13C NMR (75 MHz, CDCl3; two rotamers): d=
171.7, 170.8, 170.7, 154.6, 154.0, 136.3, 136.1, 135.4, 135.2,
133.4, 133.3, 129.0, 128.6, 128.5, 128,4, 128.4, 128.3, 128.1,
127.8, 127.2, 127.2, 72.9, 72.2, 67.3, 67.2, 67.0, 66.9, 57.9, 57.6,
˜
Experimental Section
The NMR spectra were recorded on a Bruker 300 MHz
spectrometer using CDCl3 or DMSO-d6 as solvent. Solid-
state 13C{H} CP-MAS NMR spectra was recorded on a
Bruker AV 400, 400 MHz spectrometer with samples packed
in zirconia rotors spinning at 13 kHz. FT-IR spectra were
registered with a Shimadzu FTIR 8300 infrared spectropho-
tometer. Carbon and nitrogen contents were determined by
combustion analysis in a Fisons EA 1108 elemental ana-
lyzer. Optical rotations were measured in chloroform on a
Jasco P1010 polarimeter. Hydrogenation reactions were car-
ried out using a Parr apparatus. Flash chromatography was
carried out using Macherey–Nagel (0.04–0.063 mm) silica
gel. Melting points were determined using a Kçfler hot
plate and are not corrected. Chiral HPLC analyses were per-
formed using a Shimadzu LC-10AD apparatus equipped
with an SPD-M10A UV detector and Daicel columns (OD-
H, AD-H, AS-H) using hexane/2-propanol as eluent. Aldol
products, except (S)-2-{(R)-hydroxy[3-methoxyphenyl]me-
thyl}cyclopentanone, are known compounds and showed
spectroscopic and analytical data in agreement with their
structures (see Table 12 and Table 13). The configurations of
products have been assigned by comparison with literature
data. N-Cbz-4-hydroxy-proline 2 was commercially available
(Aldrich). (2S,4R)-Dibenzyl 4-hydroxypyrrolidine-1,2-dicar-
boxylate 3 was prepared as reported in the literature.[22]
52.4, 52.1, 41.1, 36.4, 35.4; IR (nujol): nmax =1740, 1708 cmÀ1
;
anal. calcd. for C28H27NO6 (473.52): C 71.02, H 5.75, N 2.96;
found: C 71.07, H 5.79, N 3.00.
AHCTUNGTREG(NNUN 2S,4R)-Dibenzyl 4-(3-phenylpropanoyloxy)pyrrolidine-
1,2-dicarboxylate (4c): The residue was purified by column
chromatography (petroleum ether/ethyl acetate, 3:1), to give
compound 4c as a yellow oil; yield: 92%; [a]2D6: À41.6 (c
0.73, CHCl3). 1H NMR (CDCl3): d=2.22–2.31 (m, 1H),
2.35–2.45 (m, 1H), 2.68–2.73 (m, 2H), 2.98–3.04 (m, 2H),
3.66–3.87 (m, 2H), 4.50 (ddd, J=8.1, 8.1 and 32.1 Hz, 1H),
5.12 (d, J=18.3 Hz, 2H), 5.22–5.35 (m, 3H), 7.22–7.45 (m,
15H); 13C NMR (75 MHz, CDCl3; two rotamers): d=172.6,
172.6, 172.4, 172.1, 155.1, 154.5, 140.4, 140.4, 136.7, 136.6,
135.9, 135.6, 129.0, 128.9, 128.8, 128.7, 128.6, 128.6, 128.5,
128.3, 126.8, 126.7, 72.9, 72.2, 67.7, 67.5, 67.3, 58.4, 58.0, 52.9,
˜
52.5, 37.0, 36.1, 36.0, 31.3; IR (liquid film): nmax =1740,
1712 cmÀ1: anal. calcd. for C29H29NO6 (487.54): C 71.44, H
6.00, N 2.87; found: C 71.47, H 6.04, N 2.90.
AHCTUNGTREG(NNUN 2S,4R)-Dibenzyl 4-(4-phenylbutanoyloxy)pyrrolidine-1,2-
dicarboxylate (4d): The residue was purified by column
chromatography (petroleum ether/ethyl acetate, 2:1), to give
compound 4d as a pale orange oil; yield: 99%; [a]3D0: À32.4
General Procedure for the Synthesis of Compounds
4a–e
1
(c 0.63, CHCl3). H NMR (CDCl3): d=1.85–2.10 (m, 3H),
2.16–2.49 (m, 3H), 2.64–2.74 (m, 2H), 3.65–3.85 (m, 2H),
4.54 (ddd, J=7.8, 7.8 and 21.9 Hz, 1H), 5.06 (d, J=16.2 Hz,
2H), 5.19–5.34 (m, 3H), 7.16–7.44 (m, 15H); 13C NMR (75
MHz, CDCl3; two rotamers): d=172.6, 172.5, 171.8, 171.6,
154.5, 154.0, 153.8, 141.3, 140.9, 140.8, 136.1, 136.0, 135.3,
135.0, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7,
125.9, 125.8, 72.3, 71.5, 67.1, 66.9, 66.8, 57.8, 57.6, 52.4, 52.0,
˜
To a solution of compound 3 (562 mg, 1.58 mmol) in anhy-
drous dichloromethane (35 mL) the proper carboxylic acid
(2.24 mmol) was added. The mixture was stirred for 10 min
at 08C under argon. Then, 1,3-dicyclohexylcarbodimide
(DCC)
(2.24 mmol)
and
4-(dimethylamino)-pyridine
(DMAP) (0.224 mmol) in dichloromethane (10 mL) were
added and the mixture was stirred at 08C for 15 min. The re-
action mixture was stirred overnight at room temperature
under argon. After this period the dichloromethane solution
was washed with water (2ꢄ30 mL). The organic phase was
dried with MgSO4 and concentrated under reduced pressure.
34.9, 34.8, 33.3, 26.1; IR (liquid film): nmax =1732, 1705 cmÀ1
;
anal. calcd. for C30H31NO6 (501.57): C 71.84, H 6.23, N 2.79;
found: C 71.79, H 6.20, N 2.85.
(2S,4R)-Dibenzyl
4-[4-(pyren-1-yl)butanoyloxy]pyrroli-
dine-1,2-dicarboxylate (4e): The residue was purified by
column chromatography (petroleum ether/ethyl acetate,
7:1), to give compound 4e as a viscous pale yellow oil; yield:
ACHTUNGTRENNUNG(2S,4R)-Dibenzyl 4-(benzoyloxy)pyrrolidine-1,2-dicarbox-
ylate (4a): The residue was purified by column chromatogra-
phy (petroleum ether/ethyl acetate, 6:1), to give compound
4a as a pale yellow solid; yield: 85%; [a]2D6: À39. 7 (c 0.76,
1
93%; [a]24: À411.7 (c 0.72, CHCl3). H NMR (CDCl3): d=
2.06–2.13D(m, 3H), 2.25–2.34 (m, 3H), 3.21–3.30 (m, 2H),
3.52–3.69 (m, 2H), 4.41 (ddd, J=8.1, 8.1 and 23.7 Hz, 1H),
4.92 (d, J=14 Hz, 2H), 5.04–5.20 (m, 3H), 7.09–7.25 (m,
10H), 7.72 (dd, J=1.8 and 7.5 Hz, 1H), 7.85–7.91 (m, 3H),
7.98–8.08 (m, 4H), 8.16 (dd, J=2.2 and 9.3 Hz, 1H);
13C NMR (75 mhz, CDCl3; two rotamers): d=173.2, 173.1,
172.4, 172.2, 155.1, 154.5, 136.6, 135.8, 135.6, 131.8, 131.2,
130.4, 129.1, 129.0, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3,
127.9, 127.8, 127.2, 126.3, 125.5, 125.3, 125.2, 123.6, 72.9,
1
CHCl3); mp 75–778C. H NMR (CDCl3): d=2.14–2.23 (m,
1H), 2.36–2.46 (m, 1H), 3.70–3.82 (m, 2H), 4.51 (ddd, J=
7.9, 7.9 and 25.2 Hz, 1H), 4.92 (d, J=14.4 Hz, 2H), 5.02–
5.13 (m, 2H), 5.32–5.40 (m, 1H), 7.41–707 (m, 13H), 7.81
(d, J=7.5, 2H); 13C NMR (75 MHz, CDCl3; two rotamers):
d=171.9, 171.7, 165.6, 154.7, 154.1, 136.3 136.2, 135.5, 135.3,
133.3, 133.2, 129.6, 129.5, 128.5, 128.3, 128.5, 128.2, 128,1,
128.0, 127.9, 127.7, 127.7, 73.1, 72.5, 67.2, 66.9, 58.1, 57.8,
Adv. Synth. Catal. 2008, 350, 2747 – 2760
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FULL PAPERS
1
Table 12. Selected H NMR spectroscopic data for diastereoisomers and HPLC data for enantiomers of compounds obtained
in the reactions between cyclohexanone and aryl aldehydes.
Compound
1H NMR (CDCl3)
HPLC
Column Eluent [hexane/i- Flow
syn 1’H
anti 1’H
l
tR Major
tR Minor
[min]
[ppm]
[ppm]
PrOH]
[mLminÀ1] [nm] [min]
1[a,b]
5.4
4.8
4.8
4.9
5.0
AS-H
AS-H
AS-H
AS-H
90:10
0.5
1.0
0.5
0.5
238 26.7
254 33.8
217 28.4
230 86.8
29.6
29.9
30.2
75.2
2[a,b,c]
3[a,b,d]
4[a,b]
5.4
5.5
5.6
5.3
5.4
90:10
90:10
90:10
5[a,c]
4.8
4.8
OD-H 95:5
0.5
0.5
217 12.4
219 14.3
15.9
23.1
6[a,b]
AS-H
90:10
7[a,e]
5.7
5.3
5.5
5.3
4.7
4.8
OD-H 95:5
1.0
1.0
1.0
212 10.1
254 15.9
245 53.5
13.5
20.7
65.1
8[f]
AS-H
AS-H
90:10
98:2
9[a,g]
10[a]
5.4
5.4
4.9
4.9
OD-H 90:10
AD-H 90:10
1.0
1.0
210 35.9
254 30.5
32.1
33.0
11
[a]
Ref.[18e]
[b]
[c]
[d]
[e]
[f]
Ref.[5]
Ref.[23]
Ref.[12]
Ref.[4c]
Ref.[18h]
Ref.[6]
[g]
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New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts
FULL PAPERS
1
Table 13. Selected H NMR spectroscopic data for diastereoisomers and HPLC data for enantiomers of compounds obtained
in the reactions between cyclopentanone and aryl aldehydes.
Compound
1H NMR (DMSO-d6)
HPLC
Column Eluent [hexane/i- Flow
syn 1’H
anti 1’H
l
tR Major
tR Minor
[min]
[ppm]
[ppm]
PrOH]
[mLminÀ1] [nm] [min]
1[a,b]
5.1
5.4
5.0
4.8
OD-H 90:10
1.0
0.5
213 11.6
14.0
2[a,b,c]
AD-H 90:10
265 113.1
109.7
3[d]
4[e]
4[f]
5.3
5.7
5.1
5.1
5.2
5.0
AD-H 95:5
OD-H 95:5
AD-H 95:5
1.0
1.0
1.0
269 41.9
254 28.6
220 27.9
62.9
32.3
30.3
5[c,g]
6[h]
7[i]
5.2
5.1
5.1
4.7
5.2
5.0
OD-H 90:10
AD-H 90:10
AD-H 95:5
0.5
1.0
1.0
231 113.7
214 12.3
213 16.7
98.5
16.9
17.9
8[j]
5.1
5.0
5.4
4.9
AD-H 98:2
AD-H 90:10
1.0
0.5
220 28.2
270 34.9
37.8
37.0
9
10[k]
5.1
5.3
4.9
AD-H 90:10
0.5
220 28.3
32.3
40.1
11[l]
5.2
AD-H 95:5
1.0
264 36.4
[a]
[c]
[e]
[g]
[i]
[k]
Ref.[5] [b] Ref.[6]
Ref.[18e] [d] Ref.[24]
Ref.[4f] [f] Ref.[25]
Ref.[9] [h] Ref.[26]
Ref.[27] [j] Ref.[28]
Ref.[29]
[l] Ref.[8]
72.2, 67.7, 67.4, 58.4, 58.1, 53.0, 53.1, 52.6, 37.0, 36.0, 34.1,
General Procedure for the Synthesis of Compounds
1a–e
33.0, 31.3, 26.9; IR (liquid film): nmax =1738, 1713 cmÀ1; anal.
˜
calcd. for C40H35NO6 (625.71): C 76.78, H 5.64, N 2.24;
found: C 76.77, H 5.67, N 2.26.
To a solution of compounds 4 (1.91 mmol) in methanol
(65 mL) PdACTHNUTRGNEUG(N 10%)/C (308 mg) was added. The reaction mix-
Adv. Synth. Catal. 2008, 350, 2747 – 2760
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Francesco Giacalone et al.
FULL PAPERS
Figure 8. Solid state 13C NMR of compound 1e.
ture was stirred under hydrogen in a Parr apparatus for 3 h.
After this time the reaction mixture was filtered 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 1a–e.
(broad COOH), 1717 cmÀ1; anal. calcd. for C12H13NO4
(235.24): C 61.27, H 5.57, N 5.95; found: C 61.22, H 5.52, N
5.99.
AHCTUNGTREG(NNUN 2S,4R)-4-(2-Phenylacetoxy)pyrrolidine-2-carboxylic acid
(1b): Highly viscous oil; yield: 95%; [a]2D5: À5.2 (c 0.84,
1
A
CHCl3). H NMR (CDCl3): d=2.08–2.30 (m, 2H), 3.12 (d,
Pale yellow solid; yield: 96%; [a]2D7: À4.6 (c 0.32, CHCl3);
J=12.9 Hz, 1H), 3.50–3.65 (m, 3H), 4.01 (dd, J=7.8 and
10.5 Hz, 1H), 5.17–5.21 (m, 1H), 7.13–7.26 (m, 5H), 7.95 (br
s, OH); 13C NMR (75 MHz, CDCl3): d=173.9, 171.0, 133.7,
129.6, 129.1, 127.6, 74.0, 60.9, 50.6, 41.4, 35.8; IR (liquid
mp 180–1858C. H NMR (DMSO-d6): d=2.08 (ddd, J=4.8,
9.6 and 14.4 Hz, 1H), 2.24 (ddd, J=7.8, 7.8 and 14.4 Hz,
1H), 3.22 (d, J=13.0 Hz, 1H), 3.41 (dd, J=4.4 and 13.0 Hz,
1H), 3.85 (dd, J=9.4 and 9.4 Hz, 1H), 5.34–5.38 (m, 1H),
7.41–7.46 (m, 2H), 7.54–7.60 (m, 1H), 7.91–7.95 (m, 2H);
13C NMR (CDCl3): d=173.7, 165.5, 133.2, 129.7, 129.3,
film): nmax =3500–2600 (broad COOH), 1720 cmÀ1; anal.
˜
calcd. for C13H15NO4 (249.26): C 62.64, H 6.07, N 5.62;
found: C 62.67, H 6.04, N 5.60.
˜
128.3, 73.9, 60.4, 50.6, 35.5; IR (nujol): nmax =3500–2600
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New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts
FULL PAPERS
ACHTUNGTRENNUNG(2S,4R)-4-(3-Phenylpropanoyloxy)pyrrolidine-2-carboxylic
Acknowledgements
acid (1c): White-gray powder after recrystalizatiom from
hexane/dichloromethane; yield: 96%; [a]2D7: À19.8 (c 0.49,
Financial support from the University of Palermo (Funds for
selected topics) and the Italian MIUR within the National
Project “Catalizzatori, metodologie e processi innovativi per
il regio- e stereocontrollo delle sintesi organiche” and the
“Centro Grandi Apparecchiature - UniNetLab - Universitꢀ di
Palermo funded by P.O.R. Sicilia 2000–2006, Misura 3.15
Quota Regionale” (13C {1H} CP-MAS spectrum) are grateful-
ly acknowledged.
1
CH3OH); mp 202–2068C. H NMR (CD3OD): d=2.20 (ddd,
J=4.9, 10.2 and 14.9 Hz, 1H), 2.40 (dddd, J=1.5, 1.5, 7.8
and 14.9 Hz, 1H), 2.61–2.67 (m, 2H), 2.90 (t, J=7.6 Hz,
2H), 3.26–3.31 (m, 1H), 3.54 (dd, J=4.5 and 13.1 Hz, 1H),
4.06 (dd, J=8.0 and 10.2 Hz, 1H), 5.30–5.35 (m, 1H), 7.10–
7.28 (m, 5H); 13C NMR (75 MHz, CD3OD): d=173.5, 173.0,
141.7, 129.6, 129.3, 127.4, 74.8, 61.5, 51.8, 36.6, 36.5, 31.7; IR
(nujol): nmax =3500–2600 (broad COOH), 1733 cmÀ1; anal.
˜
calcd. for C14H17NO4 (263.29): C 63.87, H 6.51, N 5.32;
found: C 63.91, H 6.48, N 5.30.
ACHTUNGTRENNUNG(2S,4R)-4-(4-Phenylbutanoyloxy)pyrrolidine-2-carboxylic
acid (1d): Pale orange solid after purification by column
References
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1
78%; [a]31: À3.02 (c 0.52, CHCl3); mp 129–1338C. H NMR
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(CDCl3):Dd=1.84–2.01 (m, 2H), 2.20–2.46 (m, 4H), 2.66 (t,
J=7.5 Hz, 1H), 3.20–3.27 (m, 1H), 3.70–3.80 (m, 1H), 4.12
(dd, J=9.6 and 9.6 Hz, 1H), 5.27–5.33 (m, 1H), 7.16–7.35
(m, 5H); 13C NMR (CDCl3): d=173.9, 173.1, 141.5, 128.9,
128.8, 126.5, 73.4, 60.9, 50.7, 35.8, 35.4, 33.8, 26.6; IR (nujol):
[2] a) Z. G. Hajos, D. R. Parrish, German Patent 2102 623,
1971; b) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974,
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Am. Chem. Soc. 2000, 122, 2395–2396.
nmax =3500–2600 (broad COOH), 1732 cmÀ1; anal. calcd. for
˜
C15H19NO4 (277.32): C 64.97, H 6.91, N 5.05; found: C 65.06,
H 6.93, N 5.10.
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powder; yield: 95%; mp 206–2108C. Since this compound is
very poorly soluble, it was characterized by solid state
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˜
COOH), 1731 cmÀ1; anal. calcd. for C25H23NO4 (401.45): C
74.79, H 5.77, N 3.49; found: C 74.77, H 5.73, N 3.41.
Typical Procedure for Aldol Reaction
Catalyst 1 (0.01 mmol) was added to a mixture of the corre-
sponding aldehyde (0.5 mmol) and ketone (2.5 mmol) in dis-
tilled 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 washed with water. The
organic layer was dried (MgSO4) and concentrated under re-
1
duced pressure. The crude product was checked by H NMR
spectroscopy and HPLC, and was then purified by chroma-
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(S)-2-[(R)-hydroxy(3-methoxyphenyl)methyl]cyclopenta-
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mixture of diastereoisomers. 1H NMR (CDCl3): d=1.58–
2.58 (m, 6H, anti+syn), 2.80–2.83 (m, 1H, syn), 3.91 (s, 3H,
anti+syn), 4.66 (s, 1H, OH, anti+syn), 4.79 (d, J=9.0 Hz,
1H, anti), 5.36–5.38 (m, 1H, syn), 6.88–7.02 (m, 3H, anti+
syn), 7.32–7.38 (m, 1H, anti+syn); 13C NMR (CDCl3; anti
diastereoisomer): d =223.0, 159.6, 143.0, 129.3, 118.9, 113.4,
111.8, 75.0, 55.2, 55.1, 38.7, 26.9, 20.3; (syn diastereoisomer):
d =220.3, 159.5, 144.6, 126.3, 117.7, 112.5, 111.1, 71.2, 56.0,
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