Efficient recovery and reuse of an immobilized peptidic organocatalyst

Article abstract of DOI:10.1002/adsc.201100118

Readily reusable immobilized organocatalysts are important from a practical, economic, and environmental viewpoint. However, their successful development has proven challenging and only limited reaction and recovery cycles have been achieved. We report an

Full text of DOI:10.1002/adsc.201100118

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DOI: 10.1002/adsc.201100118
Efficient Recovery and Reuse of an Immobilized Peptidic
Organocatalyst
Yukihiro Arakawa,a Markus Wiesner,a and Helma Wennemersa,*
a
Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Fax : (+41)-61-267-0976; e-mail: Helma.Wennemers@unibas.ch
Received: February 16, 2011; Revised: March 17, 2011; Published online: May 17, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100118.
Abstract: Readily reusable immobilized organoca-
talysts are important from a practical, economic,
and environmental viewpoint. However, their suc-
cessful development has proven challenging and
only limited reaction and recovery cycles have been
achieved. We report an extraordinarily robust resin-
bound tripeptidic organocatalyst that can be readily
reused for at least 30 reaction and recovery cycles
without loss in catalytic activity or stereoselectivity.
The immobilized catalyst can be directly reused for
conjugate addition reactions between aldehydes
and nitroolefins after a simple filtration from the
reaction products. The catalytic efficiency and che-
moselectivity of the immobilized peptidic catalysts
is so high that a broad range of g-nitroaldehydes
were isolated easily after filtration and removal of
all volatiles in quantitative yields, excellent diaste-
reoselectivities and enantioselectivities and, most
remarkably, perfect analytical purities. The ease of
handling allows for a facile scale-up of reactions
catalyzed by the immobilized peptidic catalyst. In
addition, the results provide a guide for the further
development of immobilized organocatalysts.
lysts.[2,3] Organocatalysts are arguably even more at-
tractive than metal-based catalysts for immobilization
since they are typically air- and moisture-stable and
issues such as leaching of the active metal center from
the immobilized ligand are no concern.[3] Several
recent examples demonstrate the potential of immo-
bilized organocatalysts.[4] However, often catalyst de-
activation has hampered efficient catalyst reuse and
only allowed for a limited number of reaction and re-
covery cycles. This has in particular been a concern
for the development of immobilized chiral amine-
based organocatalysts that are highly valuable for imi-
nium and enamine catalysis.[5–7] Catalyst deactivation
can be caused by an intrinsic chemical instability of
the catalyst itself or by reaction of the immobilized
catalyst with the starting materials or products to
form stable, undesired adducts. For example, desilyla-
tion or product inhibition of immobilized diphenyl-
prolinol silyl ether derivatives has hindered their effi-
cient recycling and even reactivation protocols did
not allow for restoring the efficiency over more than
ꢀ6 cycles.[6a,e,m,7] Likewise, also the catalytic perfor-
mance of immobilized proline and imidazolidinone
derivatives was found to be reduced significantly after
a few reaction and recycling cycles.[3] As a result, a
readily reusable chiral amine-based organocatalyst
has so far not been developed.
Keywords: asymmetric catalysis; catalyst reuse;
conjugate addition reactions; immobilization; pep-
tides
Recently, we introduced the peptide H-d-Pro-Pro-
Glu-NH2 (1) as an efficient catalyst for asymmetric
conjugate addition reactions of aldehydes to nitroole-
fins.[8,9] In the presence of peptide 1 aldehydes and ni-
The concept of immobilizing asymmetric catalysts on troolefins react readily with each other to provide
an insoluble support is highly attractive since it allows synthetically versatile g-nitroaldehydes in excellent
in principle for easy recovery and reusability of the yields and stereoselectivities (Scheme 1). In contrast
catalyst as well as facile product isolation.[1] Readily to many other chiral amine-based organocatalysts,[5]
reusable heterogeneous catalysts have therefore ad- the peptidic catalyst is highly active, therefore allow-
vantages over soluble catalysts both from an environ- ing for catalyst loadings of as little as ꢀ1 mol%.[8,9]
mental and economic viewpoint. As a result, a lot of This high effectiveness of H-d-Pro-Pro-Glu-NH2 (1)
research has been devoted to the development of im- led us to explore whether the versatility of the pepti-
mobilized organometallic catalysts and organocata-
Adv. Synth. Catal. 2011, 353, 1201 – 1206
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Yukihiro Arakawa et al.
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Scheme 1. Conjugate addition reactions catalyzed by peptide 1.
dic catalyst can be further improved by immobiliza- (PS) resin as well as hydrophilic TentaGel (polyethy-
tion on a solid support. lene glycol-PS) and PEGA (polyethylene glycol-poly-
Within this manuscript we show that the immobi- acrylamide) resins were used to immobilize peptide 1
lized peptide H-d-Pro-Pro-Glu-TentaGel is an effi- (Table 1). The immobilization of peptide 1 onto the
cient catalyst for conjugate addition reactions of alde- different amino-functionalized solid supports was
hydes to nitroolefins.[7] We demonstrate that H-d-Pro- easily accomplished by standard solid-phase peptide
Pro-Glu-TentaGel can be easily recovered and reused synthesis following the Fmoc/t-Bu protocol (for de-
for at least 30 times with the same high catalytic per- tails see Supporting Information).[10,11]
formance. In addition, we show that analytically clean
products are isolated after a simple filtration followed was used as a test reaction to evaluate the catalytic
by removal of all volatiles. properties of the solid-supported peptidic catalysts.
The reaction between n-butanal and b-nitrostyrene
We started our investigations by exploring the Conditions were used that had previously been devel-
effect of a solid support on the catalytic performance oped for reactions with peptide 1 in homogeneous
of peptide 1 and an analysis as to which resin would phase.[8] Satisfyingly, the reactions proceeded as clean-
be best suited. Cross-linked hydrophobic polystyrene ly in the presence of all three immobilized catalysts to
Table 1. Conjugate addition reactions between n-butanal and b-nitrostyrene catalyzed by the immobilized peptidic
catalysts.[a]
Entry
Cat.
mol%
Temperature [8C]
Time [h]
Conversion [%][b]
syn:anti[b]
ee [%][c]
1[d]
2
3
4
5
6
7
8
9
1
1-PS
1
3
3
3
3
3
10
10
20
r.t.
r.t.
r.t.
r.t.
12
4
24
4
20
20
20
70
96
quant.
quant.
quant.
quant.
quant.
78
quant.
56
0
50:1
25:1
28:1
28:1
>99:1
>99:1
>99:1
>99:1
–
97
91
89
91
95
96
96
97
–
1-PEGA
1-TG
1-TG
1-TG
1-TG
1-TG
1-TG
0
À15
À15
À40
À70
[a]
Reactions were performed using 1.32 mmol of butanal, 0.44 mmol of nitrostyrene in the presence of the catalyst.
Determined by H NMR spectroscopy of the reaction mixture.
[b]
[c]
[d]
1
Determined by chiral-phase HPLC analysis.
Data taken from ref.[8c]
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Efficient Recovery and Reuse of an Immobilized Peptidic Organocatalyst
Scheme 2. Reaction, recycling and work-up protocol.
the desired conjugate addition product as those cata- lyst loading does not restrict its usefulness. Thus, we
lyzed by the soluble analogue 1 (Table 1, entries 1–4). next evaluated the reusability of the solid-supported
Side products were not observed.
The diastereoselectivities and enantioselectivities of À158C using 10 mol% of the solid-supported catalyst.
the g-nitroaldehyde were lower compared to those To explore the reusability of the immobilized pep-
catalyst 1-TG and performed these reactions at
observed with peptide 1 in solution phase but still in a tide 1-TG, reactions were carried out under the opti-
range of syn:anti ratios of ~25:1 and enantioselectivi- mized conditions described above. The reaction mix-
ties of 89–91% ee (Table 1, entries 2–4).[12] Compara- tures were not mechanically stirred but agitated by
tively small differences were observed between the gentle shaking to allow for efficient mixing of the re-
three solid-supported catalysts, demonstrating that action components but prevent destruction of the
the type of resin has only a minor effect on the prop- resin. The immobilized catalyst was used without any
erties of the peptidic catalyst (Table 1, entries 2–4). further treatment with additives. The reaction course
The best results were observed with the peptide im- was easily monitored not only by TLC analysis but
mobilized on TentaGel resin. Using 3 mol% of the also the disappearance of the yellow color of the ni-
immobilized peptide, the g-nitroaldehyde was ob- troolefin. After complete consumption of the nitro-
tained within 4 h in quantitative yield, a diastereose-
ACHTUNGTRENoNGNU lefin, the catalyst was recovered by a simple filtra-
lectivity of 28:1 (syn:anti) and an enantioselectivity of tion and then reused directly for the second reaction
91% ee (Table 1, entry 4). Thus, for all further studies cycle under the same reaction conditions (Scheme 2).
the peptide immobilized on TentaGel resin (1-TG) This reaction and recycling protocol was repeated 30
was used.
times. After each cycle, the conjugate addition prod-
With the appropriate resin in hand we next sought uct was isolated from the filtrate simply by evaporat-
to further improve the enantioselectivity of the solid- ing the solvent and the excess of the aldehyde
supported peptidic catalyst 1-TG. Whereas variations (Scheme 2).
in the solvent did not result in further improvements
This facile work-up procedure provided the g-nitro-
(see Supporting Information), reducing the tempera- aldehyde 2a in each of the reaction cycles in perfect
ture led to a significant increase both in the diastereo- syn-diastereoselectivity, an enantiomeric excess of
selectivity and the enantioselectivity. Already at 08C 96% ee, yields of ꢁ96% and, most remarkably, per-
the product was isolated in perfect diastereoselectivity fect purity (Table 2). The excellent purity of the g-ni-
(>99:1) and an enantioselectivity of 95% ee (Table 1, troaldehyde obtained after this simple protocol in-
entry 5). A further reduction of the temperature to volving reaction, filtration, and evaporation of all vol-
À158C required 10 mol% of the immobilized catalyst atiles was confirmed by NMR spectroscopic analysis
to achieve complete conversion to the product within and elemental analysis. Only in cycles 27–30 was the
20 h but allowed for a further increase in the enantio- activity of the catalyst slightly reduced requiring reac-
selectivity to 96% ee (Table 1, entries 6 and 7). At tion times of ꢁ24 h to obtain the g-nitroaldehyde 2a
lower temperature the catalytic activity was too low in the same perfect yields and high stereoselectivities
to be practical (Table 1, entries 8 and 9). Provided (Table 2).
that the catalyst can be readily reused, a higher cata-
Adv. Synth. Catal. 2011, 353, 1201 – 1206
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Yukihiro Arakawa et al.
COMMUNICATIONS
Table 2. Reusability of the solid-supported catalyst 1-TG.
Cycle
Time [h]
Conversion [%][a]
Yield [%][b]
syn:anti[c]
ee [%][d]
1
20
quant.
quant.
quant.
quant.
quant.
99
quant.
96–quant.
nd[e]
quant.
97–quant.
nd[e]
>99:1
>99:1
nd[e]
>99:1
>99:1
>99:1
>99:1
96
2–10
11–13
14
15–25
26
20–24
20–24
23
96
nd[e]
96
20–24
24
96
96
96
27–30
24 (48)[f]
ꢁ95 (quant.)
quant.
[a]
1
Determined by H NMR spectroscopy of the reaction mixture.
Isolated yields.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR spectroscopy of the isolated product.
Determined by chiral-phase HPLC analysis.
not determined.
After 24 h a trace of the nitrostyrene (ꢀ5%) was left as judged by TLC analysis which was consumed after 48 h.
These results demonstrate that the solid-supported hydes in excellent yields and stereoselectivities
peptide 1-TG is an extraordinarily robust, chemose- (Table 3). Most remarkably, all products were ob-
lective, and efficient catalyst. It does not suffer from tained in perfect purities as judged by NMR spectros-
irreversible deactivation reactions and does not re- copy and elemental analysis and did not require any
quire any kind of reactivation to maintain its excellent further purification after their simple isolation by fil-
catalytic performance.
tration and evaporation of the solvent and excess of
Also the substrate scope of the immobilized cata- the aldehydes. This facile purification protocol also
lyst 1-TG proved to be broad. A wide range of differ- prevents possible epimerisation at the a-carbon of the
ent aldehydes and nitroolefins react readily with each g-nitroaldehyde which can occur during a column
other in the presence of 1-TG to provide g-nitroalde- chromatographic work-up. Only in the case of non-
Table 3. Conjugate addition reactions between aldehydes and nitroolefins catalyzed by immobilized peptide 1-TG.[a]
Entry
R1
R2
Time [h]
Yield [%][b]
syn:anti[c]
ee [%][d]
1
2
3
Et
Ph
Ph
Ph
Ph
20
17
19
72
24
22
22
24
24
22
16
24
quant.
quant.
quant.
quant.
92
quant.
quant.
quant.
quant.
quant.
quant.
quant.
>99:1
40:1
84:1
>99:1
37:1
83:1
>99:1
72:1
>99:1
74:1
85:1
>99:1
96
96
95
95
97
95
95
95
97
95
93
92
Me
n-Bu
i-Pr
Bn
Et
Et
Et
Et
Et
4
5[e]
6
Ph
C6H4-4-Cl
C6H4-4-Br
C6H4-4-OMe
C6H4-2-CF3
C6H3-2,4-Cl2
2-thienyl
7
8
9
10
11
12
Et
Et
(CH2)5CH3
[a]
Reactions were performed using 1.32 mmol of aldehyde, 0.44 mmol of nitroolefin. Products were isolated after filtration
of the catalyst and removal of all volatiles under reduced pressure unless otherwise noted.
Isolated yields.
Determined by H NMR spectroscopy of the isolated product.
Determined by chiral-phase HPLC analysis.
[b]
[c]
[d]
[e]
1
The product was purified by flash column chromatography on silica gel.
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Adv. Synth. Catal. 2011, 353, 1201 – 1206

Efficient Recovery and Reuse of an Immobilized Peptidic Organocatalyst
volatile aldehydes (e.g., 3-phenylpropionaldehyde, Experimental Section
Table 3, entry 5) was a column chromatographic pu-
rification necessary to isolate the pure g-nitroalde- General Procedure for Conjugate Addition Reactions
hyde.
To evaluate the versatility of the immobilized pepti-
of Aldehydes to Nitroolefins Catalyzed by 1-TG
A
glass reactor with Teflon filter (MultiSynTech,
dic catalyst further, we performed the reaction on a
larger scale. 7.5 g (50.4 mmol) of nitrostyrene were re-
acted with 10.9 g (151.2 mmol) of butanal in the pres-
ence of 10 mol% of 1-TG. The conjugate addition
product 2a formed also on this scale readily and was
isolated in quantitative yield (11.2 g), perfect purity
and syn-diastereoselectivity and an enantioselectivity
of 96% ee.
Finally, we explored whether the reaction time can
be readily reduced by using higher amounts of the im-
mobilized catalyst 1-TG. Reassuringly, the use of
30 mol% instead of 10 mol% of the catalyst under the
same conditions allowed for a three-fold reduction of
the reaction time (6 h instead of 20 h) and provided
the product in the same high purity, yield and stereo-
selectivities. These results suggest that the immobi-
lized peptidic catalyst is amenable for the develop-
ment of a continuous flow system.
V050TF118) equipped with a Luer stopper (MultiSynTech,
V000 LS100) was charged with 1-TG (44 mmol, 10 mol%)
and cooled to À158C.
A solution of the aldehyde
(1.32 mmol) and the nitroolefin (0.44 mmol) in a mixture of
CHCl3 and i-PrOH (9:1, 1 mL) was added and the reaction
mixture was agitated using a shaker (IKA VIBRAX VXR
basic) at ~600 rpm at À158C for 16–72 h. After complete
consumption of the nitroolefin, the reaction mixture was di-
rectly filtered from the glass reactor and the remaining im-
mobilized catalyst was washed with a mixture of CHCl3 and
i-PrOH (9:1) ~5 times. All volatiles (solvent and excess re-
agents) of the combined filtrate and washings were removed
under reduced pressure to isolate the product. The immobi-
lized catalyst 1-TG was reused for the next reaction without
any further treatment.
Acknowledgements
In conclusion, we have developed a highly efficient
and reusable immobilized peptidic catalyst for asym-
metric conjugate addition reactions of aldehydes to b-
substituted nitroolefins. This is the first example of an
immobilized chiral amine-based organocatalyst that
can be reused after a simple filtration for at least 30
times without a loss in activity and stereoselectivity
and without requiring reactivation. Reactions cata-
lyzed by 1-TG are so clean and high-yielding that
simple removal of all volatiles under reduced pressure
suffices to provide the desired products in excellent
yields, purities and stereoselectivities. Thus, the immo-
bilized peptidic catalyst is highly cost effective both
with respect to its own reuse and the product isolation
process. The reasons for this extraordinary perfor-
mance of the solid-supported peptidic catalyst are
manifold: (i) the catalyst is highly chemoselective for
conjugate addition reactions – side reactions such as
homo-aldol reactions that are common for other
amine-based organocatalysts do not occur; (ii) addi-
tives are not required for the high catalytic efficiency
– as a result, product purification is simple and no re-
activation of the catalyst is necessary; (iii) the catalyst
is chemically stable and is not deactivated over the re-
action course by irreversible formation of undesired
stable adducts. Thus, aside from the practical advan-
ces, the research also provides a guide for the devel-
opment of other efficient immobilized organocata-
lysts. Furthermore, the results highlight the versatility
of peptidic catalysts[13] in general. Since peptidic cata-
lysts are routinely prepared by solid-phase peptide
synthesis on a solid support and are generally chemi-
cally robust, they are arguably among the most attrac-
tive catalysts for immobilization.
We thank Bachem, the Swiss National Science Foundation
and the RTN REVCAT by the European Union for support-
ing this research. H.W. is grateful to Bachem for an endowed
professorship
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