Polystyrene-supported diarylprolinol ethers as highly efficient organocatalysts for Michael-type reactions

Article abstract of DOI:10.1002/chem.201101730

α,α-Diphenylprolinol methyl- and trimethylsilyl ethers anchored onto a polystyrene resin have been prepared by a copper-catalyzed azide-alkyne cycloadditions (CuAAC). The catalytic activity and enantioselectivity displayed by the O-trimethylsilyl derivati

Full text of DOI:10.1002/chem.201101730

FULL PAPER
DOI: 10.1002/chem.201101730
Polystyrene-Supported Diarylprolinol Ethers as Highly Efficient
Organocatalysts for Michael-Type Reactions
Esther Alza,[a] Sonia Sayalero,[a] Pinar Kasaplar,[a] Diana Almas¸i,[a] and
Miquel A. Pericꢀs*[a, b]
Abstract:
a,a-Diphenylprolinol
lytic unit, the triazole linker, and the
polymeric matrix provides unprece-
dented substrate selectivity, in favor of
linear, short-chain aldehydes, when the
organocatalyzed reaction proceeds by
an enamine mechanism. High versatili-
ty is noted in reactions that proceed
via an iminium ion intermediate. The
catalytic behavior of polystyrene-sup-
ported a,a-diphenylprolinol methyl
ether was also evaluated in asymmetric
Michael addition reactions. As a gener-
al trend, the CuAAC immobilization of
diarylprolinol ethers onto insoluble
polystyrene resins offers important op-
erational advantages, such as high cata-
lytic activity, easy recovery from the re-
action mixture by simple filtration, and
the possibility of extended reuse.
methyl- and trimethylsilyl ethers anch-
ored onto a polystyrene resin have
been prepared by a copper-catalyzed
azide–alkyne cycloadditions (CuAAC).
The catalytic activity and enantioselec-
tivity displayed by the O-trimethylsilyl
derivative are comparable to those ex-
hibited by the best known homogene-
ous catalysts for the addition of alde-
hydes to nitroolefins and of malonates
or nitromethane to a,b-unsaturated al-
dehydes. The combination of the cata-
Keywords: aldehydes · asymmetric
catalysis · Michael addition · orga-
nocatalysis · solid-phase catalysts
Introduction
proper selection of the position on the homogeneous cata-
lyst to be modified to create an anchoring point, the nature
of the linker, spacer (if any), and polymer support plays also
a fundamental role in determining the catalytic activity and
stereoselectivity of the supported species. The more widely
used supports that allow homogeneous conditions to be
closely approached are highly swellable, yet insoluble, resins
made of slightly cross-linked polystyrene-based polymers.
Such polymers are readily available, can be easily function-
alized by various methods, and have high chemical inert-
ness.[2] Among them, Merrifield resins and their derivatives
are ideal carriers for catalytic species due to their easy han-
dling, optimal physical properties, and modularity.[3]
The continued and ever-growing interest in organocataly-
sis over the past two decades has led to the development of
many different types of organocatalyzed reactions that pro-
vide enantiomerically pure compounds through very simple
reaction setups.[4] However, many of these reactions lead to
rather polar products, so isolation and purification become
the main sources of solvent consumption and waste genera-
tion. Taking into account factors such as separation, catalyst
recovery, and ease of purification of the reaction products,
the immobilization of organocatalytic species appears a
promising strategy.
The covalent immobilization of chiral catalytic species onto
polymer supports has become an important research area
over the last decade,[1] mainly due to the inherent properties
of the polymer backbone, which allows easy recovery by
simple filtration, recycling, reuse, and even application in
continuous-flow processes. However, this strategy sometimes
leads to a decrease in catalytic activity with respect to the
monomeric species because of a deficient interaction be-
tween the reactants and the supported catalyst. This is ac-
companied by a decrease in enantioselectivity due to pertur-
bation of the transition state of the enantiodetermining step
by the polymer chain. Thus, appropriate design and prepara-
tion of the heterogeneous catalytic systems is essential to
achieve catalytic activities and selectivities comparable to
those provided by their homogeneous counterparts. Besides
[a] Dr. E. Alza, Dr. S. Sayalero, P. Kasaplar, Dr. D. Almas¸i,
Prof. Dr. M. A. Pericꢀs
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢁsos Catalans, 16
43007 Tarragona (Spain)
Fax : (+34)977920222
E-mail: mapericas@iciq.es
In a continued effort towards the development of chemi-
cal processes with improved sustainability characteristics, we
have introduced a variety of organocatalysts synthesized
from pyrrolidine derivatives and anchored onto insoluble
polystyrene resins[5a–g] by copper-catalyzed azide–alkyne cy-
cloaddition (CuAAC).[6] The nature of the catalytic species,
the presence of the triazole linker, and the environment pro-
[b] Prof. Dr. M. A. Pericꢀs
Departament de Quꢂmica Orgꢀnica
Universitat de Barcelona (UB)
08028 Barcelona (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101730.
Chem. Eur. J. 2011, 17, 11585 – 11595
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11585

vided by the polymer backbone have shown a synergistic
effect, which has led to remarkably high catalytic activity
and enantioselectivity.[5a–g]
Catalysis mediated by primary or secondary amines in-
clude reactions that take place via enamine and iminium ion
intermediates.[7] Among these processes, Michael reactions[8]
represent a powerful synthetic tool for the assembly of 1,5-
difunctionalized compounds (Scheme 1). Within the wide
actions and aldehydes have proven to be very reactive and
convenient donors in this process. Catalysts derived from
(S)-a,a-diarylprolinol silyl ethers have provided excellent
results in terms of activity and selectivity for aminocatalytic
enantioselective Michael reactions. For the design of a
widely applicable polymer-supported Jørgensen–Hayashi-
type organocatalyst, we reasoned that the immobilization
strategy should involve the functionalization of these sys-
tems at the most remote position from the catalytic active
amine moiety and the chiral C2 atom, to avoid perturbation
of the enantiodetermining transition state by the linker and
the polymeric backbone (Scheme 2).
Scheme 1. Michael reaction of aldehydes with nitroolefins and malonates
via enamine and iminium ion intermediates, respectively.
Scheme 2. Supported organocatalyst design.
application range of these chemical transformations, their
use as the first step in cascade processes,[9] or use of a com-
bination of the two catalysis mechanisms in tandem sequen-
ces, has aroused a great deal of interest because complex
molecular frameworks can be constructed in simple, one-pot
operations. Of particular interest are catalysts derived from
(S)-a,a-diarylprolinol silyl ethers,[10] independently intro-
duced by Jørgensen and Hayashi for the enantioselective or-
ganocatalyzed a-sulfenylation of aldehydes and asymmetric
Michael addition of aldehydes to nitroalkenes, respective-
ly.[11] The steric effect caused by the bulky substituent placed
at C2 on the pyrrolidine ring controls the enantioselectivity
of the reactions very efficiently.
We selected natural hydroxyproline as our starting materi-
al and a CuAAC reaction as the covalent strategy to anchor
the pyrrolidine moiety onto Merrifield resin (Scheme 3).
This well-established atom-economic immobilization ap-
proach[5] required some synthetic effort to prepare the key
intermediate 3 from the propargyloxy derivative (1) of com-
mercially available N-Boc-(2S,4R)-4-hydroxyproline methyl
ester (Boc=tert-butoxycarbonyl). The silylation, with con-
comitant carbamate deprotection of 2, afforded the desired
intermediate 3,[5f] ready to be attached to the support by the
selected methodology. The CuAAC reaction planned for the
We have recently reported[5f] the development of a new
immobilized, enantiopure (S)-a,a-diphenylprolinol trimeth-
ACHTUNGTRENNUNGylsilyl ether (4)—supported onto polystyrene by a CuAAC
reaction—that displays an unprecedented selectivity in favor
of linear, short-chain aldehyde donors in the highly enantio-
selective Michael addition to nitroolefins. The same strategy
was subsequently employed by Mager and Zeitler for the at-
tachment of the same monomer to soluble methoxy polyeth-
yleneglycol polymers.[5h] Herein, we report a full account of
the design and synthesis of 4, the chemical modification of
this species as a methyl ether to obtain an extended life
cycle, and the use of these catalysts in a variety of Michael
reactions with aldehyde, malonate, or nitromethane donors
and nitroolefin or a,b-unsaturated aldehyde acceptors.
Results and Discussion
Design and synthesis of polystyrene-supported (S)-a,a-di-
phenylprolinol trimethylsilyl ether (4) and its evaluation in
the Michael addition of aldehydes to nitroolefins: The asym-
metric organocatalytic Michael addition[12] has emerged as
one of the most important carbon–carbon bond-forming re-
Scheme 3. Immobilization reaction to obtain polystyrene-supported (S)-
a,a-diphenylprolinol trimethylsilyl ether (4).
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Polystyrene-Supported Diarylprolinol Ethers
FULL PAPER
conjugation step represented an important synthetic chal-
lenge because common CuI catalysts employed for the cyclo-
addition were incompatible with the free amino group pres-
ent in the substrate. Notably, the immobilization of 3 onto
azidomethylpolystyrene was efficiently catalyzed by the
tris(triazolyl)methanol–copper complex (TTM-Cu),[13] which
allowed the easy and highly reproducible synthesis of the
catalytic resin 4.
filtration of the catalyst and evaporation of the solvent. In
any case, it is also important to emphasize the excellent per-
formance of 4 in water; this reaction is the first example of
an insoluble organocatalyst successfully promoting reaction
with aldehydes in an aqueous medium.[5c]
The scope of the Michael addition between aldehydes and
nitroolefins mediated by 4 was next studied. The results are
presented in Table 2. As a general trend, the syn Michael
Notably, when the immobilization was performed at an
earlier stage (immobilization of 2 to give resin i) the un-
avoidable formation of a cyclic carbamate was observed.
Hydrolysis of this class of intermediates is feasible in homo-
geneous phase, however, it posed severe experimental diffi-
culties on polymer substrates.
Table 2. Screening of substrates in the Michael addition of aldehydes to
nitroolefins catalyzed by 4.[a]
Recently, significant progress in the development of the
organocatalytic Michael reaction has been achieved through
the introduction of a variety of catalytic species and reaction
conditions. These include reaction in aqueous media or in
less-conventional environments, such as ionic liquids.[14] In
this context, the Michael addition of propionaldehyde to b-
nitrostyrene was selected as a model reaction for optimiza-
tion of the reaction conditions with 4 as a catalyst (Table 1).
R1
R2
5
t
Conv[b] Yield[c] d.r.[b]
ee[d]
[%]
[h] [%]
[%]
1
2
3
4
5
6
7
8
9
H
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5 f
5g
72
7
5
50
>99
>99
44
98
93
98
91
–
–
>99:1
90:10
82:18
75:25
96
Me
Et
Pr
n-pent Ph
iPr
>99
>99
99
27 >99
48 99
96 <10
98
Ph
Ph
n.d.[e] n.d.
Table 1. Screening of reaction conditions for the Michael addition of pro-
Ph
48
<5
0
–
–
n.d.
n.d.
n.d.
n.d.
98
99
90
95
97
99
pionaldehyde to (E)-b-nitrostyrene.[a]
A
5h 120
5i
Me
4-BrC6H4
4-MeOC6H4 5j
2-furyl
4
8
4
>99
>99
>99
98
94
96
94
89
84
91:9
10 Me
11 Me
12 Me
13 Me
14 Me
89:11
85:15
81:19
70:30
70:30
5k
A
24 >99
64 >99
C6H11
iPr
5m
5n
96
88
[a] General conditions: nitroolefin (0.2 mmol), aldehyde (0.3 mmol), 4
(0.02 mmol), solvent (1 mL), RT. [b] Conversion and diastereomeric ratio
(d.r.) determined by 1H NMR spectroscopy of the crude reaction mixture.
[c] Isolated yield. [d] Determined by chiral HPLC analysis. [e] n.d.=not
determined.
Solvent
Additive[b] t [h] Conv [%][c] syn/anti[c] ee [%][d]
1[e] hexane/THF none
36
7
24
40
>99
>99
>99
>99
>99
>99
97
97:3
96:4
97
>99
99
2[e] CH2Cl2
3[e] CH2Cl2
4[e] CH2Cl2
none
DMAP
81:19
77:23
>99:1
86:14
87:13
96:4
PhCOOH 24
97
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
H2O
none
DMAP
PhCOOH
7
23
2
>99
>99
99
99
–
products 5 were obtained with excellent diastereo- and
enantioselectivity. Even in the challenging Michael reaction
of acetaldehyde with b-nitrostyrene (Table 2, entry 1) resin 4
compares favorably with a,a-diphenylprolinol trimethylsilyl
ether, which avoids the use of a large excess of acetaldehyde
and employs a halved catalyst loading.[15] Thus, adduct 5a
can be prepared in 96% enantiomeric excess (ee), which de-
serves special comment given the reported interest in a-un-
substituted-g-nitroaldehydes and general interest in the or-
ganocatalytic reactions of acetaldehyde.[15,16]
The catalytic activity of 4 showed a remarkable dependen-
cy on the structure of the aldehyde donor. Thus, fast reac-
tions were observed for linear, short-chain aldehydes pro-
pionaldehyde and butanal (Table 2, entries 2 and 3), whereas
the reaction time increased significantly with chain length
(Table 2, entries 4 and 5). In all of these cases, the yields
and enantioselectivities of the major syn products were ex-
cellent. Branching at the b position of the aldehyde had a
detrimental effect on reaction rate (Table 2, entries 6 and 7)
and a branching (Table 2, entry 8) completely blocked the
diMePEG 24
TFA 48
CH2Cl2
none
–
[a] General conditions: (E)-b-nitrostyrene (0.2 mmol), propionaldehyde
(0.3 mmol), and
4 (0.02 mmol), solvent (1 mL), RT. [b] Additive
(0.02 mmol). [c] Conversion determined by 1H NMR spectroscopy of the
crude reaction mixture. [d] Determined by chiral HPLC analysis. [e] Pro-
pionaldehyde (2 mmol).
It was established that CHA2CHUTNRGNENUG Cl2 was the optimal solvent for
the reaction. Although different additives were tested
(Table 1, entries 3, 4, 6–8), optimal results were recorded
with the use of 10 mol% catalyst in the absence of any addi-
tive (Table 1, entry 5). Notably, these optimal conditions in-
volve the use of a 1.5:1.0 molar ratio of aldehyde/nitrostyr-
ene, much more convenient than the usually employed 10:1
ratio. Indeed, Michael adducts were obtained in this manner
with better diastereoselectivity and from cleaner crude reac-
tion products due to the suppression of aldehyde self-con-
densation reactions. When volatile substrates were used, the
direct isolation of the pure products was possible by simple
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11587

M. A. Pericꢀs et al.
reaction. Ketones, such as ace-
tone and cyclohexanone, were
also tested as Michael donors
but they were found to be
completely unreactive.
With respect to the Michael
acceptor, various substituted
nitroolefins were tested. Under
the optimized conditions, the
addition of propionaldehyde to
b-substituted aromatic nitroal-
kenes gave the expected syn
adducts in excellent yields and
enantioselectivities after short
reaction times, independent of
the electronic properties of the
Scheme 5. Origin of the substrate selectivity [aldehydes (ald) versus ketones (ket)] in the Michael addition of
carbonyl compounds to b-nitrostyrene catalyzed by 4.
aryl or heteroaryl substituent (Table 2, entries 9–11). Reac-
tion time increased notably when the aromatic substituent
was not conjugated with the nitroolefin (Table 2, entry 12)
and for aliphatic nitroolefins (Table 2, entries 13 and 14), al-
though the Michael products 5l–n were obtained in high
yield and excellent enantioselectivity.
To ascertain if selectivity for linear aldehydes could be
achieved in the presence of branched ones, we tested resin 4
in the Michael reaction of a mixture of butanal and 2-meth-
ylpropanal, with the composition that resulted from the Rh-
catalyzed hydroformylation of propene and b-nitrostyrene
in the presence of 4 (4/b-nitrostyrene/butanal/2-methylpro-
panal 0.1:1.0:2.4:1.5; see Scheme 4). Gratifyingly, under
these conditions, only the linear aldehyde underwent Mi-
chael addition with no decrease in enantioselectivity
(99% ee, compared to Table 2, entry 3).
branched aldehydes or ketones can be rationalized through
the equilibria represented in Scheme 5.
As already mentioned, the insoluble nature of the poly-
mer allows for catalyst recovery by simple filtration. Howev-
er, the recycling process can be limited by deactivation ef-
fects and, in the case of a,a-diphenylprolinol silyl ethers, the
lability of the silyl ether group towards hydrolysis[12r] makes
the reuse of the organocatalyst sometimes difficult. In our
case, a complete absence of catalytic activity was observed
in the Michael reaction of a resin that bore free hydroxyl
groups on the a,a-diphenylprolinol moiety.
After extensive experimentation, we were able to address
the deactivation problem of catalyst 4 by selective reprotec-
tion of the hydroxyl groups of inactive diphenylprolinol-type
resins through brief treatment with trimethylsilyl N,N-di-
AHCTUNGTRENNUNG
methylcarbamate[17] in hexane/acetonitrile. This simple pro-
However, the reaction time required for complete conver-
sion (92% isolated yield) under these conditions was sub-
stantially extended (24 vs. 5 h), which suggested that unpro-
ductive enamines of 2-methylpropanal could be formed
during the reaction and lead to a decrease in the concentra-
tion of the viable enamine intermediate. This suggestion is
reinforced by the results of competition experiments that in-
volved pentanal and cyclohexanone. When an equimolar
mixture of these substrates was treated with b-nitrostyrene,
the required time for the complete conversion of pentanal
extended from 27 to 55 h. Even more noteworthy, when the
cyclohexanone/pentanal ratio was changed to 13:1, the reac-
tion time increased to 7 d. The retardation effect exerted by
cedure leads to full recovery of the catalytic activity of the
supported organocatalyst 4 and makes its reuse possible.
Thus, in six consecutive cycles of reaction/reconditioning,
the excellent performance of resin 4 in the Michael addition
of propionaldehyde to 4-bromo-b-nitrostyrene remained
intact (Scheme 6). Interestingly, the reactivation procedure
does not represent any significant inconvenience from a
practical point of view. Because the only byproduct formed
in the process is dimethylamine, the reactivated resin can be
directly reused after washing out any excess silylating re-
agent.
Synthesis and evaluation of polystyrene-supported (S)-a,a-
diphenylprolinol methyl ether (11) in the Michael reaction
of aldehydes and nitroalkenes:
Although the origin of the de-
activation of resin 4 was eluci-
dated and properly solved, we
were interested in the develop-
ment of more robust polymer-
supported
diphenylprolinol-
type catalysts with the ultimate
goal of performing the present
reaction in a continuous-flow
manner. Therefore, we aimed
Scheme 4. Selective Michael addition of butanal to b-nitrostyrene in the presence of 2-methylpropanal cata-
lyzed by 4.
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Chem. Eur. J. 2011, 17, 11585 – 11595

Polystyrene-Supported Diarylprolinol Ethers
FULL PAPER
Table 3. Evaluation of organocatalyst 11 in the Michael addition of pro-
pionaldehyde to (E)-b-nitrostyrene.[a]
Additive (10 mol%)
t [h]
Yield[b] [%]
d.r.[c]
ee[d] [%]
1
2
none
96
48
48
48
48
60
51
63
53
35
55
72
80:20
79:21
82:18
2:1
93:7
95:5
85
92
90
82
93
93
PhCOOH
PhCOOH[f]
4-NO2PhCOOH
PhCOOH
PhCOOH
3[e]
4
Scheme 6. Reconditioning and reuse of resin 4.
5[g]
6[h]
[a] General conditions: (E)-b-nitrostyrene (0.2 mmol), propionaldehyde
(0.3 mmol), 11 (0.02 mmol), solvent (1 mL), RT. [b] Isolated yield. [c] De-
termined by H NMR spectroscopy of the crude reaction mixture. [d] De-
termined by chiral HPLC analysis. [e] Catalyst 11 (0.03 mmol). [f] Ben-
zoic acid (15 mol%). [g] (E)-b-nitrostyrene (1.5 equiv). [h] (E)-b-nitro-
styrene (3 equiv).
to prepare and evaluate polymer-supported diphenylprolinol
methyl ether (11), which should be stable under the stan-
dard reaction and recycling conditions, and not show hydro-
lytic deactivation. The synthesis of resin 11 is explained in
detail in the Supporting Information and summarized in
Scheme 7.
1
acid as a co-catalyst (Table 3, entry 2) led to a slight im-
provement in the activity of catalyst 11, although deactiva-
tion was observed (after approximately 48 h) before full
conversion could be achieved.
On the other hand, the addition of benzoic acid had a
positive effect on the enantioselectivity of the process,
which increased from 85 to 92% ee, whereas the diastereo-
selectivity did not experience any change. The use of an ad-
ditional 5 mol% of catalyst and co-catalyst did not change
the results significantly (Table 3, entry 3). In turn, addition
of the more acidic p-nitrobenzoic acid had a negative effect
on both the conversion and stereoselectivity (Table 3,
entry 4). In light of recently published kinetic studies, which
revealed that the rate-limiting steps in the case of peptide-
organocatalyzed conjugate addition reactions between alde-
hydes and nitroolefins are both the reaction of the enamine
with the electrophile and the hydrolysis of the resulting
imine,[19] we decided to perform the Michael addition of
propanal to (E)-b-nitrostyrene with 1.0:1.5 and 1:3 molar
ratios of aldehyde/nitroolefin (Table 3, entries 5 and 6, re-
spectively). In these cases, the excess of nitrostyrene led to
the Michael adduct 5b with good enantioselectivity and
highly improved diastereoselectivity relative to the previous
results, even increasing the reaction time, although complete
conversion was not achieved. Based on these initial experi-
ments, we can envisage that although polystyrene-supported
methyl ether 11 does not present the problem of ether
cleavage under mild reaction conditions, it would show
worse performance as a catalyst in the Michael addition of
aldehydes to nitroolefins relative to 4. This demonstrates,
once again, the crucial role exerted by the O-silyl protecting
group in the control of catalytic activity and selectivity of di-
arylprolinol ether derivatives.
Scheme 7. Synthesis of the polymer-supported organocatalyst 11.
To avoid the difficulties associated with the small-scale
preparation of a non-supported counterpart,[18] our synthetic
approach started with the preparation of compound 6 by se-
lective protection of commercially available (2S,4R)-4-hy-
droxyproline methyl ester hydrochloride. Grignard addition
and subsequent methylation of the resulting tertiary alcohol
provided the intermediate 8, which was sequentially depro-
tected to give key intermediate 4-hydroxy diphenylprolinol
methyl ether (9). Propargylation of 9 led to the required de-
rivative 10, suitable for a TTM-Cu-mediated click reaction
with azidomethyl polystyrene.
Resin 11 was evaluated in the Michael addition of
propionACHTUNGTRENNUNGaldehyde to (E)-b-nitrostyrene (Table 3). Under the
previously optimized conditions for catalyst 4 (Table 3,
entry 1), the reaction proceeded slowly and with lower selec-
tivity than with the silylated resin 4. The addition of benzoic
Conjugate additions of malonates to a,b-unsaturated alde-
hydes catalyzed by 4: Secondary amines readily experience
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11589

M. A. Pericꢀs et al.
condensation reactions with aldehydes or ketones to form
intermediate iminium cations. These species are character-
ized by a low-lying LUMO and can often be trapped by nu-
cleophiles before proton loss converts them into imines (pri-
mary amines) or enamines (secondary amines). This nucleo-
philic trapping is the fundamental event in iminium-type
aminocatalysis. Focusing on conjugate addition reactions, a
broad range of nucleophilic intermediates, such as nitroal-
kanes, nitroesters, malonates, and ketoesters, among others,
have been used for conjugate addition to a,b-unsaturated
systems assisted by iminium-type aminocatalysis.[20] The
modularity of the products that arise from this process
makes them valuable building blocks in organic chemistry.
Chiral secondary amines, such as imidazolidinone deriva-
tives[21] and O-TMS-protected diarylprolinols,[22] have shown
high efficiency as catalysts by activating a,b-unsaturated sys-
tems through iminium-type mechanisms. Through the use of
recoverable organocatalysts, positive economic and environ-
mental aspects could complement this synthetic efficiency.
In view of our recent results obtained with dimethyl 3-ox-
oglutarate,[5g] we decided to test the 4 in the reaction of a,b-
unsaturated aldehydes with dialkyl malonates.[23] The addi-
tion of diethyl malonate to cinnamaldehyde was selected as
a model reaction and the results from the preliminary
screening of the reaction conditions are shown in Table 4.
Initially, we chose dichloromethane as the solvent because
of its good swelling properties for resin 4 and the optimal
performance of this solvent in the Michael addition of alde-
hydes to nitroalkenes discussed above. When the reaction
was performed in the absence of additives, poor activity was
recorded, with only 24% of conversion after 96 h (Table 4,
entry 1), although enantioselectivity was high (90% ee).
Benzoic acid (30 mol%), a commonly employed acidic co-
catalyst for iminium-catalyzed processes, was tested as an
additive to promote conversion, but no improvement was
observed (Table 4, entry 2). As an alternative, we attempted
to increase the activity of catalyst 4 by Lewis base/Brønsted
base co-operative catalysis.[23c] Thus, when lithium acetate
was used as a Brønsted base to activate the malonate re-
agent complete conversion was recorded after 36 h and
enantioselectivity was preserved (Table 4, entry 3). To inves-
tigate the effect of the aldehyde/malonate ratio in the reac-
tion, we tried the same reaction with diethyl malonate
(1.0 equiv), cinnamaldehyde (1.5 equiv) and lithium acetate
(10 mol%). No change in enantioselectivity was observed,
but conversion suffered a dramatic decrease and only 25%
of the starting material had reacted after 24 h (Table 4,
entry 4). Tetrahydrofuran was tested as a solvent for the op-
timal swelling of 4 but, surprisingly, resulted in total loss of
catalytic activity (Table 4, entry 5). Water was also tested as
a solvent, but after 96 h conversion was only 49% and the
ee had decreased to 53% (Table 4, entry 6). Thus, the possi-
ble environmental advantages presented by this solvent are
outbalanced by its probable negative effect on iminium ion
formation and malonate reactivity. Finally, to mitigate the
requirement for long reaction times, we decided to perform
the reaction under low-power microwave (MW) irradiation,
in line with our previous experience in other reactions cata-
lyzed by polystyrene-supported species.[5e,24] Gratifyingly, a
notable acceleration of the reaction was observed (Table 4,
entry 7).
Under low-power MW irradiation (2 W), the reaction
temperature increased from 23 to 308C and the reaction
time was reduced by a factor of six (Table 4, entry 7 versus
3), although no change in enantioselectivity was noticed.
Under these optimized conditions, the scope of the reaction
was studied. A series of dialkyl malonates and a,b-unsatu-
rated aldehydes were tested and the results are presented in
Table 5.
The addition of dimethyl, diethyl, or diisopropyl malo-
nates to cinnamaldehyde was studied at room temperature
and under MW irradiation (2 W, 6 h). In all cases, the ex-
pected products 12a–c were obtained with full conversion
and very high enantioselectivities (Table 5, entries 1–3).
Branching in the alkyl moiety of the malonate ester
(Table 5, entry 3) resulted in an extended reaction time for
complete conversion to be achieved. Given the excellent
enantioselectivity recorded from reaction with dimethyl mal-
onate (Table 5, entry 2), we evaluated the addition of this
nucleophile to a small family of a,b-unsaturated aldehydes.
Good yields and high enantioselectivities were obtained
from the reactions of cinnamaldehyde derivatives with
either an electron-donating or electron-withdrawing group
on the para position of the ring (Table 5, entries 4 and 5).
Full conversion was again observed in the addition of di-
methyl malonate to heterocyclic a,b-unsaturated aldehyde
3-(2-furyl)acrolein, but the enantioselectivity was substan-
tially lower than for previous examples (Table 5, entry 6).
To exemplify enals lacking extended conjugation, 2-heptenal
was also tested as an electrophile in the reaction (Table 5,
entry 7) and afforded the addition product 12g with good
yield and enantioselectivity. As a general observation, the
Table 4. Optimization of the reaction conditions for the asymmetric addi-
tion of diethyl malonate to cinnamaldehyde catalyzed by 4.[a]
Solvent
Additive (30 mol%)
t [h]
Conv[b] [%]
ee[c] [%]
1
2
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
none
96
24
36
24
48
96
6
24
8
>99
25
0
49
90
n.d.
90
90
n.d.
53
PhCOOH
LiOAc
LiOAc[e]
LiOAc
LiOAc
LiOAc
4[d]
5
6
H2O
CH2Cl2
7[f]
93
90
[a] General conditions: cinnamaldehyde (0.2 mmol), diethyl malonate
(0.6 mmol), 4 (0.02 mmol), solvent (1 mL), RT. [b] Conversion was deter-
1
mined by H NMR spectroscopy of the crude reaction mixture. [c] Deter-
mined by chiral HPLC analysis. [d] Reaction carried out with a 1:1.5
molar ratio of aldehyde/malonate. [e] LiOAc (10 mol%). [f] Reaction
carried out under MW irradiation (2 W) in CH2Cl2 (0.3 mL).
11590
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Chem. Eur. J. 2011, 17, 11585 – 11595

Polystyrene-Supported Diarylprolinol Ethers
FULL PAPER
Table 5. Substrate scope in the asymmetric addition of dialkyl malonates
Table 6. Recycling experiments of catalyst 4 in the asymmetric addition
to a,b-unsaturated aldehydes organocatalyzed by 4.[a]
of diethyl malonate to cinnamaldehyde.[a]
Yield[b,c] [%]
ee[b,d] [%]
Cycle
t [h]
Conv[b] [%]
ee[c] [%]
Product
t [h]
1
2
6
6
6
6
93
73
53
77
90
90
90
90
3[d]
4[e]
1
2
3
4
36
81
86
85
87
(88)
(80)
(63)
(85)
91
99
90
94
(90)
[a] General conditions: cinnamaldehyde (0.2 mmol), diethyl malonate
(0.6 mmol), LiOAc (0.06 mmol), 4 (0.02 mmol), CH2Cl2 (0.3 mL), MW ir-
radiation (2 W). [b] Conversion was determined by 1H NMR spectrosco-
py of the crude reaction mixture. [c] Determined by chiral HPLC analy-
sis. [d] Additional LiOAc (0.06 mmol) was added. [e] Resin reconditioned
by treatment with trimethylsilyl N,N-dimethylcarbamate (see referen-
ce [5f].
36
72
96
(99)
(90)
(92)
ty (Table 6, cycle 3); nevertheless, enantioselectivity re-
mained unchanged over the three runs. As already men-
tioned, we could reactivate resin 4 in the Michael addition
of aldehydes to nitroolefins by reprotection of the inactive
polymer-supported diphenylprolinol with trimethylsilyl N,N-
dimethylcarbamate.[17] In this particular case, such treatment
had a positive effect but did not lead to complete recovery
of the catalytic activity of 4 (Table 6, cycle 4).
5
36
90
(89)
92
(90)
To test the performance of polystyrene-supported methyl
ether 11 in reactions taking place via iminium ion intermedi-
ates, 11 (10 mol%) was also tested as catalyst in the addition
of diethyl malonate to cinnamaldehyde in the presence of
LiOAc (30 mol%) in CH2Cl2 under MW irradiation (2 W)
to accelerate the reaction. After 6 h, 12a could be isolated
in 27% yield and 86% ee. This result confirmed our initial
impression (see above) on the lower catalytic efficiency of
11 relative to 4.
6
7
96
96
75
85
(82)
(76)
77
79
(78)
(83)
[a] General conditions: a,b-unsaturated aldehyde (0.2 mmol), dialkyl
malonate (0.6 mmol), LiOAc (0.06 mmol), (0.02 mmol), CH2Cl2
(0.3 mL), RT or MW irradiation (6 h, 2 W). [b] The results of the experi-
ments performed under MW irradiation are shown in parentheses. [c] Iso-
lated yield. [d] Determined by chiral HPLC analysis.
Addition of nitromethane to a,b-unsaturated aldehydes cat-
alyzed by 4: Further proof of the effectiveness of resin 4 in
reactions that take place through iminium ion activation
could be obtained from its notable performance in the imi-
nium-catalyzed enantioselective synthesis of g-nitro alde-
hydes by a Henry-type reaction of nitromethane with a,b-
unsaturated aldehydes.[5h,25] Preliminary experiments in the
addition of nitromethane to cinnamaldehyde under the opti-
mal reaction conditions reported for a,a-diphenylprolinol-
type catalysts[5h,25] [MeOH, catalyst (10 mol%), benzoic acid
co-catalyst (10–20 mol%)] resulted in poor conversions.
Much better results were obtained in dichloromethane, an
optimal swelling media for 4, which was adopted as the sol-
vent for this study (Table 7). On the other hand, the use of
LiOAc (20 mol%) as a co-catalyst in the addition of nitro-
methane to cinnamaldehyde resulted in a significant reduc-
tion of activity, therefore its use was no longer considered.
Thus, the selected reaction conditions were a combination
of 4 and benzoic acid in dichloromethane.
4
results obtained from this screening showed that the co-op-
erative catalytic system 4/LiOAc is highly efficient for the
addition of malonates to a,b-unsaturated aldehydes with the
advantage of easy separation of the polymer-supported cata-
lyst from the obtained products. Experimentally, activation
of the reactions with low-power microwave irradiation
(2 W) is clearly advantageous over execution of the reac-
tions at room temperature.
The possibility of recycling and reusing resin 4 was next
studied. As shown in Table 6, conversion decreased consid-
erably when the catalytic system 4/LiOAc was directly
reused after separation of the reaction mixture and a di-
chloromethane wash (Table 6, cycle 2). Addition of fresh
LiOAc in the next cycle did not improve the catalytic activi-
Chem. Eur. J. 2011, 17, 11585 – 11595
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11591

M. A. Pericꢀs et al.
Table 7. Evaluation of organocatalyst 4 in the Michael addition of nitro-
methane to a,b-unsaturated aldehydes.[a]
tion conditions. High yields and selectivities were recorded
with both electron-poor and electron-rich substituted cinna-
maldehydes (Table 7, entries 6–8). With 3-(2-furyl)acrolein
(Table 7, entries 9 and 10) the reaction proceeded more sat-
isfactorily when run under MW irradiation at 308C, and
gave g-nitro aldehyde 13e in moderate yield but with excel-
lent enantioselectivity.
Product
T
t
Conv[b]
[%]
Yield[c]
[%]
ee[d]
[8C]
[h]
[%]
1[e]
2
RT
RT
45
45
45
65
56
20
30
6
75
>99
83
64
>99
52
86
75
51
61
96
96
95
93
96
Conclusion
3
An insoluble polystyrene-supported diarylprolinol silyl ether
(4) was prepared and used as a highly efficient, reusable or-
ganocatalyst for Michael additions that proceed by enamine
or iminium ion catalysis. In reactions via enamine intermedi-
ates, 4 exhibits a remarkable preference for linear aldehyde
donors; this preference can be used in practice for the dif-
ferentiation between linear and branched aldehydes in their
reactions with nitroolefins. In reactions taking place via imi-
nium ion intermediates, 4 efficiently mediates the addition
of dialkyl malonates and nitromethane to a,b-unsaturated
aldehydes. As a general observation, 4 exhibits a catalytic
4[e]
5[f]
6[f]
7[f]
8[f]
45
45
45
6
6
6
>99
>99
>99
80
88
85
91
90
90
performance comparable, or superior, to monoACTHNURTGNEUmGN eric, soluble
diarylprolinol silyl ethers and offers the additional advantag-
es of simplified reaction workup, easy catalyst recovery, and
the possibility of catalyst reuse. In an attempt to extend the
life cycle of 4 for repeated use, a polystyrene-supported dia-
rylprolinol methyl ether (11) was also prepared and evaluat-
ed. However, the catalytic characteristics of this species are
inferior to those of 4.
9[f]
45
30
6
7
>99
85
31
52
94
95
10[g]
[a] General conditions: a,b-unsaturated aldehyde (0.2 mmol), nitrome-
thane (0.6 mmol), benzoic acid (0.04 mmol), (0.04 mmol), CH2Cl2
4
(0.5 mL). [b] Conversion determined by 1H NMR spectroscopy of the
crude reaction mixture. [c] Isolated yield. [d] Determined by chiral GC
or HPLC analysis. [e] Catalyst 4 (10 mol%). [f] Reaction performed
under MW irradiation (7 W). [g] Reaction performed under MW irradia-
tion (3 W).
Experimental Section
When 4 (10 mol%) and benzoic acid (20 mol%) were
used to promote the reaction at room temperature, only
moderate conversion to 13a was recorded after 65 h
(Table 7, entry 1). However, the enantioselectivity compared
very favorably with that recorded when soluble a,a-diphe-
nylprolinol trimethylsilyl ethers were used.[5h,25] Increasing
the catalyst loading (20 mol%) was enough to ensure com-
plete conversion, high yield, and excellent enantiomeric
excess after a reasonable reaction time (Table 7, entry 2).
Importantly, we also found that heating the reaction mixture
at 458C accelerated the reaction but compromised both the
yield and enantioselectivity (Table 7, entries 3 and 4). Inter-
estingly, when the reaction was performed at this tempera-
ture under MW irradiation (7 W), we were able to signifi-
cantly reduce the reaction time and achieve total conversion
of cinnamaldehyde without any detriment to the enantiose-
lectivity (Table 7, entry 5). The observed decrease in the iso-
lated yield under these conditions can be attributed to poor
stability of the aldehyde product.[25b]
General procedure for the Michael addition of aldehydes to nitroolefins
catalyzed by
4 or 11 (GP1): Nitroolefin (0.2 mmol) and catalyst 4
(46.1 mg, 10 mol% according to the functionalization (f)=
0.462 mmolgÀ1) or 11 (45.1 mg, 10 mol%, f=0.443 mmolgÀ1) were mixed
with the aldehyde (0.3 mmol) in CH2Cl2 (1.0 mL). The suspension was
stirred at RT for the time specified in Table 2 and filtered to separate the
solid catalyst. The resin was washed with CH2Cl2 and the combined or-
ganic extracts were concentrated under reduced pressure. A 1H NMR
spectrum was recorded to calculate the conversion and d.r. For volatile
starting aldehydes, the Michael adduct was obtained as the evaporation
residue without further purification. In other cases, purification by flash
chromatography on silica gel (EtOAc/hexane) afforded the Michael
adduct. The enantiomeric excess was determined by HPLC on a chiral
stationary phase (Chiralpak IB or Chiralcel AD-H columns).
All of the prepared products are known and spectroscopic data are, in all
cases, in agreement with the published data. Compounds 5a–k have been
described in a preliminary communication of this work.[5f]
Starting nitroolefins (E)-(4-nitrobut-3-en-1-yl)benzene, (E)-(2-nitrovi-
nyl)cyclohexane, and (E)-3-methyl-1-nitrobut-1-ene were prepared by lit-
erature procedures.[26]
(2R, 3R) 2-Methyl-3-nitromethyl-5-phenyl-pentanal (5l):[27] Compound
AHCTUNGTRENNUNG
5l was prepared from E-(4-nitrobut-3-en-1-yl)benzene and propionalde-
hyde according to GP1 in 94% yield (44.2 mg, 0.188 mmol) as an insepa-
rable mixture of two diastereomers. 95% ee by HPLC: IB (hexane/
iPrOH 95:5, 1.0 mLminÀ1, l=220 nm); retention time (tR) (major)=
The beneficial effect of MW activation in this reaction
was additionally confirmed when a representative set of a,b-
unsaturated aldehydes was evaluated under the same reac-
18.6 min, tRACTHNUTRGNE(NUG minor)=21.3 min.
11592
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Chem. Eur. J. 2011, 17, 11585 – 11595

Polystyrene-Supported Diarylprolinol Ethers
FULL PAPER
A
0.15 mmol) following GP2. When GP3 was followed, 12 f was obtained in
82% yield (46.3 mg, 0.164 mmol). HPLC: AD-H (hexane/iPrOH 80:20,
0.8 mLminÀ1, l=210 nm); t
RACHTNUGTRENNUG(minor)=20.3 min, tRACHTUNGTREN(NGUN major)=22.2 min.
ACHTUNGTRENNUNG
(R)-1-Isopropyl 3-methyl 2-((R)-1-oxoheptan-3-yl)malonate (12g):[29]
Compound was obtained from (E)-hept-2-enal and dimethyl malonate
with catalyst 4 after 96 h in 85% yield (46.3 mg, 0.17 mmol) following
GP2. When GP3 was followed 12g was obtained in 76% yield (41.4 mg,
CTHUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
0.152 mmol). HPLC: IC (heptane/iPrOH 90:10, 1 mLminÀ1
, mass-
prepared from E-3-methyl-1-nitrobut-1-ene and propionaldehyde accord-
ing to GP1 in 84% yield (29 mg, 0.168 mmol) as an inseparable mixture
of two diastereomers. 99% ee by HPLC: AD-H (hexane/iPrOH 99:1,
APCI(À)); t
RACHUTGTNRENNUG(major)=13.3 min, tRACHTUNGTREN(NGUN minor)=14.1 min.
General procedure for the Michael addition of nitromethane to cinna-
maldehyde (GP4): Catalyst 4 (10–20 mol%, f=0.462 mmolgÀ1) and ben-
zoic acid (4.87 mg, 0.04 mmol) were placed in a vial. CH2Cl2 (0.5 mL),
cinnamaldehyde (0.2 mmol, 25 mL), and nitromethane (0.6 mmol, 32 mL)
were added successively. The mixture was stirred at the indicated temper-
ature for the time noted in Table 7. The resin was filtered and rinsed with
CH2Cl2. The combined organic extracts were concentrated under reduced
pressure and the crude product purified by flash chromatography (silica
gel, hexane/EtOAc 10:1).
0.8 mLminÀ1, l=210 nm); t
RACHTNUGTRENNUG(major)=12.6 min, tRACHTUNGTREN(NGUN minor)=13.9 min.
General procedure for the addition of malonates to a,b-unsaturated alde-
hydes (GP2): Resin 4 (10 mol%, f=0.462 mmolgÀ1) and lithium acetate
(30 mol%) were placed in a vial. CH2Cl2 (1 mL) was added, followed by
the a,b-unsaturated aldehyde (0.2 mmol) and dialkyl malonate
(0.6 mmol). The mixture was stirred at RT for the time indicated in
Table 4, until total conversion was confirmed by 1H NMR spectroscopy.
The resin was filtered off and rinsed with CH2Cl2 (3 mL). The combined
organic extracts were concentrated under reduced pressure and the crude
product purified by flash chromatography on silica gel (hexane/diethyl
ether, 10:1).
General procedure for the Michael addition of nitromethane to a,b-unsa-
turated aldehydes under MW irradiation (GP5): Catalyst 4 (86.6 mg,
0.04 mmol, f=0.462 mmolgÀ1) and benzoic acid (4.87 mg, 0.04 mmol)
were placed in a MW vial. CH2Cl2 (0.5 mL), a,b-unsaturated aldehyde
(0.2 mmol), and nitromethane (0.6 mmol, 32 mL) were added successive-
ly. The mixture was irradiated at 7 W (458C) for 6 h in a MW reactor.
The resin was filtered and rinsed with CH2Cl2. Evaporation of the solvent
under reduced pressure afforded the desired product, which was purified
by flash chromatography (silica gel, hexane/EtOAc 10:1). Products 13a–e
are known compounds and the spectroscopic data are in agreement with
the published data.[5h,25a]
(S)-4-Nitro-3-phenylbutanal (13a):[25a] Compound 13a was obtained from
cinnamaldehyde in 86% yield following GP4, and in 61% yield following
GP5. GC-MS: Chiraldex G-TA (1308C isotherm, 1.5 mLminÀ1);
tRACHTNUGTRENNUG(minor)=133.4 min, tRACHTUNGTREN(NGUN major)=139.4 min.
(S)-3-(4-Methoxyphenyl)-4-nitrobutanal (13b):[25a] Compound 13b was
General procedure for the addition of malonates to a,b-unsaturated alde-
hydes under MW irradiation (GP3): Resin
4
(10 mol%, f=
0.462 mmolgÀ1), lithium acetate (30 mol%), and CH2Cl2 (0.3 mL) were
added to a MW vial. a,b-Unsaturated aldehyde (0.2 mmol) and dialkyl
malonate (0.6 mmol) were added. The mixture was irradiated at 2 W
power (308C) for 6 h. The resin was filtered off and rinsed with CH2Cl2
(3 mL). The combined organic extracts were concentrated under reduced
pressure and the crude product purified by flash chromatography
(hexane/diethyl ether, 10:1). Products 12a–g are known compounds, and
the spectroscopic data are in agreement with the published data.[23c–g,29]
(R)-Diethyl 2-(3-oxo-1-phenylpropyl)malonate (12a):[23c] Compound 12a
was obtained from (E)-cinnamaldehyde and diethyl malonate with cata-
lyst 4 after 36 h in 81% yield (47.4 mg, 0.162 mmol) following GP2.
When GP3 was followed, 12a was obtained in 88% yield (51.5 mg,
obtained from 3-(4-methoxyphenyl)propenal in 80% yield following
GP5. HPLC: IB (hexane/iPrOH 85:15, 1.0 mLminÀ1
, l=254 nm);
0.176 mmol). HPLC: AD-H (hexane/iPrOH 80:20, 0.5 mLminÀ1
, l=
tRACHTNUGTRENNUG(minor)=11.9 min, tRACHTUNGTREN(NGUN major)=12.5 min.
210 nm); tRACHTUNGTRENNUNG(major)=17.5 min, tRAHCTUNGTRNEN(UGN minor)=21.9 min.
(S)-4-Nitro-3-(4-nitrophenyl)butanal (13c):[5h] Compound 13c was ob-
(R)-Dimethyl 2-(3-oxo-1-phenylpropyl)malonate (12b):[23c] Compound
12b was obtained from (E)-cinnamaldehyde and dimethyl malonate with
catalyst 4 after 36 h in 86% yield (45.5 mg, 0.172 mmol) following GP2.
When GP3 was followed, 12b was obtained in 80% yield (42.3 mg,
tained from 3-(4-nitrophenyl)propenal in 88% yield following GP5.
HPLC: IC (hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm); t
RACHTUNGTRENNUNG(minor)=
41.3 min, tRACTHNUTRGNE(NUG major)=44.4 min.
(S)-3-(4-Chlorophenyl)-4-nitrobutanal (13d):[25a] Compound 13d was ob-
0.16 mmol). HPLC: AD-H (hexane/iPrOH 80:20, 0.5 mLminÀ1
, l=
210 nm); tRACHTUNGTRENNUNG(major)=20.4 min, tRAHCTUNGTRNEN(UGN minor)=23.8 min.
tained from 3-(4-chlorophenyl)propenal in 85% yield following GP5.
HPLC: IC (hexane/iPrOH 10:1, 1.0 mLminÀ1, l=240 nm); t
RACHTUNGTRENNUNG(minor)=
(R)-Diisopropyl 2-(3-oxo-1-phenylpropyl)malonate (12c):[23c] Compound
12c was obtained from (E)-cinnamaldehyde and diisopropyl malonate
with catalyst 4 after 72 h in 85% yield (54.5 mg, 0.17 mmol) following
GP2. When GP3 was followed, 12c was obtained in 63% yield (40.3 mg,
18.9 min, tRACTHNUTRGNE(NUG major)=20.8 min.
(S)-3-(2-Furyl)-4-nitrobutanal (13e):[25a] Compound 13e was obtained
from 3-furyl-propenal in 52% yield following a modified version of GP5
with irradiation at 3 W for 7 h. GC-MS: Chiraldex G-TA (1308C iso-
0.126 mmol). HPLC: AD-H (hexane/iPrOH 80:20, 0.5 mLminÀ1
, l=
therm, 1.5 mLminÀ1); t
RACHTNUGTRENNUG(minor)=49.9 min, tRACHTUNGTREN(NGUN major)=54.0 min.
210 nm); tRACHTUNGTRENNUNG(major)=14.4 min,
tRACHTUNGTRENNUNG(minor)=17.6 min.
For general methods and for the synthesis and characterization of 11, see
(R)-2-Isopropyl 3-methyl 2-((R)-1-(4-methoxyphenyl)-3-oxopropyl)malo-
nate (12d):[23g] Compound 12d was obtained from (E)-3-(4-methoxyphen-
yl) acrylaldehyde and dimethyl malonate with catalyst 4 after 96 h in
87% yield (56 mg, 0.174 mmol) following GP2. When GP3 was followed,
12d was obtained in 85% yield (54.8 mg, 0.17 mmol). HPLC: AD-H
the Supporting Information.
Acknowledgements
(hexane/iPrOH 90:10, 0.8 mLminÀ1
RA(minor)=27.1 min.
, l=210 nm); tRACHTUNTGNERUGN(major)=25.3 min,
t CHTUNGTRENNUNG
This work was funded by MICINN (Grant CTQ2008–00947/BQU and
Consolider Ingenio 2010 Grant CSD2006–0003), DIUE (Grant
2009SGR623), and ICIQ Foundation. E.A. thanks the ICIQ Foundation
for a pre-doctoral fellowship. P.K. thanks MICINN for a pre-doctoral
FPI-fellowship. The authors gratefully acknowledge S. Curreli for her
help with HPLC-MS and GC-MS analysis.
(R)-1-Isopropyl 3-methyl 2-((R)-1-(4-nitrophenyl)-3-oxopropyl)malonate
(12e):[23g] Compound 12e was obtained from (E)-3-(4-nitrophenyl)acry-
laldehyde and dimethyl malonate with catalyst 4 after 36 h in 90% yield
(61 mg, 0.18 mmol) following GP2. When GP3 was followed, 12e was ob-
tained in 89% yield (60 mg, 0.178 mmol). HPLC: AD-H (hexane/iPrOH
80:20, 0.8 mLminÀ1
25.4 min.
,
l=210 nm);
t
G
tRACTHNGUTER(NNUG minor)=
(R)-1-Isopropyl 3-methyl 2-((R)-1-(furan-2-yl)-3-oxopropyl)malonate
(12 f):[23g] Compound 12 f was obtained from (E)-3-(2-furyl)acrylaldehyde
and dimethyl malonate with catalyst 4 after 96 h in 75% yield (42.7 mg,
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Chem. Eur. J. 2011, 17, 11585 – 11595
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11595