Surface-Improved Asymmetric Michael Addition Catalyzed by Amino Acids Adsorbed on Laponite

Article abstract of DOI:10.1002/adsc.201701627

An unprecedented enantioselectivity increase was observed in the presence of inorganic oxides in the asymmetric Michael addition of aldehydes to trans-β-nitrostyrene derivatives catalyzed by amino acids. The best results were reached in the l-proline cata

Full text of DOI:10.1002/adsc.201701627

Title: Surface-improved asymmetric Michael addition catalyzed by
amino acids adsorbed on laponite
Authors: György Szőllősi, Dániel Gombkötő, Attila Mogyorós, and
Ferenc Fülöp
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701627
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Surface-Improved Asymmetric Michael Addition Catalyzed by
Amino Acids Adsorbed on Laponite
György Szőllősi,a,* Dániel Gombkötő,b Attila Zsolt Mogyorós,b and Ferenc Fülöpa,c
a
MTA-SZTE Stereochemistry Research Group, University of Szeged, 6720 Szeged, Dóm tér 8, Hungary. Fax: +36 62
544 200; Tel: +36 62 544 514; e-mail: szollosi@chem.u-szeged.hu
Department of Organic Chemistry, University of Szeged, 6720 Szeged, Dóm tér 8, Hungary.
Institute of Pharmaceutical Chemistry, University of Szeged, 6720 Szeged, Eötvös utca 6, Hungary.
b
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. An unprecedented enantioselectivity increase was involvement of both the carboxylic acid and the amino
observed in the presence of inorganic oxides in the group in anchoring the organic compound on the solid
asymmetric Michael addition of aldehydes to trans-- surface. Linear natural amino acids became also active in
nitrostyrene derivatives catalyzed by amino acids. The best the asymmetric Michael addition following adsorption on
results were reached in the L-proline catalyzed addition of laponite and provided the opposite enantiomer in excess
linear aldehydes using laponite RD as additive, approaching as compared with L-proline. The heterogeneous catalyst
those obtained using synthetic chiral organocatalysts. In our was applied in reactions of various carbonyl compounds
study we have shown that the asymmetric Michael addition is and substituted nitrostyrene derivatives. Based on results
catalyzed by the organic-inorganic hybrid material formed in obtained in this study combined with the previously
situ by adsorption of the amino acid on the solid surface. The reported amino acid catalyzed reactions on solid surfaces
chiral solid catalyst could be pre-prepared and recycled and the recently revisited reaction mechanism of this
several times with maintained stereoselectivities, showing a asymmetric addition a plausible reaction pathway
slow decrease in the activity, which could be restored by occurring on the surface was proposed.
adding proline during reuse. Characterization of the chiral
hybrid material by FT-IR spectroscopy and XRD
measurements indicated anchoring of the proline on the
surface of the laponite particles. Effect of the chiral
organocatalyst structure was used to evidence the
Keywords: Michael addition; Asymmetric catalysis;
Heterogeneous catalysis; Laponite; Carbonyl
compounds; Nitrostyrene
substrate scope is a common drawback of the chirally
modified heterogeneous catalysts.
Introduction
From practical reasons similarly convenient is the
attachment of chiral soluble catalysts to solid supports
by noncovalent bonding, if the catalytic activity and
stereoselectivity of the homogeneous catalyst is
preserved. Catalysts obtained by anchoring chiral
metal complexes by electrostatic interactions,
coordinative bonds, entrapment or hydrogen bonding
were developed, which sometimes provided even
better results compared to their soluble counterparts.[6]
Noncovalent immobilizations of optically pure
organocatalysts were also reported.[3,7] Among the
methods applied prevail those in which electrostatic
interactions are exploited to attaching the chiral
organocatalyst to the support. Natural amino acids are
cheap, readily available chiral organocatalysts.
However, only few catalytic systems are known in
which these were immobilized on supports by simple
adsorption or hydrogen bonding and provided
improved activity, stereoselectivity or in few cases
altered stereochemical course in asymmetric
reactions.[8-11] From practical point of view it is
Asymmetric catalytic methods are among the most
convenient procedures for preparing optically pure
organic chemicals used as building blocks in the
pharmaceutical, agrochemical, flavor and fragrance
industries and in synthesis of natural products.[1] Often
applied chiral catalysts are biocatalysts, metal
complexes and organocatalysts developed in the last
few decades.[2] Recent requirements to decrease the
environmental impact and improve the sustainability
of the high added-value fine chemical production
motivated the development of heterogeneous, easily
separable,
recyclable
chiral
catalysts.[3]
Immobilization by covalent bonding of efficient
soluble chiral catalysts on insoluble supports is often
cumbersome. A simpler approach is the chiral
modification of catalytically active metal catalysts
with optically pure compounds, so-called, chiral
modifiers.[4] Few asymmetric reactions employing
catalytically active metal oxides in presence of chiral
additives were also disclosed.[5] However, the limited
1
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
important that anchoring of the organocatalyst on
supports by simple adsorption may be carried out in
situ, without pre-preparation of the solid catalyst.
Michael additions are among the most studied C-C
having basic surface sites, such as the anion-exchanger
layered double hydroxide Mg-Al LDH, the cation-
exchanger
layered
aluminosilicate
clays
montmorillonite (Mont), bentonite (Ben H), the
synthetic cation-exchanger layered magnesia-silicate
laponite (Lap RD) and for comparison the acid treated
montmorillonite K10 (Mont K10).
bond
forming
organocatalytic
asymmetric
reactions.[2d,2e,12] Conjugate addition of aldehydes or
ketones to nitroolefins results in formation of -
nitrocarbonyl compounds, which are valuable
intermediates in the preparation of optically pure
amines or N-heterocyclic intermediates. Various chiral
amine catalysts were developed leading to high yields
and excellent optical purities in these reactions.[13]
Excellent results were obtained with amino acid-
derived compounds, mostly pyrrolidine derivatives
and oligopeptides.[14] Attempts to immobilize these
catalysts on insoluble supports or in a separable liquid
phase often resulted in highly efficient, recyclable
chiral materials.[15] However, the preparation of the
chiral catalysts and their heterogenized variants from
the natural amino acids needed laborious synthetic
steps. Accordingly, we set as aim the development of
easily obtainable chiral heterogeneous catalysts using
natural amino acids for the Michael addition of
carbonyl compounds to -nitrostyrenes, without
needing synthetic transformation of neither the chiral
source nor the support.
Table 1. Effect of oxide additives on the Michael addition
of 2a to 1a catalysed by L-Pro[a]
Additive
Conv 1a
dssyn
eesyn
[%][b]
[%][b]
[%][b,c]
‒
SiO2
-Al2O3
MgO
ZnO
TiO2
Mg-Al LDH
Mont
Mont K10
Ben H
Lap RD
Lap RD[d]
Lap RD[e]
>99
>99
99
99
88
>99
>99
15
10
65
90
94
80
78
92
90
70
93
87
83
95
55
95
36
36
77
49
31
31
64
77
43
82
88
‒
Results and Discussion
>99
<1
97
Our initial investigations were inspired by the effect of
the -Al2O3 additive in the enantioselective aldol
addition catalyzed by L-proline (L-Pro), which was
attributed to in situ formation of L-Pro--Al2O3 hybrid
material.[10,11] Thus, we started to study the effect of
various inorganic oxide additives in the
enantioselective addition of butanal (2a) to trans--
nitrostyrene (1a). It was also known that both chiral
and achiral hydrogen-bond donor additives, such as
thioureas, improved the yields and enantioselectivities
obtained in the addition of aldehydes to 1a by in situ
formation of self-assembled catalysts with L-Pro.[16]
Moreover, addition to the reaction mixture of
inorganic salts or the use of inorganic L-Pro salts as
catalysts, also increased the enantioselectivities in
these reactions.[17]
87
[a] Reaction conditions: 0.04 mmol L-Pro, 0.4 mmol 1a, 1.2
mmol 2a, 1 cm3 solvent mixture SM1, 100 mg oxide
additive, room temperature (rt, 24 ± 1°C), 22 h.
Conversion of 1a (Conv 1a), diastereoselectivity of the
[b]
syn isomers (dssyn) and the enantiomeric excess (ee) were
determined by gas-chromatography (GC-FID).
[c] The configuration of the excess enantiomer was assigned
as 2R,3S based on the reaction catalyzed by L-Pro in
absence of additive and literature data.[14g]
[d] Reaction in absence of L-Pro.
[e] Reaction time 6 h.
Except the acidic Mont K10 all these materials had
beneficial effect on the ee as compared to the reaction
in absence of additives. To our delight the use of Ben
H or Lap RD increased the ee over 80%, surpassing
the values obtained in the presence of -Al2O3. The
best results were obtained with Lap RD, which besides
increasing the ee also gave high dssyn (95%). In the
presence of this additive good results were also
obtained in shorter reactions (6 h). In absence of L-Pro
Lap RD had very low catalytic activity. Accordingly,
we assumed that the ee increase in the presence of Lap
RD is due to involvement of the oxide surface in
directing the substrates in the reaction catalyzed by L-
Pro, and the reaction occurred on the solid surface
promoted by adsorbed L-Pro.
Results obtained using inorganic oxide additives are
summarized in Table 1. The solvent mixture,
CHCl3/iPrOH 9/1 vol/vol (SM1), was chosen based on
results obtained with tripeptide catalysts.[14g] In the
absence of oxides 1a was completely transformed by
10 mol% L-Pro in 22 h. However, low enantiomeric
excess (ee) was achieved, similarly to a previous
report.[14g] Addition of SiO2 did not influence the
results, whereas in presence of TiO2 and ZnO the ee
decreased. MgO and -Al2O3 both increased the ee, the
latter
being
more
efficient,
while
the
diastereoselectivity to the syn isomers (dssyn [%] = syn
× (syn + anti)-1 × 100) decreased. Thus, basic oxides
improved the ee value, whereas the presence of the
acidic SiO2 had only marginal effect on the results.
This motivated us to test the effect of other oxides
Effect of the reaction conditions
2
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
We continued our study by examining the influence of
the reaction conditions in presence of Lap RD. Initially
we determined the amount of Lap RD necessary for
obtaining improved stereoselectivities. The ee
increased significantly with increasing the amount of
Lap RD up to 100 mg (Figure 1). However, the best
value (88%) was obtained using 200 mg solid, above
this amount no further change in the ee was observed.
The diastereoselectivity already reached the highest
value (dssyn 95%) in the presence of 50 mg Lap RD.
Investigation of the effect of the solvent nature
(Table 2) showed that in protic polar solvents such as
alcohols the reactions proceed smoothly, but low ees
are obtained (up to 75% in iPrOH). In aprotic solvents
the conversions decreased, especially in chlorinated
solvents, however in the latter were obtained the best
ee values. Accordingly, it may be deduced that protic
solvents disturb the stereospecific interactions on the
solid surface responsible for the high ee. The
combination of chlorinated solvents, such as CHCl3
with iPrOH in the proper ratio assured high conversion,
good dssyn and ee. Changing the ratio of these solvents
as compared with the previously used 9/1 vol/vol led
to decrease either in the ee or in the conversion. Thus,
our further studies were carried out in the same
mixture (SM1). The effect of the purity of the aldehyde
was also checked (Supporting Information, SI; Table
SI1). The freshly used as received and freshly distilled
2a provided similar results. Using longer time the
same bottle of 2a led to decrease in the dssyn and
conversion, possibly due to acid formation, which may
occupy surface sites on the solid surface.
Assuming that the enantioselective reaction takes
place on the oxide surface, we considered necessary to
determine the amount of L-Pro, which is able to assure
the best results (Figure 2). High ee (90%) was obtained
even with low L-Pro amount (1 mol %), whereas the
conversion increased gradually with increasing
amount of amino acid. However, the increase in
conversion was not linear, as one could expect in a first
order homogeneous reaction. This indicated that the
active catalyst is not the dissolved L-Pro and the
catalytically active species are generated in situ. The
previously used 0.04 mmol (10 mol %) L-Pro was
necessary to completely transform 1a in the given time
(6 h), however, a slight decrease in the ee was also
observed. This we attributed to the presence of excess
L-Pro in the solution, which provided lower ee (see
Table 1).
Conv 1a
100
[%]
dssyn
eesyn
80
60
40
20
0
50
100
150
200
250
300
Lap RD amount [mg]
Figure 1. Effect of the Lap RD amount on the addition 2a
to 1a. Reaction conditions: 0.04 mmol L-Pro, 0.4 mmol 1a,
1.2 mmol 2a, 1 cm3 SM1 solvent mixture, rt, 6 h.
Table 2. Solvent effect on the addition of 2a to 1a catalysed
by L-Pro in presence of Lap RD[a]
Solvent
Conv 1a
dssyn
eesyn
[%] [b]
[%][b] [%][b,c]
MeOH
99
99
99
39
50
55
78
96
92
90
95
99
99
55
92
92
93
94
95
95
95
94
95
95
95
95
95
95
2
EtOH
25
75
90
91
90
88
85
86
87
86
85
88
89
dssyn
100
80
60
40
20
0
iPrOH
[%]
CH2Cl2
ClCH2CH2Cl
CHCl3
eesyn
toluene
iPr2O
Conv 1a
Et2O
AcOEt
acetone[d]
CHCl3/iPrOH 1/1
CHCl3/iPrOH 9/1 (SM1)
CHCl3/iPrOH 19/1
[a] Reaction conditions: 0.04 mmol L-Pro, 0.4 mmol 1a, 1.2
mmol 2a, 1 cm3 solvent, 200 mg Lap RD, rt, 6 h.
[b] Determined by GC-FID.
0
1
2
3
4
L-Pro amount [mmol x 100]
[c] The configuration of the excess enantiomer was 2R,3S.
Figure 2. Effect of L-Pro amount on the addition of 2a to 1a.
Reaction conditions: 0.4 mmol 1a, 1.2 mmol 2a, 1 cm3 SM1
solvent, 200 mg Lap RD, rt, 6 h.
[d]
Reaction of 1a and acetone didn’t occur under these
conditions.
3
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
Increasing the reaction temperature over rt
recycling the L-Pro-Lap RD catalyst as compared with
(24±1°C) decreased both the dssyn and ee (Figure SI1).
Slight increases in the stereoselectivities were
obtained at low temperatures (under rt), however,
longer reaction times were needed to obtain high
conversions. Increasing the solvent amount also led to
slightly higher ee (Figure SI2) accompanied by
decrease in the reaction rate, as shown by the lower
conversions reached in 6 h. Similarly, only small
changes of the dssyn and ee was detected by changing
the reactants concentrations while keeping their molar
ratio, solvent, catalyst and Lap RD amounts constants
(Figure SI3).
the reuse of the in situ formed material.
100
dssyn
[%]
90
eesyn
80
70
Conv 1a
Changing the amount of 2a, i.e. altering the reactant
ratio did not influence the dssyn and ee (Figure 3).
Interestingly, both at low (1) and high (4) ratios low
conversions were obtained in 6 h. It must be noted that
in all these reactions we have detected side-products
formed by self-condensation of the aldehyde.
Consumption of 2a in these side-reactions may limit
the transformation of 1a when the reactants ratio is 1.
At high 2a/1a ratios the formation of larger quantities
of side-products may block catalytically active sites,
which may explain the lower conversions. However,
this did not influence the stereoselectivity of the
remaining sites. This was also indicated by the
unaltered dssyn and ee observed during reaction (Figure
SI4). According to these high conversion (90%) was
already obtained following 2 h.
60
50
1
2
3
4
5
2a/1a molar ratio
Figure 3. Effect of the reactant ratio on the addition of 2a
to 1a catalyzed by L-Pro in presence of Lap RD. Reaction
conditions: 0.04 mmol L-Pro, 0.4 mmol 1a, 1 cm3 SM1
solvent, 200 mg Lap RD, rt, 6 h.
Table 3. Examination of the heterogeneous in situ formed
and pre-prepared Lap RD based hybrid catalysts[a]
Catalyst
Conv 1a
dssyn
eesyn
[%][b]
[%][b] [%][b,c]
Lap RD + L-Pro[d]
>99
82
35
36
88
70
71
91
>99
93
95
95
94
94
95
95
95
95
94
95
94
95
88
90
87
87
90
87
87
91
91
91
91[g]
0
Catalytic activity of the surface
reuse of the solid
Lap RD + L-Pro[d,e]
stirring the liquid
reuse of the solid
Lap RD + L-Pro[d,f]
stirring the liquid
reuse of the solid
L-Pro-Lap RD
reuse of the solid
D-Pro-Lap RD
The above presented studies indicated that the Michael
addition is catalyzed by L-Pro in situ adsorbed on the
surface of Lap RD. Our next goal was to examine the
heterogeneous nature of the stereoselective catalyst.
Reuse of the centrifuged and washed solid material
surprisingly provided even higher ee (90%) as
compared with the first reaction, though the
conversion decreased (Table 3). Moreover, with
catalysts separated following half or one hour
reactions the Michael addition proceeded similarly,
resulting in higher ee, whereas further stirring the
liquid phase did not lead to change in the composition
of the solution. Accordingly, we reached to the
conclusion that the active catalyst is indeed the solid
material formed by adsorption of L-Pro on the surface
of Lap RD. The slightly lower ee obtained in the first
reaction may be due to the excess L-Pro, which
remained dissolved in solution and provided low ee.
The above evidence of formation of an inorganic-
organic stereoselective hybrid catalyst prompted us to
attempt the ex situ preparation of the catalytically
active solid material. We have pre-adsorbed L-Pro or
D-Pro on Lap RD using the same solvent mixture,
amino acid and Lap RD concentrations as used in the
Michael additions (L-Pro-Lap RD and D-Pro-Lap RD,
respectively). To our delight these chiral hybrid
materials provided better ee values as the in situ
formed material accompanied by complete
conversions of 1a (Table 3). Moreover, higher ee and
smaller conversion decrease was observed upon
>99
97
L-Pro-Lap RD + D-Pro-
Lap RD (1/1)
D-Pro-Lap RD + L-Pro[d]
L-Pro-Lap RD + D-Pro[h]
D-Pro-Lap RD + L-Pro[h]
>99
>99
>99
95
95
95
25[g]
50
52[g]
[a]
Reaction conditions: 200 mg Lap RD or pre-prepared
catalyst, 0.4 mmol 1a, 1.2 mmol 2a, 1 cm3 SM1 solvent,
rt, 6 h.
[b] Determined by GC-FID.
[c] Excess of 2R,3S enantiomer.
[d] Using 0.04 mmol L-Pro.
[e] Reaction time 0.5 h.
[f] Reaction time 1 h.
[g] Excess of 2S,3R enantiomer.
[h] Using 0.02 mmol proline (the indicated enantiomer).
Materials prepared from opposite proline
enantiomers gave opposite product enantiomers in
excess, without influencing the diastereoselectivity of
the reaction. In the reaction using the 1/1 wt/wt
4
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
mixture of the two chiral solids prepared from the
opposite proline enantiomers racemic product was
obtained. Addition of the opposite proline enantiomer
to the suspension of a pre-prepared chiral catalyst
provided the 3aa enantiomer in excess, which resulted
in the reaction catalyzed by the pre-adsorbed
enantiomer (Table 3). The ee values obtained in the
latter experiments depended on the amount of the
proline added to the slurry, which indicated exchange
of the pre-adsorbed enantiomer to some extent.
Although, the above results indicated that the
reaction occurs on the solid surface, the relatively easy
desorption of the amino acid during reaction urged us
to examine the stability of the chiral hybrid catalyst.
Results obtained by reusing the L-Pro-Lap RD catalyst
are shown in Figure 4. The conversion decreased upon
recycling of the solid probably due to gradual
desorption of L-Pro from the surface. However, the
remaining surface active sites were stereoselective
indicated by the high ee (90%) obtained even in the
fourth run, in which the conversion decreased to 77%
(dssyn remained high, 95%, in all these experiments).
Further decrease of the catalyst activity could be
prevented by addition of small amount of amino acid
(1 mol % L-Pro). Using additional 10 mol % of L-Pro
in the sixth run reset the catalyst activity, though the
ee slightly decreased, probably caused by the
dissolved excess amino acid, as discussed previously.
The adsorption of L-Pro on the Lap RD was
investigated by infrared spectroscopy (FT-IR). Full
spectra of Lap RD and L-Pro-Lap RD are shown in
Figure SI5 (see SI), while selected parts of the spectra
are compared in Figure 5. The spectrum of Lap RD
shows the absorption bands (O-H) between 3300-
3500 cm-1 and (H-O-H) at 1620 cm-1, characteristic
of physisorbed water. Surface SiO-H and MgO-H
stretching vibrations appear as unresolved sharp bands
at 3676 cm-1 with the latter as a shoulder at 3688 cm-
1 [18]
.
The band attributed to (Si-O) stretching
vibration appeared as sharp intense peak at 1012 cm-1.
Additional bands in the spectrum of L-Pro-Lap RD
were detected between 2920-3080 cm-1 as shoulder on
the broad (O-H) band, which may be attributed to
(C-H) vibrations, showing attachment of the organic
compound to the Lap RD particles. Bands ascribed to
as(COO), (-NH2), s(COO) and (C-H) vibrations
also appeared in the 1250-1720 cm-1 region.[19,20] The
former two overlapped with the (HO-H) band causing
broadening and change in the shape of the latter. These
bands confirmed the presence of L-Pro on the surface.
Decrease in the relative intensity of the (SiO-H) band
as compared with that of (MgO-H) (Figure SI6)
showed that surface silanol groups are involved in
bonding L-Pro on the surface, as the MgO-H groups
due to their position are not accessible.
100
Conv 1a
eesyn
(-NH2)
as(COO)
[%]
91
91
90
90
89
s(COO)
88
(C-H)
(C-H)
90
80
70
60
87
(O-H)
L-Pro-Lap RD
(HO-H)
Lap RD
3600 3300 3000 2700 2400 2100 1800 1500 1200
wavenumber [cm-1]
1
2
3
4
5
(a)
6
(b)
7
(c)
use number
Figure 5. Selected fragment of the FT-IR spectra of Lap RD
Figure 4. Recycling of L-Pro-Lap RD catalyst in the
reaction of 2a and 1a (conversion black, ee red bars).
Reaction conditions: 200 mg L-Pro-Lap RD, 0.4 mmol 1a,
1.2 mmol 2a, 1 cm3 SM1 solvent, rt, 6 h; addition of 0.004
mmol (a), 0.01 mmol (b) and 0.04 mmol (c) L-Pro.
(black) and L-Pro-Lap RD (red).
To determine the location of the amino acid attached
to the Lap RD particles X-ray diffractometric (XRD)
investigations were carried out. Diffraction patterns of
Lap RD and L-Pro-Lap RD are compared in Figure 6.
The detected reflections are in accordance with those
characteristic of Lap RD.[21] The position of the (001)
reflection situated at 6.52° 2 corresponds to a basal
distance of 13.56 Å. This value upon treatment with
L-Pro increased slightly to 14.07 Å (6.28° 2) (Figure
SI7), indicating that the major part of the organic
compound was anchored on the outer surface of the
particles and the interlamellar distance hardly changed.
Similar behaviour was observed previously using
Characterization of the chiral hybrid material
Laponite RD is a synthetic cation-exchanger layered
magnesia-silicate having an octahedral magnesia layer
between two tetrahedral silica layers. The interlamellar
space contains physisorbed water and cations (Na+)
compensating the charge of the particles, which
originates from the partial substitution of the Mg2+ by
Li+.
5
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
Table 4. Effect of the chiral catalyst structure in the Michael
addition of 2a to 1a in the presence of Lap RD[a]
glutamic acid, which due to partial cyclization to
pyroglutamic acid was adsorbed on the particles
surface rather than included between the lamellae of
laponite.[19]
According to these data we suggest that L-Pro is
adsorbed on the surface of Lap RD particles with the
involvement of the surface silanol groups, i.e. by
hydrogen-bonding. This may explain the relatively
easy partial desorption of the amino acid during
reaction.
(130)
(200)
(011)
(020)
(060)
(330)
(150)
(240)
(310)
(001)
(004)
L-Pro-Lap RD
Lap RD
Catalyst
Conv 1a
dssyn
eesyn [%]
(conf)[b,c]
[%][b]
[%][b]
L-Pro[d]
99[e] (99[e]) 95 (92) 88 (38) (2R,3S)
L-Hyp[d]
L-Pro-Me[d]
Me-L-Pro
Z-L-Pro
L-Pro-
99[e] (11)
99[e] (5)
5 (2)
95 (94) 88 (69) (2R,3S)
86 (90) 38 (43) (2R,3S)
90 (87) 80 (28) (2R,3S)
3
13
23
33
43
53
63
2 theta [degree]
<1 (1)
nd (nd)
88 (94) 72 (73) (2R,3S)
nd (nd)
95[e] (12)
NHMe[d]
Gly-L-Pro[d]
(S)-4[d]
Figure 6. XRD diffractograms of Lap RD (black) and L-
Pro-Lap RD (red).
15 (40)
99 (99)
99 (97)
26 (<1)
8; 22[f]
77 (4)
62 (91) 21 (26) (2R,3S)
90 (80) 46 (40) (2R,3S)
86 (67) 36 (34) (2R,3S)
71 (nd) 56 (nd) (2S,3R)
(S)-5[d]
L-Ala
Effect of the chiral organocatalyst structure
70; 68
62; 60 (2S,3R)
The effect of Lap RD on the stereoselectivity obtained
in the addition of 2a to 1a catalyzed by L-Pro
motivated our further studies on the effect of the chiral
compound structure. Beside L-Pro derivatives, which
were used to detect the role of the functional groups of
proline in the surface reaction, several other natural
and synthetic chiral amino acids and derivatives
thereof were examined. The structure of these
compounds, except those of the natural amino acids
are shown in Figure 7 (see Figure SI8 for the structure
of all these compounds). Selected results are
summarized in Table 4. Results obtained in the
presence and absence of Lap RD were compared.
Pyrrolidine ring containing compounds such as L-
Pro, L-Hyp, L-Pro-Me, L-Pro-NHMe, (S)-4 and (S)-5
provided close to full conversion of 1a, although some
of these were inefficient in the absence of Lap RD.
However, good enantioselectivity was attained only
with compounds bearing free carboxylic acid group
and somewhat lower ee value was obtained with the
amide L-Pro-NHMe. Significantly decreased ee was
obtained when the methyl ester L-Pro-Me or the
diamine derivatives (S)-4 or (S)-5 were used. Low
conversions were obtained with N-substituted
pyrrolidine ring containing substances, such as Me-L-
Pro, Z-L-Pro or Gly-L-Pro, although the latter
possessed a primary amino group. However, due to the
distance of this amino group from the stereogenic
centre the Gly-L-Pro dipeptide also afforded low ee.
L-Val
60 (68) 80 (74) (2S,3R)
62 (74) 82 (74) (2S,3R)
L-tLeu
95 (8)
18; 88[f]
68 (4)
63; 60
78; 79 (2S,3R)
L-Ile
62 (69) 77 (69) (2S,3R)
Me-L-Ile
L-Leu
57 (1)
38 (11)
64 (nd)
62 (60)
9 (nd) (2S,3R)
65 (12[g])
(2S,3R)
L-Ser
L-Cys
L-Met
L-Asn
L-Asp
L-Asp-Et
36 (2)
33 (<1)
44 (15)
35 (<1)
15 (<1)
34 (5)
71 (85) 43 (30) (2S,3R)
83 (nd) 28 (nd) (2S,3R)
65 (58)
71 (nd) 61 (nd) (2S,3R)
77 (nd) 25 (nd) (2S,3R)
58 (65)
61 (1) (2S,3R)
23 (15[g])
(2R,3S)
L-Gln
55 (<1)
33; 30[f]
18 (<1)
34 (17)
64 (<1)
10 (<1)
53 (8)
26 (<1)
70 (<1)
6; 62[f]
65 (nd) 64 (nd) (2S,3R)
61; 63 65; 63 (2S,3R)
77 (nd) 50 (nd) (2S,3R)
62 (61) 80 (4) (2S,3R)
57 (nd) 74 (nd) (2S,3R)
71 (nd) 85 (nd) (2S,3R)
64 (63) 76 (17) (2S,3R)
66 (nd) 72 (nd) (2R,3S)
60 (nd) 77 (nd) (2R,3S)
L-Glu
L-Phe
L-His
L-Tyr
L-Trp
D-PhGly
D-CyGly
63; 60
72; 74 (2R,3S)
[a]
Reaction conditions: 0.08 mmol chiral catalyst, 200 mg
Lap RD, 0.4 mmol 1a, 1.2 mmol 2a, 1 cm3 SM1 solvent,
rt, 22 h; results obtained in the absence of Lap RD are
shown in brackets; nd: not determined.
6
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
[b] Determined by GC-FID.
increased or decreased only slightly, indicating that in
these reactions still the chiral surface centres are active.
Addition of the corresponding chiral compound during
the third use of the recovered solid restored its activity
close that observed in the first use (with the exception
of L-Gln) without a major decrease in the ee.
[c] Configuration of the excess enantiomer.
[d] Using 0.04 mmol chiral compound.
[e] Reaction time 6 h.
[f]
Results obtained in the first and second recycling of the
catalyst, in the latter 0.08 mmol amino acid was also
added.
Opposite enantiomer in excess compared with the
[g]
Scope of the heterogeneous chiral catalyst
reaction in the presence of Lap RD.
Our investigations were continued with examination
of the scope of the heterogeneous catalyst formed in
situ from L-Pro and Lap RD. Various carbonyl
compounds (2a-2i) and several nitrostyrene
derivatives (1a-1i) were examined both in the absence
and presence of Lap RD (see Table 5). It must be
stressed out that changing the carbonyl compound
structure often made necessary changes in the reaction
conditions. Results summarized in Table 5 are selected
following the examination of the effect of some crucial
reaction parameters, such as the L-Pro amount,
reaction time and temperature, in each reaction.
Aliphatic aldehydes with linear catena ensured high
conversions and increased enantioselectivities when
Lap RD was used, contrary to the poor ee values
reached in the absence of the solid material. The most
significant ee increase was detected in the reaction of
hexanal (2d), having the longest aliphatic chain.
Moreover, the second use of the hybrid catalyst in the
latter reaction afforded better, 95% ee (not included in
Table 5). In the reaction of the -branched aldehyde 2e
the conversion slightly decreased, as compared with
that catalyzed by L-Pro in solution and this aldehyde
needed longer reaction time for obtaining over 90%
conversion.
Significant conversion increase was also attained in
the reaction of -branched aldehydes 2f and 2g in the
presence of Lap RD. Although, in reactions of both
compounds higher L-Pro amount, increased
temperature or extended reaction time was necessary,
in the reaction of 2g the conversion remained low
(31%). The ee values also increased in these reactions,
however, remained much lower as compared with
those obtained with the linear aldehydes. Addition of
ketones (2h or 2i) to 1a was also accelerated by the
presence of Lap RD. Although the ee also increased in
these reactions the values obtained in reactions of both
remained low (up to 30%). The above observations
suggested that the surface of the Lap RD may have
steric influence on the addition reaction catalyzed by
L-Pro, confirming that the reaction takes place on the
solid surface.
Primary amino acids were less efficient as
compared with L-Pro or L-Hyp both as concern their
activity and stereoselectivity (dssyn and eesyn). These
compounds, with few exceptions (such as L-Phe, L-
Met or L-Leu), were inefficient catalysts in the absence
of Lap RD, i.e. less than 10% conversions were
obtained. However, in the presence of the inorganic
solid these also catalyzed the reaction. The best results
were reached with L-tLeu, L-Val, D-CyGly and L-Ile,
all of these having -branched catena. In contrast the
best dssyn were attained using amino acids bearing
additional hydrogen-bond donor functional groups in
the molecule, such as L-Cys, L-Asp and L-Glu.
Although, lower ees were obtained as compared with
L-Pro, high values (approaching or in few cases even
exceeding 80%) were reached with the above
mentioned -branched amino acids and with amino
acids bearing aromatic rings (L-Tyr, L-Phe and L-Trp).
Thus, among the primary amino acids L-tLeu and the
natural L-Val were the most efficient if both the
conversion and the ee values are taken into account.
The N-methyl derivative of L-Ile provided low ee,
whereas the half ester L-Asp-Et provided similar ee
and decreased ds in comparison with L-Asp. It is
noteworthy that the configuration of the excess syn
enantiomer obtained using natural primary amino
acids both in the absence (if reaction occurred) and
presence of Lap RD was opposite as compared to that
formed in reactions catalyzed by L-Pro. Moreover, in
reactions catalyzed by some aliphatic amino acids (L-
Ile and L-Asp-Et) the configuration of the excess
enantiomer changed even due to the presence of Lap
RD.
According to these results not only L-Pro and
pyrrolidine derivatives may form efficient
heterogeneous catalyst by adsorption on Lap RD
surface, but other amino acids also became active on
the solid surface. Results obtained with the in situ
formed chiral inorganic-organic hybrid materials are
significantly influenced by the structure of the amino
acid used. Previously it was observed that upon
recycling the catalyst formed in situ from L-Pro the ee
increased in the second run (Table 3), accompanied by
a small decrease in the conversion of 1a. Next we
examined the reuse of catalysts formed in situ from
Lap RD and primary amino acids (selected results
were included in Table 4). The conversions decreased
drastically upon reuse of these solids as compared with
the first reactions, however, the decrease was lower
with L-Gln, which may be attributed to the additional
anchoring amide group. However, the ee values either
Substituents on the phenyl ring of nitrostyrene had
slight effect on the results obtained in reactions with
2a (see reactions of 1b-1i in Table 5). Decrease in
conversion was obtained in the presence of Lap RD
with 3-Cl, 3-Br and 2,4-diCl substituted derivatives.
Similarly, low (86%) conversion was reached in the
reaction of 1i though its value increased by addition of
Lap RD. The ee values obtained in these reactions
were significantly higher as compared with those
obtained without addition of the solid and were close
7
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
Table 5. Scope of the in situ formed L-Pro-Lap RD chiral hybrid catalyst in the asymmetric addition of carbonyl compound
to -nitrostyrene derivatives[a]
Conv 1a-1i [%][b] dssyn [%][b] eesyn [%][b]
Nitrostyrene; Carbonyl compound
Product
X
R1
R2
Me
Et
R3
H
1a; H
2b
2a
2c
2d
2e
2f
H
3ab[c]
3aa
99 (65)
99 (98)
99 (94)
99 (95)
91 (99)
89 (18)
31 (17)
84 (30)
96 (80)
99 (99)
99 (97)
97 (95)
90 (99)
92 (99)
93 (99)
97 (83)
86 (66)
92 (93)
95 (94)
91 (91)
93 (93)
95 (93)
‒
86 (43)
88 (39)
90 (28)
94 (26)
86 (40)
74 (33)
77 (25)
30 (3)
1a; H
H
H
1a; H
H
Pr
H
3ac
1a; H
H
Bu
iPr
Me
H
3ad
1a; H
H
H
3ae[d]
3af[d,e,f]
3ag[f,g]
3ah[e,f,h]
3ai[f,g]
3ba
1a; H
H
Me
‒
1a; H
2g
2h
2i
H
-(CH2)5-
‒
1a; H
Me
H
H
H
H
H
H
H
H
H
H
H
90 (94)
94 (94)
94 (93)
93 (94)
93 (90)
97 (99)
93 (91)
94 (95)
94 (93)
25 (16)
89 (35)
87 (42)
89 (33)
91 (40)
89 (24)
91 (40)
92 (3)
1a; H
-(CH2)4-
1b; 2-F
1c; 4-F
1d; 2-Cl
1e; 3-Cl
1f; 2,4-Cl2
1g; 3-Br
1h; 2-MeO
1i; 4-MeO
2a
2a
2a
2a
2a
2a
2a
2a
H
H
H
H
H
H
H
H
Et
Et
Et
Et
Et
Et
Et
Et
3ca
3da
3ea
3fa
3ga
3ha
90 (30)
3ia
[a] Reaction conditions: 0.04 mmol L-Pro, 200 mg Lap RD, 0.4 mmol 1a-1i, 1.2 mmol 2a-2i, 1 cm3 SM1 solvent, rt, 6 h;
results obtained in the absence of Lap RD are shown in brackets.
[b] Determined by GC-FID.
[c] Reaction time 2 h.
[d] Reaction time 22 h.
[e] Reaction at 50°C.
[f] Using 0.08 mmol L-Pro.
[g] Reaction time 168 h.
[h] Reaction time 70 h.
to that obtained in the reaction of 1a and 2a. The best
ees were reached in the reactions of the 3-Cl, 3-Br and
2-MeO substituted nitrostyrenes. The most significant
ee increase in the presence of Lap RD was observed in
the reaction of the latter compound (1h). According to
these results the size and position of the substituents
have also slight effect on the surface reaction, mostly
due to their steric effect.
The preparative value of the heterogeneous catalyst
was tested using several aldehydes. Products formed
in reactions carried out at 1 mmol scale were isolated
by flash chromatography, without separation of the
diastereomers. Good yields and ee approaching or
Figure 7. Isolated products obtained in experiments scaled-
up to 1 mmol 1a (for reaction conditions see Table 5).
identical as in reaction carried out in previous
experiments with 0.4 mmol 1a (Figure 7).
8
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
Suggested reaction pathways on the Lap RD
surface
The present study on using inorganic oxide additives
in the asymmetric Michael addition of aldehydes to
trans--nitrostyrene derivatives catalyzed by L-Pro
showed a surprising increase in the enantioselectivity
in presence Lap RD. Such improvement in the ee on a
solid surface is without precedent in asymmetric
organocatalysis, although examples of peculiar
behaviour of surface-adsorbed chiral organocatalysts
has been observed previously.[8-11]
It is known that the organocatalytic Michael
addition of aldehydes to nitroolefins occurs through
formation of an enamine intermediate and several
steps of the reaction are accelerated by acids.[22] Chiral
secondary amine catalysts were used either as
ammonium salts or in combination with an acid or
hydrogen-bond donor.[14a,14j,16,23] Proline metal salts
were also efficient in this reaction.[17] The aqueous
suspension of Lap RD is basic and hydrogen-bond
donor silanol groups are available on the surface.
Adsorption of the amino acid may occur both through
the secondary amino group and by the carboxylic acid
group, the latter may interact with the charge
compensating cations, too. During our study we have
obtained increased ee using several oxide additives (-
Al2O3, Mg-Al LDH, Mont, Ben H). Thus, the
adsorption mode of L-Pro on the surface may be
assumed to be similar with that suggested in previous
studies employing L-Pro--Al2O3 or L-Pro-Mg-Al
LDH catalysts in asymmetric aldol or Michael
additions, respectively.[9-11] However, on cation-
exchanger layered material, such as Lap RD, the
formation of the corresponding salt-like adsorbed
amino acid is also possible by interaction with the
charge compensating cation, as shown in Scheme 1
(A). Surface anchored enamine intermediate (B) is
formed by reaction with the aldehyde. These surface
intermediates react with nitrostyrene, which may also
be adsorbed on the surface.[9] In this step a zwitterionic
surface intermediate (similarly with the homogeneous
reaction[22]) is formed. The stereocentres are formed
through the assumed surface transition state (C). Steric
constrains imposed by the surface during this step may
lead to the increased ee.
Results obtained with pyrrolidine derivatives
showed that the carboxylic acid group play role in
anchoring the amino acid on the surface. Acceleration
of the reaction may be attributed to the presence of the
acidic surface silanol groups.[22] During homogeneous
reactions decrease in the transition state energy by
interaction of the acidic group with the developing
nitronate anion (transition state C) was suggested to be
responsible for this effect, rather than a ground state
activation of the nitroolefin. Accordingly, the above
supposed pre-adsorption of the nitrostyrene is unlikely.
As the acid additives influenced only the
diastereoselectivity of the reaction, while the ee was
not affected, the ee increase observed in the surface
reactions may be ascribed mostly to steric effects.
Scheme 1. Suggested reaction pathways in the asymmetric
Michael addition of butanal (2a) to -nitrostyrene (1a)
catalyzed by surface adsorbed amino acids.
The inversion of the sense of the enantioselectivity
in reactions using aliphatic amino acids as compared
with the addition catalysed by L-Pro may not be
ascribed to the presence of the surface, as the inversion
was observed both in absence and presence of Lap RD.
However, it was amplified by the presence of Lap RD,
as a consequence of the involvement of the surface in
the transition states through which the reactions
proceed (Scheme 3, C and D). The significant loss of
the activity observed upon reuse of the catalyst
obtained with aliphatic amino acids, indicated that the
amino group may be involved in anchoring the
organocatalyst with the secondary cyclic amino group
ensuring stronger attachment to the surface. The high
ee values obtained with -branched amino acids (L-
tLeu, L-Val, D-CyGly and L-Ile) showed the
importance of the steric effect of the aliphatic chain,
whereas results reached using aromatic ring containing
amino acids (L-Tyr, L-Phe and L-Trp) and the effect of
9
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10.1002/adsc.201701627
Advanced Synthesis & Catalysis
Michael additions: general procedure
the structure of the aldehydes (2a-2d vs 2f and 2g)
indicated the steric effect of the surface.
The reactions were carried out in 4 cm3 closed glass vials.
The slurries were stirred magnetically (1000 rpm) and if
higher than room temperature was necessary the vials were
immersed in a heated oil bath. In a typical reaction the given
amount of amino acid and Lap RD (or another solid
additive) were introduced into reactor followed by addition
of the solvent, nitrostyrene derivative and finally the
carbonyl compound. The slurry was stirred for the given
reaction time. In reactions without oxide additives the
catalyst was extracted with 1 mL saturated NH4Cl aq.
solution. The aqueous solution was washed twice with 2 cm3
CHCl3 and the unified organic phases were dried over
anhydrous MgSO4. The solution was analysed by GC-MSD
and GC-FID following addition of 50 L n-decane internal
standard. When solid additive (Lap RD) or pre-prepared
hybrid catalyst (L-Pro-Lap RD) was used the slurry was
diluted with 2 mL CHCl3 and centrifuged. The catalyst was
twice re-suspended in 3 cm3 CHCl3 and again centrifuged.
The unified supernatants were treated similarly as described
previously for the reaction carried out in the absence of
oxides to remove the amino acids leached into solution. The
remaining solid catalysts were dried at room temperature
under vacuum overnight and used in subsequent runs. When
the heterogeneous character of the reactions was monitored
dilution and treatment with aqueous NH4Cl was omitted
before centrifugation.
Products were identified by mass spectrometry using
GC-MSD (see SI). Quantitative analysis was carried out by
gas-chromatography using GC-FID equipped with chiral
capillary column (separation of the enantiomers are shown
in the SI). Conversions (Conv 1a-1i), diastereoselectivities
(dssyn) and enantioselectivities (eesyn) were calculated based
on the relative concentrations determined from
chromatograms. The absolute configuration of the excess
enantiomers were assigned based on reactions catalyzed by
L-Pro and literature reports describing the same reactions.
Addition products obtained in scale-up experiments were
purified by flash chromatography on silica gel using
hexane/ethyl acetate eluent (10/1 – 20/1). Following
determination of the isolated yields the products were
identified by 1H and 13C NMR spectroscopy (see SI).
Finally, it must be mentioned, that low amount of L-
Pro is sufficient to reach maxima in the ee value over
the solid surface. Accordingly, the catalytic surface
species have increased activities as compared with
dissolved organocatalysts. Fortunately the bare solid
surface is catalytically inactive, accordingly had no
detrimental effect on the ee. The small decrease of the
ee obtained at high L-Pro amounts may be considered
a warning that the amino acid quantity is in excess
compared to the amount needed on the surface. The
slight increase in the ee during the first reuse of the in
situ formed hybrid catalyst confirmed this conclusion.
Conclusion
In conclusion a novel, highly efficient organic-
inorganic hybrid heterogeneous catalyst formed in situ
from amino acids was described. The material formed
by addition of laponite RD to the reaction mixture was
applied in the asymmetric addition of aldehydes to
nitrostyrenes. In the chiral surface catalyzed reaction
improved activities and increased enantioselectivities
were obtained as compared with the homogeneously
catalyzed reactions. Surface-improved asymmetric
reactions occurred using natural amino acids.
Inversion of the sense of the enantioselectivity was
obtained upon changing L-proline to primary L-amino
acids. Results achieved in the addition of aliphatic
aldehydes to -nitrostyrenes with the hybrid material
formed from proline and laponite RD approached
those obtained with laboriously prepared synthetic
chiral organocatalysts.
Acknowledgements
Experimental Section
Financial support of the Hungarian National Science Foundation
through OTKA Grant K 109278 is appreciated.
Materials and methods
Laponite RD (Lap RD), Southern Clay Products; layered
double hydroxide (Mg-Al LDH), Plural MG50, Sasol,
MgO/Al2O3 1/1, carbonate form; montmorillonite K10
(Mont K10), Aldrich; montmorillonite (Mont), Aldrich;
bentonite, Bentolite H (Ben H), Southern Clay Products and
the oxides (-Al2O3, SiO2, ZnO, MgO, TiO2) were
commercially available materials. All chiral compounds
used as catalysts, chiral amino acids, derivatives thereof
were obtained from Aldrich and were used as received.
Reactants: trans--nitrostyrene derivatives, aldehydes,
ketones and solvents were of analytical grade and used as
provided by the suppliers (Aldrich, Fluka, VWR).
FT-IR measurements were recorded on a Bio-Rad
Digilab Divison FTS-65A/896 spectrometer operating in
diffuse reflectance mode (DRIFT) between 4000-400 cm-1
using 2 cm-1 resolution by averaging 256 scans. Powder X-
ray diffractograms of the solids were measured on a Rigaku
Miniflex-II diffractometer using Cu K radiation source.
Gas-chromatographic analysis of the products were carried
out using Agilent Techn. 6890 N GC-5973 MSD (GC-
MSD) equipped with a 60 m long HP-1MS capillary column
for mass spectrometric identification of the products and
Agilent 7890A GC-FID (GC-FID) equipped with chiral
capillary columns (Cyclosil-B, 30 m, Agilent, J&W or
Hydrogex g-TBDAc, 25 m, Macherey-Nagel) for
quantitative analysis, including separation of the
enantiomers. NMR spectra were recorded on a Bruker
AVANCE DRX 400 spectrometer using CDCl3 solvent.
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Advanced Synthesis & Catalysis
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FULL PAPER
Surface-improved asymmetric Michael addition
catalyzed by amino acids adsorbed on laponite
Adv. Synth. Catal. Year, Volume, Page – Page
György Szőllősi,* Dániel Gombkötő, Attila Zsolt
Mogyorós, and Ferenc Fülöp
13
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