α-Amino Acids and α,β-Dipeptides Intercalated into Hydrotalcite: Efficient Catalysts in the Asymmetric Michael Addition Reaction of Aldehydes to N-Substituted Maleimides

Article abstract of DOI:10.1002/ejoc.202100877

In this work, a series of α-amino acids (L-Phe, D-Phe, L-Trp) and several α,β-dipeptides (H₂N-L-Val-N-Bn-β-Ala-COOH and H₂N-L-Leu-N-Bn-β-Ala-COOH) intercalated into hydrotalcite (Mg/Al, x=0.333) were prepared by high speed ball milling (HSBM) assisted rehydration/reconstruction methods, followed by sonication and mechanical stirring. All organic-inorganic hybrid samples were characterized by powder X-ray diffraction (XRD) and FTIR-ATR spectroscopy. The catalytic activity of the resulting hydrotalcite-supported materials (natural and hybrid) was evaluated in the asymmetric Michael addition reaction of α,α-disubstituted-aldehydes to N-substituted-maleimides. Pristine (HTS), calcined (HTC) and water-reconstructed (HTR-l) hydrotalcite-derived materials exhibited very low catalytic activities, affording racemic mixtures of the anticipated Michael adduct. By contrast, hybrid materials showed better activities, especially HTR-α-amino acid catalysts afforded Michael products in up to 94 % yield and with rather high enantioselectivity (enantiomeric ratio (e.r.) up to 99 : 1) at room temperature under neat reaction conditions. The effect of solvents and Br?nsted basic or acidic additives was evaluated using the best hybrid catalyst, HTR-L-Phe. In addition, recycling and reuse of the catalyst (up to 4 cycles) and large-scale experiments was successfully carried out.

Full text of DOI:10.1002/ejoc.202100877

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: α-Amino Acids and α,β-Dipeptides Intercalated into Hydrotalcite:
Efficient Catalysts in the Asymmetric Michael Addition Reaction
of Aldehydes to N-Substituted Maleimides
Authors: José M Landeros, Carlos Cruz-Hernández, and Eusebio
Juaristi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100877
Link to VoR: https://doi.org/10.1002/ejoc.202100877
01/2020

10.1002/ejoc.202100877
European Journal of Organic Chemistry
FULL PAPER
α-Amino Acids and α,β-Dipeptides Intercalated into Hydrotalcite:
Efficient Catalysts in the Asymmetric Michael Addition Reaction
of Aldehydes to N-Substituted Maleimides
José M. Landeros,*[a] Carlos Cruz-Hernández,[a] and Eusebio Juaristi*[a][b]
Abstract: In this work, a series of -amino acids (L-Phe, D-Phe, L-
Trp) and several α,β-dipeptides (H2N-L-Val-N-Bn-β-Ala-COOH and
H2N-L-Leu-N-Bn-β-Ala-COOH) intercalated into hydrotalcite (Mg/Al,
x = 0.333) were prepared by high speed ball milling (HSBM) assisted
rehydration/reconstruction methods, followed of sonication and
mechanical stirring. All organic-inorganic hybrid samples were
characterized by powder X-ray diffraction (XRD) and FTIR-ATR
spectroscopy. The catalytic activity of the resulting hydrotalcite-
supported materials (natural and hybrid) was evaluated in the
asymmetric Michael addition reaction of α,α-disubstituted-aldehydes
to N-substituted-maleimides. Pristine (HTS), calcined (HTC) and
water-reconstructed (HTR-l) hydrotalcite-derived materials exhibited
very low catalytic activities, affording racemic mixtures of the
anticipated Michael adduct. By contrast, hybrid materials showed
better activities, especially HTR--amino acid catalysts afforded
Michael products in up to 94% yield and with rather high
enantioselectivity (enantiomeric ratio, e.r., up to 99:1) at room
temperature under neat reaction conditions. The effect of solvents
and Brønsted basic or acidic additives was evaluated using the best
hybrid catalyst, HTR-L-Phe. In addition, recycling and reuse of the
precursors of various natural products. Furthermore, chiral
succinimides constitute a structural motif in effective drugs
against HIV, as well as in antibacterial and antibiotic
ingredients.[3,4] In this regard, a straightforward route to access
enantioenriched chiral succinimides consists in the asymmetric
Michael
addition
of
α,α-disubstituted
aldehydes
to
maleimides.[5,6] Following the seminal work of Córdova et al. in
the organocatalyzed addition of α,α-disubstituted aldehydes to
maleimides,[5] several chiral organocatalysts have been
developed achieving high efficiency in this transformation. Such
chiral organocatalysts comprise primary amines (PA) and 1,2-
[7]
diamines,[6] bifunctional PA-guanidines,
bifunctional PA-
thioureas,[8] amino acids and peptidic derivatives,[9] among
others.[10] Despite of the high performance exhibited by these
organocatalysts, most of them present drawbacks including the
use of harmful solvents as reaction media, difficult separation
from products and null recyclability, which reduces their
sustainability,
convenience. [11]
economic
attractiveness
and
practical
In order to overcome these issues, different approaches
based on the principles of green chemistry have been applied in
order to render organocatalysts more sustainable.[12] For
example, green solvents such as ionic liquids and deep eutectic
solvents,[13] or solvent-free conditions have been used to
synthetize chiral succinimides.[9d] Furthermore, both covalently
and non-covalently immobilized organocatalysts,[14,15] represent
advantages such as easy recovery and reuse of the
heterogenized catalyst. In this regard, Szőllősi et al. reported a
series of chiral 1,2-diamines supported on polyester resin by
means of sulfonamide linkers, affording the corresponding chiral
succinimides in high enantioselectivity (up to 97% ee) even after
5 cycles; nevertheless, a significant decrease in conversion was
observed throughout the cycles.[14] Very recently, Szőllősi et al.
reported the use of L-proline adsorbed on the solid surface of
diverse inorganic oxides and ion exchanger layered materials,
where Laponite RD (synthetic cationic exchanger layered
magnesia-silicate) afforded the best results in the Michael
addition of carbonyl compounds to β-nitrostyrenes using the
mixture of solvents chloroform:isopropanol, 9:1.[15] As part of this
study, hydrotalcite was evaluated as additive affording excellent
conversion (>99% yield). Nevertheless, the Michael addition
reactions proceeded with low diastereo- (70% ds) and
enantioselectivity (64% ee).
catalyst (up to
4 cycles) and large-scale experiments was
successfully carried out.
Introduction
The asymmetric Michael addition reaction is widely recognized
as one of the most important synthetic method for the formation
of C−C bonds.[1] Indeed, during the last two decades, several
reports have disclosed a wide range of its application in the
synthesis of bioactive compounds by means of novel chiral
organocatalysts.[2]
Among the plethora of Michael acceptors used in the
stereoselective synthesis of fine chemicals, maleimides are
particularly attractive for the preparation of chiral succinimides.[3]
Indeed, enantioenriched succinimide scaffolds are key
[a]
Dr. J.M. Landeros, Dr. C. Cruz-Hernández, Prof. Dr. E. Juaristi
Departamento de Química
Centro de Investigación y de Estudios Avanzados, Instituto
Politécnico Nacional
Avenida IPN # 2508, 07360 Ciudad de México, Mexico.
E-mail: ejuarist@cinvestav.mx and/or jose.landeros@cinvestav.mx
http://www.relaq.mx/RLQ/EusebioJuaristi.html
In view of the above precedents, we envisioned the
development of an alternative way to incorporate amino acids
and peptides into the interlaminar space of hydrotalcite by
means of the reconstruction method, rather than by surface
adsorption. It was anticipated that this strategy could provide an
augmented catalytic effect in the confined space rendered by the
layered material.[16]
[b]
Prof. Dr. E. Juaristi.
El Colegio Nacional
Luis González Obregón 23, Centro Histórico, 06020 Ciudad de
México, Mexico.
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/ejoc.202100877
European Journal of Organic Chemistry
FULL PAPER
Hydrotalcites (HT’s) are natural anionic clays with lamellar
Upon consideration of the above results, it became
apparent that there is still a need to develop synthetic strategies
that result in the preparation of well-structured nanohybrid HT’s
that are efficient in asymmetric aldol and Michael addition
reactions.
Taking into account this background information and
motivated by the success achieved in our previous works
employing both free and supported ,-dipeptides as catalysts
for asymmetric Michael addition of ,-aldehydes to prochiral
structure.[17] Hydrotalcite-derived
materials exhibit unique
properties with tunable structural elements and potential
biocompatibility, which are useful in applications such as drug
carriers in medicine,[18] as well as in catalysis.[19] Hydrotalcite-
type materials present the general formula [M2+
1–
xM3+x(OH)2]x+(An−)x n·mH2O, where x (0.2 ≤ x ≤ 0.33) corresponds
/
to the molar ratio M2+/(M3+ + M2+) of metal ions in the brucite
layers, m is water of coordination and (An−) is the compensating
anion in the interlayer space that is required to balance the
electrical charges.[17a]
maleimides
for
the
preparation
of
enantioenriched
succinimides,[ 9d,e] herein we report the convenient preparation of
various organic-inorganic hybrid catalysts based on the
intercalation of -amino acids (L- and D-phenylalanine, L-
tryptophan) or ,-dipeptides (H2N-L-Val-β-N-Bn-Ala-COOH and
An interesting property of any HT-type material is the so-
called “memory effect”, that refers to its calcination (at ca. 450-
600 ºC) to form mixed oxides of metals with the concomitant
collapse of the interlaminar space, so that when the resulting
oxides are exposed to water (vapor or liquid) this triggers the
rehydration and reconstruction of the interlaminar space of
hydrotalcite structure but now with H2O and OH− hydroxide as
compensation anion, modifying the original basic properties.[20]
When the water of rehydration is accompanied by organic
anions (or biomolecules), these can be intercalated to some
extent into the interlamellar space during the reconstruction
process, forming organic-inorganic hybrid nanomaterials.[17]
Indeed, several synthetic methodologies have been developed
to incorporate biomolecules and organic guest into
hydrotalcite.[21] In particular, the intercalation of amino acids and
peptides into HT materials involve coprecipitation,[22] ion
exchange[23] and reconstruction methods,[24] commonly assisted
by ultrasound irradiation or mechanochemical activation.[25]
While several examples have been reported concerning
the intercalation of amino acids and their derivatives into
hydrotalcites,[22-25] to date very few examples have been reported
regarding the use of amino acids and peptides intercalated into
hydrotalcites as hybrid catalysts in asymmetric aldol and Michael
addition reactions.[22j,23h,24c,24e,25b] In this regard, Choudary and
co-workers reported several asymmetric C−C bond forming
reactions catalyzed by L-proline anchored to HT (Mg/Al). This
catalytic material was prepared by means of anion exchange
and coprecipitation methods.[22j] Disappointingly, Michael
addition of diethyl malonate to cyclohexenone catalyzed by this
modified HT afforded the addition product in low yield (40%) and
essentially null enantioselectivity.
On the other hand, Pitchumani and co-workers
immobilized L-proline (L-Pro) into the interlaminar space of
hydrotalcite (Mg/Al, 3:1) by means of the reconstruction
method.[24e] The resulting hybrid catalyst HT-L-Pro was
evaluated in the asymmetric Michael addition reaction of
acetone to different β-nitrostyrenes, as well as nitromethane to
several benzylideneacetones affording Michael adducts in
modest to excellent yields, although with low to moderate
enantioselectivity (up to 73:27 e.r.).
In this context, Medina and coworkers reported that during
L-Leucine (L-Leu) intercalation into hydrotalcite (Mg/Al, 2:1) by
reconstruction and ion exchange methods,[25b] parameters such
as time, temperature and ultrasound irradiation play a major role
in the extent of L-Leu immobilization. The resulting catalysts
were evaluated in the asymmetric aldol reaction between
different carbaldehydes and cyclohexanone, obtaining good to
excellent yields, but low diastereoselectivity (up to 61:39 dr).
H2N-L-Leu-N-Bn-β-Ala-COOH)
in
reconstructed
Mg/Al-
hydrotalcite. These materials proved to be efficient catalysts in
the asymmetric Michael addition reaction of ,-aldehydes to
prochiral N-substituted-maleimides. To the best of our
knowledge, this is the first time than α-amino acids and α,β-
dipeptides intercalated into hydrotalcite Mg/Al have been
evaluated in the asymmetric Michael addition reaction of
aldehydes to maleimides under solvent-free reaction conditions.
Results and Discussion
Synthesis of reconstructed hydrotalcite incorporating -amino
acids or ,-dipeptides
Table 1 summarizes the conditions under which the
synthesis of the organic-inorganic hybrid catalysts performed by
the reconstruction method was carried out. In particular, the
chemical synthesis was assisted by any one of three different
procedures: a) magnetic stirring at ambient temperature for 20 h
(method M1 in Table 1, entries 1-2), b) ultrasonic irradiation at
42 kHz for 90 min. (method M2 in Table 1, entry 3), and c)
mechanochemical activation under High-Speed Ball milling
(HSBM) at 25 Hz for 90 min (Method M3 in Table 1, entry 4). In
addition, several variations involving alternative sequences of
these methods were evaluated (Methods M4 to M6, Table 1,
entries 5-8). Calcined Mg/Al mixed oxides (HTC) of commercial
Mg/Al-hydrotalcite (HTS,
x
=
0.333) was used for all
reconstructed samples. Typical in-water reconstructed
hydrotalcite (HTR-l) was synthetized as benchmark material,
using HTC and decarbonated water according to method M1,
obtaining a hydrotalcite material with interlaminar water and HO−
anion (Table 1, entry 1).[20] In order to optimize the
reconstruction conditions of hybrid materials, a mixture of L-
phenylalanine (L-Phe) and HTC was adjusted to pH 13 with
aqueous NaOH solution (to ensure that the amino acid species
is present in ionic form). The resulting mixture was then
subjected to the reconstruction conditions (Table 1, entries 2 to
6).
Materials HTR-M1, HTR-M2 and HTR-M3 were obtained
by methods M1 to M3, respectively (Table 1, entries 2-4).
Application of High Speed Ball milling followed by magnetic
stirring afforded HTR-M4 material (Table 1, entry 5). Sonication
followed by magnetic stirring provided material HTR-M5 (Table 1,
entry 6) and HSBM followed by sonication, and then magnetic
stirring were used to prepare HTR-M6 (Table 1, entry 7). Finally,
material HTR-M7 was obtained by method M6, but with the initial
reaction mixture adjusted to pH 11 (Table 1, entry 8).
Nevertheless,
the
reaction
proceeded
with
good
enantioselectivity after 7 days of reaction in DMSO/H2O.[25b]
2
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10.1002/ejoc.202100877
European Journal of Organic Chemistry
FULL PAPER
Table 1. Procedures followed for the preparation of reconstructed
hydrotalcites assisted by mechanical stirring, ultrasonic irradiation or
mechanochemical activation.
Entry
Sample
HTR-l[b]
HTR-M1
HTR-M2
HTR-M3
HTR-M4
Method[a]
1
2
3
4
5
M1: Mechanical stirring for 20 h at rt.
M1: Mechanical stirring for 20 h at rt.
M2. Sonication for 90 min.[c]
M3: HSBM at 25 Hz for 90 min.[d]
M4: HSBM at 25 Hz for 90 min, then magnetic
stirring for 20 h. [d][c]
6
7
HTR-M5
HTR-M6
M5: Sonication for 60 min, then magnetic stirring
for 20 h.[c]
M6: HSBM at 25 Hz for 90 min, then sonication
for 90 min, followed by mechanical stirring for 20
h at rt.[d][c]
M6: HSBM at 25 Hz for 90 min, then sonication
for 90 min, followed of mechanical stirring for 20 h
at rt.[e]
8
HTR-M7[e]
[a] Experimental conditions: 0.56 g (ca.1.6 mmol) of calcined hydrotalcite
(HTC), L-phenylalanine (0.46 g, 2.8 mmol) and aqueous NaOH (1% w/w),
in order to adjust to pH 13); this protocol was followed for all organic-
inorganic samples. Decarbonated water (20 mL) was used as reaction
media with magnetic stirring and ultrasonic irradiation. [b] HTC and
decabonated water were used. [c] Ultrasonic bath at a frequency of 42
kHz. [d] High-speed ball milling (HSBM) employing a jar of PTFE (15 mL,
2.0 cm diameter) and two milling balls with core of stainless steel and a
cover of PTFE (1 cm diameter, mass 1.757 g), under wet conditions. [e]
Reaction mixture was adjusted to pH 11.
Figure 1. Powder X-ray diffractograms of pristine hydrotalcite (HTS), calcined
material (HTC) and reconstructed hydrotalcite in presence of L-Phe, prepared
according to the different approaches detailed in Table 1 (HTR-M1 to HTR-
M7).
Based on these observations, method M6 was chosen as
the best to optimize the incorporation of both ,-dipeptides
(H2N-L-Val-N-Bn-β-Ala-COOH (2, α,β-L-Val) and H2N-L-Leu-β-
N-Bn-Ala-COOH (3, α,β-L-Leu)) and -amino acids (D-
phenylalanine (D-Phe, 4) and L-tryptophan (L-Trp, 5)) into the
hydrotalcite structure.
The molecular structures of the chiral -amino acids and
,-dipeptides employed in this work are shown in Figure 2.
Previously these free amino acids and ,-dipeptides had
proved to be highly efficient organocatalysts in asymmetric
Michael addition reactions.[9b,d] According to powder XRD
patterns for reconstructed hydrotalcite with amino acids (HTR-
D-Phe, HTR-L-Phe and HTR-L-Trp) and α,β-dipeptides (HTR-
α,β-L-Val and HTR-α,β-L-Leu) (see Figure 3), all samples
incorporated the organic guest to essentially the same extent in
the hydrotalcite structure and were associated to hydrotalcite
type materials with low crystallinity, as indicated by broad and
low intensity peaks of basal planes (003) and (006), which is in
line with previous literature reports.[22d,22k]
Figure 1 shows powder XRD patterns of pristine (HTS), calcined
(HTC) and reconstructed (HTR-M1 to HTR-M7) hydrotalcites
that were prepared by the different methods detailed in Table 1.
HTS samples exhibit typical diffraction patterns, which can be
divided in two groups: i) symmetric and sharp reflection with high
intensity at low 2θ angle (11.6º, 23.3º and 34.8º), corresponding
to basal planes (003), (006) and (009), indicating good
crystallinity, and ii) asymmetric and broad reflection at high 2θ
angles (60.7º. and 62.0º) associated to non-basal planes (110)
and (113).[17a]
Patterns recorded with calcined hydrotalcite (HTC) exhibit two
broad reflections with low intensity at high 2θ angle (43.4º and
63.1º) associated with planes (400) and (440), which correspond
to typical Mg-Al mixed oxides.[17a,24] Rehydrated hydrotalcite
(HTR-l) exhibits patterns of diffraction similar to those obtained
with HTS, although presenting low intensity of the basal planes
(003), (006) and (009) (see Supporting Information, Figure
S2).[20] On the other hand, hybrid samples exhibited different
degrees of reconstruction, the largest being observed with
sonication (HTR-M2), followed by samples obtained with
magnetic stirring (HTR-M1). Finally, poorest reconstruction was
achieved by mechanochemical activation (HTR-M3). Among
sequential methods HTR-M4 to HTR-M6 materials, the lattest
showed the major recovery of HT structure. Finally, sample
HTR-M7 presented similar degree of reconstruction relative to
that found in HTR-M6. Nevertheless, two additional small peaks
(highlighted * in Figure 1) were observed, suggesting a different
disposition of the amino acid on the interlaminar space (see
Figure 1). [22d,22e,24b,25b]
3
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10.1002/ejoc.202100877
European Journal of Organic Chemistry
FULL PAPER
Figure 2. Molecular structures of a) α-amino acid (L-phenylalanine (1, L-Phe),
D-phenylalanine (4, D-Phe) and L-tryptophan (L-Trp, 5)). b) α,β-dipeptides
(H2N-L-Val-N-Bn-β-Ala-COOH (2, α,β-L-Val) and H2N-L-Leu-N-Bn-β-Ala-
COOH (3, α,β-L-Leu)).
near the laminar edges, as suggested by the studies of
Palinko[25c] and Medina,[25b] respectively.
Table 2. Structural properties of hydrotalcite-type materials prepared in this
work.
Entry
Catalyst
Basal
spacing
Interlayer
space d(006)
(nm) [b]
Amount
Interlayer
space
d(003) (nm) [a]
(wt %)[c]
1
2
3
4
5
6
7
HTS
0.762
0.761
0.772
0.762
0.764
0.770
0.780
0.381
0.383
0.386
0.382
0.384
0.384
0.386
n.d.[d]
n.d.[d]
10.3
12.1
14.7
17.5
8.7
HTR-l
HTR-L-Phe
HTR-,-L-Val
HTR-,-L-Leu
HTR-L-Trp
HTR-D-Phe
[a] Calculated by Bragg’s Law equation using the (003) plane. [b] Calculated
by Bragg’s Law equation using the (006) plane. [c] Determined by a calibration
curve in PBS (pH = 2.1). [d] n.d. no determined.
The amount of organic species incorporated into hybrid
catalysts is reported in Table 2 (For details see Supporting
Information). In the case of HTR-L-Phe, the amount of
incorporation turned out to be 10 weight percent of L-Phe (Table
2, entry 3). This means that for each 100 mg of HTR-L-Phe
there are 10 mg of L-Phe, that is a relatively low value. This
could be a consequence of associated to the high pH value that
prevents major loading into material and restoration.
Figure 3. Powder X-ray diffractograms of reconstructed hydrotalcite (HTR) by
method M6 in the presence of amino acid L-Phe (HTR-L-Phe), D-Phe (HTR-D-
Phe), L-Trp (HTR-L-Trp), and α,β-dipeptides α,β-L-Leu (HTR-α,β-L-Leu) and
α,β-L-Val (HTR-α,β-L-Val).
Basal spacing and interlayer space of the hydrotalcite-derived
samples were measured according to Bragg’s law using the
peaks at basal planes (003) and (006), respectively. The results
are summarized in Table 2. Basal spacing (d003) corresponds to
the distance between tops of two adjacent brucite type layers
and interlayer space (d006), also known as gallery height is the
distance between top and bottom of two adjacent brucite-type
layers. Taking reflection planes of HTS as reference, no
apparent shift of (003) and (006) planes are noticed in all
samples (Cf. Figures 1 and 3), which suggests similar distances
of basal spacing and gallery height (Table 2, entries 1-7). On the
other hand, basal layer corresponds to the thickness of brucite-
type layer, and it was determined by the difference between
basal spacing and interlayer space. The values calculated for all
samples fall in the range of 0.38 to 0.39 nm. These relatively low
values, less than 0.48 nm that is commonly found in basal layer
of Mg/Al hydrotalcite are in line with data recently reported by
Chao and coworkers.[22k]
FTIR-ATR spectra of free L-Phenylalanine (L-Phe),
calcined hydrotalcite (HTC),
a
1:1 mixture HTC/L-Phe
(homogenized by milling with mortar and pestle), L-Phe
intercalated into hydrotalcite (HTR-Phe), and pristine
hydrotalcite (HTS) are depicted in Figure 4. The FTIR spectrum
of L-Phe presents typical vibration bands for N-H and C-H
+
(2900-3300 cm−1), NH3 (1623 and 1494 cm−1) and the
carboxylate group (1556 and 1406 cm−1) in amino acids. The
spectrum of the mixture HTC/L-Phe presents major bands
associated to L-Phe and minor bands associated to HTC, in the
range of 1000 to 550 cm−1.[17a,20] Furthermore, the FTIR
spectrum of HTC shows characteristic bands assigned to mixed
oxide Mg(AlO) at 3449 cm−1, 1435 cm−1 and Metal-Oxygen (M-
O) bonds. [17a,20] On the other hand, spectra of HTS and HTR-L-
Phe exhibit bending vibrations at 1365 and 3027cm−1 ascribed to
2‒
CO3 and CO32‒–H2O, respectively. The vibration at 1640 cm−1
It is clear then that the degree of intercalation of amino
acids into the interlaminar space of HT is dependent on the
method of preparation, reaction temperature, pH, and the
concentration of the amino acids or peptide. These reaction
parameters induce different arrangements (horizontal or vertical,
mono- or bilayers) of the amino acid or peptide into the
interlaminar space.[22,23,24]
Based on the recorded gallery heights, a horizontal
disposition of the intercalated amino acid and ,-dipeptides is
proposed. Apparently, in such orientation the organic molecules
was ascribed to interlayer water, while the bending bands at 929
cm-1 and 771 cm-1 were associated to Al-O, and the stretching
bands 3415-3440 cm−1 were assigned to –OH and H2O in
interlaminar zone. Finally, the salient vibration at 1558 cm-1 was
ascribed to the carboxylate group in L-Phe.[24b, c] Comparison of
the FTIR spectra of HTR-L-Phe and the homogeneous mixture
HTC:L-Phe reveals major differences between them. The former
is similar to typical HTS, whereas the latter is rather similar to
free L-Phe. These results are in line with those obtained by
powder DRX, corroborating the prevalence of the hydrotalcite
structure after the incorporation of L-Phe.
can occupy
a specific interlamellar site that avoids an
energetically unfavorable increase of the gallery height.
Alternatively, this orientation allocates the organic molecules
4
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10.1002/ejoc.202100877
European Journal of Organic Chemistry
FULL PAPER
product with opposite configuration (Table 3, entry 17).
Interestingly, the catalytic material with a larger aryl moiety HTR-
L-Trp did not provide better results than those obtained with
HTR-L-Phe (Table 3, entries 16 and 18). Finally, it is worthy of
mention that free L-phenylalanine (L-Phe) was not able to
catalyze the Michael addition reaction under neat reaction
conditions (Table 3, entry 19). This observation suggests that
the conformational rigidity attained by confined amino acids and
,-dipeptides in the hydrotalcite adducts plays an important role
for the successful reaction under solvent free conditions. An
additional advantage is that the present HT-derived catalysts, in
contrast with previously reported work, avoid the use of harmful
solvents such as CH2Cl2.[9b]
Table 3. Michael addition reaction of isobutyraldehyde to N-phenyl maleimide
with various hydrotalcite-derived materials.
Figure 4. Comparison of FTIR-ATR spectra of a) pristine hydrotalcite (HTS),
b) reconstructed hydrotalcite intercalated with L-phenylalanine (HTR-L-Phe),
c) calcined hydrotalcite HTC, d) grinded mixture HTC:L-Phe (1:1), and e) free
L-phenylalanine (L-Phe).
Entry[a]
Catalyst
Amount
(mg)
6a
(mmol)
Time
(h)[b]
Yield
(%)[b]
e.r.[c]
Catalytic evaluation of HT-derived materials in Michael addition
reactions
1
2
HTS
HTC
30
30
5.5
5.5
48
48
48
48
48
48
18
24
48
72
24
24
24
24
24
24
24
24
24
2
3
50:50
50:50
50:50
96:4
87:13
86:14
98:2
98:2
98:2
98:2
97:3
96:4
90:10
98:2
98:2
98:2
2:98
96:4
n.d.
Pristine and modified hydrotalcites were evaluated as catalysts
in the Michael addition reaction between isobutyraldehyde 6a
and N-phenyl maleimide 7a. It was decided to initiate the study
employing our previously reported optimized reaction
conditions;[9d] that is, under neat conditions using 5.5 mmol of
the aldehyde 6a, 0.5 mmol of the Michael acceptor 7a, 30 mg of
the hydrotalcite-derived materials, and a reaction time of 48 h at
room temperature (Table 3, entries 1-6).
3
HTR-l
30
5.5
2
4
HTR-L-Phe
HTR-α,β-L-Val
HTR-α,β-L-Leu
HTR-L-Phe
HTR-L-Phe
HTR-L-Phe
HTR-L-Phe
HTR-L-Phe
HTR-L-Phe
HTR-L-Phe
HTR-L-Phe
HTR-L-Phe
HTR-L-Phe
HTR-D-Phe
HTR-L-Trp
L-Phe
30
5.5
35
36
38
72
87
85
86
81
86
88
79
82
87
82
83
trace
5
30
5.5
6
30
5.5
Pristine (HTS), calcined (HTC) and reconstructed
hydrotalcite (HTR-l) were examined as heterogeneous bases
lacking chirality. As it turned out, these materials afforded the
anticipated Michael adducts as racemic mixtures in rather poor
yields (2-8%) (Table 3, entries 1-3). By contrast, reconstructed
hydrotalcites HTR-α,β-Val, HTR-α,β-Leu and HTR-L-Phe, that
incorporate enantiopure -amino acids or dipeptides containing
functional groups able to activate one or both reaction
components in the Michael addition reaction, exhibited much
better performance, affording the expected addition products in
35-38% yield and good to excellent enantiomeric ratios in the
range of 87:13 to 96:4 e.r. (Table 3, entries 5-6). According to
these results, among all catalysts examined, HTR-L-Phe
provided the best balance between yield and enantioselectivity.
Therefore, this catalytic system was chosen to continue the
optimization process. In particular, several catalyst and aldehyde
loadings, and reaction times were evaluated. Salient results are
summarized in Table 3 entries 7-16. Analysis of these results
demonstrate that the best performance (87 % yield and 98:2
e.r.) was obtained with 1.75 mmol of isobutyraldehyde, 75 mg of
HTR-L-Phe and 24 h of reaction time at ambient temperature
(Table 3, entry 16).
7
75
5.5
8
75
5.5
9
75
5.5
10
11
12
13
14
15
16
17
18
19
75
5.5
100
125
150
75
5.5
5. 5
5.5
1.0
75
1.5
75
1.75
1.75
1.75
1.75
75
75
8.2[d]
[a] Reaction conditions: isobutyraldehyde (6a, mmol), N-phenyl-maleimide (7a,
0.5 mmol), at room temperature. [b] Isolated yield. [c] Determined by chiral
HPLC. [d] Equivalent to 10 mol%.
Subsequently, catalytic materials HTR-D-Phe and HTR-L-
Trp were evaluated under the optimized conditions (Table 3,
entries 17 and 18). As anticipated, the catalyst HTR-D-Phe
afforded similar yield and enantioselectivity but providing the
5
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10.1002/ejoc.202100877
European Journal of Organic Chemistry
FULL PAPER
In spite of the fact that neat reaction conditions are
considered environmental friendly, we decided to evaluate the
effectiveness of the reaction in solution, since solvents can have
a great influence in the reaction’s yields, as well as in the
stereoselectivity.[6d] The results from the screening of solvents
are summarized shown in Table 4.
In contrast with observations reported by Kokotos,[9b]
where the use of CH2Cl2 as solvent increased the reaction yield,
here we observed lower yields relative to reactions under neat
reaction conditions (Table 4, entry 1). On the other hand, the
use of green solvents such as H2O, MeOH and EtOAc gave
good to excellent enantioselectivities, but rather poor yields
relative to the reaction performed with CH2Cl2 (Table 4, entries
2-4). The use of low polarity solvents such as tetrahydrofuran,
toluene and acetonitrile (Table 4, entries 5-7), and polar solvents
such as DMSO, DMF and the mixture of DMF/H2O (Table 4,
entries 8-10) did not give any improvement. From these results,
it is concluded that neat reaction conditions are superior to in-
solution conditions (Table 4, entry 11 with entries 1-10).
NaOH, KOH and Cs2CO3 did not improve the yield (82-84%),
although the enantioselectivity was maintained (Table 5, entries
4-6). By contrast, organic bases such as DMAP afforded lower
yield (16%) as well as lower enantioselectivity 91:9 (Table 5,
entry 7). The lower yield could be the consequence of the
formation of by-products. The presence of DABCO as additive
affords better reaction yield (88%), but lower enantioselectivity,
up to 95:5 e.r. (Table 5, entry 8). The use of imidazole as
additive provided the Michael adduct in lower yield (74%) but
good enantioselectivity, 97:3 (Table 5, entry 9). Finally, TFA and
benzoic acid as additives did not improved the reaction yield but
preserved the high enantioselectivity (Table 5, entries 10-11). It
is worthy of mention that reaction times were shorter with
sulphamide, DABCO and PhCO2H. Nevertheless, the small
increase in yield (1-4%) seems to be insufficient to justify the
use of additives. Therefore, the best reaction conditions are
those given in Table 4, entry 11.
Table 5. Screening of H-donors as additives in the asymmetric Michael
addition reaction of isobutyraldehyde to N-phenylmaleimide catalyzed by HTR-
L-Phe.
Table 4. Solvent effect in the performance of the Michael addition reaction
catalyzed by HTR-L-Phe.
Entry[a]
Additive
Urea
Yield (%)[b]
e.r.[c]
97:3
97:3
97:3
98:2
97:3
97:7
91:9
95:5
97:3
97:3
97:3
Entry[a]
Solvent
CH2Cl2
H2O
Yield (%)[b
e.r.[c]
98:2
90:10
98:2
98:2
96:4
98:2
97:3
89:11
94:6
89:11
98:2
1
2
69
80
90
82
82
84
16
88
74
78
85
1
2
70
23d
40
39
45
55
25
60
35
48
87
Sulphamide
Thiourea
NaOH
3
3
MeOH
EtOAc
THF
4
4
5
KOH
5
6
Cs2CO3
DMAP
6
Toluene
CH3CN
DMSO
DMF
7
7
8
DABCO
Imidazole
TFA
8
9
9
10
11
10
11
DMF/H2O
neat
PhCO2H
[a] Experimental conditions: N-phenyl-maleimide (0.5 mmol), isobutyraldehyde
(1.75 mmol), H-donor or additive (10 mol%), 24 h at room temperature. [b]
Isolated yield. [c] Determined by chiral HPLC.
[a] Reaction conditions: isobutyraldehyde (6a, 1.75 mmol), N-phenyl-
maleimide (7a, 0.5 mmol), solvent (1 mL), 24 h at room temperature. [b]
Isolated yield. [c] Enantiomeric ratio, determined by chiral HPLC.
The scope of Michael addition reaction was evaluated with
catalyst HTR-L-Phe under the optimized reaction conditions
described in Table 4, entry 11, employing several N-substituted
maleimides and aldehydes (Table 6). As it was previously
mentioned, with catalyst HTR-D-Phe the enantiomer with
opposite configuration is produced in 82% yield (compare
entries 1 and 2 in Table 6). Halogenated derivatives of
maleimides afford the expected products with high
enantioselectivity (91:9 to 99:1 e.r.) and rather good yields
(Table 6, entries 3-5). As anticipitated, the addition of
Additionally, in order to improve the effectiveness of the
reaction both in terms of yield and enantioselectivity, a screening
of the potential influence of common additives including H-bond
donors, or acids and bases (at 10 mol%) was carried out. Table
5 summarizes the most salient results. When urea, sulphamide
and thiourea were evaluated as H-bond donors, the observed
yields were 69%, 80% and 90%, respectively, whereas the
recorded enantioselectivity was the same in the three cases,
97:3 (Table 5, entries 1-3). On the other hand, inorganic bases
6
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10.1002/ejoc.202100877
European Journal of Organic Chemistry
FULL PAPER
isobutyraldehyde 6a to N-methyl maleimide 7e, afforded the
corresponding succinimide 8e in high enantioselectivity (3:97)
and slightly lower yield Table 6, entry 6. By contrast, introduction
of ethyl groups in the aldehyde provided succinimide 8f in 80%
On the other hand, when larger scale, up to ten times
larger, were carried out (5 mmol of 6a), the results indicate that
HTR-L-Phe can be reused with no significant loss of activity and
enantioselectivity (Table 7, entry 5).
yield
and
excellent
enantioselectivity
(99:1
e.r.).
Cyclohexanecarbaldehyde 6c afforded product 8g in 94% and
99:1 e.r. (Table 6, entry 8). Assignment of the absolute
configuration of the Michael adducts 8a-g was achieved by
comparison with data reported in the literature.[ 6b,7a,9b]
Table 7. Recycling of catalysts and large scale Michael addition reaction of
isobutyraldehyde to N-phenyl maleimide.
Table 6. Scope of the Michael addition reaction of several aldehydes to N-
substituted maleimides 7a-e.
Entry[a]
Recycle of
Catalyst
Yield (%)[b]
e.r.[c]
1
2
3
4
5
--
1
2
3
--
87
80
98:2
98:2
98:2
98:2
98:2
Entry[a]
Aldehyde
R1, R2
Maleimide
R3
Michael
adduct
Yield
(%)[b]
e.r.[c]
68
1
2
3
4
5
6
7
8
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Et, Et
Ph
Ph
8a
ent-8a[d]
8b
87
82
52
86
80
70
80
94
98:2
2:98
91:9
99:1
94:6
3:97
99:1
99:1
45
85[d]
4-Br-Ph
4-Cl-Ph
3-Cl-Ph
Me
[a] Unless otherwise specified the experimental conditions were N-phenyl-
maleimide (0.5 mmol, 1 equiv.), isobutyraldehyde (3.5 equiv.), catalysts HTR-
L-Phe (75 mg), neat, 24 h at room temperature. [b] Isolated yield. [c]
Determined by chiral HPLC. [d] N-Phenyl-maleimide (5 mmol),
isobutyraldehyde (17.5 mmol) and HTR-L-Phe (750 mg).
8c
8d
8e
Ph
8f
Based on previous reports where free α-amino acids and
α,β-dipeptides have been used as organocatalysts,[9a,9d]
a
–(CH2)5–
Ph
8g
plausible enamine cycle is proposed for the catalytic process
described herein (Scheme 1). Nucleophilic activation takes place
following the condensation of isobutyraldehyde and L-
phenylalanine giving rise to the well established enamine
intermediate. Subsequently, the electrophilic maleimide is
activated by coordination with the Lewis acidic hydrotalcite host
and suitably positioned to react with the nucleophilic enamine.
Following conjugate addition, the Michael product is liberated via
hydrolysis of the iminium ion, and the cycle is begun again. It is
worthy of mention that the hydrophobic character of the
hydrotalcite interlayer space allows for the easy access of the
reagents and establishes and adequate environment for a tight
and ordered transition state, which induces the observed high
enantioselectivities.
[a] Reaction conditions: N-substituted-maleimide (0.5 mmol), aldehyde (1.75
mmol), 24 h at room temperature. [b] Isolated yield. [c] Determined by chiral
HPLC. [d] HTR-D-Phe was used as catalyst
An important feature of the heterogenized organocatalysts
reported herein is their easy separation (e.g. by filtration) and
therefore the possibility of recycling. This represents an
advantage from the economic and environmental points of view.
With this in mind, recycling of the catalyst and large-scale
reactions were evaluated. The results are summarized in Table
7.
In particular, catalyst HTR-L-Phe was removed from the
reaction mixture by centrifugation-decantation, washed with
ethyl acetate (2 x 2 mL) and ethanol (2 x 2.5 mL), and dried at
60 ºC for 2 h under reduced pressure. The catalyst was carefully
removed from the reaction medium, but a gradual loss of weight
(5 - 8%) and catalytic activity was noticed after each recycle,
affording 8a in 45% of yield after the third cycle. Nevertheless,
the high enantioselectivity of the reaction was maintained (Table
7, entries 1-4). The lower catalytic activity in the recovered
catalyst can be attributed to
a gradual deactivation of
hydrotalcites material or leaching of the amino acid L-Phe, in the
process of separation and recovery. Similar observations were
reported in the deintercalation process of amino acids on
hydrotalcites.[24a]
7
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10.1002/ejoc.202100877
European Journal of Organic Chemistry
FULL PAPER
Experimental Section
Materials and apparatus
All reagents were purchased from Sigma-Aldrich and used as received
unless otherwise indicated. Organic solvents (tetrahydrofuran, N,N-
dimethyl formamide, methylene chloride, toluene, etc.) were reagent
grade and purchased from Tecsiquim. Column chromatography was
performed with Merck Silica Gel (0.040-0.063 mm). TLC were developed
on Merck DC-F254 plates using UV light as revelator. Centrifuge Z-326-K
(Hermle), operated to 3820 rpm at 5 °C. Sonication was performed on
Bransonic ultrasonic cleaner 2510R-DTH. Calcination was carried out on
a Muffle Furnace Thermolyne FB1415M. Mechanochemical activation
was conducted on a Retsch MM200 ball mill, jar of PTFE (15 mL, 2.0 cm
diameter) and two balls with core of stainless steel and cover of PTFE (1
cm diameter, mass 1.757 g), for 90 min at 25 Hz. UV-vis spectra were
recorded in a PerkinElmer UV/vis spectrometer Lambda25, using Quartz
cuvettes.
Characterization of hydrotalcite-derived materials. Powder X-ray patterns
were recorded on Bruker D8 Advanced diffractometer, with Bragg-
Brentano geometry, using Cu Kα (λ = 0.15418 nm) at 45 Kv and 20 mA,
in the 2θ range of 3°–70°. FTIR spectra were recorded on a Varian 640-
IR Spectrometer with diamond ATR accessory. Absorption spectra were
recorded on Perkin Elmer UV/vis spectrometer Lambda25.
Characterization of organic compounds. NMR spectra were recorded on
a JEOL ECA-500 spectrometer, and the chemical shifts were referenced
to the deuterate solvent peak. Optical rotations were determined in an
Anton Paar MCP-100 polarimeter using reagent grade solvents. Mass
spectra (MS) were measured on a HPLC 1100 coupled to an MSD-TOF
Agilent Technologies HR-MSTOF 1069A. Determination of enantiomeric
excess was carried out on a Dionex HPLC Ultimate 3000 with UV/Visible
detector, diode array, at 210 and 254 nm, using a suitable chiral column.
Scheme 1. Proposed catalytic cycle in the Michael addition reaction of L-Phe
organocatalyst intercalated in hydrotalcite.
Synthesis of hydrotalcite type materials
Conclusions
Calcined hydrotalcite (HTC).[20] 10 g of commercial hydrotalcite Mg/Al
(HTS, x = 0.333, Aldrich Id. No.652288) was placed in a porcelain
capsule and calcined at 475 ºC (heat rate 20 ºC/min) for 8 h under static
air atmosphere, then allowed to cool to room temperature to obtain 5.65
g of HTC as white powder. The sample was stored under N2 atmosphere.
In summary, we have developed a simple an efficient protocol
for the intercalation of α-amino acids and α,-dipeptides into the
interlamellar space of Mg/Al-hydrotalcites by the reconstruction
method assisted by mechanochemical milling, ultrasound
activation and mechanical stirring. Powder XRD analysis
demonstrated the intercalation of the chiral molecules of interest,
with a preferred horizontal arrangement between HT layers. The
resulting hydrotalcite materials proved to be catalytically active
in the asymmetric Michael addition reaction of isobutyraldehyde
to N-phenyl-maleimide. Whereas pristine (HTS), calcined (HTC)
and water-reconstructed (HTR-l) hydrotalcite alone afforded
Michael adducts as racemic mixtures in very low yield (<3%), the
organic-inorganic catalysts developed in this work exhibited
good catalytic activity under solvent-free conditions, avoiding the
usage of solvents and additives. Among the hybrid catalysts
developed in this work, those incorporating α-amino acids
afforded higher enantioselectivity (96:4 e.r. in average) relative
to α,β-dipeptides (87:13 e.r. in average). In particular, HTR-L-
Phe proved to be a most efficient organocatalyst affording highly
enantioenriched substituted succinimides under solvent-free
reaction conditions. Some of the advantages of this protocol are
(1) easy preparation of the hybrid catalysts from commercial
sources, (2) potential biodegradability of the hydrotalcite-derived
catalytic materials, (3) easy recovery and reuse of the catalyst,
and (4) the catalytic reaction does not require of additives nor
solvents.
Reconstructed hydrotalcite in presence of water (HTR-l). An adequation
of the standard procedure described elsewhere was followed.[20] In an
Erlenmeyer flask of 50 mL equipped with stirring bar was added HTC
(0.56 g) and decarbonated water (20 mL), and then the system was
purged and fitted with N2 atmosphere. The resulting solution was
vigorously stirred at room temperature for 20 h. The resulting mixture
was transferred to an Eppendorf flask of 50 mL and centrifuged at 3860
rpm for 20 min. The supernatant was decanted, and the remaining gel
was dried under vacuum at 60 ºC for 3 h, followed by 12 h at room
temperature to afford HTR-l (1.7 g) as a white powder.
Synthesis of ,-dipeptides. H2N-L-Val-N-Bn-β-Ala-COOH (2, α,β-L-Val)
and H2N-L-Leu-N-Bn-β-Ala -COOH (3, α,β-L-Leu) were prepared
according to the procedure previously reported (See supporting
information, Scheme S1).[26]
Reconstructed hydrotalcite in the presence of -amino acids and ,-
dipeptides. (HTR-L-Phe). Method M6, into a jar of PTFE (15 mL, 2.0 cm
diameter) equipped with two balls (each with core of stainless steel and
cover of PTFE,1 cm diameter and mass 1.757 g) was added 0.56 g of
HTC (~1.6 mmol), 0.46 g and L-Phe (2.8 mmol) and the resulting mixture
was milled for 1 min at 25 Hz, before the addition of aqueous NaOH (1%
w/w) to adjust pH 13. Milling was then continued for 90 min. The resulting
suspension was transferred to an Erlenmeyer flask of 50 mL (equipped
8
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10.1002/ejoc.202100877
European Journal of Organic Chemistry
FULL PAPER
with stirring bar and rubber septum), washing the jar with decarbonated
water (15 mL), and purged with argon. The flask was immersed into an
ultrasonic bath and sonicated for 60 min at 45 °C. The flask was then
placed on a stirring plate and the reaction mixture was stirred for 20 h at
room temperature. The resulting suspension was placed into an
Eppendorf vial and centrifuged for 10 min, the supernatant was decanted,
the remaining material was washed with decarbonated water (30 mL)
and again centrifugated and decantated. This process was repeated until
supernatant reached pH ~7. The remaining material was dried for 3 h at
60 °C under reduced pressure, followed of 12 h at room temperature.
Affording 0.78 g of HTR-L-Phe as a white powder. A similar process was
followed for the preparation of HTR-D-Phe, HTR-L-Trp, HTR-α,β-L-Val
and HTR-α,β-L-Leu.
[1]
[2]
a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 2007, 1701−1716; b) T.
Jerphagnon, M. G. Pizzuti, A. J. Minnaard, B. L. Feringa, Chem. Soc.
Rev. 2009, 38, 1039−1075; c) Y. Zhang, W. Wang, Catal. Sci. Technol.
2012, 2, 42−53; d) M. Hayashi, R. Matsubara, Tetrahedron Lett. 2017,
58, 1793−1805; e). G. Koutoulogenis, N. Kaplaneris, C. G. Kokotos,
Beilstein J. Org. Chem., 2016, 12, 462-495.
For reviews of asymmetric organocatalysis, see for example: a) J.
Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719−724; b) D. Enders, C.
Grondal, M. R. M. Hüttl, Angew. Chem., Int. Ed. 2007, 46, 1570−1581;
c) P. I. Dalko, “Comprehensive Enantioselective Organocatalysis:
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132143. f) M. Tsakos, C. G. Kokotos, Tetrahedron, 2013, 69, 10199-
10222.
Determination of amino acid and α,β-dipeptide content in the hybrid
catalysts. The concentration of amino acid and α,β-dipeptide into the
hybrid catalysts was determined by means of calibration curves using
UV-vis absorption spectra. Phosphate buffer solution (PBS, pH = 2.1)
was used for all measurements. All calibration curves were plotted with
average data from at least three sets of measurements made with
[3]
[4]
P. Chauhan, J. Kaur, S. S. Chimni, Chem. Asian J. 2013, 8, 328–346.
a) K. Tang, J.‑T. Zhang, Neurol. Res. 2002, 24, 473−478; b) C.
Freiberg, H. P. Fischer, N. A. Brunner, Antimicrob. Agents Chemother.
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Waldrop, J. Med. Chem. 2014, 57, 8947–8959; d) A. M. Hansen, G.
Bonke, C. J. Larsen, N. Yavari, P. E. Nielsen, H. Franzyk, Bioconjugate
Chem. 2016, 27, 863–867; e) S. E. Michalak, S. Nam, D. M. Kwon, D.
A. Horne, C. D. Vanderwal, J. Am. Chem. Soc. 2019, 141, 9202–9206.
G.-L. Zhao, Y. Xu, H. Sundén, L. Eriksson, M. Sayah, A. Córdova,
Chem. Commun. 2007, 734−735.
a) F. Yu, Z. Jin, H. Huang, T. Ye, X. Liang, J. Ye, Org. Biomol. Chem.
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Chinchilla, Eur. J. Org. Chem. 2015, 2015, 1218−1225; e) P. Vízcaíno-
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solutions of amino acids (or α,β-dipeptides) in the range 20-300 μmol·L−1
.
Hybrid catalysts (5 to 10 mg) were dissolved in 25 mL of PBS and stirred
for 4 h at room temperature, before recording of UV-vis spectra.
Absorption maxima for L-phenylalanine and D-phenylalanine were
recorded at 207 nm, L-Tryptophan at 280 nm, and H2N-L-Val-N-Bn-β-
Ala-COOH and H2N-L-Leu-N-Bnβ-Ala- COOH at 203 nm.
[5]
[6]
Catalyst evaluation in asymmetric Michael addition reactions
General catalyst evaluation in Michael addition reaction. Into a vial (8 mL)
equipped with magnetic stirring bar and rubber septum, 86.5 mg (0.5
mmol, 1 equiv.) of N-phenyl maleimide and 75 mg of catalyst HTR-L-Phe
was added. The vial was then capped before the dropwise addition of
0.16 mL (1.75 mmol, 3.5 equiv.) of isobutyraldehyde via syringe. The
reaction mixture was stirred at room temperature for 24 h. Once the
reaction was complete, (verified by TLC), in order to separate the catalyst
from the crude reaction mixture, ethyl acetate (2 ᵡ 2.5 mL) was added
and the resulting mixture was centrifuged for 5 min at 3820 rmp. The
supernatant was decanted over a funnel with filter paper. The combined
organic layers were concentrated under reduced pressure and the
resulting crude product was purified by flash chromatographic column
(hexanes/EtOAc, 7:3) affording 107 mg (87 % yield) of Michael adduct 8a
as a pale-yellow solid. Enantiomeric ratio (e.r.) was determined by chiral
HPLC (see Supporting Information), and the absolute configuration of the
Michael adducts (8a-8g) was assigned by comparison with literature
data.[6b,7a,9a] The same procedure was conducted for the remaining
aldehydes and N-substituted maleimides.
[7]
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Acknowledgements
We are grateful to Consejo Nacional de Ciencia y Tecnología
(CONACYT, Mexico) for financial support via grant No. A1-S-
44097 and to fund SEP-CINVESTAV for financial support via
grant 126. We also thank M. T. Cortez-Picasso for the recording
of NMR spectra, M. A. Leiva-Ramirez for powder XRD analysis
and G. Cuéllar-Rivera for MS-TOF analysis.
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Conflict of Interest
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The authors declare no conflict of interest.
Keywords: Asymmetric Michael addition • Ball milling • Green
chemistry • Hydrotalcite• Supported catalysts
9
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Entry for the Table of Contents
José M. Landeros,*[a] Carlos Cruz-
Hernández,[a] and Eusebio Juaristi*[a][b]
Page No. – Page No.
α-Amino acids and α,β-dipeptides
intercalated into hydrotalcite:
efficient catalysts in the asymmetric
Michael addition reaction of
aldehydes to N-substituted
maleimides
Recoverable hybrid materials for heterogeneous enantioselective organocatalyzed Michael addition reaction. Developed
through the ready intercalation of α-amino acids and α,β-dipeptides into reconstructed hydrotalcite (Mg/Al) by means of sustainable
technics such as mechanochemical and ultrasound activation. The conjugate addition of aldehydes to maleimides under mild and
solvent free conditions proceeded with high yield and excellent enantioselectivity (up to 99:1 e.r.).
11
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