Efficient, enantioselective iminium catalysis with an immobilized, recyclable diarylprolinol silyl ether catalyst

Article abstract of DOI:10.1021/ol100166z

(Figure Presented) A highly efficient approach for the synthesis, application, and recycling of immobilized diarylprolinol silyl ethers was developed. The MeOPEG-supported Jorgensen-Hayashi catalyst provides unchanged reactivity and selectivity as compared to the homogeneous catalyst, as demonstrated for the Michael addition of nitromethane to α,β- unsaturated aldehydes via iminium activation. In addition, the immobilization allows for a simple, column-free isolation of pure, sensitive aldehyde products and therefore may be useful for application in more complicated syntheses.

Full text of DOI:10.1021/ol100166z

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1480-1483
Efficient, Enantioselective Iminium
Catalysis with an Immobilized,
Recyclable Diarylprolinol
Silyl Ether Catalyst
Ina Mager and Kirsten Zeitler*
Institut fu¨r Organische Chemie, UniVersita¨t Regensburg, UniVersita¨tsstrasse 31,
D-93053 Regensburg, Germany
kirsten.zeitler@chemie.uni-regensburg.de
Received January 22, 2010
ABSTRACT
A highly efficient approach for the synthesis, application, and recycling of immobilized diarylprolinol silyl ethers was developed. The MeOPEG-
supported Jørgensen-Hayashi catalyst provides unchanged reactivity and selectivity as compared to the homogeneous catalyst, as demonstrated
for the Michael addition of nitromethane to r,ꢀ-unsaturated aldehydes via iminium activation. In addition, the immobilization allows for a
simple, column-free isolation of pure, sensitive aldehyde products and therefore may be useful for application in more complicated syntheses.
Starting from a few unusual transformations showing non-
traditional reactivities, organocatalysis has emerged as an
inspiring area of general concepts during the past decade
and is now appreciated as the third branch of enantioselective
catalysis that complements the fields of enzyme and (orga-
no)metal catalysis.1 In particular, catalysis of transformations
with secondary amines (aminocatalysis) can be considered
as one of the most applicable methods in terms of reaction
diversity and due to the versatility of the different activation
modes (enamine, iminium, dienamine, SOMO catalysis as
well as their combinations in multiple domino processes).2
Among the multitude of known amine-based catalysts,
R,R-diarylprolinol derivatives inter alia have proven to be
privileged catalysts.3 High catalyst loadings, however, as well
as complicated purification processes due to the similarity
of catalyst and (often sensitive) products are major draw-
backs.
Catalyst immobilization4,5 may offer a solution to these
problems in facilitating both product separation as well as
catalyst recovery and reuse, and hence can contribute to more
efficient chemical syntheses. Despite these options and the
increasing number of applications6 due to the versatility of
the Jørgensen-Hayashi catalyst 1, only a few approaches
(2) For recent reviews, see: (a) Bertelsen, S.; Jørgensen, K. A. Chem.
Soc. ReV. 2009, 38, 2178. (b) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (c) Yu, X.; Wang, W.
Org. Biomol. Chem. 2008, 6, 2037.
(1) (a) Special issue on organocatalysis : Chem. ReV. 2007, 107 (12),
5413-5883. (b) Asymmetric Organocatalysis; List, B., Ed.;Top. Curr. Chem.
291; Springer: Berlin, 2010. (c) Berkessel, A.; Gro¨ger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005. (d) Dondoni, A.; Massi,
A. Angew. Chem., Int. Ed. 2008, 47, 4638.
(3) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4284. For a comprehensive
review, see: (c) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922.
10.1021/ol100166z  2010 American Chemical Society
Published on Web 03/04/2010

for its immobilization have been described,7 while most
recycling attempts implied complications that are often
attributed to desilylation processes.
this well-established atom-economic immobilization ap-
proach9 for the synthesis of a widely applicable Jørgensen-
Hayashi-type amino catalyst.
Scheme 2. Synthesis of the MeOPEG-Immobilized
Diphenylprolinol Trimethylsilyl Ether from L-Hyp
Herein, we report the design of a soluble-polymer sup-
ported diarylprolinol silyl ether catalyst and its successful
application and recycling for the iminium-catalyzed enan-
tioselective synthesis of γ-nitroaldehydes (Scheme 1).
Scheme 1
.
Iminium-Catalyzed Enantioselective Synthesis of
γ-Nitroaldehydes
We started the synthesis from inexpensive, commercially
available trans-L-hydroxy proline (L-Hyp) and could obtain
the versatile enantiopure alkyne-precursor 7 over five steps
in a very good overall yield of 45% (Scheme 2). It is
noteworthy that an attempted route starting from
L-Boc-Hyp-OMe led to significant deterioration of the
catalyst’s optical purity. Effective linkage of this TMS-
prolinol 7 to the azido-functionalized MeOPEG support was
achieved in the presence of TBTA as Cu ligand10,11 to
suppress the undesired complexation by the secondary
amine.9d Catalyst loading was conveniently determined by
1H NMR analysis using the singlet of the polymer’s methoxy
group as reference for integration.
To evaluate the performance of our polymer-supported
catalyst, we selected the iminium-catalyzed synthesis of
γ-nitro aldehydes via a Henry-type reaction of nitromethane
with R,ꢀ-unsaturated aldehydes as published by Hayashi et
al.12a While these valuable synthetic precursors can be
quickly accessed by this route, their purification can prove
difficult due to the sensitivity of the γ-nitro aldehydes.12b
As a model reaction we performed the Michael addition of
nitromethane and cinnamaldehyde with the MeOPEG-
supported catalyst under Hayashi’s best conditions (Table
1, entry 1) and gratifyingly found highly comparable results
(entry 2) for our immobilized catalyst. A short survey of a
With respect to the crucial prerequisite of retaining activity
and selectivity upon immobilization and the hereby often
inherently associated limitations of insoluble polymer cata-
lysts, soluble supports provide a useful blend between the
advantages of both heterogeneous and homogeneous cataly-
sis.8 They allow for highly simplified workup procedures,
e.g., via polarity-triggered precipitation and filtration, but also
provide improved transferability of established homogeneous
reaction conditions minimizing additional optimization stud-
ies. Based on our experience in the preparation of MeOPEG-
supported carbene-catalysts via regioselective, Cu-catalyzed
[3 + 2]-cycloaddition to create a stable 1,2,3-triazole
linkage,9c we extended our efforts toward the application of
(4) (a) Ding, K.; Uozumi, Y. Handbook of Asymmetric Heterogeneous
Catalysis, Wiley-VCH: Weinheim, 2008. (b) Benaglia, M. RecoVerable and
Recyclable Catalysts; Wiley-VCH: Weinheim 2009.
(5) For reviews on the immobilization of organocatalysts, see: (a) Cozzi,
F. AdV. Synth. Catal. 2006, 348, 1367. (b) Benaglia, M. New J. Chem.
2006, 30, 1525. (c) Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc.
ReV. 2008, 37, 1666.
(6) For some selected recent applications, see: (a) Ishikawa, H.; Suzuki,
T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304. (b) Franze´n, J.;
Fisher, A. Angew. Chem., Int. Ed. 2009, 48, 787. (c) Jiang, H.; Elsner, P.;
Jensen, K. L.; Falcicchio, A.; Marcos, V.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2009, 48, 6844. (d) Hong, B.-C.; Kotame, P.; Tsai, C.-W.; Liao,
J.-H. Org. Lett. 2010, DOI: 10.1021/ol902840x.
(9) For catalyst immobilization via [3 + 2]-cycloaddition, see: (a) Font,
D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Perica`s, M. A. Org. Lett. 2008,
10, 337. (b) Scha¨tz, A.; Hager, M.; Reiser, O. AdV. Funct. Mater. 2009,
19, 2109. (c) Zeitler, K.; Mager, I. AdV. Synth. Cat. 2007, 349, 1851. (d)
Chouhan, G.; Wang, D.; Alper, H. Chem. Commun. 2007, 4809. (e) Luo,
J.; Pardin, C.; Lubell, W. D.; Zhu, X. X. Chem. Commun. 2007, 3406. (f)
Alza, E.; Rodr´ıguez-Escrich, C.; Sayalero, S.; Bastero, A.; Perica`s, M. A.
Chem.sEur. J. 2009, 15, 10167, and references cited within these articles.
(10) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
(7) Enamine examples: (a) Zu, L.; Li, H.; Wang, J.; Yu, X.; Wang, W.
Tetrahedron Lett. 2006, 47, 5131. (b) Li, Y.; Liu, X.-Y.; Zhao, G.
Tetrahedron: Asymmetry 2006, 17, 2034. (c) During the finalization of this
manuscript a paper describing enamine catalysis with a PS-supported catalyst
related to 3 appeared: Alza, E.; Perica`s, M. A. AdV. Synth. Catal. 2009,
351, 3051. (d) Zheng, Z.; Perkins, B. L.; Ni, B. J. Am. Chem. Soc. 2010,
132, 50. Iminium examples: (e) Ro¨ben, C.; Stasiak, M.; Janza, B.; Greiner,
A.; Wendorff, J. H.; Studer, A. Synthesis 2008, 2163. (f) Maltsev, O. V.;
Kucherenko, A. S.; Zlotin, S. G. Eur. J. Org. Chem. 2009, 5134. Combined:
(g) Varela, M. C.; Dixon, S. M.; Lam, K. S.; Schore, N. E. Tetrahedron
2008, 64, 10087.
2004, 6, 2853
.
(11) For a novel, highly efficient ligand promoting Cu-catalyzed 1,3-
dipolar cycloadditions, see: Ozc¸ubukc¸u, S.; Ozkal, E.; Jimeno, C.; Perica`s,
M. A. Org. Lett. 2009, 11, 4680
.
(8) For recent reviews, see: (a) Bergbreiter, D. E.; Tian, J.; Hongfa, C.
Chem. ReV. 2009, 109, 530. (b) Dickerson, T. J.; Reed, N. N.; Janda, K. D.
Chem. ReV. 2002, 102, 3325.
(12) (a) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307.
(b) Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S.
Angew. Chem., Int. Ed. 2007, 46, 8431.
Org. Lett., Vol. 12, No. 7, 2010
1481

Table 1. Scope of the Asymmetric Michael Addition of
CH3NO2 to R,ꢀ-Unsaturated Aldehydes with
MeOPEG-Supported Catalyst 3
Table 2. Survey of Recycling Experimentsa of Catalyst 3 in the
Michael Addition of Nitromethane and Cinnamaldehyde 8a
time
(d)
yieldb
(%)
eec
[%]
time )
22 h
yieldb
(%)
eec
(%)
cycle
1
2
3
4
5
1
2
3
4
94
90
83
87
93
91
91
91
94
62
70
67
50
90
96f
93
92
92
91
91
93
93
entry
R
yielda (lit.)b (%)
eec (lit.)b (%)
d
1#
1d
2
3
4
5
Ph
Ph
a
a
b
c
d
e
f
90/52e
94
80 (88)
90
48
87 (76)
95 (82)
95/77e
94
94 (95)
93
92
89 (95)
90 (93)
d,e
2#
a Left column: “full conversion” experiments. Right column: isochron
experiments (t ) 22 h). b Isolated yields. c See table 1. d 8c was used as
starting material. e Run after regeneration procedure (stirring with 8c in
MeOH). f Yield less the potential “preloaded” 0.1 equiv of extra
aldehyde 8c.
p-MeO-Ph
o-MeO-Ph
p-NMe2-Ph
p-NO2-Ph
furyl
6
7
a Isolated yields. b Literature values according to Hayashi et al.12a using
10 mol % of 1 and 0.2 equiv of PhCOOH. c Determined by chiral-phase
HPLC. d Literature values for catalyst 1.12a e Literature values for
catalyst 2.
deactivation of our catalyst (Table 2, cycle 1-5; right
column). Despite the activity loss within these five isochron
experiments the catalyst still achieves a valuable average
yield of 68% for each of the five runs with an unchangingly
high selectivity of 92% ee.
number of different solvents did not allow for any improve-
ments. Interestingly, in water our fully soluble catalyst proved
to be inefficient, thus suggesting a boundary occurring or
“on water”13 promoted catalysis for other water-compatible
iminium catalysts, such as Palomo’s pyrrolidine catalysts
bearing long hydrophobic aliphatic chains.12b
We therefore could directly adopt the published conditions
without any further optimization. Importantly, a simple basic
wash (satd NaHCO3) of the reaction mixture after diethyl
ether-induced precipitation and subsequent filtration of the
catalyst was sufficient to get access to pure γ-nitro aldehydes
in high yields and enantiomeric excess without the need of
any further chromatographic purification.
Application of our catalyst showed a similar generality in
the scope of the reaction as was demonstrated for the
nonsupported counterpart. For both electron-rich (entries 3,
4, and 7) and electron-poor aromatic substituents (entry 6)
of the unsaturated aldehyde the corresponding products could
be obtained in high enantiomeric excess and often with higher
yields as a result of the greatly facilitated workup procedure.
Next we turned our attention to recycling studies. While
the mass recovery of the catalyst was greater than 95% and
the catalyst showed excellent selectivities in five subsequent
cycles, we, however, noticed increasing reaction times to
reach full conversion (see Table 2). Despite this obvious sign
of decreasing catalyst activity in various immobilization
studies such elongated reaction times are frequently over-
looked or are difficult to identify due to the diverse and
differing data presentation.14 The performance of time-
constant (isochron, t ) 22 h) recycling reactions revealed a
With respect to other immobilization studies of diaryl-
prolinol silyl ethers7 the loss of catalytic activity is well-
known and commonly attributed to a desilylation event of
the catalyst7c,g and the subsequent trapping of this free
prolinol derivative in a cyclic unreactive hemiaminal spe-
cies.15 Having selected this model reaction with a reported
high difference in both efficiency and selectivity for the
catalysis with the TMS-diarylprolinol ether 1 or its non-
silylated counterpart 2 (90%, 95% ee vs 52%, 77% ee) we
could directly judge our recycling results by comparison of
yield and ee. While no erosion in the high stereoselectivity
was observed for our catalyst, we questioned whether the
possible loss of the TMS group was decisive for the
deactivation problem.
To test our hypothesis of other deactivation modes than a
desilylation we decided to perform additional recycling
studies with the immobilized methyl ether catalyst 4 which
should not be prone to a detrimental ether cleavage under
the standard reaction and recycling conditions. In fact, we
found a similar loss in activity for the methoxy catalyst 4
(run 1: 95%, 78% ee; run 2: 80%,16 81% ee) together with
an a priori decreased ee due to the reduced sterical demand
of this methyl ether if compared to its TMS counterpart 3
(cf. 4 (78% ee) vs 3 (94% ee)).
Preliminary NMR experiments taking advantage of the
solubility of the MeOPEG-supported methoxy catalyst 4 were
undertaken to gain further insights in the catalysts deactiva-
tion mode. Making use of the catalyst’s methoxy group as a
“probe” pointed to the presence of at least one additional
catalyst-derived species besides the main unchanged recycled
catalyst, which could presumably stem from catalyst with
(13) For a detailed discussion on the role of water in organocatalytic
reactions, see: (a) Gruttadauria, M.; Giacalone, F.; Noto, R. AdV. Synth.
Catal. 2009, 351, 33. (b) Raj, M.; Singh, V. K. Chem. Commun. 2009,
6687. (c) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103. (d) Brogan,
A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45,
8100.
(15) (a) Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42,
1498. (b) Franze´n, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.
(16) Reaction time of second cycle: 2 days (first cycle: 1 day).
(14) Gladysz, J. A. Pure Appl. Chem. 2001, 73, 1319.
1482
Org. Lett., Vol. 12, No. 7, 2010

nonreleased product indicating a deactivation via product
inhibition. Based on these first hints, we could develop a
waste-free catalyst regeneration without the need of extra
reagents. We were pleased to find that simple stirring of the
recovered and washed TMS catalyst 3 with a solution of the
R,ꢀ-unsaturated aldehyde (being the starting material for the
next cycle) could fully restore the catalyst’s initial activity
(Table 2, cycle 1# and 2#). In fact, during this treatment the
release of some additional product (stemming from the
former cycle) could be observed while other byproducts
could not be detected. Consequently, this displacement
approach allows for complete recyclability of the im-
mobilized catalyst providing almost quantitative yield after
the standard reaction time without any loss of enantioselec-
tiVity.
immobilized diarylprolinol ether catalysts providing un-
changed reactivity and selectivity as compared to the
nonsupported catalyst. In addition, our immobilization allows
for a simple, column-free isolation of pure, sensitive aldehyde
products and therefore may be useful for application in more
complicated syntheses.
Acknowledgment. Generous support from the DBU
(Deutsche Bundesstiftung Umwelt, fellowship for I.M.), the
Fonds der Chemischen Industrie, and the DFG is gratefully
acknowledged. We also thank Markus Schmid (Universita¨t
Regensburg) for NMR measurements of the recycled catalyst
and Evonik Degussa for the donation of amino acids.
Supporting Information Available: Experimental details
and spectroscopic and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed a highly efficient
approach for the synthesis, application, and recycling of
OL100166Z
Org. Lett., Vol. 12, No. 7, 2010
1483