A general approach for preparation of polymer-supported chiral organocatalysts via acrylic copolymerization

Article abstract of DOI:10.1021/jo902585j

(Figure Presented) Polymer-supported chiral organocatalysts, as well as most other forms of immobilized catalysts, are traditionally prepared by a postmodification approach where modified catalyst precursors are anchored onto prefabricated polymer beads. Herein, we report an alternative and more scalable approach where polymer-supported chiral enamine and iminium organocatalysts are prepared in a bottom-up fashion where methacrylic functional monomers are prepared in an entirely nonchromatographic manner and subsequently copolymerized with suitable comonomers to give cross-linked polymer beads. All syntheses have been conducted on multigram scale for all intermediates and finished polymer products, and the catalysts have proven successful in reactions taking place in solvents spanning a wide range of solvent polarity. While polymer-supported proline and prolineamides generally demonstrated excellent results and recycling robustness in asymmetric aldol reactions of ketones and benzaldehydes, the simplest type of Joargensen/Hayashi diarylprolinol TMS-ether showed excellent selectivity, but rather sluggish reactivity in the Enders-type asymmetric cascade. The polymer-supported version of the first-generation MacMillan imidazoHdinone had a pattern of reactivity very similar to that of the monomeric catalyst, but is too unstable to allow recycling.

Full text of DOI:10.1021/jo902585j

pubs.acs.org/joc
A General Approach for Preparation of Polymer-Supported Chiral
Organocatalysts via Acrylic Copolymerization
Tor E. Kristensen, Kristian Vestli, Martin G. Jakobsen, Finn K. Hansen, and Tore Hansen*
Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, NO-0315 Oslo, Norway
tore.hansen@kjemi.uio.no
Received December 7, 2009
Polymer-supported chiral organocatalysts, as well as most other forms of immobilized catalysts, are
traditionally prepared by a postmodification approach where modified catalyst precursors are
anchored onto prefabricated polymer beads. Herein, we report an alternative and more scalable
approach where polymer-supported chiral enamine and iminium organocatalysts are prepared in a
bottom-up fashion where methacrylic functional monomers are prepared in an entirely nonchromato-
graphic manner and subsequently copolymerized with suitable comonomers to give cross-linked
polymer beads. All syntheseshavebeen conducted on multigram scale for all intermediates and finished
polymer products, and the catalysts have proven successful in reactions taking place in solvents
spanning a wide range of solvent polarity. While polymer-supported proline and proline-
amides generally demonstrated excellent results and recycling robustness in asymmetric aldol
reactions of ketones and benzaldehydes, the simplest type of Jorgensen/Hayashi diarylprolinol
TMS-ether showed excellent selectivity, but rather sluggish reactivity in the Enders-type asymmetric
cascade. The polymer-supported version of the first-generation MacMillan imidazolidinone had a
pattern of reactivity very similar to that of the monomeric catalyst, but is too unstable to allow
recycling.
Introduction
separation, reuse of catalyst) are complemented with the
additional benefit of a modulated reactivity that in some
cases may prove valuable.1 Unfortunately, widespread use
of polymer-supported versions of any catalyst tends to be
hampered by the considerable costs usually associated with
such polymeric immobilization, as has also been the case for
organocatalysis.
Traditionally, polymer-supported organocatalysts (as
well as most other immobilized catalysts) are prepared by
anchoring modified catalyst precursors onto prefabri-
cated polymer supports, a strategy originally developed for
Polymer-supported organocatalysts are valuable materials
for conducting catalytic asymmetric transformations under
simple and environmentally benign conditions.1 Because orga-
nocatalysts typically operate via enzyme-mimetic strategies, a
polymer scaffold can to a certain extent be considered to be a
peptide-backbone substitute that can influence the selectivity of
the catalysts, often in a highly beneficial manner.1 In this way,
organocatalysts hold promise for polymeric immobilization
as the traditional benefits for catalyst immobilization (ease of
1620 J. Org. Chem. 2010, 75, 1620–1629
Published on Web 02/08/2010
DOI: 10.1021/jo902585j
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2010 American Chemical Society

Kristensen et al.
JOCArticle
solid-phase peptide synthesis in the 1960s and subsequently
adopted for immobilization of reagents, scavengers, and
catalysts.2,3 However, it is important to keep in mind that
this strategy was developed for the immobilization of high-
value substrates (peptides) during a lengthy synthetic
sequence that (often) involved rather harsh reaction condi-
tions, and as such required inert polymer scaffolds.2,3 On the
other hand, many organocatalysts can be considered rather
low value substrates, and they are in an especially fortunate
position because the mild reaction conditions under which
they operate make an especially broad range of polymeric
materials useful for their immobilization. In such cases, it can
make sense to undertake the polymeric immobilization in a
bottom-up fashion where polymer products are prepared via
a copolymerization strategy, implying that functional mono-
mers are copolymerized with suitable comonomers in ana-
logy to industrial procedures for preparation of more simple
functionalized resins. The excellent chemical tolerance of
free radical polymerization provides useful leverage for
accommodation of a very broad range of functionalities in
the catalyst monomers, and as such can be advantageously
integrated into the overall synthetic sequence. As such, a
traditional postmodification strategy can perhaps be con-
sidered a first-generation approach with high convenience,
but low cost-efficiency, while a copolymerization strategy
can be considered a second-generation approach in higher
need of interdisciplinary research, but one that in the end
achieves a better overall cost-efficiency and versatility. As a
simple example, this is mirrored in the preparation of the
Merrifield resin, which was previously prepared by post-
modification (chloromethylation) of polystyrene beads, but
is currently prepared by copolymerization of functional
monomer (4-vinylbenzyl chloride) with comonomers
(styrene/divinylbenzene).
Herein, we report the polymeric immobilization of pro-
lines, prolineamides, the simplest Jorgensen/Hayashi diaryl-
prolinol TMS-ether, and the first-generation MacMillan
imidazolidinone through such a copolymerization strategy,
the most generalized system for polymeric immobilization of
chiral enamine/iminium organocatalysts reported to date.
The procedures have an advantageous scalability, both
through the use of only affordable feedstock acrylics and
the avoidance of any chromatographic purification. In addi-
tion, control of catalyst loading is improved as compared to
the traditional postmodification scheme, and the strategy
can be easily adjusted for preparation of polymer supports
useful for reactions taking place in both nonpolar as well as
polar solvents like aqueous systems, lower alcohols, and
MeCN, something of crucial importance within asymmetric
organocatalysis.
Results and Discussion
Polymer-Supported Prolines. The immobilization of pro-
line within a postmodification scheme, using the hydroxyl
group in position 4 of trans-4-hydroxy-L-proline and either
linear polyethyleneglycol/polystyrene or cross-linked
beaded polystyrene-based supports, has been disclosed on
several occasions since 2001.4,5 Especially hydroxyproline
anchored by means of a linker onto the hydrophobic Merri-
field resin via the Huisgen-Meldal-Sharpless cycloaddition
or the thiol-ene coupling has proven to be a very efficient
catalyst for the asymmetric aldol reactions of ketones and
benzaldehydes, taking place under neat conditions with
water as additive.5b-h These systems resemble and work in
close parallel to the amphiphilic proline derivatives that for
the first time proved the efficiency of proline under aqueous
reaction conditions,6 which can readily outperform proline
itself.5b-h These cross-linked polymer systems also seem to
offer an advantageous recyclability when compared to pro-
line immobilized on linear supports (which are homoge-
nously soluble in the reaction medium).1d,4,5b-5h The
excellent performance of these systems prompted us to
investigate the polymeric immobilization of proline in a more
efficient manner, one that would retain the excellent perfor-
mance, but that could be scaled up to work on preparatory
scale.7
To avoid complicated synthetic procedures where doubly
carbamate-protected hydroxyproline was involved, we de-
veloped the selective O-acylation of hydroxyproline in
CF3CO2H, a quite general method for the direct preparation
of O-acyl derivatives of hydroxyproline.7a This procedure
was founded upon the fragmented knowledge that existed in
the literature on acidic activation of hydroxyproline,8 and
has been reported by us earlier.7a With it, we could, in
addition to preparing amphiphilic proline derivatives useful
as catalysts by themselves, also prepare acrylic proline
derivatives 2-4 (Scheme 1).7 Together with the correspond-
ing and more hydrophobic Boc-derivatives 5 and 6
(4) For linear supports, see: (a) Benaglia, M.; Celentano, G.; Cozzi, F.
Adv. Synth. Catal. 2001, 343, 171. (b) Benaglia, M.; Cinquini, M.; Cozzi, F.;
Puglisi, A.; Celentano, G. Adv. Synth. Catal. 2002, 344, 533. (c) Benaglia, M.;
Cinquini, M.; Cozzi, F.; Puglisi, A.; Celentano, G. J. Mol. Catal. A 2003,
204-205, 157. (d) Gu, L.; Wu, Y.; Zhang, Y.; Zhao, G. J. Mol. Catal. A 2007,
263, 186. (e) Liu, Y.-X.; Sun, Y.-N.; Tan, H.-H.; Liu, W.; Tao, J.-C.
Tetrahedron: Asymmetry 2007, 18, 2649. (f ) Liu, Y.-X.; Sun, Y.-N.; Tan,
H.-H.; Tao, J.-C. Catal. Lett. 2008, 120, 281.
(5) For cross-linked supports, see: (a) Kondo, K.; Yamano, T.;
Takemoto, K. Makromol. Chem. 1985, 186, 1781. (b) Font, D.; Jimeno, C.;
ꢀ
Pericas, M. A. Org. Lett. 2006, 8, 4653. (c) Font, D.; Bastero, A.; Sayalero, S.;
Jimeno, C.; Pericas, M. A. Org. Lett. 2007, 9, 1943. (d) Font, D.; Sayalero, S.;
ꢀ
ꢀ
Bastero, A.; Jimeno, C.; Pericas, M. A. Org. Lett. 2008, 10, 337. (e) Alza, E.;
Rodrıguez-Escrich, C.; Sayalero, S.; Bastero, A.; Pericas, M. A. Chem.;Eur.
ꢀ
J. 2009, 15, 10167. (f ) Giacalone, F.; Gruttadauria, M.; Marculescu, A. M.;
Noto, R. Tetrahedron Lett. 2007, 48, 255. (g) Gruttadauria, M.; Giacalone,
F.; Marculescu, A. M.; Meo, P. L.; Riela, S.; Noto, R. Eur. J. Org. Chem.
2007, 4688. (h) Giacalone, F.; Gruttadauria, M.; Marculescu, A. M.;
D’ Anna, F.; Noto, R. Catal. Commun. 2008, 9, 1477. (i) Kehat, T.; Portnoy,
M. Chem. Commun. 2007, 2823.
(6) (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.;
Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958. (b) Hayashi, Y.; Aratake, S.;
Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2006,
45, 5527. (c) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 734. Numerous publications
followed later on.
(1) For relevant reviews, see: (a) Benaglia, M.; Puglisi, A.; Cozzi, F.
Chem. Rev. 2003, 103, 3401. (b) Cozzi, F. Adv. Synth. Catal. 2006, 348, 1367.
(c) Altava, B.; Burguete, I.; Luis, S. V. In The Power of Functional Resins in
Organic Synthesis; Tulla-Puche, J., Albericio, F., Eds.; Wiley-VCH: Weinheim,
Germany, 2008; p 247. (d) Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc.
Rev. 2008, 37, 1666. (e) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth.
Catal. 2009, 351, 33. (f ) Trindade, A. F.; Gois, P. M. P.; Afonso, C. A. M. Chem.
Rev. 2009, 109, 418. (g) Fraile, J. M.; Garcia, J. I.; Mayoral, J. A. Chem. Rev.
2009, 109, 360. (h) Bergbreiter, D. E.; Tian, J.; Hongfa, C. Chem. Rev. 2009, 109,
530. (i) Chem. Rev. 2007, 107 (Issue 12), 5413, special issue on organocatalysis.
(2) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
(7) (a) Kristensen, T. E.; Hansen, F. K.; Hansen, T. Eur. J. Org. Chem.
2009, 387. (b) Kristensen, T. E.; Vestli, K.; Fredriksen, K. A.; Hansen, F. K.;
Hansen, T. Org. Lett. 2009, 11, 2968.
(3) For an introduction to the use of functional resins in organic synthesis,
see: The Power of Functional Resins in Organic Synthesis; Tulla-Puche, J.,
Albericio, F., Eds.; Wiley-VCH: Weinheim, Germany, 2008.
(8) (a) Sakami, W.; Toennies, G. J. Biol. Chem. 1942, 144, 203. (b)
Wilchek, M.; Patchornik, A. J. Org. Chem. 1964, 29, 1629. (c) Kawasaki,
T.; Komai, T. Polymer J. 1983, 15, 743.
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Kristensen et al.
JOCArticle
SCHEME 1. Acrylic Proline Building Blocks for Copolymerization
(Scheme 1), we now had available a set of building blocks on
multigram scale on which to build our copolymerization
strategy for immobilization of proline. Although hydroxy-
proline is a simple catalyst and subsequently not of prime
interest for polymeric immobilization, it remains an extre-
mely useful proving ground for the development of new
immobilization strategies as its three basic functionalities are
notoriously difficult to manage in a cost-efficient manner,
usually requiring double carbamate protection.4,5 As we
have pointed out earlier, however, there exists an erroneous
perception within academia that trans-4-hydroxy-L-proline is
an expensive compound.7a In addition, the reported proce-
dures for polymer-supported prolines have not disclosed
methods for preparation of enantiomeric/diastereomeric
catalysts for preparation of chiral products of the opposite
stereochemistry, as the enantiomer of trans-4-hydroxy-L-
proline is prohibitively expensive. Again, we resorted to the
informative literature of hydroxyproline chemistry, and the
conversion of trans-4-hydroxy-L-proline into the diastereo-
mer cis-4-hydroxy-D-proline is curiously facile.9 The second-
ary alcohol of hydroxyproline locks the carboxylic acid in a
cis-relationship from a planar acyl-intermediate during treat-
Copolymerization of the acrylic proline building blocks gave
access to polymer-supported prolines (Schemes 2 and 3), either
through solution, suspension, or dispersion copolymeriza-
tion.10 As methacrylates are much less prone to decomposition
by conjugate addition than acrylates (decomposing rapidly as
unprotected amine), methacrylates are preferred as monomeric
building blocks. Especially the traditional beaded products
prepared by suspension polymerization seemed attractive
because of the especially practical nature of the relatively large
spherical polymer beads. Unfortunately, this mode of poly-
merization necessitates that the monomers do not have a
considerable degree of water-solubility, which was not the case
for amino acid hydrochlorides 2-4 (Scheme 1). We therefore
suspension copolymerized Boc-derivatives 5, 6, and8 in slightly
alkaline water (containing polyvinyl alcohol stabilizer) together
with either benzyl methacrylate and 2 mol % ethyleneglycol
dimethacrylate (EGDMA) or styrene and 2 mol % divinyl-
benzene (DVB) to give polymer-supported prolines 9-12 after
deprotection (Scheme 2). Therefore, the use of the Boc-pro-
tected derivatives within the copolymerization scheme served
merely to endow the proline derivatives with the correct
hydrophobicity for suspension polymerization, and not for
chemical inertness (although its presence is crucial for post-
modification into prolineamides, as we describe later). In fact,
the free radical polymerization is one of the remarkably few
reactions that can withstand the presence of reactive function-
alities like unprotected carboxylic acids, alcohols, and many
ment with Ac2O.9b As such, cis-4-hydroxy-D-proline HCl
3
was available on >30 g scale, and as this was an equally
useful starting point for our O-acylation, we later added
proline building blocks 7 and 8 to our selection of monomers
(Scheme 1).
(9) (a) Robinson, D. S.; Greenstein, J. P. J. Biol. Chem. 1952, 195, 383. (b)
Dalla Croce, P.; La Rosa, C. Tetrahedron: Asymmetry 2002, 13, 197. (c)
Baker, G. L.; Fritschel, S. J.; Stille, J. R.; Stille, J. K. J. Org. Chem. 1981, 46,
2954.
(10) For a thorough distinction between suspension, emulsion, and
dispersion polymerization, see: Arshady, R. Colloid Polym. Sci. 1992, 270,
717.
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SCHEME 2. Polymer-Supported Prolines by Suspension Copolymerization
TABLE 1. Initial Screening of Polymeric Catalysts for Asymmetric
Aldol Reactions
amines, something we wanted to use to our advantage. Of the
worldwide production of synthetic polymers of nearly 40 kg per
person per year (with sales of over $250 billion in the United
States alone), about half is based on copolymers prepared by
radical polymerization.11 Still, its widespread use within synth-
esis in general remains limited.
In addition to the traditional beaded products, we also
prepared a high-load linear polymer (13) by solution copoly-
merization.7 We found this amphiphilic polymer to be of
little use in organocatalysis because of its restricted solubi-
lity.7b Very recently, and independently of us, other research-
ers have also reported the preparation of such high-load
linear polymers, and their properties now have been been
investigated more thoroughly.12 Within the copolymeriza-
tion scheme, it is also possible to prepare cross-linked
copolymers containing proline on multigram scale without
any resort to protecting groups at all. Using dispersion
copolymerization,10 we prepared a granulated cross-linked
product (14) by copolymerizing proline methacrylate 3 with
benzyl methacrylate and EGDMA from an initially homo-
geneous medium of a MeOH solution of monomers (the
solution containing polyvinylpyrrolidone as stabilizer).7b
Generally, dispersion polymerization gives microspheres in
the size range of 1-10 μm,10 but we lowered the amount of
stabilizer to allow for a controlled agglomeration that furni-
shed a granulated product that can be handled in the same
manner as polymer spheres from suspension polymerization.
However, although the dispersion mode of copolymerization
allows for the combinations of monomers with near ortho-
gonal solubility properties, the precipitation mechanism
means that the polymer composition is no longer a more or
less direct reflection of the monomeric composition, as is the
case for suspension polymerization with its excellent control
of catalyst loadings.
catalyst
f [mol %]a
yield [%]b
anti:sync
ee [%]d
11
11
12
12
12
12
9
9
14
14
10e
10 f
10e
10 f
5e
85
67
85
91
71
85
88
83
76
65
94:6
91:9
98:2
96:4
97:3
97:3
95:5
99:1
93:7
88:12
97
98
98
98
98
98
99
98
98
98
1e
10e
10 f
10e
10 f
af = catalyst loading. Isolated yield. Determined by 1H NMR of
crude product. dDetermined by chiral HPLC analysis. eIn H2O. fIn H2O/
CHCl3.
b
c
typical aldol reaction of cyclohexanone and benzaldehydes
(Table 1).7b All catalysts provided good results, with water as
sole additive. This was surprising, as even supports that do
not contain any form of linker (11 and 14) showed promising
results (Table 1). The presence of a linker does seem to affect
the anti:syn ratio to an appreciable extent (especially for 14 in
a highly expanded state in H2O/CHCl3), but has little effect
on enantioselectivity (97-99% ee in all cases). As for
chemical yields, we found them to be more dependent
on the ease of which we could retrieve the aldol product
than on any observable difference of activity/conversion at
10 mol % catalyst loading. Of more interest was the fact
that such acrylic polymer beads, in the form of acrylic-
styrenic hybrid 12, retained good activity and selectivity at
only 1 mol % of catalyst loading, something that is very rare
for proline.13
As reported by us earlier, we benchmarked polymer beads
9, 11, and 12 together with polymer granulate 14 in the
(11) Matyjaszewski, K.; Tsarevsky, N. V. Nat. Chem. 2009, 1, 276.
(13) For a discussion of loading issues of proline and prolineamides, see:
Lombardo, M.; Easwar, S.; Pasi, F.; Trombini, C. Adv. Synth. Catal. 2009,
351, 276 and references cited therein.
€
ꢁ
(12) Doyaguez, E. G.; Parra, F.; Corrales, G.; Fernandez-Mayoralas, A.
Polymer 2009, 50, 4438.
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SCHEME 3. Polymer-Supported Prolines by Solution and Dispersion Copolymerization
TABLE 2. Asymmetric Aldol Reactions in Water with Polymer-
Supported Prolines 9 and 10
see that cis-catalyst 10 in general exhibited a selectivity that
was only modestly lower than that of trans-catalyst 9, and
nearly identical for several derivatives (Table 2). To our
knowledge, quasi-enantiomeric catalyst pair 9/10 (from a
common source of chirality) is the first example of polymer-
supported proline on hydroxyproline-basis that can be used
for preparation of both enantiomeric series of a given
product. As for other polymer-supported prolines, such
acrylic supports are readily recyclable, and polymer support
12 was reused five times with unaffected results.7b This is
consistent with other prolines immobilized on cross-linked
supports.5b-h
catalyst
R
yield [%]a
anti:synb
ee [%]c
Polymer-Supported Prolineamides. Amides of proline and
certain amino alcohols are highly efficient catalysts for
asymmetric aldol reactions, efficient even down to the 0.5
mol % level of catalyst loading.14 Unlike proline, they also
efficiently catalyze aldol reactions with the water-soluble
acetone.14 Gruttadauria and co-workers have investigated
such prolineamides immobilized on Merrifield-resin in great
detail.15 We used the precursors for polymer-supported
prolines 9 and 10 (before deprotection), and coupled them
with diphenyl phenylglycinol 15 (S-15 for 16 and R-15 for 17)
through a standard peptide coupling to give prolineamides
16 and 17 (Scheme 4) after a mild Boc-deprotection with
HCO2H. As the starting material for 15 is synthetic phenyl-
glycine, both enantiomers are nearly equally affordable.16
As we have shown earlier, while an analogous proline-
amide to 16 (made from 12) gave more than 90% ee and
9
10
9
10
9
10
9
10
9
10
9
10
9
10
9
2-NO2
2-NO2
3-NO2
3-NO2
4-NO2
4-NO2
4-CF3
4-CF3
H
H
4-Br
4-Br
4-MeO
4-MeO
3,4-Cl
3,4-Cl
63
77
81
80
88
91
72
76
49
57
66
83
7
97:3
96:4
95:5
94:6
95:5
94:6
97:3
96:4
93:7
93:7
95:5
95:5
91:9
93:7
95:5
96:4
89
91
95
90
99
86
98
91
97
95
99
98
97
97
96
93
13
68
73
10
aIsolated yield. bDetermined by 1H NMR of crude product. cDeter-
mined by chiral HPLC analysis.
(14) (a) Raj, M.; Maja, V.; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8,
4097. (b) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593. (c) Raj, M.;
Maja, V.; Singh, V. K. J. Org. Chem. 2009, 74, 4289.
(15) (a) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.; Noto, R.
Adv. Synth. Catal. 2008, 350, 1397. (b) Gruttadauria, M.; Salvo, A. M. P.;
Giacalone, F.; Agrigento, P.; Noto, R. Eur. J. Org. Chem. 2009, 5437.
(16) Kristensen, T. E.; Vestli, K.; Hansen, F. K.; Hansen, T. Eur. J. Org.
Chem. 2009, 5185–5191.
We investigated acrylic polymer-supported prolines 9 and
10 in aldol reactions of cyclohexanone with an assortment of
substituted benzaldehydes (Table 2). Because catalysts 9 and
10 are C-2 epimeric, it would be interesting to see whether a
trans- versus cis-relationship of the hydroxyproline would
affect the catalyst selectivity. We were positively surprised to
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Kristensen et al.
JOCArticle
SCHEME 4. Polymer-Supported Prolineamides
TABLE 4. Recycling of Polymer-Supported Prolineamide
cycle
yield [%]a
ee [%]b
1
2
3
4
5
76
85
79
82
81
84
99
98
91
90
aIsolated yield. bDetermined by chiral HPLC analysis.
catalyst with a cis-relationship (17) generally gave somewhat
lower enantioselectivity, but again, for some derivatives, the
selectivity is more or less identical. We also investigated the
recycling of prolineamide support 16 (Table 4), and it has an
interesting pattern of activity where a slightly enhanced acti-
vity isseen after the first time usage. Nearly 3 g of aldol product
(acetone/4-nitrobenzaldehyde) with a weighted average of
92% ee was prepared through five repetitive reaction cycles
(Table 4). All in all, our synthesis of prolineamides combines
our copolymerization strategy with a traditional postmodi-
fication. As for the postmodification, its strength is the reliance
on only the most well-proven reaction of all in solid-phase
synthesis, namely the peptide coupling, a reaction with an ever-
widening scope on solid-phase.
Polymer-Supported Jorgensen/Hayashi Diarylprolinols.
The Jorgensen/Hayashi diarylprolinols are arguably the most
useful of all the organocatalysts because of their ability to
undertake both enamine and iminium catalysis with excellent
selectivities.1i,17 In contrast to proline and prolineamides, work
within supported silylated diarylprolinols is very sparse.18
Again, unlike the hydrophilic proline, the usual methodology
has met limited success with the diarylprolinols because of the
much lower hydrophilicity of these catalysts.18a-c When bound
to resins, proline can confer useful swelling properties in polar
solvents upon hydrophobic supports such as polystyrene,
although use of water with proline or prolineamide supports
should be regarded as an additive more than a true solvent as
other components dominate the reaction mixture. The diaryl-
prolinols have important use in solvents like MeOH, EtOH, or
MeCN, and a polystyrene network with diarylprolinols shows
negligible swelling in such solvents, limiting reactions to take
place mainly in solvents like PhMe, CH2Cl2, or CHCl3.18a The
main reason for this shortcoming is the fact that polymer-
supported Jorgensen/Hayashi diarylprolinols reported until
now are mainly silylated versions of polymer-supported
Corey-Bakshi-Shibata (CBS) reduction catalysts,19
TABLE 3. Asymmetric Aldol Reactions in Water with Polymer-
Supported Prolineamides 16 and 17
catalyst
R
yield [%]a
ee [%]b
16
17
16
17
16
17
16
17
16
17
16
17
2-NO2
2-NO2
3-NO2
3-NO2
4-NO2
4-NO2
4-CF3
4-CF3
H
90
88
87
88
72
82
77
82
29
47
56
79
91
82
99
99
91
85
90
86
91
86
91
83
H
4-Br
4-Br
(17) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.; Hayashi,
aIsolated yield. bDetermined by chiral HPLC analysis.
ꢁ
T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (c) Franzen, J.; Marigo,
M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jorgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 18296.
(18) (a) Varela, M. C.; Dixon, S. M.; Lam, K. S.; Schore, N. E. Tetra-
80-90% yield in the aldol reaction of 4-nitrobenzaldehyde
and acetone, the same support in its proline form (12) only
managed a mediocre ∼30% ee in very poor yields.7b As for
supported prolines 9/10, prolineamides 16/17 also form a
quasienantiomeric pair, and we investigated the aldol reac-
tions of acetone with substituted benzaldehydes catalyzed by
16/17 (Table 3). As for supported prolines 9 and 10, the
€
hedron 2008, 64, 10087. (b) Roben, C.; Stasiak, M.; Janza, B.; Greiner, A.;
Wendorff, J. H.; Studer, A. Synthesis 2008, 2163. (c) Alza, E.; Pericas, M. A.
ꢀ
Adv. Synth. Catal. 2009, 351, 3051. (d) Maltsev, O. V.; Kucherenko, A. S.;
Zlotin, S. G. Eur. J. Org. Chem. 2009, 5134.
(19) (a) Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org. Chem.
2002, 8086. (b) Varela, M. C.; Dixon, S. M.; Price, M. D.; Merit, J. E.; Berget,
P. E.; Shiraki, S.; Kurth, M. J.; Schore, N. E. Tetrahedron 2007, 63, 3334.
J. Org. Chem. Vol. 75, No. 5, 2010 1625

Kristensen et al.
JOCArticle
SCHEME 5. Polymer-Supported Jorgensen/Hayashi O-TMS Diphenylprolinol
a reaction with entirely different reaction constraints compared
to most enamine/iminium organocatalytic reactions.
procedures such as addition of PhMgBr to silylprotected
proline (from proline and HMDS/Me3SiCl).22e Of special
interest to us was the curious fact that for hydroxyproline,
the likely starting point for immobilization of proline, the
addition of PhMgBr to the ethyl carbamate of hydroxy-
proline methyl ester followed by alkaline hydrolysis, as
reported for proline in 1993,22d seemed to be the only method
in general use for preparation of the diphenylprolinol of
hydroxyproline.23 As we needed this material on the scale of
tens of grams for our copolymerization approach, and as this
was clearly not obtainable through the methods in use,23 we
instead turned our attention to the original disclosure from
1933.21 In this work, addition of PhMgBr directly to hydroxy-
proline ethyl ester hydrochloride gave a yield of ca. 50%, a yield
comparable to that of the standard method and superior to that
for normal proline, a fact clearly not generally comprehended.
We wanted to use the superior crystallinity of the hydroxy-
proline derivatives as compared to the proline derivatives, as for
example the diphenylprolinol of hydroxyproline has a melting
point approximately 100 deg higher than that of the poorly
crystalline diphenylprolinol of proline.21
We prepared two types of acrylic polymer beads (22 and
23) with supported O-TMS-diphenylprolinol as shown in
Scheme 5, one of them for use in nonpolar solvents (PhMe,
CH2Cl2, etc.) and one for use in solvents such as lower
alcohols and MeCN. As discussed in the previous section,
treatment of the ethyl ester hydrochloride of trans-4-hydro-
xy-L-proline (18) directly with PhMgBr/Et2O gave diphenyl-
prolinol hydrochloride 19 after a novel workup with use of a
CF3CO2H/HCl exchange. The diphenylprolinol of hydro-
xyproline, as opposed to that for proline, is a poorly soluble
material requiring disproportionate amounts of solvents for
extraction and recrystallization, which in our hands were
found unworkable on larger scales. A method was therefore
Because of the CBS reduction,20 unusually large efforts,
especially in the late 1980s and early 1990s, have gone into
research directed toward efficient large-scale preparations of
the simplest diphenylprolinol (R,R-diphenyl-2-pyrrolidine-
methanol).20-22 Despite its simple nature, its synthesis is
challenging as the normal mode of preparation for such
diphenylamino alcohols, the addition of PhMgBr to an alkyl
ester hydrochloride of the corresponding amino acid, works
poorly for proline (20-26% yield, ca. 80% ee).21,22b Of
the methods developed over the years, probably the most
important are the original preparation of Corey through
the addition of PhMgCl to Cbz-protected proline methyl
ester,20a,c addition of PhMgBr to proline-N-carboxyan-
hydride (prepared from proline and COCl2),22b addition of
PhMgBr to N-benzylproline ethyl ester followed by catalytic
hydrogenolysis,22a addition of PhMgBr to the N-ethyl car-
bamate of proline methyl ester (conveniently prepared in
only one step from proline and ethyl chloroformate in
MeOH) followed by alkaline hydrolysis,22d enantioselective
deprotonation of N-Boc-pyrrolidine with s-butyllithium/
(-)-sparteine followed by reaction with benzophenone,22c
addition of PhMgCl to methyl pyroglutamate followed by
reduction with borane and resolution of the racemate with
O-acetylmandelic acids,20b as well as some less well-known
(20) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925. (c) Corey, E. J.; Shibata, S.; Bakshi,
R. K. J. Org. Chem. 1988, 53, 2861.
(21) Kapfhammer, J.; Matthes, A. Hoppe-Seylers Z. Physiol. Chem. 1933,
223, 43.
~
(22) (a) Enders, D.; Kipphardt, H.; Gerdes, P.; Brena-Valle, L. J.;
Bhushan, V. Bull. Soc. Chim. Belg. 1988, 97, 691. (b) Mathre, D. J.; Jones,
T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Jones,
E. T. T.; Hoogsteen, K.; Baum, M. W.; Grabowski, E. J. J. J. Org. Chem.
1991, 56, 751. (c) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708.
(d) Kanth, J. V. B.; Periasamy, M. Tetrahedron 1993, 49, 5127. (e) Itsuno, S.;
Watanabe, K.; Koizumi, T.; Ito, K. React. Polym. 1995, 24, 219.
(23) (a) Nakano, H.; Takahashi, K.; Okuyama, Y.; Senoo, C.; Tsugawa,
N.; Suzuki, Y.; Fujita, R.; Sasaki, K.; Kabuto, C. J. Org. Chem. 2004, 69,
7092. (b) Li, Y.; Liu, X.; Yang, Y.; Zhao, G. J. Org. Chem. 2007, 72, 288.
1626 J. Org. Chem. Vol. 75, No. 5, 2010

Kristensen et al.
JOCArticle
SCHEME 6. Asymmetric Cascade Reaction Catalyzed by
Polymer-Supported Jorgensen/Hayashi O-TMS-Diarylprolinols
22 and 23
the work of Varela et al.18a where an analogous product was
obtained in 45% yield after 7 days with the best of their
polymer-supported catalysts. In our case, the minor enantio-
mer was completely undetectable by chiral HPLC analysis.
As the prolonged reaction time is probably much more than
what can be reasonably explained through the more
restricted rate of diffusion in a polymer network, it is
definitely a sign of the challenges that are met when con-
ducting more complicated reactions than the standard aldol
reactions on solid phase. Interestingly, further investigations
demonstrated the product of the first step of the cascade, the
Michael adduct of propionaldehyde and nitrostyrene, to
form rapidly and then accumulate. However, its further
conversion into the final product (24) was very slow (see
the Supporting Information for more details). Furthermore,
in trials with the monomeric catalyst, we found the cascade
to operate nicely in MeCN, something not mentioned in the
original disclosures on this cascade.25 Therefore, we tried out
the organocatalytic cascade in MeCN with PEG-based sup-
port 23. While the initial Michael-adduct formed rapidly, the
conversion to final product was virtually nonexistent. In
summary, it seemed like only the strongly swollen micro-
porous network of 22 in PhMe was able to provide product
24 in appreciable quantities.
devised in which the product is brought into solution as its
soluble CF3CO2H-salt and precipitated as its crystalline
hydrochloride. Hydroxyprolinol 19, as hydroxyproline,
had the amino alcohol motif and as such was a substrate
for our acidic O-acylation. Gratifyingly, selective O-acyla-
tion of 19 in CF3CO2H gave methacrylate 20 on a 30 g scale
as a storage-stable crystalline solid in only three steps overall.
24
Subsequent silylation with HMDS/I2 gave Jorgensen/
Hayashi methacrylate 21 in quantitative yield.
Polymer-Supported MacMillan Imidazolidinone. Since the
pioneering disclosure by the research group of MacMillan in
2000,26 there have been reported a few versions of polymer-
supported MacMillan imidazolidinone.27 Although its labile
nature makes it a quite unattractive target for polymeric
immobilization when based solely on recovery and reuse, it
nevertheless presented useful challenges for a system of
polymer-supported enamine/iminium organocatalysts that
aimed to be general in its nature. In addition, as it typically
operates in highly polar media, it is especially useful for the
development of polymer networks that are operational in
solvents as lower alcohols and MeCN. We therefore also
developed a large-scale approach to the first-generation
MacMillan imidazolidinone organocatalyst (Scheme 7).
The traditional way of immobilizing the MacMillan
imidazolidinone is by substituting phenylalanine with tyro-
sine,27b-d although linkage via the amide is also possi-
ble.27d None of the reported procedures using tyrosine had
to our knowledge furnished building blocks in a robust
nonchromatographic manner, and this was also the case in
our hands because of the problematic phenolic functionality
of tyrosine. Instead, we utilized the incorporation of ethano-
lamine instead of methylamine in the original MacMillan
procedure, as the pendant alcohol together with the amine of
phenylalanine would later on give an amino alcohol sub-
strate (25) viable for selective O-acylation. Treatment
of phenylalanine methyl ester hydrochloride with ethanol-
amine under neat conditions, followed by selective extrac-
tion of ethanolamine gave pure L-phenylalanylamino-
ethanol. A novel azeotropic ring-closure with acetone in
Standard suspension copolymerization with methyl
methacrylate and 2 mol % of EGDMA gave microporous
polymer beads 22, useful for reactions in nonpolar solvents.
In complete analogy, by substituting the methyl metha-
crylate/EGDMA with a 50:50 mixture of feedstock PEG
400 methyl ether methacrylate and PEG 600 dimethacrylate,
we prepared polymer beads 23, a swellable macroporous
support extremely useful for reactions in lower alcohols,
MeCN, or aqueous solvents. The classic way of utilizing
PEG for immobilization is by anchoring the catalyst onto
linear PEG to give a homogeneously soluble polymer that is
subsequently precipitated after reaction by addition of a
nonsolvent.4a-d However, we realized that PEG derivatives,
which at room temperature can be completely miscible with
water, can still be readily suspension polymerized in water
because PEG derivatives have the unusual ability of being
much less soluble in water at elevated temperatures and then
partitioning favorably into toluene. Therefore, we found
that use of PEG can be undertaken in the same practical
bead form as for classical styrene supports by the use of
PEG-methacrylates, in the practical sense a clear advantage
when compared to linear PEG.
We used polymer supports 22 and 23 in the asymmetric
Enders cascade-reaction,25 an enamine and iminium orga-
nocatalytic triple cascade reaction forging a tetrasubstituted
cyclohexene carbaldehyde with four stereogenic centers
(Scheme 6).25 We found an interesting reaction pattern for
these polymer-supported versions when compared to the
standard monomeric catalyst, as has also been observed by
others.18a While polymeric Jorgensen/Hayashi prolinol 22
gave product 24 in decent 32% yield and superb selectivity, it
required 7 days of reaction time. This compares usefully with
(26) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243.
€ €
(27) (a) Selkala, S. A.; Tois, J.; Pihko, P. M.; Koskinen, A. M. P. Adv.
Synth. Catal. 2002, 344, 941. (b) Benaglia, M.; Celentano, G.; Cinquini, M.;
Puglisi, A.; Cozzi, F. Adv. Synth. Catal. 2002, 344, 149. (c) Puglisi, A.;
Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano, G. Eur. J. Org. Chem.
2004, 567. (d) Zhang, Y.; Zhao, L.; Lee, S. S.; Ying, J. Y. Adv. Synth. Catal.
2006, 348, 2027. (e) Haraguchi, N.; Takemura, Y.; Itsuno, S. Tetrahedron
Lett. 2010, 51, 1205.
(24) Karimi, B.; Golshani, B. J. Org. Chem. 2000, 65, 7228.
€
(25) (a) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006,
441, 861. (b) Enders, D.; Huttl, M. R. M.; Raabe, G.; Bats, J. W. Adv. Synth.
€
Catal. 2008, 350, 267. (c) Shinisha, C. B.; Sunoj, R. B. Org. Biomol. Chem.
2008, 6, 3921.
J. Org. Chem. Vol. 75, No. 5, 2010 1627

Kristensen et al.
JOCArticle
SCHEME 7. Polymer-Supported MacMillan Imidazolidinone
TABLE 5. Asymmetric Diels-Alder Reactions with Polymer-
Supported MacMillan Imidazolidinone
catalysta
yield [%]b
exo:endoc
exo ee [%]d
endo ee [%]d
28 HCle
91
92
86
92
73
82
1.27:1
1.29:1
1.23:1
1.22:1
1.26:1
1.31:1
86
85
75
78
54
46
92
89
81
84
62
51
3
27 HCl f
27 TFA
3
3
27 TFAg
3
27 TFAh
3
27 TFAi
3
aAll reactions undertaken at 1.5 mmol scale unless otherwise noted.
bIsolated yield. cDetermined by 1H NMR. dDetermined by chiral HPLC
analysis after reduction to the alcohol and conversion to the benzoyl
ester. e28 = (5S)-(-)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone HCl.
3
fGram scale (7.5 mmol). gSecond cycle. hThird cycle. Fourth cycle
(replenished with CF3CO2H before use).
i
analysis might indicate. We therefore believe that for simple
organocatalysts, a synthetic strategy conducted in a bottom-up
fashion where functional monomers are copolymerized into
finished beaded products can advantageously compete with
most postmodification strategies. Because of the mild reaction
conditions prevailing in organocatalytic transformations, the
vast assortment of acrylics is probably a favorable alternative
to the more limited styrenics. We have used the copolymeri-
zation strategy for the preparation of polymer-supported
prolines, prolineamides, Jorgensen/Hayashi diphenylproli-
nols, and the first-generation MacMillan imidazolidinone.
As some of these represent simple catalysts not very attractive
for polymeric immobilization, they nevertheless pose interest-
ing challenges in the developmental phase because they operate
in reaction media that span a wide range of solvent polarity,
and as such cannot be readily encompassed in a postmodifica-
tion strategy by using a small number of specialized and
prefabricated polymer supports. We have also undertaken a
quite considerable investigation into hydroxyproline chemis-
try relevant for the development of efficient syntheses of
useful intermediates in the preparation of polymer-supported
enamine/iminium organocatalysts.
i-PrOH gave crystalline imidazolidinone 25 on a robust 60 g
scale as a crystalline solid. Selective O-acylation with metha-
cryloyl chloride in cheap MeSO3H (see the Supporting
Information for more details) gave MacMillan methacrylate
26. As for the Jorgensen/Hayashi diphenylprolinols, the
entire sequence does not involve any protective groups or
chromatographic purifications.
Suspension copolymerization of functional methacrylate 26
with a 50:50 mixture of feedstock PEG 400 methyl ether
methacrylate and PEG 600 dimethacrylate gave (in the same
manner as for preparation of Jorgensen/Hayashi support 23)
polymer beads 27. These polymer beads were fully functional in
aqueous MeCN, and we benchmarked them in a classical
asymmetric Diels-Alder reaction of cyclopentadiene and
4-nitrocinnamaldehyde (Table 5). Supported MacMillan
imidazolidinone 27 gave results (as its HCl-salt) only slightly
inferior to those obtained with standard monomeric
MacMillan imidazolidinone (28), slightly poorer in the form
of its CF3CO2H-salt. However, as known from others, recy-
cling of the MacMillan imidazolidinones is coupled to a rather
rapid erosion of the catalyst selectivity,27 even after just 2-3
reaction cycles (Table 5). It was nevertheless interesting to see
that our copolymerization strategy could encompass a member
of this important class of organocatalysts.
While the initial successes connected to the use of polymer-
supported prolines in asymmetric aldol reactions hold pro-
mise for future work, more complicated transformations
such as the demanding Enders cascade are probably indica-
tions of the challenges laying ahead for the preparation of
polymer-supported organocatalysts spanning a more com-
prehensive range of transformations.
Experimental Section
Conclusions
The synthesis and characterization of the acrylic derivati-
ves O-acryloyl-trans-4-hydroxy-L-proline hydrochloride (2),
O-methacryloyl-trans-4-hydroxy-L-proline hydrochloride (3),
and O-(2-methacryloyloxyethylsuccinoyl)-trans-4-hydroxy-L-
proline hydrochloride (4) together with their corresponding
Boc-derivatives (5 and 6) have been reported by us previously.7
Polymer-supported prolines 9 and 11-14 have also been
reported in a preliminary report.7b
Work within polymer-supported organocatalysts, like most
other forms of polymeric immobilization, tends to do little to
overcome the most important limitation for the widespread
utilization of polymer-supported reagents and catalysts,
namely its restraining cost issues. For simple reagents and
organocatalysts, overall expenditures are much more closely
connected to the synthetic strategy of immobilization in its
entirety than any cost of starting materials, as a superficial
General Procedure for the Asymmetric Aldol Reaction of
Benzaldehydes with Cyclohexanone. Benzaldehyde derivative
1628 J. Org. Chem. Vol. 75, No. 5, 2010

Kristensen et al.
JOCArticle
(0.40 mmol) was dissolved in cyclohexanone (2.0 mmol), con-
tained in a small vial (by gentle heating on a water bath if
necessary). Water (0.14 mL) was added, followed by the poly-
mer beads (9 or 10, 10 mol %). For noncrystalline benzalde-
hydes, the vial is charged with polymer beads first, followed by
the benzaldehyde derivative and solvents/additives. The reac-
tion was mixed gently with a closed capillary tube and then left
without stirring for 24 h. The reaction mixture was diluted with
EtOAc and transferred to a small folded paper filter. The
polymer beads were washed with additional small quantities
of EtOAc (20 mL in total for dilution and washing), and the
filtrate was evaporated in vacuo to yield the crude product.
Purification by flash column chromatography on silica gel with
EtOAc/hexanes yielded the pure aldol product. The diastereo-
with a stirring bar, cinnamaldehyde (1.05 mmol), and propanal
(1.20 mmol). The reaction mixture was stirred for approxi-
mately 2 h, in which time the polymer beads had swollen
considerably, and further stirring was discontinued. The reac-
tion mixture was then left at room temperature for the indicated
time. The reaction mixture was transferred to a filter paper with
a small amount of EtOAc. The vial and the polymer beads were
washed several times with small amounts of EtOAc (50 mL in all
for transfer and washing). The mixture was concentrated in
vacuo, and the residue was purified by column chromatography
on silica gel (0-20% EtOAc in hexanes) to give the product as a
white solid. This is a well-known compound.25a
Asymmetric Diels-Alder Reactions of 4-Nitrocinnamaldehyde
and Cyclopentadiene. A vial was charged with PEG-methacrylic
polymer beads (27, 15 mol %) and 4-nitrocinnamaldehyde
(1.5 mmol). A solvent mixture of MeCN and water (95:5,
1.50 mL) was added, followed shortly by CF3CO2H (∼0.23
mmol) and freshly cracked cyclopentadiene (4.5 mmol). The
mixture was stirred gently at room temperature for 24 h and then
diluted with EtOAc and filtered. The polymer beads were
washed with EtOAc (totally 25 mL for dilution and washing)
in small portions. The organic phase was washed with brine
(25 mL), dried over anhydrous MgSO4, and evaporated in vacuo
to give the crude product as a brown oil. The crude product was
purified by loading onto a column of silica gel and eluting with
n-pentane followed by 40% Et2O in n-pentane. The exo/endo
relationship was determined by 1H NMR analysis. The
enantiomeric excess was determined by HPLC analysis after
reduction of the product to the corresponding alcohol with
NaBH4 and subsequent conversion to the benzoyl ester.30 This
is a well-known compound.31
1
meric ratio was determined by H NMR analysis of the crude
product, and the enantiomeric excess was determined by HPLC
analysis of the purified product. All the aldol products are well-
known compounds with spectroscopic data in accordance with
literature.28
General Procedure for the Asymmetric Aldol Reaction of
Benzaldehydes with Acetone. Benzaldehyde derivative (0.40
mmol) was dissolved in acetone (8.0 mmol), contained in a small
vial. Water (0.14 mL) was added, followed by the polymer beads
(16 or 17, 10 mol %). For noncrystalline benzaldehydes, the vial
is charged with polymer beads first, followed by the benzalde-
hyde derivative and solvents/additives. The reaction was mixed
gently with a closed capillary tube and then left without stirring
for 24 h. The reaction mixture was diluted with EtOAc and
transferred to a small folded paper filter. The polymer beads
were washed with additional small quantities of EtOAc (20 mL
in total for dilution and washing), and the filtrate was eva-
porated in vacuo to yield the crude product. Purification by
flash column chromatography on silica gel with EtOAc/hexanes
yielded the pure aldol product. The enantiomeric excess was
determined by HPLC analysis of the purified product. All the
aldol products are well-known compounds with spectroscopic
data in accordance with literature.29
Full experimental procedures and characterization for all new
compounds and polymer-supported organocatalysts can be
found together with supporting details (pictures, comments etc.)
in the Supporting Information.
Acknowledgment. This work has been supported by
Birkeland Innovasjon, the Technology Transfer Office of
the University of Oslo. Hydroxyproline was generously
donated by Evonik Degussa GmbH.
General Procedure for Asymmetric Cascade Reaction. A vial
was charged with polymer beads (22, 20 mol %) and 2-chloro-β-
nitrostyrene (1.00 mmol). Toluene (4.0 mL) was added together
(28) (a) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J.
Org. Lett. 2005, 7, 4543. (b) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S.
Org. Lett. 2006, 8, 4417. (c) Chimni, S. S.; Singh, S.; Mahajan, D. Tetra-
hedron: Asymmetry 2008, 19, 2276.
(29) (a) Da, C.-S.; Che, L.-P.; Guo, Q.-P.; Wu, F.-C.; Ma, X.; Jia, Y.-N.
J. Org. Chem. 2009, 74, 2541. (b) Gandhi, S.; Singh, V. K. J. Org. Chem. 2008,
73, 9411. (c) Tong, S.-T.; Harris, P. W. R.; Barker, D.; Brimble, M. A. Eur. J.
Org. Chem. 2008, 164. (d) Wu, F.-C.; Da, C.-S.; Du, Z.-X.; Guo, Q.-P.; Li,
W.-P.; Yi, L.; Jia, Y.-N.; Ma, X. J. Org. Chem. 2009, 74, 4812. (e) Choudary,
B. M.; Chakrapani, L.; Ramani, T.; Kumar, K. V.; Kantam, M. L. Tetra-
hedron 2006, 62, 9571.
Supporting Information Available: Full experimental pro-
cedures, pictures, and spectroscopic properties for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(30) He, H.; Pei, B.-J.; Chou, H.-H.; Tian, T.; Chan, W.-H.; Lee,
A. W. M. Org. Lett. 2008, 10, 2421.
(31) Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7, 4141.
J. Org. Chem. Vol. 75, No. 5, 2010 1629