Dynamic kinetic resolution of primary amines with a recyclable Pd nanocatalyst for racemization

Article abstract of DOI:10.1021/ol070130d

(Chemical Equation Presented) A practical procedure for the dynamic kinetic resolution (DKR) of primary amines has been developed. This procedure employs a palladium nanocatalyst as the racemization catalyst, a commercial lipase (Novozym-435) as the resol

Full text of DOI:10.1021/ol070130d

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1157-1159
Dynamic Kinetic Resolution of Primary
Amines with a Recyclable Pd
Nanocatalyst for Racemization
Mahn-Joo Kim,* Won-Hee Kim, Kiwon Han, Yoon Kyung Choi, and Jaiwook Park*
Department of Chemistry, Pohang UniVersity of Science and Technology, San-31,
Hyojadong, Pohang 790-784, Korea
mjkim@postech.ac.kr; pjw@postech.ac.kr
Received January 18, 2007
ABSTRACT
A practical procedure for the dynamic kinetic resolution (DKR) of primary amines has been developed. This procedure employs a palladium
nanocatalyst as the racemization catalyst, a commercial lipase (Novozym-435) as the resolution catalyst, and ethyl acetate or ethyl methoxyacetate
as the acyl donor. Eleven primary amines and one amino acid amide have been efficiently resolved with good yields (85
−99%) and high
enantiomeric excesses (97 99%).
−
The complete transformation of a racemic mixture into a
single enantiomer is one of the challenging problems in chiral
synthesis. Recently, a novel strategy has attracted great
attention as a solution to this problem: dynamic kinetic
resolution (DKR) by the coupling of an enzymatic resolution
with a metal-catalyzed racemization.1 Several groups includ-
ing ours have developed enzyme-metal combinations as
useful catalysts for such DKRs and demonstrated that
racemic substrates can be efficiently transformed by them
into enantiomerically enriched products with high yields and
excellent enantiomeric excesses, both approaching 100%.2
Now a pair of complementary enzyme-metal combinations,
lipase-Ru and subtilisin-Ru, are available for the DKR of
a wide range of racemic secondary alcohols.3 The (R)-
selective DKR can be performed with the former, whereas
the (S)-selective DKR can be done with the latter. The DKR
of amines including amino acids, however, is more chal-
lenging, and few practical procedures have been developed
for such a DKR.4-7 We herein wish to report for the first
time a practical procedure using a palladium nanocatalyst
for amine racemization, which is applicable for the DKR of
primary amines as well as amino acid amides.
(2) (a) Choi, J. H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.-J.;
Park, J. Angew. Chem., Int. Ed. 2002, 41, 2373-2376. (b) Kim, M.-J.;
Chung, Y. I.; Choi, Y. K.; Lee, H. K.; Kim, D.; Park, J. J. Am. Chem. Soc.
2003, 125, 11494-11495. (c) Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park,
E. S.; Kim, E. J.; Kim, M.-J.; Park, J. J. Org. Chem. 2004, 69, 1972-
1977. (d) Martin-Matute, B.; Edin, M.; Bogar, K.; Ba¨ckvall, J. E. Angew.
Chem., Int. Ed. 2004, 43, 6535-6539. (e) Kim, N.; Ko, S.-B.; Kwon, M.
S.; Kim, M.-J.; Park, J. Org. Lett. 2005, 7, 4523-4526. (f) Martin-Matute,
B.; Edin, M.; Bogar, K.; Kaynak, F. B.; Ba¨ckvall, J. E. J. Am. Chem. Soc.
2005, 127, 8817-8825.
(3) Kim, M.-J.; Kim, H. M.; Kim, D. H.; Park, J. Green Chem. 2004, 6,
471-474.
(4) Reetz, M. T.; Schimossek, K. Chimia 1996, 50, 668-669.
(5) Choi, Y. K.; Kim, M.-J.; Ahn, Y. Org. Lett. 2001, 3, 4099-4101.
(6) Parvulescu, A.; Vos, D. D.; Jacobs, P. Chem. Commun. 2005, 5307-
5309.
(7) Paetzold, J.; Ba¨ckvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620-
17621.
(1) Reviews: (a) Kim, M.-J.; Ahn, Y.; Park, J. Curr. Opin. Biotechnol.
2002, 13, 578-587. (b) Pamies, O.; Ba¨ckvall, J. E. Chem. ReV. 2003, 103,
3247-3262. (c) Kim, M.-J.; Park, J.; Ahn, Y. In Biocatalysis in the
Pharmaceutical and Biotechnology Industries; Patel, R. N., Ed.; CRC
Press: Boca Raton, FL, 2006; pp 249-272.
10.1021/ol070130d CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/10/2007

The first DKR of amine was reported by the Reetz group
in 1996.4 The DKR was done by the combination of Pd/C
as the racemization catalyst and a lipase as the resolution
catalyst in the presence of ethyl acetate as the acyl donor.
Only one substrate, 1-phenylethylamine 1a, was tested for
DKR in this work. The reaction required a long reaction time
and gave a moderate yield. Later, we reported the DKR of
several amines by the lipase-Pd combination starting from
ketoximes, giving better yields at shorter reaction times.5
Lately, the Jacobs group reported an improved procedure
using a modified lipase-Pd combination, in which Pd on
alkaline earth metals was employed as the racemization
catalyst.6 On the other hand, the Ba¨ckvall group introduced
the use of a diruthenium complex as an alternative racem-
ization catalyst, which displayed satisfactory activity at high
temperature (90 °C).7 Several primary amines were resolved
with this catalyst and a lipase.
Table 1. Dynamic Kinetic Resolution of Primary Aminesa
Our Pd nanocatalyst, Pd/AlO(OH), was prepared as
palladium nanoparticles entrapped in aluminum hydroxide.8
Its activity was examined in the racemization of optically
active 1-phenylethylamine ((S)-1a, >99% ee) and compared
with that of commercially available Pd/Al2O3. The racem-
ization reactions were carried out with 1 mol % of palladium
in toluene at 70 °C, and the change in the enantiomeric excess
(ee) of the substrate was analyzed by HPLC. With the Pd
nanocatalyst, the ee decreased to 29% at 12 h and reached
near zero (2%) at 24 h. Meanwhile, it changed slowly to
94% and 88%, respectively, at 12 and 24 h with the
commercial catalyst. These data clearly indicate that the
racemization by the Pd nanocatalyst proceeds much more
rapidly than by the commercial catalyst. It was also observed
that the formation of some hydrolyzed and condensation
products such as acetophenone and di(1-phenylethyl)amine
took place in the prolonged racemization.9 These byproducts
amounted to 18% in the 24 h racemization. However, the
amounts of byproducts become significantly small or neg-
ligible in DKR itself because the enzymatic acylation of
amine proceeds more rapidly than the side reactions.
The DKR with the Pd nanocatalyst was explored with a
commercial lipase (Novozym-435). First of all, 1a was
chosen as the first substrate to be resolved through the DKR.
The DKR of 1a was performed in the presence of molecular
sieves with ethyl acetate as the acyl donor, 1 mol % of Pd/
AlO(OH), and Novozym-435 (120 mg/mmol of substrate)
in toluene at 70 °C for 3 days (Scheme 1). The DKR afforded
a All the reactions except four cases (entries 15-18) were carried out in
toluene at 70 °C under two different conditions: (1) 1 mol % of Pd
nanocatalyst, 120 mg/mmol of Novozym-435, 3 equiv of AcOEt, and 700
mg/mmol of molecular sieves. (2) 1 mol % of Pd nanocatalyst, 15 mg/
mmol of Novozym-435, and 1.7 equiv of ethyl methoxyacetate. In the
exceptional cases, the reactions were done with 12 mol % of Pd nanocatalyst,
120 mg/mmol of Novozym-435, and 3 equiv of AcOEt in toluene at 100
b
c
°C. Isolated yield. Determined by HPLC using a chiral column.
Scheme 1. Dynamic Kinetic Resolution of
1-Phenylethylamine
added to reduce the content of water mainly coming from
the commercial enzyme, which could cause the hydrolysis
of the imine intermediate to acetophenone. Later, it was
found that the addition of molecular sieves, however, was
unnecessary with the use of an activated acyl donor, ethyl
methoxyacetates, and a significantly reduced amount of
enzyme (15 mg/mmol of substrate). In this case, a better
isolated yield (98%) was obtained with a high optical purity
(>99% ee). These results encouraged us to test seven
additional benzyl amines 1b-h for DKR. For each substrate,
a good yield (conversion, 97%; isolated yield, 92%) and a
high optical purity (98% ee). Here, molecular sieves were
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Org. Lett., Vol. 9, No. 6, 2007

two DKR reactions were carried out with a variation in the
acyl donor: one with ethyl acetate and the other with ethyl
methoxyacetate. The results (entries 1-14) described in
Table 1 indicate that all the DKRs proceeded successfully
with good isolated yields and high optical purities.
lipase under the conditions described above. The complete
conversion was achieved until the 8th recycling, and then a
gradual decrease in conversion yield was observed. The
conversion yield, however, was still good (89%) even for
the 10th recycling and fully recovered to the completion level
by the addition of some fresh enzymes (half of the initial
amount) in the 11th run. On the other hand, the ee value
decreased by less than 1% every recycling until the 10th
recycling (from 99% to 92%) and then increased to a good
level (95%) in the 11th run. These results clearly indicate
that the Pd nanocatalyst is robust and sustainable. It is also
noteworthy that the lipase is thermostable and recyclable even
at 100 °C.
In summary, we have demonstrated that the DKR of
amines can be efficiently performed by using a Pd nano-
catalyst for racemization together with a lipase as the
resolution catalyst. Both benzyl and aliphatic amines are
transformed by these catalysts to the corresponding amides
with good yields and high optical purities. The DKR of
amino acid amide also proceeds equally well with the same
catalysts. Because the catalysts are highly thermostable, the
DKR reactions can be operated at 100 °C with the multiple
recycling of these catalysts. The products from the DKR
reactions can be readily deacylated to give primary amines
or reduced to the corresponding secondary amines. Therefore,
our DKR method provides a useful route to optically active
primary and secondary amines.11 It is concluded that this
work presents an excellent illustration for the complete
conversion of racemic substrates to single enantiomeric
products by enzyme-metal combination.
Next, we explored the DKR of aliphatic amines which
are more difficult to racemize than benzyl amines. The
reaction conditions were modified to facilitate racemization.
Molecular hydrogen (1 atm) was employed with an increased
amount of Pd/AlO(OH) (12 mol %) at higher temperature
(100 °C). Here, the use of hydrogen not only enhances the
racemization efficiency through the hydrogenation of the
imine intermediate but also makes the addition of molecular
sieves unnecessary because it reduces the level of the imine
intermediate prone to the hydrolysis. Surprisingly, the DKR
of 1i in the presence of ethyl acetate as the acyl donor
reached completion at a short time (4 h) and afforded the
products of high optical purity in an almost quantitative yield
(entry 15). Additional aliphatic amines, 1j and 1k, were also
successfully resolved under these conditions (entries 16 and
17). For these aliphatic amines, the DKRs in the presence
of ethyl methoxyacetate instead of ethyl acetate were not
tried because the chemical acylation of amine by the activated
acyl donor was observed at 100 °C.
The successful procedure for the DKR of aliphatic amines
was then applied to the DKR of an amino acid amide,
phenylalanine amide, which afforded an almost quantitative
yield with high optical purities (entry 18). This is the first
example for the DKR of an amino acid amide by the
combination of enzyme and metal.10
Finally, we examined the stability of the Pd nanocatalyst
through the recycling experiments. The first recycling
experiment was done for the racemization of (S)-1i. The
racemization reaction was performed 10 times with the
recycling of the nanocatalyst (8 mol %), each time under
hydrogen (1 atm) in toluene at 100 °C for 24 h. No significant
decrease in racemization efficiency was observed until the
10th recycling. The second recycling experiment was done
for the DKR of 1i. The DKR reaction was carried out 11
times with the recycling of both the Pd nanocatalyst and
Acknowledgment. This work was supported by the
Korean Ministry and Science and Technology through
KOSEF (Center for Integrated Molecular System and R01-
2006-000-10696-0) and the Korean Ministry of Education
and Human Resources through KRF (BK21 program and
KRF-2006-311-C00089).
Supporting Information Available: Experimental pro-
cedures and data for racemization, DKR, and recycling and
the analytical data of products. This material is available free
of charge via the Internet at http://pubs.acs.org.
(8) (a) Kwon, M. S.; Kim, N.; Park, C. M.; Lee, J. S.; Kang, K. Y.;
Park, J. Org. Lett. 2005, 7, 1077-1079. (b) Kwon, M. S.; Kim, N.; Seo, S.
H.; Park, I. S.; Cheedrala, R. K.; Park, J. Angew. Chem., Int. Ed. 2005, 44,
6913-6915.
OL070130D
(9) The hydrolysis of the imine intermediate (Ph(CH3)CdNH) from the
racemization gives acetophenone, which in turn reacts with 1-phenylethyl
amine, followed by hydrogenation, to yield di(1-phenylethyl)amine. The
secondary amine product may be formed through the condensation of imine
with 1-phenylethylamine.
(10) For the purely enzymatic DKR of amino acid amides, see: Asano,
Y.; Yamaguchi, S. J. Am. Chem. Soc. 2005, 127, 7696-7697.
(11) For a chemoenzymatic deracemization route to these amines, see:
(a) Alexeeva, M.; Enright, A.; Dawson, M. J.; Mahmoudian, M.; Turner,
N. J. Angew. Chem., Int. Ed. 2002, 41, 3177-3180. (b) Carr, R.; Alexeeva,
M.; Dawson, M. J.; Gotor-Ferna´ndez, V.; Humphrey, C. E.; Turner, N. J.
ChemBioChem 2005, 6, 637-639. (c) Dunsmore, C. J.; Carr, R.; Fleming,
T.; Turner, N. J. J. Am. Chem. Soc. 2006, 128, 2224-2225.
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