An enantioselective recyclable polystyrene-supported threonine-derived organocatalyst for aldol reactions

Article abstract of DOI:10.1002/adsc.201400033

A series of primary amino acids covalently supported onto polystyrene through alkyne-azide cycloaddition reactions has been synthesized and evaluated as catalysts in asymmetric aldol reactions. A polymer-supported threonine behaves as an easily recyclable, highly reactive and stereoselective (up to 99% ee) catalyst in the aldol reaction of both cyclic and acyclic ketone donors with aromatic aldehydes in aqueous environments. While cyclic ketones react with anti diastereoselectivity, syn adducts are predominantly obtained with acyclic substrates. The heterogenized threonine catalyst has been used for the sequential synthesis of a small library of enantiopure aldol products.

Full text of DOI:10.1002/adsc.201400033

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DOI: 10.1002/adsc.201400033
An Enantioselective Recyclable Polystyrene-Supported
Threonine-Derived Organocatalyst for Aldol Reactions
Andrea H. Henseler,a Carles Ayats,a and Miquel A. Pericꢀsa,b,*
a
Institute of Chemical Research of Catalonia (ICIQ), Avda. Paꢁsos Catalans, 16. E-43007, Tarragona, Spain
Fax : (+34)-977-920-222; phone: (+34)-977-920-247; e-mail: mapericas@iciq.es
Departament de Quꢂmica Orgꢀnica, Universitat de Barcelona (UB), E-08028 Barcelona, Spain
b
Received: January 9, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400033.
Abstract: A series of primary amino acids covalently with anti diastereoselectivity, syn adducts are pre-
supported onto polystyrene through alkyne–azide cy- dominantly obtained with acyclic substrates. The het-
cloaddition reactions has been synthesized and eval- erogenized threonine catalyst has been used for the
uated as catalysts in asymmetric aldol reactions. A sequential synthesis of a small library of enantiopure
polymer-supported threonine behaves as an easily re- aldol products.
cyclable, highly reactive and stereoselective (up to
99% ee) catalyst in the aldol reaction of both cyclic
and acyclic ketone donors with aromatic aldehydes Keywords: aldol reaction; amino acids; organocataly-
in aqueous environments. While cyclic ketones react sis; polymers; supported catalysts
Introduction
They involve soluble species and in all cases extrac-
tion of the catalyst is required for recovery and re-
Catalyst immobilization onto different solid sup- use.[6h,m–o,r,v] In contrast with this, solid-supported cata-
ports[1] such as polymers,[2] nanoparticles[3] or mesopo- lysts would offer the advantage of easy recovery by
rous materials[4] represents an attractive approach to- simple filtration and could allow the implementation
wards increased sustainability in catalytic asymmetric of continuous flow processes.[13] Anchoring of highly
synthesis. Thus, simplicity of catalyst separation, recy- polar organocatalysts (such as free amino acids) is
cling and, as a consequence thereof, reduced effective also advantageous because common solubility prob-
catalyst loading are the main advantages offered by lems of the homogeneous counterparts can be easily
immobilized catalytic species. Proline and its deriva- circumvented. Thus, functional polystyrene resins
tives have found ample use in asymmetric organoca- swell in the presence of organic reagents in a variety
talysis as highly selective organocatalysts in asymmet- of solvents including water.
ric synthesis.[5] Natural primary amino acids and their
The asymmetric aldol reaction catalyzed by amino
derivatives, in turn, have found more limited applica- acids is one of the most powerful methods to form
tion as organocatalysts, and only recently has their carbon-carbon bonds in nature and in synthetic organ-
use in aldol,[6] Michael,[7] Mannich,[6e,u,8] a-amination[9] ic chemistry.[14] While a better catalytic activity of
and cyanosilylation[10] reactions been reported.[11] In threonine compared to other primary amino acids as
contrast to polymer-supported proline-derived orga- catalysts for aldol reactions has been noted in some
nocatalysts,[12] to the best of our knowledge, there are instances,[6h,u,v,15] examples are also known where other
no examples of solid-supported primary amino acids amino acids such as serine or phenylalanine display
used in enantioselective catalysis. If one considers a superior catalytic performance in these proces-
that organocatalytic processes mediated by primary ses.[6j,n,16] In the context of our efforts towards the de-
amino acids often require catalyst loadings of up to velopment of a basic toolkit of solid-supported orga-
30%,[6b,d,g,l,q] the interest in immobilizing these species nocatalytic species with improved sustainability char-
and decreasing through recycling the effective catalyst acteristics,[12p,r,17] we report herein the first synthesis of
loading becomes evident.
a series of highly selective primary amino acid-de-
Until now, only a few examples of recyclable pri- rived, polystyrene-supported analogues for asymmet-
mary amino acid-derived organocatalysts are known. ric aldol reactions.
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Andrea H. Henseler et al.
Table 1. Catalyst screening for the asymmetric aldol reaction
of para-nitrobenzaldehyde 9a with cyclohexanone 10a.
Results and Discussion
The performance of immobilized organocatalysts im-
portantly depends on the level of cross-linking of the
polymer matrix.[12p,r] Therefore, polystyrene (PS) sup-
ported catalysts 1–6 were prepared via “click” reac-
tions[12c,j,l,p,r,18,19] with Merrifield resins with two differ-
ent levels of cross-linking [1% and 8% 1,4-divinylben-
zene (DVB)]. The synthesis of catalysts 1a and 1b as
a representative example is depicted in Scheme 1. For
comparison purposes, homogeneous unnatural amino
acid 1c[20] was also prepared and tested in catalysis
(Figure 1).
The series of catalysts was initially evaluated in the
reaction of para-nitrobenzaldehyde 9a with cyclohexa-
none 10a (Table 1). According to previous experience
with polymer-supported proline,[12r] a DMF-water
mixture was used as solvent. We found that in the
case of cysteine-derived systems (1a–c) the supported
derivatives (1a, b) showed a significantly higher activ-
ity than their homogeneous analogue 1c (entries 1–3).
A similar behaviour, suggesting a cooperative effect
of polymer backbone, triazole linker and catalytic
unit was already noted for proline.[12c,j] Catalysts 4a,
b were synthesized from l-serine-b-lactone via ring-
opening with NaN3.[21] These molecules were designed
Entry
Catalyst
Conv.[a]
anti:syn[b]
ee[c]
1
2
3
4
5
6
7
8
1a
1b
1c
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
38
38
–
31
45
52
74
–
–
50
–
70
73
82:18
81:19
–
88:12
92:8
83:17
76:24
–
64
51
–
79
81
57
60
–
–
51
–
96
93
9
–
10
11
12
13
83:17
–
93:7
83:17
[a]
In [%]; determined by 1H NMR spectroscopy of the
crude mixture.
Determined by H NMR spectroscopy on the crude mix-
[b]
[c]
1
ture.
In [%]; determined by HPLC using a chiral stationary
phase after purification.
to feature a close structural similarity with immobi-
lized trans-4-azidoproline, since resins incorporating
this species via CuAAC reaction depict optimal cata-
lytic performance in aqueous aldol reactions.[12j,r] Sur-
prisingly enough, no catalytic activity was observed
with catalysts 4a, b (Table 1, entries 8 and 9). In turn,
catalysts 5a, b derived from 5-hydroxytryptophan cat-
alyzed the test reaction with moderate to high levels
of activity and stereoselectivity (Table 1, entries 10
and 11).
Scheme 1. Synthesis of catalytic resins 1a and 1b.
PS-supported threonine derivatives 6a, b, which
only differ from the serine-derived resins 2a, b by an
additional methyl group, showed the best catalytic
performance (Table 1, entry 12) and approached and
even surpassed the selectivity displayed by immobi-
lized prolines. Based on these results, the threonine-
derived catalyst 6a involving slightly cross-linked
polystyrene (1% DVB) was selected for optimization
studies.
To further improve reaction rates and stereoselec-
tivities, the influence of the amount of water in the
solvent system was studied (Table 2). Interestingly,
catalyst 6a remains active over the full range of
water/DMF binary mixtures. In pure water and in
pure DMF (entries 1 and 2) the recorded diastereose-
lectivity is not optimal, and the results with anhydrous
DMF (entry 3) suggest that water is crucial to acceler-
ate the reaction. The accelerating effect of water in
Figure 1. Primary amino acid-derived catalysts developed in
this study.
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An Enantioselective Recyclable Polystyrene-Supported Threonine-Derived
Table 2. Solvent effects on the aldol reaction of para-nitro-
benzaldehyde 9a with cyclohexanone 10a catalyzed by resin
6a.
benzaldehyde 9a afforded the corresponding anti-
aldol products with good yields and enantioselectivi-
ties, albeit with low to moderate diastereoselectivity.
While many studies on amino acid-catalyzed aldol
reactions have been limited to cyclohexanone or
cyclic ketones as a donor component, the use of 6a
with acyclic ketones in front of aromatic aldehydes
(entries 12–15) was also tested. Reactions with acyclic
ketones afforded the corresponding syn-aldol prod-
ucts with moderate to excellent enantioselectivities.
Contrary to proline, primary amino acids preferential-
ly mediate aldol reactions with acyclic ketones via
(Z)-enamine intermediates, thus yielding syn-aldol
products.[6f] Therefore, primary amino acid catalysis in
asymmetric aldol reactions with acyclic ketones can
be considered complementary to proline catalysis.
The aldol reaction of para-nitrobenzaldehyde 9a
and acetone 10e proceeded in the presence of catalyst
6a albeit with moderate yield and enantioselectivity.
Hydroxyacetone 10f could also be applied as a sub-
strate to afford syn-1,2-diols, which are important
building blocks for numerous biologically active mole-
cules.[6u] Notably, catalyst 6a also allows for the forma-
tion of the corresponding syn-1,2-diols derived from
protected dihydroxyacetone, which are particularly in-
Entry
Solvent
Yield[a]
anti:syn[b]
ee[c]
1
2
3
4
H2O
DMF
anh. DMF
H2O/DMF (92:8)
H2O/DMF (50:50)
H2O/DMF (8:92)
H2O/DMF (8:92)
65
33
27
54
62
72
90
80:20
68:32
76:24
86:14
92:8
94
93
93
94
93
96
96
5
6
92:8
91:9
7[d]
[a]
Isolated yield in [%].
Determined by H NMR spectroscopy on the crude mix-
ture.
In [%]; determined by HPLC using a chiral stationary
phase after purification.
20 mol% of catalyst 6a was used and the reaction time
was reduced to 8 h.
[b]
[c]
[d]
1
catalysis by primary amino acids has been previously teresting substrates during the synthesis of carbohy-
observed.[6b,d,i–k,s] In these studies, the beneficial effect drates.[6e]
of water is described as the result of a hydrophobic
These are, in fact, the first examples of aldol reac-
interaction, which assembles catalyst and reagents in tions involving hydroxyacetone or dihydroxyacetone
a polar aqueous environment.[6s] Although this effect performed by an insoluble, polymer-supported cata-
might be enhanced by the hydrophobic polystyrene lyst. When the highly polar nature of the correspond-
backbone of catalyst 6a, the possible role of the tri- ing aldol products is considered, the advantages for
ACHTUNGTRENNUNG
a small number of water molecules should also be
As already mentioned, the use of immobilized cata-
considered.[12j] The optimal performance with respect lysts offers the inherent advantages of easy recovery
to yield and selectivity was achieved in a mixture of and reuse. In the present case, we explored the recy-
water and DMF (8:92, Table 2, entry 6). When the clability of catalyst 6a in the test reaction of para-ni-
catalyst loading is increased to 20 mol% (Table 2, trobenzaldehyde 9a with cyclohexanone 10a. The
entry 7), the reaction time could be decreased to standard reaction conditions of Table 3 (20 mol% of
eight hours.
6a, 8 h reaction time) were used in these experiments.
On the basis of these findings, the optimized reac- After each run, the catalyst could be recovered by
tion conditions [20 mol% of catalyst in water/DMF simple filtration and reused in the next cycle by
(8:92)] were used in further aldol reactions. The scope simple addition of fresh reactants and solvent. As
of catalyst 6a was examined in aldol reactions of a rep- shown in Figure 2, resin 6a was recycled five times, af-
resentative set of ketones, including both cyclic and fording the aldol product with constant stereoselectiv-
acyclic examples, with aromatic aldehydes (Table 3). ity and only marginal erosion in conversion (from 99
The reaction of cyclohexanone 10a with a series of ar- to 90%) for a constant reaction time.
omatic aldehydes provided anti-aldol products in
As a further demonstration of the synthetic poten-
good to excellent yields and enantioselectivities (up tial of 6a, we planned to use this immobilized catalyst
to >99% ee and 88:12 dr). Notably, good yields and for the sequential synthesis of a small library of enan-
high levels of stereoselectivity could also be achieved tioenriched aldol products. From a general perspec-
with electron-rich aldehydes (Table 3, entries 7 and tive, the fast and directed synthesis of closely related
8). Other cycloalkanones (entries 9–11) performed enantiopure compounds is a common need in discov-
nearly equally well in this reaction. Thus, the direct ery-oriented industries, such as the pharmaceutical,
aldol reaction of cyclopentanone 10b, cycloheptanone agrochemical or high-performance materials sectors.
10c and tetrahydropyran-4-one 10d with para-nitro- For its easy separation from the reaction mixture, im-
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Table 3. Asymmetric aldol reactions with different aldehydes and ketones catalyzed by 6a.
Entry
1
Product
Yield[a]
90
anti:syn[b]
ee[c]
Time
8 h
88:12
95
94
95
2
3
87
90
88:12
87:13
30 h
16 h
4
5
6
7
81
94
74
75
88:12
78:22
78:22
69:31
94
95
94
99
16 h
39 h
48 h
72 h
8
70
75
76
78
79
86
68:32
58:42
68:32
80:20
–
92
89
73
89
46
85
72 h
8 h
9
10
11
12[d]
13
55 h
40 h
96 h
24 h
25:75
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An Enantioselective Recyclable Polystyrene-Supported Threonine-Derived
Table 3. (Continued)
Entry
Product
Yield[a]
96
anti:syn[b]
ee[c]
Time
24 h
14
21:79
78
15[e,f]
73
12:88
87
96 h
[a]
Isolated yield in [%].
Determined by H NMR spectroscopy on the crude mixture.
In [%]; determined by HPLC using a chiral stationary phase after purification.
Reaction performed in acetone (25.0 equiv.) as reactant and solvent.
7.0 equiv. of the ketone were used.
[b]
[c]
[d]
[e]
[f]
1
The ee was determined after acetylation (see the Supporting Information for details).
mobilized catalysts with high activity profile and good
recycling characteristics present unique advantages
for this application and provide a satisfactory re-
sponse to this demand.
To simultaneously show the scalability of the reac-
tion, these experiments were performed using a single
sample of 0.500 g (0.52 mmol) of catalyst 6a and
2.6 mmol of each reactant aldehyde. We have repre-
sented in Scheme 2 the way in which the library of
aldol products was prepared. The resin was initially
swollen with DMF/water (92:8), the first reactant
partners (9a and 10a) were added in the same propor-
tion used in the general procedure (1:5 molar ratio),
and the reaction mixture was shaken for the reaction
time specified in Table 3 for this combination of reac-
tants. After separation of the reaction mixture by fil-
tration, washing the resin with ethyl acetate (4ꢄ
4 mL), and vacuum drying, the whole procedure was
sequentially repeated with 9a/10b, 9c/10a, and with
9a/10f. The results obtained for the whole library
Figure 2. Asymmetric aldol reactions of para-nitrobenzalde-
hyde 9a with cyclohexanone 10a in a series of identical recy-
cling experiments. Light bars: conversion [%]; black bars:
dr [%]; grey bars: ee [%].
Scheme 2. Catalyst recycling in the sequential synthesis of a small library of enantioenriched aldol adducts.
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band of the azide (2092 cmÀ1) had completely disappeared,
the reaction product was filtered off and the resin was suc-
cessively washed with 1N HCl, H2O (until pH neutral),
H2O/MeOH (1:1), MeOH, MeOH/THF (1:1), THF and
DCM. The solid was dried under vacuum at 408C for 24 h.
Elemental analysis (%): N 5.15, C 76.39, H 7.25; f=
0.92 mmolgÀ1. The N-Boc-protected polystyrene resin was
swollen in DCM (10 mL). After 10 min shaking, trifluoro-
acetic acid (1.1 mL) was added and the reaction vessel was
shaken at room temperature for 3 h. The reaction was moni-
tored by FT-IR spectroscopy. When the IR band of the Boc
group had completely disappeared, the reaction product was
filtered off and suspended in a solvent mixture of MeOH/
H2O (1:1) and 1N NaOH was added dropwise until pH 6.
The solid was filtered and washed successively with H2O,
H2O/MeOH (1:1), MeOH, MeOH/THF (1:1), THF and
DCM. The solid was dried in vacuo at 408C for 24 h. Ele-
have been summarized in Scheme 2, and essentially
replicate those obtained individually for the same
four adducts 11aa, 11ab, 11ca, and 11af (see entries 1,
9, 3, and 13 in Table 3).
Conclusions
In summary, anchoring strategies for a series of pri-
mary amino acids onto polystyrene resins using “click
chemistry” have been developed. Out of the different
immobilized catalysts prepared, polystyrene-support-
ed threonine 6a shows the best performance in asym-
metric aldol reactions in aqueous environments with
enantioselectivities of up to 99%.
We have also shown that catalyst 6a allows aldol re-
actions of aromatic aldehydes with a variety of ke-
tones including different cyclic ketones, hydroxyace-
tone and protected dihydroxyacetone generating aldol
products of high enantiomeric purity with anti- or
syn-selectivity depending on the cyclic or acyclic
nature of the ketone donor. The catalyst can be re-
covered by filtration and reused five times without
showing any symptoms of deactivation. From an op-
erational point of view, the ease of catalyst separation
has a very positive impact on the isolation of highly
polar aldol products like those derived from hydrox-
yacetone. An interesting application arising from the
combination of these characteristics in 6a is the use of
this heterogenized catalyst for the sequential synthesis
of focused libraries of enantiopure aldol products.
mental analysis (%):
N 5.82, C 75.83, H 7.00; f=
1.04 mmolgÀ1.
Synthesis of Catalysts 1b–6a, b
Amino acid-derived catalysts 1b–6a, b were prepared ac-
cording to the procedure used for catalyst 1a. Experimental
details, spectra and spectroscopic data are provided in the
Supporting Information.
General Procedure for the Asymmetric Aldol
Reactions
The polystyrene-supported amino acid (20 mol%) was swol-
len in a mixture of DMF/H2O (92 mL:8 mL). Aldehyde 9
(314 mmol) and ketone 10 (1.6 mmol, 5.0 equiv.) were
added, and the reaction mixture was shaken at room tem-
perature. After the indicated time, the resin was filtered off,
washed with ethyl acetate (3ꢄ1 mL), and dried under
vacuum. The combined liquid phases were dried over anhy-
drous magnesium sulfate and concentrated under reduced
pressure. Conversion and diastereomeric ratio were deter-
mined by performing 1H NMR spectroscopy on the crude
samples after removal of the resin. The aldol products were
purified by column chromatography. The enantiomeric
excess was determined by HPLC on a chiral stationary
phase after purification. For the recycling experiments the
dried resin could be used in the next reaction without fur-
ther treatment. The up-scaled experiments were conducted
under identical conditions.
Experimental Section
General Remarks
Liquid aldehydes were purified by distillation prior to use.
Other commercial reagents were used as received and all re-
actions were carried out under air, unless stated otherwise.
Elemental analyses of the polystyrene (PS) resins were per-
formed on a LECO CHNS 932 micro-analyzer at the Uni-
versidad Complutense de Madrid, Spain. The degree of
functionalization was calculated on the basis of elemental
analysis.[22] The spectroscopic data of all aldol products were
identical to data reported in the literature.
Characterization of Aldol Products
1
All obtained aldol products are literature known. H NMR
and HPLC spectra are provided in the Supporting Informa-
tion.
Typical Procedure for the Synthesis of Catalyst 1a
(R)-2-[(tert-Butoxycarbonyl)amino]-3-(prop-2-yn-1-yl-thio)-
propanoic acid 7[19] (468 mmol, 468 mg, 1.4 equiv.), DIPEA
(2.3 mL, 12.9 mmol, 10.0 equiv.) and CuI (14 mg, 75 mmol,
6 mol%) were added to a suspension of azidomethyl poly-
styrene 8a, b[12p] (1.0 g, 1.3 mmol, f=1.29 mmolgÀ1,
1.0 equiv., 1% DVB) in a solvent mixture of THF/DMF
(1:1) and the mixture was shaken at 408C for 30 h. The reac-
tion was monitored by FT-IR spectroscopy. When the IR
Acknowledgements
This work was funded by MINECO (grants CTQ2008-00947/
BQU
and
CTQ2012-38594-C02-01),
DEC
(grant
2009SGR623), and ICIQ Foundation. C. A. thanks MICINN
for a Juan de la Cierva postdoctoral fellowship. A. H. H
thanks the MECD for an FPU fellowship.
6
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8
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
An Enantioselective Recyclable Polystyrene-Supported
Threonine-Derived Organocatalyst for Aldol Reactions
9
Adv. Synth. Catal. 2014, 356, 1 – 9
Andrea H. Henseler, Carles Ayats, Miquel A. Pericꢀs*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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These are not the final page numbers!