Unusual enantioselectivities in heterogeneous organocatalyzed reactions: Reversal of direction using proline di- versus tri-peptides in the aldol addition

Article abstract of DOI:10.1016/j.molcata.2013.11.011

The heterogeneous asymmetric direct aldol reactions between aldehydes (2-nitrobenzaldehyde, 2-methylpropanal) and ketones (acetone, cyclohexanone) in the presence of polystyrene (PS) resin supported di- and tripeptides were studied under otherwise identic

Full text of DOI:10.1016/j.molcata.2013.11.011

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Journal of Molecular Catalysis A: Chemical 382 (2014) 86–92
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Unusual enantioselectivities in heterogeneous organocatalyzed
reactions: Reversal of direction using proline di- versus tri-peptides
in the aldol addition
György Szo˝ llo˝ sia, Antal Csámpaib, Csaba Somlaic, Mónika Feketed, Mihály Bartóka,d,∗
a MTA-SZTE Stereochemistry Research Group, Dóm tér 8, H-6720 Szeged, Hungary
b Institute of Chemistry, Eötvös Loránd University, P.O. Box 32, H-1518 Budapest-112, Hungary
c Department of Medical Chemistry, Faculty of Medicine, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
d Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The heterogeneous asymmetric direct aldol reactions between aldehydes (2-nitrobenzaldehyde, 2-
methylpropanal) and ketones (acetone, cyclohexanone) in the presence of polystyrene (PS) resin
supported di- and tripeptides were studied under otherwise identical experimental conditions at room
temperature in batch reactor. For all three asymmetric aldol reactions reversal of enantiomeric excess
was observed on H-Pro-Pro-Glu(OH)-PS catalyst (ee 39–50%) as compared to the H-Pro-Glu(OH)-PS cata-
lyst (ee 52–95%). The determinant role of the conformation of the intermediate adducts held responsible
for chiral induction is interpreted by quantum chemical calculations.
Received 11 July 2013
Received in revised form
27 September 2013
Accepted 9 November 2013
Available online 20 November 2013
Keywords:
Aldol reaction
© 2013 Elsevier B.V. All rights reserved.
Asymmetric synthesis
Organocatalysis
Heterogeneous catalysis
Peptides
1. Introduction
by Kagan et al. [33]. As a first step, the pertinent literature was
reviewed [34], and it was found that at the present stage of research
Asymmetric organocatalysis has become an important method
in the production of chiral compounds [1–5]. Easily available,
optically active compounds of natural origin are advantageously
applied as catalysts for these synthetic procedures. A widely used
group of chiral catalysts – especially in the aldol addition studied
in this manuscript – is l-proline (Pro) and its synthetic derivatives
[6–8]. In our studies on heterogeneous catalytic asymmetric syn-
theses, in addition to enantioselective hydrogenations [9–11], the
use of immobilized Pro was also initiated for the catalysis of certain
aldol reactions [12]. In the meantime, considerable progress has
been made in the research of peptide-type organocatalysts [13–16].
Some short peptides (in particular tripeptides) have proved to act
as especially active and enantioselective catalysts [17–27].
it was not possible to draw general conclusions so far. Further
reports have since been published presenting important experi-
mental observations in this field [35–39]. Regarding the sense of
enantioselection, the data in Table 1 demonstrate the present sta-
tus of research in the asymmetric direct aldol reaction between
4-nitrobenzaldehyde and acetone catalyzed by Pro-peptides. The
first studies published in 2003 (Table 1, entries 1–4) confirmed
that H-Pro-di-, tri- and tetra-peptide catalysts promote the for-
mation of (R)-products. In 2005, however, a breakthrough was
achieved. Whereas certain tripeptides were repeatedly found to
exhibit enantioselectivities similar to that of dipeptides [20,21],
Wennemers et al. developed a catalyst, H-Pro-Pro-Asp-NH2, which
catalyzes the formation of the (S)-product in 80% ee [19]. They pre-
sented a reasonable interpretation of the reversed ee, comparing
the effect of this tripeptide with that of H-l-Pro-d-Ala-d-Asp-NH2
[19]. In spite of further efforts, and although the conditions for
the favourable functioning of the catalyst (activity, ee, position
of functional groups) have been determined, several unanswered
questions regarding the stereochemistry of the reaction per-
sist, which necessitate further research. The present manuscript
wishes to make a contribution to these efforts by presenting some
experimental observations obtained using MBHA-polystyrene (PS)
In the course of investigating the mechanism of enantioselective
heterogeneous catalytic hydrogenations, an unexpected inversion
observed [28–32] turned our attention to studying the role of this
phenomenon in the origin of chiral induction, earlier recognized
∗
Corresponding author at: MTA-SZTE Stereochemistry Research Group, Dóm tér
8, H-6720 Szeged, Hungary. Tel.: +36 62 544279; fax: +36 62 544200.
E-mail address: bartok@chem.u-szeged.hu (M. Bartók).
1381-1169/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2013.11.011

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87
Table 1
resins 3 and 5 the peptides were cleaved from the resins with simul-
taneous side chain deprotection by acidolysis with anhydrous HF
(10 mL) at 0 ◦C for 30 min without scavenger. The crude peptides
were dissolved in aqueous acetic acid and lyophilized following
which H-Pro-Glu(OH)-NH2 and H-Pro-Pro-Glu(OH)-NH2, respec-
tively were obtained. Analysis of these materials was performed
on LKB Bromma HPLC apparatus, column: Phenomenex Luna
5C18(2), 250 mm × 4.6 mm; mobile phase: aqueous acetonitrile
with 0.1 vol% TFA; flow rate 1.2 mL/min, gradient elution 5–95 vol%,
30 min, detection at 220 nm wavelength; retention times: H-Pro-
Glu(OH)-NH2: 2.71 min and H-Pro-Pro-Glu(OH)-NH2: 2.56 min.
According to HPLC analysis the purities of both crude peptides
were higher than 95%. The ESI-MS analysis were carried out on
TSQ 7000 triple-quad mass spectrometer (Finnigan) equipped with
an electrospray ion source (ESI) performing the measurements in
positive ion mode (spray voltage was 4.0 kV, capillary temperature
240 ◦C). Samples were dissolved in 50 vol% aqueous methanol with
0.5 vol% acetic acid; H-Pro-Glu(OH)-NH2: 243.7 (M+1) and H-Pro-
Pro-Glu(OH)-NH2: 340.75 (M+1).
Aldol reaction between 4-nitrobenzaldehyde and acetone catalyzed by di-, tri- and
tetra-peptides (2003–2008).
Entry Dipeptides
ee (%)a Tri/tetrapeptides
ee (%)a Ref.
1
2
3
4
5
6
7
8
9
H-Pro-Asp-NH2
<5 R
46 R
74 R
68 R
–
H-Pro-Glu-Leu-Phe-OH 66 R
H-Pro-Asp-Leu-Phe-OH 50 R
[17]
H-Pro-Glu-OH
H-Pro-Asp-OH
H-Pro-Glu-OH
H-Pro-Asp-NH2
[17]
[18]
[18]
[19]
[20]
[21]
[26]
[26]
H-Pro-Gly-Gly-OH
H-Pro-His-Ala-OH
H-Pro-Pro-Asp-NH2
H-Pro-Ser-Phe-NH-TG
H-Pro-Phe-Phe-NH-PS
H-Pro-Pro-Glu-NH2
H-Pro-Pro-Asn-OH
53 R
56 R
80 S
77 R
34 R
64 S
73 S
H-Pro-Ser-NH-TG 63 R
H-Pro-Phe-NH-PS 27 R
H-Pro-Glu-NH2
H-Pro-Pro-OH
–
–
a
Enantiomeric excess and the configuration of the major enantiomer.
resin-supported Pro-di- and tripeptides as catalysts for direct
asymmetric aldol reactions. Furthermore, the use of peptides
immobilized on resin insoluble in the reaction media results in a
heterogeneous catalytic system, having all the known advantages
of these systems, such as easy separation, recovery and reuse of
the catalysts. Accordingly, in our study immobilized peptides were
used, which following further developments may lead to materials
for preparative application in future studies.
2.3. General procedure for the direct aldol additions
The aldehydes: 2-nitrobenzaldehyde (8) and 2-methylpropanal
(9) were purchased from Aldrich and used as received. The reac-
tions were carried out in closed glass reactors. The given amount
of immobilized catalyst (containing 0.04 mmol peptide) was sus-
pended in 2 mL acetone or the given solvent (reaction 3) followed
by addition of the given amount of imidazole additive (when used),
the corresponding aldehyde (and cyclohexanone in reaction 3) and
5 ␮L n-tetradecane (as internal standard). The reaction mixture was
stirred at 25 ◦C. After the specified reaction time the catalyst was
removed by centrifugation and products (aldol products: 10, 11 and
12) were analyzed by gas chromatography (GC).
Products were identified by their mass spectra using Agilent
Techn. 6890N GC-5973 inert MSD and HP-1MS 60 m × 0.25 mm
i.d. capillary column. Quantitative analysis including enantiomeric
separation was performed using GC equipped with flame ioniza-
tion detector (FID): Agilent Techn. 6890N GC-FID and Cyclosil-B
30 m × 0.25 mm i.d. chiral capillary column. Analysis conditions
and retention times of the aldol products are summarized in Table 2.
Enantiomeric excesses (ee) were calculated using the formula ee
[%] = |conc R − conc S|/(conc R + conc S) × 100, where conc R and conc S
are the concentrations of the aldol product enantiomers. The repro-
ducibility of the reactions was 3%. The absolute configurations
of the aldol products were assigned by analogy with previously
reported results and data obtained using l- and d-proline as cata-
lysts.
Here we report the use of the following resin-supported Pro-
di- and tripeptides as catalysts: H-Pro-MBHA (1); H-Pro-Pro-MBHA
(2); H-Pro-Glu(OH)-MBHA (3); H-Pro-Pro-Pro-MBHA (4); H-Pro-
Pro-Glu(OH)-MBHA (5) (Fig. 1). In case of catalysts 3 and 5 unusual
phenomenon was observed, namely opposite enantiomers were
obtained in aldol reactions. The structures of catalysts 3 and 5 are
presented in Fig. 1.
2. Experimental
2.1. Preparation of resin-bonded peptides
The immobilized peptide catalysts (1–7) were synthetized by
a solid-phase technique. All reagents and solvents of reagent
grade were purchased from Sigma–Aldrich. 9-Fluorenylmethoxy-
carbonyl-l-aminoacids (Fmoc-acids) were purchased from Orpe-
gen Pharma GmbH. Solid-phase synthesis was carried out manually
on p-methylbenzhydrylamine polystyrene resin (MBHA resin) pur-
chased from Bachem GmbH with standard methodology using
Fmoc-strategy. 3.2 g MBHA resin (1.06 mmol/g) was treated with
10 vol% TEA in DMF solution to liberate the amino function
from the HCl salt form. Fmoc-l-amino acid was coupled in DMF
(5–10 mL) in the presence of N,Nꢀ-dicyclohexylcarbodiimide (DCC,
2.5 equiv.) and 1-hydroxybenzotriazole (HOBt, 2.5 equiv.) until
completion (3 h) judged by Kaiser ninhydrin test. After coupling
Fmoc-protected l-amino acids, the resin was acetylated with Ac2O
(3 mL) in CH2Cl2 (7 mL) for 30 min then washed with CH2Cl2, MeOH
and CH2Cl2 three times (10 mL each). Fmoc-deprotection was car-
ried out by using 20 vol% piperidine in DMF for 5 min first then
repeated for 15 min following washing process with DMF, MeOH
and DMF three times (10 mL of each). The resin was filtered out and
dried. The synthetic cycle was repeated to obtain di- and tripeptide
MBHA-resin catalysts.
2.4. Theoretical calculations
The calculations were carried out at B3LYP/6-31G(d) level
[40–42] of DFT [43,44]. All calculations were performed using
Gaussian 03 program package [45].
3. Results and discussion
Fig. 1 shows the schematic structures of catalyst 3 and 5. The
peptide catalysts were synthesized and reactions were performed
using well-known methods [12,26,46,47]. The resin-supported
peptides were characterized by IR spectroscopy and by HPLC and
ESI-MS analysis of the peptides obtained by cleavage from the
resins. The spectra of 3, 4 and 5 catalysts as compared with the spec-
tra of crystalline l-proline and the as received MBHA × HCl resin are
presented in Fig. 2.
2.2. Characterization of the catalysts
IR spectra were collected on a Bio-Rad Digilab Division FTS-
65A/896 FT-IR spectrometer operated in diffuse reflectance mode
(DRIFT) between 4000 and 400 cm−1 at 2 cm−1 resolution by aver-
aging 256 scans.
The resin bonded peptides were also characterized by HPLC
analysis of the peptides cleaved from the resins and by electro-
spray ionization mass spectrometry (ESI-MS). For example from
One can see that following immobilization of the peptides new
vibrational bands appeared in the IR spectra of these materials.

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G. Szo˝llo˝si et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 86–92
CH3
CH3
O
O
H
N
H
N
N
H
N
N
H
N
H
O
O
O
PS
PS
NH
COOH
COOH
(3)
(5)
Fig. 1. Schematic structures of catalysts H-Pro-Glu(OH)-MBHA (3) and H-Pro-Pro-Glu(OH)-MBHA (5).
Table 2
Chromatographic conditions used for analysing the aldol products.a
Substrates
Analysis conditionsb
Rt of the aldol products (min)c
Aldehyde
Ketone
S or S,S
R or R,R
8
Acetone
Acetone
Cyclohexanone
115 ◦C 10 min, 1◦/min 165 ◦C 50 min; 22
40 ◦C 5 min, 2◦/min 120 ◦C 30 min; 20
40 ◦C 5 min, 2◦/min 160 ◦C 15 min; 20
94.6
36.6
53.8
96.5
36.1
54.4
9
9d
a
GC analysis over Cyclosil-B capillary column.
b
c
Column temperature programme; He head pressure (psi).
Retention times of the aldol addition product enantiomers.
The retention times of the syn isomers were: 55.5 and 55.9 min.
d
Although, assignment of the vibrational bands is impeded by the
superimposed bands of the polymeric support material, the appear-
ance of new bands as compared with the parent resin confirmed the
immobilization of the peptides. Furthermore, the cleavage of the
peptides from the resins using HF and analysis of the obtained com-
pounds by HPLC and ESI-MS confirmed the presence of the desired
peptides on the surface in about 95% purity (see Section 2.2).
Results of aldol additions using the immobilized peptides are
summarized in Tables 3–5. Tables 3–5 list experimental results
for all three asymmetric aldol addition reactions studied (reactions
1–3). The most interesting observation is the reversal of the ee in the
reactions of tripeptide catalysts containing Pro and l-glutamic acid
(Glu) as compared to the reactions of dipeptide catalysts (and also
as compared with the results obtained over the tripeptide catalysts
containing only Pro units). In the latter reactions the sense of enan-
tioselection is identical with that obtained with Pro. To our best
knowledge, results obtained in liquid phase using di- and tripeptide
catalysts or their immobilized variants by an identical method, have
not been described in the literature (see Table 1 [13–27]). Based on
the data presented in Tables 3–5, reversal of enantioselection took
place in all three aldol reactions studied, supporting the universal
character of the phenomenon in organocatalyzed asymmetric aldol
reactions (see Table 3, entries 7, 8 vs. 9, 10; Table 4, entry 2 vs. 3;
Table 5, entry 2 vs. 5). We note that the presence of imidazole addi-
tive, which is used to decrease the amount of side products formed
by elimination reaction, didn’t influence the stereochemistry of the
reactions, usually increasing the activity of the catalysts. Optimiza-
tion of the individual reactions was not among our goals, but the
phenomenon is significant even without it: in reaction 1 (Table 3,
entries 2–10) 52% (R)-10 vs. 39% (S)-10, in reaction 2 (Table 4,
entries 2, 3) 94% (R)-11 vs. 50% (S)-11, and in reaction 3 (Table 5,
entries 2–7) 95% (S,S)-12 vs. 41% (R,R)-12 are formed in excess.
Recovery and two times reuse of catalysts 3 and 5 in reaction 1
(entries 9, 10, 13, 14; Table 3) resulted in slightly decreased conver-
sions and ee, however, no such decrease was observed in reaction 2
upon reuse of 5. Accordingly the reactions indeed occurred on the
surface of the catalysts and were catalyzed by the corresponding
immobilized peptides.
In general there are experimental observations of reversal of
enantioselection occurring due to heterogenization on immobi-
lized Pro catalysts [48–50]. It was therefore expedient to study the
aldol reaction 1 in liquid phase on Pro-Glu(OH)-NH2 (conv. 25%,
ee (R)-10 32%) and Pro-Pro-Glu(OH)-NH2 (conv. 5%, ee (S)-10 42%)
catalysts as well. Since the phenomenon was also observable in
homogeneous liquid phase, i.e. on non-immobilized catalysts, it
was proven that structural factors rather than heterogenization are
responsible for the reversal of enantioselection. In the aldol reaction
the reversal of enantioselectivity on the same tripeptide catalyst
was recently observed upon changing the solvent [51]. In view of
this observation, we examined the role of the solvent effect in the
reaction 3, following the example of the published experiments
(Table 5, entries 2–7). According to the results obtained, in our case
Fig. 2. IR spectra of the MBHA-resin supported peptides.

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89
Table 3
Aldol addition between 2-nitrobenzaldehyde and acetone.a
NO2
O
NO2 OH
O
NO2
O
O
10 mol % catalyst
rt
+
+
*
(8)
(10)
(reaction 1)
Entry
Catalyst
Imidazole
Conversion (%)
Selectivityb (%)
eec (%)
Config.c
1
2
3
4
5
6
7
8
1
1
2
2
4
4
3
3
3
3
5
5
5
5
−
+
21
40
80
86
60
82
35
55
47
45
51
77
61
55
89
80
94
88
94
89
60
85
84
80
69
72
77
84
24
24
29
24
34
29
50
52
49
32
37
39
31
18
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
−
+
−
+
−
+
9d
10d
11
12
13d
14d
+
+
−
+
+
+
a
Reaction conditions: 0.04 mmol catalyst, 0.4 mmol 8, 2 mL acetone, 0.044 mmol imidazole (when used), 4 h, rt.
Selectivity of the aldol addition product 10 determined by GC analysis.
Enantiomeric excess of 10 and the absolute configuration of the excess enantiomer determined by chiral GC analysis.
Reactions carried out over catalyst recovered from the previous run.
b
c
d
Table 4
Aldol addition between 2-methylpropanal and acetone.a
O
OH
O
O
O
16 mol % catalyst
+
+
*
rt
(9)
(11)
(reaction 2)
Entry
Catalyst
Conversion [%]
Selectivityb [%]
eec [%]
Config.c
1
2
1
3
5
5
5
31
28
31
31
33
99
98
97
98
98
76
94
50
51
51
(R)
(R)
(S)
(S)
(S)
3
4d
5d
a
Reaction conditions: 0.04 mmol catalyst, 0.25 mmol 9, 2 mL acetone, 0.044 mmol imidazole, 22 h, rt.
Selectivity of the aldol addition product 11 determined by GC analysis.
Enantiomeric excess of 11 and the absolute configuration of the excess enantiomer determined by chiral GC analysis.
Reactions carried out over catalyst recovered from the previous run.
b
c
d
Table 5
Aldol addition between 2-methylpropanal and cyclohexanone.a
O
OH O
O
O
16 mol % catalyst
rt, solvent
*
+
+
*
(12)
(9)
(reaction 3)
Entry
Catalyst
Solvent [mL]
Conversion [%]
Selectivityb [%]
anti/sync
eed [%]
Config.d
1
2
3
4
5
6
7
1
DMSO, 0.5
DMSO, 0.5
DMSO, 0.45 + H2O, 0.05
DMSO, 0.25 + H2O, 0.25
DMSO, 0.5
69
22
28
35
24
30
52
97
93
91
83
93
92
87
94/6
98/2
98/2
97/3
84/16
86/14
83/17
38
95
93
81
34
41
27
(S,S)
(S,S)
(S,S)
(S,S)
(R,R)
(R,R)
(R,R)
3
3
3
5
5
5
DMSO, 0.45 + H2O, 0.05
DMSO, 0.25 + H2O, 0.25
a
Reaction conditions: 0.04 mmol catalyst, 0.5 mL solvent, 0.4 mmol 9, 1 mmol cyclohexanone, 0.044 mmol imidazole, 68 h, rt.
Selectivity of the aldol addition product 12 determined by GC analysis.
Diastereomeric ratio of 12.
b
c
d
Enantiomeric excess of 12 and the absolute configuration of the excess enantiomer determined by chiral GC analysis.