Enantioselective 1,3-Dipolar Cycloadditions of Unsaturated Aldehydes Promoted by A Poly(ethylene glycol)-Supported Organic Catalyst

Article abstract of DOI:10.1002/ejoc.200300571

We have developed a polymer-supported version of MacMillan's catalyst by anchoring a tyrosine-derived imidazolidin-4-one by means of a spacer to the monomethyl ether of poly(ethylene glycol) (M_W = 5000 Da). The supported organic catalyst was employed in some 1,3-dipolar cycloadditions involving α,β-unsaturated aldehydes and nitrones. The products were obtained in enantiomeric excesses very similar to those observed with the non-supported catalyst, but the chemical yields were somewhat lower. Exploiting the solubility profile of the polymeric support, the catalyst was readily separated from the reaction products, recovered, and recycled. Catalyst recycling was accompanied by a very marginal erosion (if any) of the enantioselectivity and a more-substantial decrease in chemical efficiency. We ascribe the latter phenomenon mainly to the intrinsic instability of the catalyst under the reaction conditions, which is, however, a common feature of both the non-supported and supported catalysts. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300571

FULL PAPER
Enantioselective 1,3-Dipolar Cycloadditions of Unsaturated Aldehydes
Promoted by A Poly(ethylene glycol)-Supported Organic Catalyst
Alessandra Puglisi,[a] Maurizio Benaglia,*[a] Mauro Cinquini,[a] Franco Cozzi,[a] and
Giuseppe Celentano[b]
Keywords: Catalyst immobilization / Chiral organic catalysts / Cycloadditions / Polymers
We have developed a polymer-supported version of Mac-
Millan’s catalyst by anchoring a tyrosine-derived imidazoli-
din-4-one by means of a spacer to the monomethyl ether of
separated from the reaction products, recovered, and re-
cycled. Catalyst recycling was accompanied by a very mar-
ginal erosion (if any) of the enantioselectivity and a more-
poly(ethylene glycol) (MW = 5000 Da). The supported organic substantial decrease in chemical efficiency. We ascribe the
catalyst was employed in some 1,3-dipolar cycloadditions in- latter phenomenon mainly to the intrinsic instability of the
volving α,β-unsaturated aldehydes and nitrones. The prod- catalyst under the reaction conditions, which is, however, a
ucts were obtained in enantiomeric excesses very similar to
those observed with the non-supported catalyst, but the
chemical yields were somewhat lower. Exploiting the solubil-
common feature of both the non-supported and supported
catalysts.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ity profile of the polymeric support, the catalyst was readily Germany, 2004)
Introduction
In principle, organic catalysts are more readily amenable
than metal-based catalysts to anchoring on a support with
the aim of facilitating the separation of the product from
the catalyst and the recovery and recycling of the latter.[3,4]
Indeed, it has been shown repeatedly that the use of a me-
tal-based catalyst immobilized on a support is often affec-
ted by extensive metal leaching and requires catalyst re-gen-
eration by metal replenishment before recycling.[3a][3b]
The expression ‘‘organic catalyst’’ has been introduced
recently to define an organic compound (of relatively low
molecular weight and simple structure) capable of promot-
ing a given transformation in a substoichiometric quantity.
In this context, ‘‘organic’’ hints to the metal-free nature of
the catalyst, and emphasizes the advantages of performing
a reaction under metal-free conditions. These advantages
Over the last few years, we have been interested in the
might include, inter alia, the possibility of: i) working in development of poly(ethylene glycol)-supported versions of
wet solvents and under an aerobic atmosphere; ii) dealing both organic and metal-based catalysts.[5] The choice of
with a stable and robust catalyst; and iii) avoiding the prob- poly(ethylene glycol) (PEG) as the support is suggested by a
lem of a (possibly) expensive and toxic metal leaching into number of considerations, including the polymer’s low cost,
the organic product.
commercial availability, easy functionalization, and, most
Organic catalysts, and especially chiral organic cata- importantly, its very favorable solubility profile. Indeed,
lysts,[1] can be regarded as minimalist versions of enzymes, PEGs of Mw Ն 2000 Da are soluble in many organic sol-
from which they are derived conceptually and to which they vents and in water, and insoluble in a few other solvents,[6]
are often compared.[2] Even though they rarely display the which, thus, allows catalyzed reactions to be run under
remarkable selectivity that is characteristic of enzymes, or- homogeneous (and, likely, best-performing) conditions and
ganic catalysts generally are more stable than bio-catalysts the isolation and recovery of the catalyst as if it were bound
and enjoy a wider application under a variety of conditions to an insoluble polymer.[7]
that are unsustainable for enzymes.
Very recently, MacMillan and co-workers reported the
use of imidazolidin-4-ones, such as 1a,b (Scheme 1), as ef-
ficient organic catalysts for a variety of highly enantioselec-
[a]
tive reactions involving α,β-unstaurated aldehydes.[8] In a
Dipartimento di Chimica Organica e Industriale Ϫ Universita’
degli Studi di Milano
preliminary communication,[9] we have reported the immo-
via Golgi 19, 20133 Milano, Italy
bilization of an enantiopure imidazolidin-4-one on a deriva-
tive of PEG monomethyl ether of average MW ϭ 5000 Da
(MeOPEG) to afford an efficient supported catalyst for the
enantioselective DielsϪAlder reaction of α,β-unstaurated
Fax. (internat.) ϩ 39-02-50314159
E-mail: maurizio.benaglia@unimi.it
[b]
Istituto di Chimica Organica Ϫ Facolta’ di Farmacia Ϫ
Universita’ degli Studi di Milano,
via Venezian 21, 20133 Milano, Italy
Eur. J. Org. Chem. 2004, 567Ϫ573
DOI: 10.1002/ejoc.200300571
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
567

A. Puglisi, M. Benaglia, M. Cinquini, F. Cozzi, G. Celentano
FULL PAPER
nine to generate an imidazolidinone already equipped with
a properly located and chemically suitable handle for PEG
supporting.[12] Thus, starting from (S)-tyrosine methyl ester
hydrochloride 2, the imidazolidinone 3 was easily obtained
in 69% yield by N-butyl amide formation and treatment
with acetone (Scheme 1). Reaction of the Cs salt of (S)-3
with the readily available mesylate 4[13] in DMF afforded
the MeOPEG-supported imidazolidinone 5 in 87% yield.
Conversion of this compound to the catalytically active
species involved the addition of an equimolar amount of a
protic acid. While in the case of the DielsϪAlder cycload-
ditions the supported catalyst could be prepared in situ,[9]
the 1,3-dipolar cycloaddition reactions required only pre-
formed catalyst samples.
1,3-Dipolar Cycloadditions
The synthesis of the isoxazolidine 6 by reaction of N-
benzyl-C-phenyl nitrone (1 mol equiv.) with acrolein (4 mol
equiv.), carried out in the presence of 0.20 mol equiv. of
different 5/HX combinations in wet nitromethane, was used
as a model reaction (Scheme 2 and Table 1). The product
was obtained as mixtures of trans (generally dominant) and
cis isomers, the ratio of which was determined readily by
1H NMR spectroscopy on the crude product and confirmed
on the isolated adducts; enantiomeric excesses (ee) were de-
termined by HPLC on a chiral stationary phase after quan-
titative reduction of aldehyde 6 to the corresponding al-
cohol with NaBH4.[14]
Scheme 1. Synthesis of PEG-supported imidazolidinone 5
aldehydes with dienes.[10] Here we describe the extension of
the use of the PEG-supported catalyst to the 1,3-dipolar
cycloaddition of α,β-unstaurated aldehydes with nitrones.
Results and Discussion
Synthesis of the Supported Imidazolidinone
The data reported in Table 1 show a strong dependence
In principle, the synthesis of imidazolidin-4-ones such as of the efficiency of the reaction on the nature of the acid
1 (Scheme 1) offers three different sites for polymer attach- employed to generate the catalyst. We observed that catalyst
ment: the amide nitrogen atom at position 3, the carbon samples that afford reproducible results were obtained by
atom at position 2, and the aryl residue. It was easy to using HBF4, and in particular by adding a 54% w/w solu-
recognize, however, that the introduction of a PEG/spacer tion of HBF4 in diethyl ether to a dichloromethane solution
fragment at position 2 would generate an additional stere- of 5 and then isolating the catalyst by precipitation with
ocenter close to the reactive site that possibly would inter- diethyl ether. With 5/HBF4 as the catalyst (Entries 6Ϫ8),
fere with the stereochemical course of the reaction.[8e] On we obtained reasonable yields of adduct 6 with good values
the other hand, exploitation of the amide nitrogen atom of ee for its trans isomer. In general, we observed that the
would require the ad hoc synthesis of a spacer containing use of lower reaction temperatures led to higher values of
a terminal amino group and its subsequent anchoring to ee (Entries 5 vs. 4, and 8 vs. 7 vs. 6).
PEG.[11]
Extending the use of the supported catalyst 5/HBF4 to
Therefore, these options were discarded in favor of the other reagents was studied by performing the reactions de-
much simpler use of (S)-tyrosine instead of (S)-phenylala- scribed in Scheme 2. The data collected in Table 2 show that
Table 1. Catalytic stereoselective synthesis of isoxazolidine 6
Entry
Catalyst
T (°C)
Time (h)
Yield (%)[a]
trans/cis[b]
trans ee (%)[c][d]
1
2
3
4
5
6
7
8
5/CF3CO2H
5/CF3SO3H
5/HCl
5/HClO4
5/HClO4
5/HBF4
Ϫ10
Ϫ10
Ϫ10
Ϫ10
Ϫ20
0 to 24
Ϫ10
Ϫ20
68
68
68
68
96
24
68
120
18
22
34
46
30
73
67
71
75:25
50:50
40:60
86:14
86:14
86:14
81:19
85:15
68
36
71
85
90
72
78
87
5/HBF4
5/HBF4
[a]
[b]
Yields of isolated products.
As determined by 1H NMR spectroscopy (300 MHz) on the crude products and confirmed on the
[c]
isolated products. As determined by HPLC on a chiral stationary phase using the corresponding alcohol; yields and values of ee are
averages of duplicate experiments. The values of ee of the cis isomers ranged from 10 to 40% (by HPLC).
[d]
568
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Enantioselective 1,3-Dipolar Cycloadditions
FULL PAPER
Table 3. Comparison of catalysts derived from 1a and 5 in the syn-
thesis of adducts 6Ϫ9
Catalyst (20% mol) T (°C) Product Yield trans/cis trans ee
(%)
(%)
1a/CF3SO3H
5/HBF4
1a/HClO4
5/HBF4
1a/CF3SO3H
5/HBF4
1a/CF3SO3H
5/HBF4
Ϫ20
Ϫ20
Ϫ10
0 to 24
Ϫ20
Ϫ20
Ϫ20
Ϫ20
6
6
7
7
8
8
9
9
80
71
86
59
83
64
80
70
86:14
86:14
94:6
93:7
91:9
90:10
80:20
85:15
90
87
90
87
90
84
91
60
As mentioned before, two other imidazolidinone-based
catalysts precursors, namely 11, supported on JandaJel, and
12, supported on silica (Figure 1),[10] have recently been re-
ported. A comparison between the catalytic efficiency of
their salts with that of 5/HX[9] was possible only in the case
of the DielsϪAlder cycloadditions, since 11 and 12 have
not been tested in any 1,3-dipolar cycloadditions (Table 4).
Considering the catalytic enantioselective syntheses of ad-
ducts 13 and 14 (Figure 1), one can see that the use of the
insoluble catalyst 11/HCl anchored on JandaJel (Entries 3/
7) performed better, not only with respect to the PEG- and
silica-supported catalysts, but also relative to the non-sup-
ported catalyst,[8a] in both reactions (Entries 2/6, 4/8 and 1/
5, respectively). On the other hand, the catalysts immobil-
ized on PEG and silica behaved almost identically, but
slightly less efficiently, than the non-supported catalyst (En-
tries 2 vs. 4 vs. 1, and 6 vs. 8 vs. 5).
Scheme 2. Synthesis of adducts 6Ϫ10 by 1,3-dipolar cyclo-
addition reactions
Table 2. Catalytic stereoselective synthesis of isoxazolidines 7Ϫ10
in the presence of 5/HBF4
T (°C)
Time(h) Product Yield (%)[a] trans/cis[b] trans ee (%)[c]
0 to 24 24
7
59
64
60
41
93:7
87
84
60
80
Ϫ20
Ϫ20
96
96
8
90:10
85:15
90:10
9
10
0 to 24[d] 72
[a]
1
Yields of isolated products. [b] As determined by H NMR spec-
troscopy (300 MHz) on the crude products and confirmed on the
isolated products. [c] As determined by HPLC on a chiral stationary
phase using the corresponding alcohol; yields and values of ee are
[d]
averages of duplicate experiments. Carried out in wet CH3CN.
N-benzyl-C-phenyl nitrone reacted with crotonaldehyde to
afford a 93:7 mixture of 3,4-trans/3,4-cis isomers of com-
pound 7 in 59% yield; the major product had 87% ee. The
cycloaddition between acrolein and the N-benzyl nitrones
derived from 4-methoxy- and 4-chlorobenzaldehyde, and
cyclohexanecarboxyaldehyde, in the presence of the same
catalyst were also successful and led predominantly to trans
adducts 8Ϫ10 in fair-to-good yields (41Ϫ64%) and ee
(60Ϫ84%).[14]
A comparison of the results obtained with the PEG-sup-
ported catalyst in the 1,3-dipolar cycloaddition reactions
with those obtained by MacMillan using catalysts derived
from imidazolidinone 1a,[8c] (Table 3) indicates that the
major difference between the PEG-supported and the non-
supported catalyst resides in the chemical, rather than the
stereochemical, efficiency. Indeed, while the supported cata-
lyst gave trans/cis ratios almost identical to, and values of
ee only 3Ϫ6% lower than, those obtained using the non-
supported catalyst (compound 9 being an exception), the
Figure 1. Structures of insoluble polymer-supported imidazolidi-
nones 11 and 12 and of DielsϪAlder adducts 13 and 14
Catalyst Recovery and Recycling Experiments
In addition to facilitating the separation of the catalyst
difference in chemical yields was larger, ranging from 9 to from the reaction products, catalyst immobilization on a
27%.[15]
polymer should allow simple recovery and recycling. In this
Eur. J. Org. Chem. 2004, 567Ϫ573
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
569

A. Puglisi, M. Benaglia, M. Cinquini, F. Cozzi, G. Celentano
Table 4. Comparison of non-supported and supported catalysts in the synthesis of adducts 13 and 14
FULL PAPER
Entry
Catalyst; mol equiv.
Support
Product
Yield (%)
endo/exo
Major isomer ee (%)
1
2
3
4
5
6
7
8
1a/HCl; 0.05
5/CF3CO2H; 0.10
11/HCl; 0.20
12/HCl; 0.20
1a/HCl; 0.05
5/HBF4; 0.10
11/HCl; 0.20
12/HCl; 0.033
none
13
13
13
13
14
14
14
14
82
67
30
83
99
68
70
33
93:7
94:6
93:7
93:7
43:57
44:56
45:55
52:48
94
92
98
90
93
88
99
90
MeOPEG
JandaJel
silica
none
MeOPEG
JandaJel
silica
study, the separation of the catalyst was easily achieved by protons of the linker, which remained unchanged; particu-
concentrating the reaction mixture under vacuum, dissolv- larly evident was the partial disappearance of the imidazoli-
ing the residue in a small amount of dichloromethane dinone gem-dimethyl signals.
(2 mL/g of catalyst), and adding diethyl ether to the mixture
To check whether the instability of the PEG-supported
(40 mL of diethyl ether/mL of dichloromethane). The pre- catalyst was induced by the presence of the polymer, the
cipitated PEG-supported catalyst was then isolated by fil- triflate salt of imidazolidinone 1c (Scheme 1) was kept at 24
tration in 80Ϫ95% yield and the diethyl ether phase was °C for 120 h in a CD3CN/D2O (95:5) mixture both in the
worked-up to obtain the products. The recovered catalyst presence and in the absence of the dimethyl ether of
was then dried for a short time under vacuum to remove PEG2000. We did not observe degradation in either case by
traces of solvent and then recycled. In contrast to the NMR spectroscopy, which, thus, suggests that the polymer
DielsϪAlder cycloadditions, in which recycling was more is not playing a leading role in provoking the instability
efficient if the recycled catalyst was treated in situ with a of the supported catalysts. These findings seem to point to
fresh equimolecular amount of acid before adding the re- catalyst degradation induced by the presence of the re-
agents,[9] acid addition resulted in extensive decomposition agents. To assess this hypothesis, we prepared nitromethane
of the nitrone when the polymer was applied to the 1,3- solutions containing commercial 1a/HCl (1 mol equiv.), an
dipolar cycloadditions. Catalyst recycling was studied by unsaturated aldehyde (20 mol equiv.), and water (15 mol
performing the synthesis of cycloadducts 6 and 7.
equiv.) and kept them at 24 °C for 20 h to mimic the con-
The data collected in Table 5 indicate that the enantiose- ditions of the 1,3-dipolar cycloaddition. After evaporation
lectivity of the recovered catalyst was maintained almost of the solvent, NMR spectroscopic analysis showed that
intact for at least three reaction cycles, while the chemical extensive catalyst degradation occurred with acrolein, less
efficiency of the recovered catalyst slowly eroded upon its degradation with crotonaldehyde, and essentially no degra-
iterative re-use.
dation with cinnamaldehyde as the aldehyde.[16]
In agreement with the results of these experiments, we
also observed that the non-supported catalyst 1a/HCl
showed a decrease in chemical efficiency when recycled.[17]
For instance, the yield of compound 7 (obtained by a reac-
tion involving crotonaldehyde) dropped from 64 to 49%
upon one recycling, while the value of ee of trans-7 changed
from 89 to 87%. It is also interesting to note that the degra-
dation byproducts do not interfere with the enantioselectiv-
ity of the surviving catalyst.
Table 5. Catalyst recycling experiments in the synthesis of adducts
6 and 7.
Catalyst
Cycle Product Yield (%) trans/cis trans ee (%)
[a]
[a]
[a]
[b]
[b]
[b]
5/HBF4
5/HBF4
5/HBF4
5/HBF4
5/HBF4
5/HBF4
1
2
3
1
2
3
6
6
6
7
7
7
73
56
38
59
34
26
86:14
73:27
74:26
93:7
94:6
90:10
72
71
72
87
86
88
Conclusion
[a]
[b]
Reaction conditions the same as Entry 6, Table 1.
conditions the same as Entry 1, Table 2.
Reaction
We have shown that catalysts derived from the PEG-sup-
ported imidazolidinone 5 and different acids can be em-
To explain the latter phenomenon, we carried out several ployed conveniently to promote some 1,3-dipolar cycload-
experiments. First, the supported catalysts were examined ditions of α,β-unsaturated aldehydes with nitrones. The
by 1H NMR spectroscopy after each recovery, which supported catalysts behave very similarly to their non-sup-
showed that the degree of degradation increased after each ported counterparts in terms of enantioselectivity, but are
cycle. The NMR spectroscopic analysis showed the appear- somewhat less efficient in terms of chemical yield. The im-
ance of broad signals close to those of the imidazolidinone mobilization on the polymer greatly simplifies the process
moiety and the decrease of the intensity of the peaks of of catalyst recovery. Recycling experiments showed that the
the imidazolidinone with respect to those of the aromatic supported catalyst maintains its stereochemical efficiency
570
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Enantioselective 1,3-Dipolar Cycloadditions
FULL PAPER
3JH,H ϭ 6.2, 3.1 Hz, 1 H, one H of NCH2), 1.43Ϫ1.49 (m, 2 H,
for up to three reaction cycles. In contrast, the chemical
efficiency slowly eroded upon recycling. In this respect, the
supported and non-supported catalysts display analogous
behavior. We ascribe the decrease in chemical efficiency to
an intrinsic instability of the imidazolidinone catalyst that
is induced by some unsaturated aldehydes.
NCH2CH2), 1.21Ϫ1.31 (m, 2 H, CH3CH2), 1.27 (s, 3 H, CMe),
3
1.17 (s, 3 H, CMe), 0.90 (t, JH,H ϭ 7.3 Hz, 3 H, CH2CH3) ppm.
13C NMR: δ ϭ 174.2, 155.8, 130.7, 127.2, 115.7, 76.4, 58.9, 40.4,
35.5, 31.3, 27.8, 26.3, 20.3, 13.7 ppm. IR: ν˜ ϭ 3270, 1675, 1620
cmϪ1. C16H24N2O2 (276.4): calcd. C 69.53, H 8.75, N 10.14; found
C 69.71, H 8.64, N 10.23.
Synthesis of Catalyst Precursor 5: Compound (S)-3 (0.200 g,
0.72 mmol) dissolved in DMF (3 mL) and Cs2CO3 (0.562 g,
1.725 mmol) were added to a solution of 4[13] (3.0 g, 0.575 mmol,
loading 0.192 meq/g), previously dried under vacuum at 90 °C for
1 h, in dry DMF (7 mL). After stirring at 60 °C for 24 h, the mix-
ture was cooled to room temp., the solvent was evaporated under
vacuum, and the residue was dissolved in CH2Cl2 (3 mL). The re-
sulting solution was added dropwise to Et2O (150 mL). The pre-
cipitated white solid was filtered, washed with Et2O (2 ϫ 25 mL),
and dried under vacuum to give 5 (2.69 g, 0.50 mmol, loading 0.186
meq/g). 1H NMR: δ ϭ 7.05Ϫ7.11 (m, 4 H, aromatic protons),
Experimental Section
General: 1H NMR spectra were recorded at 300 MHz in CDCl3
solutions and are referenced to tetramethylsilane (TMS) at δ ϭ
0.00 ppm. 13C NMR spectra were recorded at 75 MHz and are ref-
erenced to 77.0 ppm in CDCl3. IR spectra were recorded as thin
films or as solutions in CH2Cl2.
All the PEG samples employed in the synthesis of 5 were melted
at 80 °C under vacuum for 30 min before use to remove traces
of moisture. Purification of the PEG-supported products involved
evaporation of the reaction solvent in vacuo, dissolving the residue
in CH2Cl2 (a few mL), and adding it to Et2O stirred and cooled to
0 °C. After stirring at 0 °C for 20Ϫ30 min, the obtained suspension
was filtered through a sintered glass filter, and the solid repeatedly
washed on the filter with Et2O.
3
6.77Ϫ6.81 (m, 4 H, aromatic protons), 4.07 (t, JH,H ϭ 4.7 Hz,
2 H, PEGCH2OAr), 3.84Ϫ3.88 (m, 4 H, PEGOCH2CH2Ar and
3
CH2CH2CH2OAr), 3.37 (t, JH,H ϭ 5.2 Hz, 1 H, CHN), 3.30 (s, 3
H, MeOPEG), 3.21Ϫ3.30 (m, 1 H, one H of NCH2), 3.04 (ddd,
3
2JH,H ϭ 15.0, JH,H ϭ 5.2, 4.7 Hz, 2 H, ArCH2), 2.80Ϫ2.91 (m, 1
3
H, one H of NCH2), 2.70 (t, JH,H ϭ 7.8 Hz, 2 H, PEGOArCH2),
1.95Ϫ2.08 (m,
2 H, CH2CH2CH2), 1.40Ϫ1.50 (m, 2 H,
Determining Yield and Purity of PEG-Supported Compounds: The
yields of the PEG-supported compounds were determined by
weight with the assumption that Mw for the PEG fragment was
5000 Da. The Mw actually ranged from 4500 to 5500. The indicated
yields were for pure compounds. The purity of these compounds
was determined by 1H NMR spectroscopic analysis in CDCl3 at
300 MHz with pre-saturation of the methylene signals of the poly-
mer centered at δ ϭ 3.63 ppm. In recording the NMR spectra, a
relaxation time of 6 s and an acquisition time of 4 s were used to
ensure complete relaxation and accuracy of the integration. The
relaxation delay was selected after T1 measurements. The signals of
the PEG CH2OCH3 fragment at δ ϭ 3.30 and 3.36 ppm were used
as internal standards. The estimated integration error was Ϯ 5%.
NCH2CH2), 1.20Ϫ1.30 (m, 2 H, CH3CH2), 1.23 (s, 3 H, CMe),
1.13 (s, 3 H, CMe), 0.88 (t, JH,H ϭ 7.2 Hz, 3 H, CH2CH3) ppm.
3
General Procedure for the 1,3-Dipolar Cycloadditions: The synthesis
of 4-formyl-3-phenyl-2-(phenylmethyl)isoxazolidine (6) under the
conditions of Entry 6, Table 1, is illustrative of the procedure. A
54% w/w solution of HBF4 in Et2O (0.026 mL, 0.186 mmol) was
added to a stirred solution of 5 (0.500 g, 0.093 mmol) in CH2Cl2
(2 mL). The mixture was stirred at 24 °C for 1 h, and then the
catalyst was precipitated by the addition of Et2O. The precipitate
was filtered and dried under vacuum to remove traces of solvent.
Water (0.024 mL, 1.32 mmol) and acrolein (0.118 mL, 1.756 mmol)
were added, in that order, to a mixture of the catalyst (0.480 g,
0.0877 mmol) and N-benzyl-C-phenylnitrone (0.093 g, 0.439 mmol)
in nitromethane (4.4 mL) cooled to 0 °C, and then the mixture was
stirred for 24 h while the temperature was allowed to rise slowly to
24 °C. The volatile materials were then evaporated under vacuum.
The residue was dissolved in the minimum amount of CH2Cl2 and
then poured in Et2O (20 mL). The precipitate was filtered off, and
the solid was washed with Et2O (5 mL) and with an Et2O/EtOAc
mixture (9:1, 5 mL). The average recovery of catalyst ranged from
80 to 95% (0.385 to 0.455 g) after drying under high vacuum. The
filtrate was concentrated under vacuum and the residue was ana-
Synthesis of the Imidazolidinone 5
Synthesis of Compound (S)-3: (S)-Tyrosine methyl ester hydrochlo-
ride (1.81 g, 7.4 mmol) was added in one portion to a stirred solu-
tion of butylamine (2.5 mL, 25.3 mmol) in dry CH3CH2OH
(3.0 mL) kept under nitrogen. The mixture was stirred at 30 °C for
48 h. The solvent was then evaporated under vacuum and the resi-
due was treated with Et2O (20 mL). The resulting pale-yellow solid
was washed with another portion of Et2O (20 mL), filtered, and
dried under vacuum. The crude product thus obtained was sus-
pended in saturated aqueous NaHCO3 (10 mL) and stirred for
20 min. The resulting mixture was extracted with a 2% v/v solution
of CH3OH in CH3Cl (3 ϫ 33 mL) and the organic solution was
dried and concentrated under vacuum. The residue was dissolved
in a mixture of CH3OH (15 mL) and acetone (25 mL) and PTSA
(0.015 g) was added. The mixture was heated under reflux for 20 h
and concentrated under vacuum to afford a crude product that was
purified by flash chromatography (CH2Cl2/CH3OH, 9:1). The pure
product (1.411 g) was isolated in 69% overall yield. M.p. 99Ϫ101
1
lyzed by H NMR spectroscopy to establish the trans/cis ratio by
integrating the CHO signals at δ ϭ 9.80 (trans) and 9.29 (cis) ppm.
The crude product was then purified by flash chromatography (hex-
anes/EtOAc, 85:15) to give the product (0.086 g, 73%), which had
1H NMR spectroscopic data in agreement with those reported.[8c]
To determine ee, the aldehyde was converted into the correspond-
ing alcohol by reduction with an excess NaBH4 in CH3OH at 24
°C for 1 h. The crude product (no aldehyde signals observed by 1H
NMR spectroscopy) was analyzed by HPLC [Chiralcel AD, flow
rate 0.8 mL/min, λ ϭ 230; hexane/CH3CH2OH, 92.5:7.5; for the
trans isomer, tR: 11.2 min (minor) and 13.4 min (major); for the cis
isomer, tR: 15.8 min (minor) and 20.4 min (major)].
1
°C. [α]2D3 ϭ Ϫ78.2 (c ϭ 0.72 in CH2Cl2). H NMR (CDCl3/D2O):
3
δ ϭ 7.04 (B part of AB system, JH,H ϭ 8.5 Hz, 2 H, aromatic
protons), 6.74 (A part of AB system, 3JH,H ϭ 8.5 Hz, 2 H, aromatic
3
2
protons), 3.73 (t, JH,H ϭ 5.8 Hz, 1 H, CHN), 3.29 (ddd, JH,H
ϭ
4-Formyl-5-methyl-3-phenyl-2-(phenylmethyl)isoxazolidine (7): The
12.0, 3JH,H ϭ 6.7, 3.2 Hz, 1 H, one H of NCH2), 3.04 (ddd, 2JH,H ϭ
12.0, JH,H ϭ 5.8, 5.4 Hz, 2 H, ArCH2), 2.89 (ddd, JH,H ϭ 12.0, the trans/cis ratio by integrating the CHO signals at δ ϭ 9.79 (trans)
crude product was analyzed by 1H NMR spectroscopy to establish
3
2
Eur. J. Org. Chem. 2004, 567Ϫ573
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 571

A. Puglisi, M. Benaglia, M. Cinquini, F. Cozzi, G. Celentano
FULL PAPER
and 9.28 (cis) ppm. The crude product was then purified by flash
chromatography (hexanes/EtOAc, 85:15) to give a product that had
1H NMR spectroscopic data in agreement with those reported.[8c]
Starting from nitrone (0.439 mmol), the product was obtained
(0.076 g, 0.26 mmol, 59% yield; Entry 1, Table 2). To determine
ee, the aldehyde was converted into the corresponding alcohol by
reduction with NaBH4 (see above). The crude product (no aldehyde
signals by 1H NMR spectroscopy) was analyzed by HPLC [Chiral-
cel AD, flow rate 0.8 mL/min, λ ϭ 230; hexane/CH3CH2OH, 95:5;
for the trans isomer, tR: 12.05 min (minor) and 15.5 min (major)].
Acknowledgments
This work was supported by CNR and MURST (Progetto Nazion-
ale Stereoselezione in Sintesi Organica. Metodologie ed Applica-
zioni).
[1]
P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840Ϫ3864;
Angew. Chem. Int. Ed. 2001, 40, 3726Ϫ3748.
[2]
R. Breslow, Science 1982, 218, 532Ϫ537.
[3] [3a]
Chiral Catalyst Immobilization and Recycling (Eds.: D. E.
De Vos, I. F. J. Vankelecom, P. A. Jacobs), Wiley-VCH,
4-Formyl-3-(4-methoxyphenyl)-2-(phenylmethyl)isoxazolidine
(8):
Weinheim, 2000. [3b]An issue of Chemical Reviews::, Chem.
1
The crude product was analyzed by H NMR spectroscopy to es-
tablish the trans/cis ratio by integrating the CHO signals at δ ϭ 9.78
(trans) and 9.34 (cis) ppm. The crude product was then purified by
flash chromatography (hexanes/EtOAc, 85:15) to give a product
Rev. 2002, 102, 3215Ϫ3289) has recently been devoted to recov-
[3c]
erable catalysts and reagents.
For an early review on sup-
ported catalysts, see: G. Manecke, W. Storck, Angew. Chem.
1978, 90, 691Ϫ705; Angew. Chem. Int. Ed. Engl. 1978, 17,
657Ϫ670.
1
that had H NMR spectroscopic data in agreement with those re-
[4]
ported.[8c] Starting from the nitrone (0.439 mmol), the product were
obtained (0.083 g, 0.28 mmol, 64% yield; Entry 2, Table 2). To de-
termine ee, the aldehyde was converted into the corresponding al-
cohol by reduction with NaBH4 (see above). The crude product
For a recent review on polymer-supported organic catalysts,
see: M. Benaglia, A. Puglisi, F. Cozzi, Chem. Rev. 2003, 103,
3401Ϫ3429.
[5] [5a]
R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, M.
[5b]
Pitillo, J. Org. Chem. 2001, 66, 3160Ϫ3166.
M. Benaglia,
1
(no aldehyde signals by H NMR spectropscopy) was analyzed by
M. Cinquini, F. Cozzi, G. Tocco, Tetrahedron Lett. 2002, 43,
HPLC [Chiralcel AD, flow rate 0.8 mL/min, λ ϭ 230; hexane/
CH3CH2OH, 95:5; for the trans isomer, tR: 23.4 min (minor) and
31.2 min (major)].
[5c]
3391Ϫ3393, and references cited therein.
M. Benaglia, M.
Cinquini, F. Cozzi, A. Puglisi, G. Celentano, Adv. Synth. Catal.
2002, 344, 533Ϫ542, and references cited therein. [5d] M. Benag-
lia, T. Danelli, F. Fabris, D. Sperandio, G. Pozzi, Org. Lett.
[5e]
3-(4-Chlorophenyl)-4-formyl-2-(phenylmethyl)isoxazolidine (9): The
crude product was analyzed by 1H NMR spectroscopy to establish
the trans/cis ratio by integrating the CHO signals at δ ϭ 9.78 (trans)
and 9.29 (cis) ppm. The crude product was then purified by flash
chromatography (hexanes/EtOAc, 85:15) to give a product that had
1H NMR spectroscopic data in agreement with those reported.[8c]
Starting from nitrone (0.439 mmol), the product were obtained
(0.079 g, 0.26 mmol, 60% yield; Entry 3, Table 2). To determine
ee, the aldehyde was converted into the corresponding alcohol by
reduction with NaBH4 (see above). The crude product (no aldehyde
signals by 1H NMR spectroscopy) was analyzed by HPLC [Chiral-
cel AD, flow rate 0.8 mL/min, λ ϭ 230; hexane/CH3CH2OH, 97:3;
for the trans isomer tR: 39.5 min (minor) and 41.8 min (major)].
2002, 4, 4229Ϫ4232.
T. Danelli, R. Annunziata, M. Benag-
lia, M. Cinquini, F. Cozzi, G. Tocco, Tetrahedron: Asymmetry
[5f]
2003, 14, 461Ϫ467.
M. Benaglia, T. Danelli, G. Pozzi, Org.
Biomol. Chem. 2003, 1, 454Ϫ456.
[6]
D. J. Gravert, K. D. Janda, Chem. Rev. 1997, 97, 489Ϫ509.
[7] [7a]
For a review on PEG-supported catalysts, see: T. J. Dicker-
son, N. N. Reed, K. D. Janda, Chem. Rev. 2002, 102,
3325Ϫ3344. [7b] For the use of other soluble polymer-supported
catalysts, see: D. E. Bergbreiter, Chem. Rev. 2002, 102,
3345Ϫ3384.
[8] [8a]
For DielsϪAlder cycloadditions, see: K. A. Ahrendt, C. J.
Borths, D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122,
[8b]
4243Ϫ4244.
A. B. Northrup, D. W. C. MacMillan, J. Am.
[8c]
Chem. Soc. 2002, 124, 2458Ϫ2460.
For nitrone cycload-
ditions, see: W. S. Jen, J. J. M. Wiener, D. W. C. MacMillan, J.
Am. Chem. Soc. 2000, 122, 9874Ϫ9875. [8d] For FriedelϪCrafts
alkylations, see: N. A. Paras, D. W. C. MacMillan, J. Am.
Chem. Soc. 2002, 124, 7894Ϫ7895, and references cited therein.
3-Cyclohexyl-4-formyl-2-(phenylmethyl)isoxazolidine (10): The
1
crude product was analyzed by H NMR spectroscopy to establish
the trans/cis ratio by integrating the CHO signals at δ ϭ 9.78 (trans)
and 9.86 (cis) ppm. Purification by flash chromatography (hexanes/
EtOAc, 90:10) gave the product as a pale yellow oil. Starting from
nitrone (0.439 mmol), the product were obtained (0.049 g,
[8e]
J. F. Austin, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 1172Ϫ1173. [8f] For Mukaiyama-Michael reactions, see: S.
P. Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am. Chem.
[8g]
Soc. 2003, 125, 1192Ϫ1194. See also:
WO 03/002491 A2, 2003.
D. W. C. MacMillan,
1
0.18 mmol, 41% yield; Entry 4, Table 2). H NMR (trans isomer):
[9]
3
M. Benaglia, G. Celentano, M. Cinquini, A. Puglisi, F. Cozzi,
Adv. Synth. Catal. 2002, 344, 149Ϫ152.
The immobilization of MacMillan-type catalysts on other sup-
ports and their use in DielsϪAlder reactions has also been re-
ported: S. A. Selkälä, J. Tois, P. M. Pihko, A. M. P. Koskinen,
Adv. Synth. Catal. 2002, 344, 941Ϫ945. See Figure 1 for the
structures of these catalysts.
δ ϭ 9.78 (d, JH,H ϭ 2.6 Hz, 1 H, CHO), 7.25Ϫ7.45 (m, 5 H,
2
3
aromatic protons), 4.29 (dd, JH,H ϭ 8.5, JH,H ϭ 6.4, 1 H, one H
[10]
2
3
of H2C-5), 4.06 (t, JH,H ϭ JH,H ϭ 8.5 Hz, 1 H, one H of H2C-
2
5), 3.97 (B part of AB system, JH,H ϭ 13.3 Hz, 1 H, one benzylic
H), 3.88 (A part of AB system, 2JH,H ϭ 13.3 Hz, 1 H, one benzylic
H), 3.23Ϫ3.30 (m, 1 H, HC-4), 3.03Ϫ3.08 (m, 1 H, HC-3),
1.65Ϫ1.90 (m, 4 H, cyclohexyl protons), 1.40Ϫ1.60 (m, 1 H, CH
of cyclohexyl), 0.87Ϫ1.30 (m, 6 H, remaining cyclohexyl protons)
ppm. 13C NMR (trans isomer): δ ϭ 200.0, 137.1, 129.2, 128.7,
127.4, 71.2, 65.7, 61.2, 58.9, 41.3, 30.5, 29.1, 26.4 ppm. IR: ν˜ ϭ
1725 cmϪ1. C17H23NO2 (273.4): calcd. C 74.69, H 8.48, N 5.12;
found C 74.82, H 8.66, N 5.02. To determine ee, the aldehyde was
converted into the corresponding alcohol by reduction with NaBH4
[11]
[12]
For examples of the use of the amide nitrogen atom as the
handle for polymer attachment, see ref.[10]
.
For a previous example of this strategy for anchoring a phenyl-
alanine- containing organic catalyst to a polymer, see: H. J.
Kim, W. R. Jackson, Tetrahedron: Asymmetry 1992, 3,
1421Ϫ1430.
R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, Chem.
Eur. J. 2000, 6, 133Ϫ138.
The absolute configuration of 6 and the other 1,3-dipolar
cycloaddition products 7؊9 was established by comparison of
the sign of optical rotation with the value reported for the same
compounds of known configuration (see ref.[8c]). The absolute
[13]
[14]
1
(see above). The crude product (no aldehyde signals by H NMR
spectroscopy) was analyzed by HPLC [Chiralcel AD, flow rate
0.8 mL/min, λ ϭ 230; hexane/CH3CH2OH, 95:5; for the trans iso-
mer tR: 13.1 min (major) and 13.8 min (minor)].
572
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 567Ϫ573

Enantioselective 1,3-Dipolar Cycloadditions
FULL PAPER
configuration of the previously unreported adduct 10 was as-
signed on the assumption that the reaction leading to 10 fol-
lowed the same stereochemical course as those leading to 6؊9.
dation of 5/HX upon recovery was independent of the catalyst’s
water content (from 3 to 49 equiv. of water/equivalent of cata-
lyst; determined by KarlϪFischer titrations).
[15]
[17]
As previously observed in the DielsϪAlder reaction (see ref.[9]),
The recycling of 1a/HCl involved evaporation of the reaction
mixture and addition of diethyl ether to the residue. The sol-
vent was decanted and the residue was washed at least five
times with diethyl ether to completely remove the reaction
products. The combined ethereal phases were worked-up to iso-
late the product, and the catalyst was dried under vacuum to
afford a waxy solid that was analyzed for degradation, by
NMR spectroscopy, and then recycled.
in the synthesis of compounds 6 and 7 the use of either com-
mercial 1a/HCl or ad hoc-prepared 1a/CF3SO3H resulted, in
our hands, in yields and ee lower than those reported by Mac-
Millan (see ref.[8c]). For instance, when 1a/HCl was employed
as the catalyst, compound 7 was obtained in 64% yield and
89% ee, in contrast to the reported 70% yield and 95% ee.
[16]
In additional control experiments, we found that N-benzyl-C-
phenylnitrone did not degrade 1a/HCl, and that the degra-
Received September 10, 2003
Eur. J. Org. Chem. 2004, 567Ϫ573
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
573