Dynamic kinetic resolution of β-amino esters by a heterogeneous system of a palladium nanocatalyst and candida antarctica lipase A

Article abstract of DOI:10.1002/ejoc.201001714

A dynamic kinetic resolution (DKR) of β-amino esters have been developed by the use of a heterogeneous racemization catalyst and an immobilized enzyme that accepts aromatic, heteroaromatic and aliphatic substrates. The reaction conditions were optimized to yield an efficient catalytic system without by-product formation. The products are obtained in 96-99 % ee and high yields. Copyright

Full text of DOI:10.1002/ejoc.201001714

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001714
Dynamic Kinetic Resolution of β-Amino Esters by a Heterogeneous System of
a Palladium Nanocatalyst and Candida antarctica Lipase A
Karin Engström,[a][‡] Mozaffar Shakeri,[a][‡] and Jan-E. Bäckvall*[a]
Keywords: Dynamic kinetic resolution / β-Amino esters / Candida antarctica lipase A / Palladium / Nanocatalysts /
Heterogeneous catalysis
A dynamic kinetic resolution (DKR) of β-amino esters have
been developed by the use of a heterogeneous racemization
catalyst and an immobilized enzyme that accepts aromatic,
heteroaromatic and aliphatic substrates. The reaction condi-
tions were optimized to yield an efficient catalytic system
without by-product formation. The products are obtained in
96–99% ee and high yields.
thereby overcoming the drawback of maximum 50% yield
that applies to kinetic resolutions.[7] DKR of secondary
alcohols has been reported under mild reaction condi-
tions,[8] but DKR of amines requires higher tempera-
tures.[9,10]
We have recently reported the immobilization of CalA in
functionalized mesocellular foam (GAmP-MCF; see Sup-
porting Information), which dramatically improved the
enantioselectivity of the enzyme towards a β-amino ester.[10]
Also, the thermostability of the enzyme was improved. One
single example of DKR of a β-amino ester was demon-
strated by the combination of the immobilized CalA and a
derivative of the homogeneous Shvo catalyst resulting in
89% ee and 85% conversion at 90 °C.
Introduction
Enantiomerically pure β-amino acids (and their corre-
sponding esters) are important intermediates in the phar-
maceutical and agrochemical industry; they have interesting
pharmacological properties and are valuable as building
blocks in β-peptides and natural products.[1] In nature, bac-
teria incorporate β-amino acids in secondary metabolites as
a defense mechanism; therefore, these compounds often
show high biological and physiological potency, both in free
form and as part of larger structures.[2] β-Amino acids are
often incorporated into peptide-based and peptidomimetic
drugs since they increase the stability towards degradation
by proteases.[3]
Despite the importance of enantiomerically pure β-
amino acids, so far their synthesis has remained a chal-
lenge.[4] There are several chemical approaches available for
their preparation including homologation of α-amino ac-
ids,[5a] addition of enolates to imines,[5b] aminohydroxyl-
ation,[5c] and ring-opening of β-lactams.[5d] Some of these
procedures suffer from being tedious and giving low
enantioselectivities. An environmentally benign method to
obtain enantiomerically pure β-amino esters is to employ
enzymes; reduction with ene-reductases[5e] or a kinetic reso-
lution by the use of lipases, e.g. Candida antarctica lipase A
(CalA).[5f,6]
Heterogeneous catalysts, in contrast to homogeneous
ones, have the advantage that they can be separated from
the reaction mixture and reused. Thus, it would be desirable
to replace the racemization catalyst used in our previous
system by a heterogeneous catalyst. We have now investi-
gated a heterogeneous palladium nanocatalyst, where Pd0
is attached to a basic AlO(OH) support that operates at
lower temperatures.[11] We report that this catalyst allows a
larger number of substrates to be used in the DKR and
leads to superior enantioselectivities compared to the pre-
viously used homogeneous catalyst.
Dynamic kinetic resolution (DKR) is an efficient ap-
proach for obtaining high yields of enantiomerically pure
organic compounds. In this method, the kinetic resolution
is combined with an in situ racemization of the substrate,
Results and Discussion
CalA was immobilized in two different mesoporous ma-
terials: (i) periodic mesoporous organosilica (PMO) with
ethane bridging groups and (ii) functionalized mesocellular
foam (GAmP-MCF) indicated as CalA/PMO and CalA/
GAmP-MCF, respectively (see Supporting Information).[10]
The Pd nanocatalyst was prepared according to a literature
procedure[11] and characterized by transmission electron
microscopy (TEM).[12]
[a] Department of Organic Chemistry, Arrhenius Laboratory,
Stockholm University,
10691 Stockholm, Sweden
Fax: +46-8-154-908
E-mail: jeb@organ.su.se
[‡] K. E. and M. S. contributed equally to this paper
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001714.
Eur. J. Org. Chem. 2011, 1827–1830
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. Engström, M. Shakeri, J.-E. Bäckvall
SHORT COMMUNICATION
Ethyl 3-amino-3-phenylpropanoate (1a) was used as increased to 80 °C (Table 1, Entry 3), the ee of 2a increased
model substrate, and we first investigated its racemization to the same level as for Entry 1 due to faster racemization.
with the Pd nanocatalyst [Pd0/AlO(OH)]. An initial study No change in the amount of by-product was observed. The
of the racemization of 1a by the Pd nanocatalyst under H2 use of an increased amount of enzyme led to a decrease in
at 70 °C showed that at prolonged reaction times the sub- 3a at the expense of a lower ee of 2a (Table 1, Entry 4),
strate was completely transformed into a the deaminated indicating that the racemization was not fast enough com-
by-product 3a.[9c,9d] We and others previously noted that pared to the enzymatic acylation.
in DKR processes, by-product formation is less than that
The racemization occurs through abstraction of hydro-
observed in isolated racemization due to transformation of gen from the amine to form an imine, followed by re-ad-
one enantiomer by the enzyme in the DKR.[9b,9e] Therefore, dition of hydrogen; hence the hydrogen pressure might in-
rather than to study the racemization separately, the DKR fluence the racemization.[9c,9d] The reaction was therefore
process was optimized with both Pd nanocatalyst and CalA conducted under H2, but this only resulted in a small de-
present.
crease of the amount of by-product 3a to 37% (Table 1,
The DKR of 1a was performed under the previously ap- Entry 5).
plied reaction conditions for KR/DKR of β-amino esters
Pretreatment of the Pd nanocatalyst with NaOH was
(2,2,2-trifluroethyl butyrate as acylating agent, dibutyl ether previously shown to increase the selectivity of the racemiza-
as solvent)[6a,10] but at lower temperature (70 °C) in the tion.[9e] Thus, the Pd nanocatalyst was treated with 0.1 m
presence of 6 mg of CalA/PMO and 6.9 mol-% of Pd nano- NaOH. This combined with a slight increase in enzyme
catalyst. The reaction was almost complete in 24 h, with loading resulted in a decreased amount (23%) of the by-
91% enantiomeric excess (ee) of the product 2a, but 45% product 3a (Table 1, Entry 6), but a decrease in ee of 2a to
of the substrate had been converted into by-product 3a 79% was also observed. Further attempts to decrease the
(Table 1, Entry 1). To reduce the by-product formation and, amount of by-product were made by using a proton sponge
if possible, improve the ee of the product, we started to [1,8-bis(dimethylamino)naphthalene].[13] By using a proton
optimize the reaction conditions by changing catalyst load- sponge and dilution did not decrease the by-product forma-
ing and enzyme loading.[7a]
Use of lower amounts of the Pd nanocatalyst and CalA version with only 73% ee (Table 1, Entry 7).
tion further, but instead the reaction stopped at 80% con-
resulted in longer reaction times and lower ee of the prod-
Since none of the above-mentioned approaches sup-
uct 2a but no change in the amount of by-product 3a pressed by-product formation significantly, we instead fo-
(Table 1, Entry 2). The reason for the lower ee was probably cused on a decrease of the temperature. Gratifyingly, a
due to a too slow racemization reaction as a result of the DKR at 50 °C by the use of CalA/GAmP-MCF and the Pd
lower Pd nanocatalyst loading. When the temperature was nanocatalyst yielded 2a in 96% ee and 99% conversion af-
Table 1. Optimization of the DKR conditions of the model substrate ethyl 3-amino-3-phenylpropanoate (1a) by using the Pd nanocatalyst
and CalA immobilized in mesoporous materials.[a]
Entry
Enzyme
[mg]
Pd nanocatalyst
[mol-%]
Temperature
[°C]
Additive
ee [%]
Yield [%][c]
2a[b]
2a
3a
1
6
4
4
20
4
5
6.9
4.6
4.6
70
70
80
80
70
80
80
50
–
–
–
91
77
89
81
91
79
73
96
54
51
55
76
62
76
62
99
45
44
44
23
37
23
18
0
2[d]
3[d]
4
3.5
Na2CO3
5
7.0
H2
–
6[e]
7[f]
8[h]
7.0[g]
3.5[g]
7.0[g]
5
6
proton sponge
–
[a] Conditions: 1a (0.1 mmol), CalA/PMO, Pd nanocatalyst and 2,2,2-trifluroethyl butyrate (0.2 mmol) in dibutyl ether (2 mL) for 24 h
unless otherwise noted. [b] Determined by chiral GC. [c] Determined by 1H NMR spectroscopy. [d] 48 h. [e] 40 h. [f] 44 h. [g] Pretreatment
of the Pd nanocatalyst with NaOH. [h] CalA/GAmp-MCF.
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Dynamic Kinetic Resolution of β-Amino Esters
ter 24 h (Table 1, Entry 8). Moreover, no by-product was mation. The products were obtained in 96–99% ee and high
detected. The lower temperature was advantageous for the yields. The current system is superior to our previous sys-
enantioselectivity; the ee of 2a was higher in the DKR at tem that used the homogeneous Shvo catalyst, and it works
50 °C compared to that at 70 °C, and the reason for this is with lower enzyme catalyst loading (one third) and at lower
the higher enantioselectivity for the enzyme at lower tem- temperatures.
peratures.
The optimized DKR reaction conditions were then ap-
plied to investigate the substrate scope of the reaction by
the use of CalA/GAmP-MCF and the Pd nanocatalyst. The
CalA/GAmP-MCF was used instead of CalA/PMO be-
cause of a slightly higher enantioselctivity toward 1a (data
Experimental Section
General Procedure for the Dynamic Kinetic Resolution of β-Amino
Esters: β-Amino ester 1a–1e (0.1 mmol) and 2,2,2-trifluroethyl but-
yrate (0.2 mmol) were dissolved in dibutyl ether (2 mL) in a flame-
dried Schlenk tube. The reaction was started by simultaneous ad-
not shown). Furthermore, because of a slightly lower ac-
tivity of CalA toward some of the studied β-amino esters
compared to that towards the model substrate,[6] a larger
amount of CalA/GAmP-MCF was employed.
dition of the Pd nanocatalyst [150 mg of AlO(OH)-Pd, 0.75 mg of
Pd, 7.0 mol-%] and CalA/GAmP-MCF (10 mg), and the reaction
mixture was stirred at 50 °C until the reaction had reached comple-
tion. The progress of the reaction was monitored by 1H NMR spec-
troscopy.
As we already showed, the DKR of the aromatic β-
amino ester 1a gave 96% ee and full conversion after 24 h
(Table 2, Entry 1). DKR of the heteroaromatic β-amino es-
ters 1b and 1c resulted in 99 and 97% ee, respectively, and
with full conversion after 30 h (Table 2, Entries 2 and 3).
DKR was also conducted with two aliphatic β-amino esters,
1d and 1e, which in both cases resulted in 99% ee with full
conversion in 48 h and 24 h, respectively (Table 2, Entries 4
and 5).
Supporting Information (see footnote on the first page of this arti-
cle): General remarks and procedures, and compound characteriza-
tion data.
Acknowledgments
The Berzelius Center EXSELENT, the European FP7 network
INTENANT (“Integrated synthesis and purification of single
enantiomers”), and the K & A Wallenberg foundation are grate-
fully acknowledged for financial support. We thank Dr. Cheuk-wai
Tai for assistance with the TEM.
Table 2. DKR of β-amino esters.[a]
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Conclusions
We have developed a DKR of β-amino esters by the use
of a heterogeneous racemization catalyst and an immobi-
lized enzyme that accepts aromatic, heteroaromatic and ali-
phatic substrates. The reaction conditions were optimized
to yield an efficient catalytic system without by-product for-
Eur. J. Org. Chem. 2011, 1827–1830
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1829

K. Engström, M. Shakeri, J.-E. Bäckvall
SHORT COMMUNICATION
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Received: December 22, 2010
Published Online: January 27, 2011
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1827–1830