Highly enantioselective Michael additions in water catalyzed by a PS-supported pyrrolidine

Article abstract of DOI:10.1021/ol071366k

The development of a highly efficient, polymer-supported organocatalyst for the Michael addition of ketones to nitroolefins is described. A 1,2,3-triazole ring, constructed through a click 1,3-cycloaddition, plays the double role of grafting the chiral pyrrolidine monomer onto the polystyrene backbone and of providing a structural element, complementary to pyrrolidine, key to high catalytic activity and enantioselectivity. Optimal operation in water and full recyclability make the triazole linker attractive for the immobilization of organocatalysts.

Full text of DOI:10.1021/ol071366k

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3717-3720
Highly Enantioselective Michael
Additions in Water Catalyzed by a
PS-Supported Pyrrolidine
Esther Alza,† Xacobe C. Cambeiro,†,‡ Ciril Jimeno,† and Miquel A. Perica`s*,†,‡
Institute of Chemical Research of Catalonia (ICIQ), AVda. Pa¨ısos Catalans, 16,
43007 Tarragona, Spain, and Departament de Qu´ımica Orga`nica, UniVersitat de
Barcelona (UB), 08028 Barcelona, Spain
mapericas@iciq.es
Received June 9, 2007
ABSTRACT
The development of a highly efficient, polymer-supported organocatalyst for the Michael addition of ketones to nitroolefins is described. A
1,2,3-triazole ring, constructed through a click 1,3-cycloaddition, plays the double role of grafting the chiral pyrrolidine monomer onto the
polystyrene backbone and of providing a structural element, complementary to pyrrolidine, key to high catalytic activity and enantioselectivity.
Optimal operation in water and full recyclability make the triazole linker attractive for the immobilization of organocatalysts.
C-C bond-forming reactions occupy the central position in
the playground of organic synthesis because they are key to
the construction of molecular frameworks of increasing
complexity. In recent times, a growing interest has arisen in
achieving this goal in an enantioselective manner through
the use of purely organic, metal-free catalysts. As a result,
different catalytic systems (quite often based on proline) have
been developed providing very useful solutions for almost
every reaction involving classical carbonyl chemistry.1
circumvent this difficulty, the development of immobilized,
easily recoverable, and reusable catalysts appears as one of
the most promising strategies.2
For optimal performance, ligands to be supported must
be designed to allow anchoring through positions remote
from the catalytic sites because, in this way, interference by
the bulky polymer backbone is avoided. Working according
to this principle, we have developed polystyrene-supported
ligands for organometallic reactions which keep intact the
catalytic activity and enantioselectivity of their homogeneous
counterparts.3 Quite recently, we have shown that trans-4-
hydroxyproline can be properly immobilized onto polysty-
rene (PS) resins through copper-mediated 1,3-dipolar cy-
cloaddition between azides and alkynes (click chemistry)4
and that the resulting resins show improved catalytic proper-
ties over homogeneous counterparts in the direct aldol
Organocatalytic processes are generally considered as
environmentally benign because the use of metals is avoided.
However, their catalytic efficiency is usually lower than in
metal-catalyzed processes in terms of turnover number. To
† ICIQ.
‡ UB.
(1) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b)
List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122,
2395. (c) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis: From
Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley
VCH: New York, 2005.
(2) For reviews on immobilized organocatalysts, see: (a) Benaglia, M.;
Puglisi, A.; Cozzi, F. Chem. ReV. 2003, 103, 3401. (b) Cozzi, F. AdV. Synth.
Catal. 2006, 348, 1367.
10.1021/ol071366k CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/21/2007

reaction in water5 and in the R-aminoxylation of ketones and
aldehydes,6 while offering important operational advan-
tages.7
In this paper, we report on the preparation of new
immobilized organocatalysts (Figure 1) through Cu-catalyzed
In the context of our efforts toward the implementation
of copper-mediated 1,3-dipolar cycloadditions as a general
immobilization strategy for organocatalysis, we turned our
attention to the catalytic enantioselective Michael addition
of ketones to nitrostyrenes.8 This reaction is a powerful
synthetic tool that provides access to synthons of many
interesting types9 and has been studied from the perspective
of organocatalysis following two different approaches: (i)
the use of bifunctional catalysts that simultaneously activate
the ketone and nitroolefin partners10 and (ii) the use of simple
2-substituted cyclic amines (mostly pyrrolidines), where the
side chain is believed to act as a steric controller that directs
the reactivity toward the less hindered diastereotopic face
of the intermediate enamine.11 Within this category, systems
bearing highly nitrogen-rich substituents such as tetrazoles
and 1,2,3-triazoles have shown promising activity-selectivity
profiles in the asymmetric Michael reactions.11d,e,g,h
Figure 1. Structure of the supported catalysts.
1,3-dipolar cycloadditions between (S)-2-azidomethylpyrrol-
idine and alkynyl-functionalized Merrifield resins and on the
development of optimal conditions for the use of these resins
as highly efficient catalysts for the asymmetric Michael
addition.
The catalysts were prepared by a straightforward route as
shown in Scheme 1 and the Supporting Information. Azi-
Scheme 1. Functionalization of the PS Resin
However, in spite of the interest of the reaction, the first
efforts toward the development of recyclable catalysts have
only been published quite recently,12 and nothing has been
known until now on the use of insoluble, polymer-supported
organocatalysts in this process.
(3) (a) Vidal-Ferran, A.; Bampos, N.; Moyano, A.; Pericas, M. A.; Riera,
A.; Sanders, J. K. M. J. Org. Chem. 1998, 63, 6309. (b) Perica`s, M. A.;
Castellnou, D.; Rodr´ıguez, I.; Riera, A.; Sola`, Ll. AdV. Synth. Catal. 2003,
345, 1305. (c) Fraile, J. M.; Mayoral, J. A.; Serrano, J.; Perica`s, M. A.;
Sola`, Ll.; Castellnou, D. Org. Lett. 2003, 5, 4333. (d) Castellnou, D.; Sola`,
L.; Jimeno, C.; Fraile, J. M.; Mayoral, J. A.; Riera, A.; Perica`s, M. A. J.
Org. Chem. 2005, 70, 433. (e) Castellnou, D.; Fontes, M.; Jimeno, C.; Font,
D.; Sola`, L.; Verdaguer, X.; Perica`s, M. A. Tetrahedron 2005, 61, 12111.
(4) (a) Tornøe, C. W.; Meldal, M. In Proc. Second Intl. and SeVenteenth
Amer. Peptide Soc. Symp.; Lebl, M., Houghten, R. A., Eds.; American
Peptide Society and Kluwer Academic Press: San Diego, 2001; pp 263-
264. (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057. (c) Rostovtsed, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem., Int. Ed. 2002, 41, 2596. For a review on the concept of
click chemistry, see: (d) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2001, 40, 2004.
(5) Font, D.; Jimeno, C.; Perica`s, M. A. Org. Lett. 2006, 8, 4653.
(6) Font, D.; Bastero, A.; Sayalero, S.; Jimeno, C.; Perica`s, M. A. Org.
Lett. 2007, 9, 1943.
(7) For assessments on the suitability of click chemistry as a supporting
strategy in metal catalysis, see: (a) Gissibi, A.; Finn, M. G.; Reiser, O.
Org. Lett. 2005, 7, 2325-2328. (b) Bastero, A.; Font, D.; Perica`s, M. A. J.
Org. Chem. 2007, 72, 2460.
(8) For a review, see: Sulzer-Mosse´, S.; Alexakis, A. Chem. Commun.
2007, 3123.
(9) For a review, see: Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J.
Org. Chem. 2002, 1877.
(10) (a) Cao, C.; Ye, M.; Sun, X.; Tang, Y. Org. Lett. 2006, 8, 2901.
(b) Wei, S.; Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S. Catal. Today
2007, 121, 151. (c) Liu, K.; Cui, H.; Nie, J.; Dong, K.; Li, X.; Ma, J. Org.
Lett. 2007, 9, 923.
(11) (a) Andrey, O.; Alexakis, A.; Bernardinelli, G. AdV. Synth. Catal.
2004, 346, 1147. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212. (c) Mosse, S.; Laars, M.; Kriis, K.; Kanger,
T.; Alexakis, A. Org. Lett. 2006, 8, 2559. (d) Luo, S.; Xu, H.; Mi, X.; Li,
J.; Zheng, X.; Cheng, J. J. Org. Chem. 2006, 71, 9244. (e) Yan, Z.; Niu,
Y.; Wei, H.; Wu, L.; Zhao, Y.; Liang, Y. Tetrahedron: Asymmetry 2007,
17, 3288. (f) Vishnumaya; Singh, V. K. Org. Lett. 2007, 9, 1117. For
examples of pyrrolidine-type catalysts with protic groups: (g) Cobb, A. J.
A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2004,
16, 1808. (h) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett 2005,
4, 611. (i) Prieto, A.; Halland, N.; Jorgensen, K. A. Org. Lett. 2005, 7,
3897. (j) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas,
C. F., III. J. Am. Chem. Soc. 2006, 128, 4966.
domethylpyrrolidine 5 was prepared from L-proline by
reduction with lithium aluminum hydride and subsequent
protection of the unstable aminoalcohol with di-tert-butyl
dicarbonate. The alcohol 3 was then activated as a tosylate,
and azide was introduced via SN2 substitution.13
On the other hand, a Merrifield resin (1% DVB, fo ) 0.74
mmol/g) was treated with propargyl alcohol under basic
(12) Approaches to recyclable organocatalysts for Michael additions,
Soluble polymers: (a) Gu, L.; Wu, Y.; Zhang, Y.; Zhao, G. J. Mol. Catal.
A 2007, 263, 186. Ionic liquids: (b) Luo, S.; Mi, X.; Zhang, L.; Liu, S.;
Xu, H.; Cheng, J. Angew. Chem., Int. Ed. 2006, 45, 3093. (c) Kotrusz, P.;
Toma, S.; Schmalz, H.; Adler, A. Eur. J. Org. Chem. 2004, 7, 1577.
Fluorous catalysts: (d) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006,
8, 3077.
(13) (a) Boyle, G. A.; Govender, T.; Kruger, H. G.; Maguire, G. E. M.
Tetrahedron: Asymmetry 2004, 15, 2661. (b) Koh, D. W.; Coyle, D. L.;
Mehta, N.; Ramsinghani, S.; Kim, H.; Slama, J. T.; Jacobson, M. K. J.
Med. Chem. 2003, 46, 4322.
3718
Org. Lett., Vol. 9, No. 19, 2007

conditions (NaH in DMF) to provide the alkyne-function-
alized resin 6. Azide 5 was grafted onto this resin by a Cu-
catalyzed Huisgen cycloaddition to afford, upon deprotection
with TFA, the immobilized catalyst 1. In a similar manner,
catalyst 2 was prepared from the same Merrifield resin,
through intermediate functionalization with 4-ethynylbenzyl
alcohol (resin 8).
As already mentioned, resin 2 behaved as much more
enantioselective in the considered process, and water (no
TFA additive) turned out to be the solvent of choice for the
reactions where it was used. In sharp contrast with what is
Table 2. Michael Addition of Ketones to Nitrostyrenes*
Both resins were tested as catalysts for the Michael
addition of cyclohexanone to â-nitrostyrene in a variety of
solvents (Table 1). As a general trend, resin 1 was clearly
more active but less enantioselective than 2.
Table 1. Optimization of the Reaction Conditions*
entry catalyst solvent
additive
% conve d.r.e,f % eeg
1a
2a
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
-
TFAc
TFAc
TFAc
TFAc
80
55
31
67
72
27
66
35
19
42
17
84
87
77
15
19
23
94:6
96:4
97:3
93:7
93:7
93:7
95:5
94:6
95:5
94:6
97:3
95:5
95:5
67
60
75
67
62
79
77
85
84
82
76
87
89
H2O
DMF
THF
3a
4a
5a
toluene TFAc
6a
H2O
H2O
H2O
brine
-
DMF
H2O
H2O
H2O
tolueneh
-
-
-
-
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b
TFAc
TFAc
TFAc
DiMePEGd
TFAc + DiMePEGd
90:10 87
-
95:5
91:9
93:7
85
83
84
toluenei TFAc
toluenej DiMePEGd
* All reactions performed with 0.5 mmol of nitrostyrene and 6 mol % of
a
b
catalyst in 2 mL of solvent. 5 equiv of cyclohexanone. 20 equiv of
cyclohexanone. c 2.5 mol %. d 10 mol %. e Determined by 1H NMR of the
crude material. Diasteromeric ratio, anti/syn. Determined by HPLC.
79 ppm of water. 579 ppm of water. 560 ppm of water.
f
g
h
i
j
The best conversion with resin 1 was achieved with
trifluoroacetic acid (TFA) as an additive under neat condi-
tions (entry 1).14 In turn, the highest ee was recorded when
water (no TFA) was used as the solvent (79% ee, entry 6),
although conversion was significantly lower under these
conditions. Quite interestingly, conversion increased to 66%
by simply increasing the amount of cyclohexanone employed
in the reaction (compare entries 6 and 7). It is thus strongly
suggested that the role of TFA in these reactions is limited
to facilitating the formation and hydrolysis of the intermedi-
ate enamine and that 2-triazolylmethylpyrrolidines do not
behave as bifunctional catalysts.15
* All reactions performed with 0.25 mmol of the nitroolefin, 20 equiv
of the ketone, 10 mol % of DiMePEG, and 10 mol % of catalyst 2 in 1 mL
a
1
of water, at room temperature for 24 h. Determined by H NMR of the
(14) For a review, see: Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L.
Angew. Chem., Int. Ed. 2005, 44, 1758.
(15) The configuration of the chiral center in the cyclohexanone ring of
9a indicates that attack to â-nitrostyrene by the intermediate enamine takes
place by the face opposite to the triazolylmethyl substituent.
b
c
d
crude products. Isolated yield. Determined by HPLC. After a single
recrystallization. e 19% of the double addition product also observed. f 31%
of attack by the primary carbon also observed.
Org. Lett., Vol. 9, No. 19, 2007
3719

observed with 1, the use of organic solvents was deleterious
for conversion with this resin (compare entries 1/10, 3/11,
and 5/16).
cyclohexanones had a detrimental effect on the performance
of the catalyst. Thus, the use of acetone as a Michael donor
(entry 11) resulted in a dramatic drop in both yield and ee,
a mixture of the single and double addition products being
obtained. With 2-butanone (entry 12), in turn, a mixture of
regioisomers was obtained. The regioisomer arising from the
most substituted enamine could be isolated in 64% yield and
with 70% ee.
The catalytic performance of resin 2 in water could be
improved by addition of two different additives. On one hand,
and in contrast with 1, addition of TFA (2.5 mol %) led to
increased catalytic activity without deterioration in enantio-
selectivity (compare entries 2 and 6 for 1, and 8 and 12 for
2). On the other hand, the use of DiMePEG as an additive
in the reactions led to an even greater improvement both in
conversion and in ee (entry 13). Those were in fact the
conditions of choice for the reaction because the simultaneous
use of both additives, TFA and DiMePEG (entry 14), did
not lead to any synergistic effect. Results for the test reaction
in water (entries 12-14) are particularly remarkable when
compared with the corresponding ones in toluene (entries
15-17) because resin 2 swells in toluene but not in water.
When the structures of resins 1 and 2 are compared, the
p-phenylene group present in the linker in resin 2 possesses
increased size and hydrophobicity with respect to the
corresponding linker in 1. Hence, the presence in 2 of a
single, small hydrophilic moiety (the pyrrolidine-triazole
system) embedded in a vast hydrophobic domain (the
polymer backbone and the linker) appears to be key to the
high enantioselectivity shown by this resin in the presence
of water.
The resin was also tested in the Michael addition of
aldehydes to nitrostyrene (Scheme 2). High conversions and
Scheme 2. Michael Addition of Aldehydes to Nitrostyrene
a
b
At 4 °C. At rt.
diastereoselectivities were obtained for linear aldehydes,
although ee’s were only moderate. A â-branched aldehyde
such as isovarelaldehyde gave poor conversion and ee.
Cyclohexanecarbaldehyde, in turn (R-branched), did not react
at all.
In summary, a highly efficient, polymer-supported orga-
nocatalyst for the highly diastereo- and enantioselective
Michael addition of nitroolefins to ketones has been devel-
oped. This catalytic system, constructed through the use of
click chemistry, represents the first insoluble mediator for
this reaction and approaches the performance of referable,
soluble catalysts for the same process. The exact role of water
and the hydrophobic polymer backbone in the reaction is
being studied, and results will be reported in due course.
This is the same phenomenon already observed for a PS-
supported hydroxyproline catalyst5 and suggests the presence
of combined hydrophobic-hydrophilic effects that might
stabilize the transition states leading to products, thus
speeding up the reaction. We suggest that the combination
of both effects might be a general activation mode in
organocatalysis and particularly important with polymer-
supported organocatalysts.
To establish the scope of the reaction with resin 2, a series
of substrates (nitroolefins and ketones) were tested under
the optimized reaction conditions (Table 2).
â-Nitrostyrenes with different substitution patterns on the
phenyl ring, including electron-releasing and electron-
withdrawing groups, were tested as Michael acceptors. All
the addition products where obtained in good yields and with
excellent diastereo- and enantioselectivities, with no signifi-
cant dependence on the electronic or steric properties of the
substrate (entries 1 to 8). Recycling of the catalyst was tested
with the reagent combination of entry 2. After three
consecutive uses, no decrease was observed in the isolated
yield of adduct 12b or in the stereoselectivity parameters.
When major structural changes were introduced on the
Michael acceptor (entry 9), a slight decrease was observed
in diastereo- and enantioselectivity, whereas the reaction yield
remained high. On the other hand, use of ketones other than
Acknowledgment. We thank MEC (Grant CTQ2005-
02193/BQU), DURSI (Grant 2005SGR225), Consolider
Ingenio 2010 (Grant CSD2006-0003), and ICIQ Foundation
for financial support. X.C.C. thanks MEC for a predoctoral
fellowship. E.A. thanks ICIQ Foundation for a predoctoral
fellowship.
Supporting Information Available: Experimental pro-
cedures and preparation and characterization of resins 1 and
2. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL071366K
3720
Org. Lett., Vol. 9, No. 19, 2007