Chemoenzymatic dynamic kinetic resolution of primary amines using a recyclable palladium nanoparticle catalyst together with lipases

Article abstract of DOI:10.1021/jo500508p

A catalyst consisting of palladium nanoparticles supported on amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF) was used in chemoenzymatic dynamic kinetic resolution (DKR) to convert primary amines to amides in high yields and excellent ee's.

Full text of DOI:10.1021/jo500508p

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pubs.acs.org/joc
Chemoenzymatic Dynamic Kinetic Resolution of Primary Amines
Using a Recyclable Palladium Nanoparticle Catalyst Together with
Lipases
Karl P. J. Gustafson, Richard Lihammar, Oscar Verho, Karin Engstrom, and Jan-E. Backvall*
̈
̈
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: A catalyst consisting of palladium nanoparticles supported
on amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF) was
used in chemoenzymatic dynamic kinetic resolution (DKR) to convert
primary amines to amides in high yields and excellent ee’s. The efficiency
of the nanocatalyst at temperatures below 70 °C enables reaction
conditions that are more suitable for enzymes. In the present study, this is
exemplified by subjecting 1-phenylethylamine (1a) and analogous benzylic
amines to DKR reactions using two commercially available lipases,
Novozyme-435 (Candida antartica Lipase B) and Amano Lipase PS-C1
(lipase from Burkholderia cepacia) as biocatalysts. The latter enzyme has
not previously been used in the DKR of amines because of its low stability
at temperatures over 60 °C. The viability of the heterogeneous Pd-AmP-
MCF was further demonstrated in a recycling study, which shows that the
catalyst can be reused up to five times.
to which the particles are attached.4c,d Many different supports
INTRODUCTION
■
have been used for catalytic applications such as metal oxides,5
metal organic frameworks (MOFs),6 carbon-based polymers,7
and silicas.8 Within the last group mentioned, siliceous
mesocelluar foam (MCF) has shown to be an excellent
material for supporting metal nanoparticles, enzymes, and
various heterogeneous complexes.9 The MCF has a three-
dimensional morphology with large pores and a high surface
area. In addition, the material possesses a high surface
concentration of silanol groups that enables grafting with a
variety of functional groups in a straightforward fashion.9
Recently, we have reported on an amino-functionalized MCF
as a support for Pd nanoparticles and demonstrated several
applications of this nanocatalyst.10 For instance, the Pd
nanocatalyst was found to efficiently racemize primary amines
at low temperatures,10a which generally has been an issue with
previously reported transition metal-based protocols. In the
latter protocols elevated temperatures are required for
racemization to occur at a useful rate.11 The necessity of
increased temperatures in the DKR has so far limited the use of
enzymes to essentially thermostable lipases such as Candida
antarctica Lipase A and B (CALA and CALB, respectively),
where the latter is by far the most utilized owing to its high
selectivity and activity.12 Moreover, it has been shown that the
formation of byproducts increases at elevated temperatures,
mainly as a consequence of undesired side reactions with the
sensitive imine intermediate that is formed during the course of
During the past three decades, a significant part of synthetic
organic chemistry has been dedicated toward the development
of new and efficient methods for the preparation of
enantiomerically enriched compounds. Many of these methods
utilize chiral catalysts in the enantiodetermining step, thereby
increasing the reaction efficiency and minimizing the amount of
reagents required.1 A common way to prepare enantiomerically
enriched molecules is to utilize the chiral environment of an
enzyme in a kinetic resolution.2 In this process, the enzyme
catalyzes the chemical transformation of one enantiomer faster
than that of its mirror image, resulting in a separation of the
two enantiomers. The drawback of this process is that the yield
of the enantiomerically enriched product can never exceed 50%.
An excellent way to circumvent this limitation is to carry out
the kinetic resolution in parallel with an in situ racemization,
thus creating a dynamic kinetic resolution (DKR), theoretically
increasing the yield up to 100% of a single product
enantiomer.3 The enzymes employed are usually immobilized
onto a solid support to increase stability, whereas the
racemization is often catalyzed by homogeneous transition
metal complexes. An attractive way to make the process more
environmentally friendly and to enhance the recyclability is to
attach the racemization catalysts to a heterogeneous support.
Recently, heterogeneous metal nanoparticles have attracted
considerable attention as they have been found to be highly
efficient and selective catalysts for a wide range of organic
transformations.4 It has been demonstrated that the selectivity
and reactivity exhibited by the nanoparticles are dependent on
the size and shape of the particles as well as the type of support
Received: March 3, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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a
the racemization (cf. Scheme 1). The imine intermediate can
easily undergo hydrolysis to the corresponding ketone or self-
Table 1. Optimization of the DKR of 1a at 70 °C
Scheme 1. Illustration of an (R)-Selective Dynamic Kinetic
Resolution of Primary Benzyl Amines Using Palladium
Nanoparticles as Racemization Catalyst and a
Methoxyacetate Ester as Acyl Donor
b
c
Pd-loading
(mol %)
time
(h)
toluene
(mL)
conv
ee
entry
1
additive
(%)
(%)
2.5
Na2CO3
(1 equiv)
24
4
63
99
2
2.5
Na2CO3
(1 equiv)
16
1.5
99
99
3
4
2.5
mol sieves 4 Å
mol sieves 4 Å
6
6
1.5
1.5
99
99
99
99
1.25
a
All reactions were carried out in dry toluene (1.5 mL) under 1 atm of
hydrogen gas using 1a (0.6 mmol), 3 (1.2 mmol), Novozyme-435
(CALB, 15 mg), molecular sieves (300 mg) or Na2CO3 (60 mg), and
b
pentadecane as internal standard. Determined using chiral GC and
c
pentadecane as internal standard. Determined using by chiral GC (99
0.02)
condense with another molecule of amine to form a secondary
amine. The secondary amine can then further react under
reductive conditions, yielding the starting material and
ethylbenzene.11
reaction at 50 °C. To maintain an efficient racemization even at
this temperature, 5 mol % of Pd-MCF was used. Both
molecular sieves and Na2CO3 could be used as additives to give
full conversions and excellent ee’s; however, the latter showed
slightly higher ee (Table 2, entries 1 and 2). A control
To date, only a few enzyme-compatible metal complexes
exist that are capable of racemizing amines.12a,13 Among these
complexes, a homogeneous dimeric ruthenium hydride
complex is still to date the most versatile catalyst for the
DKR of amines.12a,13a However, the protocol required elevated
temperatures (90 °C and higher), diluted reaction conditions,
and suffered from long reaction times (3 days).12a,13a Kim and
Park developed a nanostructured palladium catalyst supported
on Al(O)OH that was optimized to perform the racemization
at lower temperatures than the ruthenium catalyst; however,
dilute reactions conditions and long reaction times were still
required.13b,c By applying our recently developed Pd-AmP-
MCF as racemization catalyst in a chemoenzymatic DKR, we
envision addressing these drawbacks and allowing the use of
less thermostable enzymes.
Table 2. Optimization of the Reaction at 50 °C and
Evaluation of Two Different Lipases
a
b
c
Pd-loading
(mol %)
time
(h)
conv
ee
entry
additive
lipase
(%)
(%)
1
2
5
5
mol sieves 4 Å
24
24
CALB
CALB
99
99
98
99
Na2CO3
(1 equiv)
RESULTS AND DISCUSSION
3
2.5
5
Na2CO3
(1 equiv)
36
36
CALB
99
99
99
■
To find the optimal reaction conditions, 1-phenylethylamine
(1a) was selected as the model substrate and subjected to a
DKR at 70 °C using CALB as resolving agent, 2 equiv of ethyl
methoxyacetate (3) as acyl donor,14 2.5 mol % of Pd-AmP-
MCF as racemization catalyst, and 1 equiv of Na2CO3 in dry
toluene under H2 atmosphere (1 atm). The DKR was found to
proceed smoothly and resulted in 63% conversion after 24 h
(Table 1, entry 1). By concentrating the reaction from 0.15 to
0.4 M, the efficiency of the DKR was significantly increased
(entry 2), reaching completion after 16 h. To our delight, we
were able to isolate amide 2a in quantitative yield with no sign
of byproduct formation. The most significant improvement was
observed upon addition of molecular sieves (4 Å) to the
reaction as this reduced the reaction time to 6 h (entry 3).
Moreover, it proved to be possible to reduce the loading of the
Pd nanocatalyst to 1.25 mol % and still maintain high yields and
excellent enantioselectivity of the desired amide 2a (entry 4).
To the best of our knowledge, this is the lowest catalyst loading
(Pd and CALB) ever used for these short reaction times in the
DKR of primary amines.
d
e
4
Na2CO3
(1 equiv)
Lipase
PS
82
a
All reactions were carried out in dry toluene (1.5 mL) under 1 atm of
hydrogen gas using 1a (0.6 mmol), 3 (1.2 mmol), Novozyme-435
(CALB, 15 mg), molecular sieves (300 mg) or Na2CO3 (60 mg), and
pentadecane as internal standard. Determined using chiral GC and
pentadecane as internal standard. Determined by chiral GC (98
0.02; 99 0.02). The reaction was carried out in dry toluene (2 mL)
under 1 atm hydrogen gas using 1a (0.6 mmol), 3 (1.2 mmol), Amano
Lipase PS-C1 (200 mg), and dry Na2CO3 (60 mg). Isolated yield.
b
c
d
e
experiment on 1a, where CALB was omitted, showed that
molecular sieves caused a slow background amidation which
could explain the lower ee obtained when the reaction time is
prolonged.15 When the amount of Pd nanocatalyst was reduced
from 5 to 2.5 mol %, the reaction still gave 2a in 99% ee but
required a longer reaction time (36 h) to reach completion
(entry 3). The possibility to run the reactions at lower
temperatures also enables a broader range of enzymes to be
used in the DKR, which potentially could widen the substrate
scope. This novel feature was demonstrated by employing
Amano Lipase PS-C1 (lipase from Burkholdera cepacia
Inspired by the efficient DKR at 70 °C, we set out to
optimize the protocol to also provide a functioning DKR
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immobilized on ceramic beads) in a DKR with 5 mol % of Pd-
AmP-MCF which afforded 2a in a good isolated yield and
excellent ee (entry 4).16 This enzyme has previously been used
in the kinetic resolution of 1a, but to the best of our knowledge,
this is the first example of a DKR of amines using this
biocatalyst.17
After we established the optimized protocols for the DKR at
70 and 50 °C, a set of substrates were studied in the reaction at
70 °C (Table 3). Four benzylic amines substituted with
Finally, the stability of the heterogeneous Pd nanocatalyst
was assessed in a recycling study where the DKR of 1a was
carried out under the optimized conditions with 2.5 mol % of
Pd nanocatalyst over five cycles. The DKR was allowed to
continue for 15 h after which the Pd-AmP-MCF was separated,
washed, and used in a new DKR reaction. In this recycling, the
catalytic system showed excellent conversion and ee until the
fifth run where the conversion dropped to 90% and the ee was
98% (see Table 4).18
a
Table 3. Substrate Scope of the DKR at 70 °C Using Pd-
AmP-MCF as Racemization Catalyst
Table 4. Recycling of the Catalyst in the DKR
b
b
cycle
conv (%)
ee (%)
1
2
3
4
5
99
99
98
99
90
99
99
99
99
98
a
All reactions were carried out in dry toluene (1.5 mL) under 1 atm of
hydrogen gas at 70 °C using 1a (0.6 mmol), 3 (1.2 mmol),
Novozyme-435 (15 mg), molecular sieves 4 Å (300 mg), and
b
pentadecane as internal standard. Determined using chiral GC and
pentadecane as internal standard. For error in ee, see Table 2.
In summary, we have developed a protocol for the DKR of
primary benzylic amines using a recyclable catalyst consisting of
palladium nanoparticles immobilized on siliceous amino-
functionalized mesocellular foam. It was found that the DKR
proceeds well at both 70 and 50 °C and that a range of benzylic
amines can be used as substrates. The DKR reactions with
these relatively short reaction times were carried out with much
lower catalytic loading than previously reported. To our delight,
we could also demonstrate the first successful application of
lipase PS in the DKR of amines. Future efforts will aim at
incorporating other lipases and proteases in the present
protocol. Work will be dedicated to further improving the
performance of the racemization part of the DKR reaction by
developing related nanostructured catalysts.
a
Method A: Reaction was performed in dry toluene (1.5 mL) under 1
atm of hydrogen gas using Pd-AmP-MCF (10 mg, 1.25 mol %), amine
1 (0.6 mmol), ethyl methoxyacetate (1.2 mmol), Novozyme-435 (15
mg), and molecular sieves (300 mg). Method B: Reaction was
performed in dry toluene (1.5 mL) under 1 atm hydrogen gas using
Pd-AmP-MCF (20 mg, 2.5 mol %), amine 1 (0.6 mmol), ethyl
methoxyacetate (1.2 mmol), Novozyme-435 (15 mg), and dry
b
c)
Na2CO3 (60 mg). 2.0 mol % of racemization catalyst was used.
EXPERIMENTAL PROCEDURES
■
General Methods. 1H and 13C NMR spectra were recorded at 400
and 100 MHz, respectively. GC analysis was made either on a system
equipped with a CP-Chirasil-DEX CB column (25 m × 0.32 mm ×
0.25 μm) with H2 as a carrier gas or IVADEX-I column (25 m × 0.25
mm × 0.25 μm) with N2 as carrier gas. Both GCs had a gas flow of 1.8
mL/min and were equipped with FID detectors. The high-resolution
mass spectra (HRMS) were recorded on an ESI-TOF mass
spectrometer. 1-Phenylethylamine 1a was distilled and stored on
molecular sieves before use. The remaining chemicals were purchased
from commercial sources and used without further purification. Dry
toluene was obtained from a VAC-solvent purifier. Flash chromatog-
raphy was performed on an automated flash machine equipped with a
UV detector using 12 g silica columns (particle size 40−63 μm
irregular, mesh size 230−400, pore size 60 Å) with a solvent flow of 30
mL/min. Reactions were monitored by thin-layer chromatography
(TLC) using aluminum-backed plates (1.5 Å, 5 cm) precoated (0.25
mm) with silica gel and UV light for visualization. The Pd-AmP-MCF
was synthesized according to previously described methods.10b CALB
aliphatic substituents were chosen, and were all converted into
their corresponding enantiomerically enriched amides in high
yields as well as excellent ee’s (2a−d). Bicyclic tetrahydro-
naphthyl compound 2e was also isolated in close to quantitative
yield and perfect ee. For the heteroatom-substituted benzyl
amines 1f and 1g the molecular sieves needed to be exchanged
for Na2CO3, and the catalyst loading was increased to 2.5 mol
% in order to avoid unwanted background amidation. Substrate
1f bearing an electron-donating substituent worked excellently,
while 2g, with an electron-withdrawing substituent, was
obtained in slightly lower yield (89%) but still high ee. The
amount of Pd nanocatalyst used in these DKR reactions with
reasonably short reaction times is lower than previously
reported for these compounds, and the reactions are made at
a substrate concentrations of 0.4 M, which is significantly
higher than those previously reported.11
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(Novozyme-435) and Lipase PS (Amano Lipase PS-C1) are available
from commercial sources.
solid in 97% ee. Experimental data were in accordance with those
previously reported.13b 1H NMR (CDCl3, 400 MHz): δ = 7.37−7.24
(m, 5H), 6.75 (br s, 1H), 4.96−4.89 (m, 1H), 3.96−3.83 (m, 2H),
3.41 (s, 3H), 1.90−1.81 (m, 2H), 0.90 (t, 3H, J = 7.4 Hz). Chiral GC
separation: IVADEX-I column 140−1 °C/min to 200 °C, tR1 = 12.8
min (S), tR2 = 13.0 (R) min.
(R)-2-Methoxy-N-(1-p-tolylethyl)acetamide (2d). The reaction was
performed according to method A using 1.25 mol % of Pd-AmP-MCF.
The product was isolated after column chromatography (SiO2,
pentane/EtOAc 100:0 → 0:100) to give 113 mg (91%) as a white
solid in 98% ee. Experimental data were in accordance with those
previously reported.13b 1H NMR (CDCl3, 400 MHz): δ = 7.24−7.13
(m, 4H), 6.71 (br s, 1H), 5.20−5.10 (m, 1H), 3.95−3.83 (m, 2H),
3.39 (s, 3H), 2.33 (s, 3H), 1.50 (d, 3H, J = 7.2 Hz). Chiral GC
separation: CP-Chirasil-DEX CB column 125−3 °C/min to 160 °C,
tR1 = 14.5 min (S), tR2 = 14.8 (R) min.
(R)-2-Methoxy-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acetamide
(2e). The reaction was performed according to method A using 1.25
mol % of Pd-AmP-MCF. The product was isolated after column
chromatography (SiO2, pentane/EtOAc 100:0 → 0:100) to give 125
mg (95%) as a white solid in 99% ee. Experimental data were in
accordance with those previously reported.13b 1H NMR (CDCl3, 400
MHz): δ = 7.28−7.25, (m, 1H), 7.20−7.16 (m, 2H), 7.13−7.09 (m,
1H), 6.75 (br s, 1H), 5.28−5.20 (m, 1H), 3.95 (s, 2H), 3.39 (s, 3H),
2.89−2.72 (m, 2H), 2.14−2.02 (m, 1H), 1.90−1.78 (m, 3H). Chiral
GC separation: CP-Chirasil-DEX CB column 125−20 °C/min to
150−0.5 °C/min to 163 °C, tR1 = 18.5 min (S), tR2 = 18.9 (R) min.
(R)-2-Methoxy-N-(1-(4-methoxyphenyl)ethyl)acetamide (2f). The
reaction was performed according to method B using 2.5 mol % of Pd-
AmP-MCF. The product was isolated after column chromatography
(SiO2, pentane/EtOAc 100:0 → 0:100) in 129 mg (96%) as a white
solid in 99% ee. Experimental data were in accordance with those
previously reported.13b 1H NMR (CDCl3, 400 MHz): δ = 7.29−7.22
(m, 2H), 6.91−6.84 (m, 2H), 6.69 (br s, 1H), 5.19−5.09 (m, 1H),
3.94−3.83 (m, 2H), 3.79 (s, 3H), 3.39 (s, 3H) 1.50 (d, 3H, J = 6.8
Hz). Chiral GC separation: IVADEX-I column 140−1 °C/min to 200
°C, tR1 = 21.8 min (S), tR2 = 22.3 (R) min.
(R)-2-Methoxy-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide
(2g). The reaction was performed according to method B using 2.5
mol % of Pd-AmP-MCF. The product was isolated after column
chromatography (SiO2, pentane/EtOAc 100:0 → 0:100) in 140 mg
(89%) as a white solid in 97% ee. Experimental data were in
accordance with those previously reported.13b 1H NMR (CDCl3, 400
MHz): δ = 7.59 (d, 2H, J = 8.3 Hz), 7.43 (d, 2H, J = 8.3 Hz), 6.77 (br
s, 1H), 5.24−5.17 (m, 1H), 3.95−3.85 (m, 2H), 3.42 (s, 3H), 1.53 (d,
3H, J = 7.0 Hz) Chiral GC separation: IVADEX-I column 145−2 °C/
min to 200 °C, tR1 = 10.6 min (S), tR2 = 11.4 (R) min.
General Procedure for the Dynamic Kinetic Resolution.
Method A: Pd-AmP-MCF (1.25−5 mol %, 10−40 mg), drying agent
[method A: molecular sieves 4 Å (300 mg); method B: dry Na2CO3
(60 mg)] and Novozyme-435 (15 mg) were added to a vial equipped
with a magnetic stirring bar and sealed with Teflon cap. The vial was
evacuated three times and refilled with hydrogen gas. Dry toluene (1.5
mL) was added to the vial, and then the system was evacuated
followed by refilling with hydrogen gas. The mixture was heated to the
indicated temperature followed by addition of ethyl methoxyacetate
(141 μL, 1.2 mmol) and amine substrate (0.6 mmol) while being
stirred at 750 rpm. After reaching completion, the reaction was diluted
with ethyl acetate and washed with saturated sodium bicarbonate and
brine. The organic phase was dried using Na2SO4, filtered, and
concentrated in vacuo. Purification was carried out using column
chromatography.
Procedure for Dynamic Kinetic Resolution with Lipase PS.
Pd-AmP-MCF (5 mol %, 40 mg), dry Na2CO3 (60 mg), and Amano
lipase PS-C1 (200 mg) were added to a vial and sealed. The vial was
evacuated three times and refilled with hydrogen gas. Dry toluene (2.0
mL) was added to the vial, and the system was evacuated followed by
refilling with hydrogen gas. The mixture was heated to 50 °C followed
by addition of ethyl methoxyacetate (141 μL, 1.2 mmol) and amine 1a
(0.6 mmol) while being stirred at 750 rpm. Additional ethyl
methoxyacetate (70 μL, 0.6 mmol) was added after 12 and 24 h.
After 36 h, the reaction was diluted with ethyl acetate and washed with
saturated sodium bicarbonate and brine. The organic phase was dried
using Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by column chromatography (SiO2, pentane/EtOAc 100:0
→ 0:100) to give 95 mg (82%) of a white solid in 99% ee.
Procedure for Recycling of the Pd-MCF Catalyst. Pd-AmP-
MCF (2.5 mol %, 20 mg), molecular sieves 4 Å (300 mg) and
Novozyme-435 (15 mg) were added to a vial and sealed; the vial was
evacuated three times and refilled with hydrogen gas. Dry toluene (1.5
mL) and internal standard pentadecane were added to the vial, which
was then evacuated followed by refilling of hydrogen gas. The mixture
was heated to 70 °C followed by addition of ethyl methoxyacetate
(141 μL, 1.2 mmol) and amine 1a (0.6 mmol). After 15 h, the reaction
was analyzed using chiral GC, and the catalyst was separated using a
pipet and washed in a separate tube using 4.5 mL of toluene and
centrifuged (4100 rpm for 8 min). Excess toluene was removed, and
the procedure was repeated three times. The catalyst was dried under
vacuum overnight before use, and the procedure was repeated.
(R)-2-Methoxy-N-(1-phenylethyl)acetamide (2a). The reaction
was performed according to method A using 1.25 mol % of Pd-
AmP-MCF. The product was isolated after column chromatography
(SiO2, pentane/EtOAc 100:0 → 0:100) and afforded 115 mg (99%) as
a white solid in 99% ee. Experimental data were in accordance with
those previously reported.13b 1H NMR (CDCl3, 400 MHz): δ = 7.38−
7.23 (m, 5H), 6.75 (br s, 1H), 5.23−5.14 (m, 1H), 3.95−3.84 (m,
2H), 3.40 (s, 3H), 1.52 (d, 3H, J = 7.1 Hz). Chiral GC separation: CP-
Chirasil-DEX CB column 125−3 °C/min to 160 °C, tR1 = 11.9 min
(S), tR2 = 12.3 (R) min.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Investigation of the background chemical amidation, H NMR
of 2a−f and 13C NMR of 2b, as well as GC chromatograms of
compound 2a-f. This material is available free of charge via the
Internet at http://pubs.acs.org.
(R)-2-Methoxy-N-(1-m-tolylethyl)acetamide (2b). The reaction
was performed according to method A using 1.25 mol % of Pd-
AmP-MCF. The product was isolated after column chromatography
(SiO2, pentane/EtOAc 100:0 → 0:100) and afforded 108 mg (87%) as
a white solid in 99% ee. 1H NMR (CDCl3, 400 MHz): δ = 7.26−7.21
(m, 2H), 7.15−7.06 (m, 2H), 6.73 (br s, 1H), 5.20−5.10 (m, 1H),
3.95−3.84 (m, 2H), 3.40 (s, 3H), 2.35 (s, 3H), 1.50 (d, 3H, J = 6.9
Hz); 13C NMR (CDCl3, 100 MHz): δ = 168.6, 143.1, 138.5, 128.7,
128.3, 127.1, 123.2, 72.1, 59.2, 48.2, 22.1, 21.6. Chiral GC separation:
AUTHOR INFORMATION
Corresponding Author
*E-mail: jeb@organ.su.se.
■
Notes
The authors declare no competing financial interest.
IVADEX-I column 145−2 °C/min to 200 °C, tR1 = 13.7 min (S), tR2
=
ACKNOWLEDGMENTS
■
14.1 (R) min. HRMS (ESI): calcd for [M + Na] C12H17NO2Na
Financial support from the Berzelii Center EXSELENT, the
European Research Council (ERC AdG 247014), the Knut and
Alice Wallenberg Foundation, and the Swedish Research
Council is gratefully acknowledged. We thank Dr. Mozaffar
Shakeri for carrying out preliminary experiments of this study.
230.1151, found 230.1143; [α]25 = +99.5 (c 0.2, CHCl3), 99% ee.
D
(R)-2-Methoxy-N-(1-phenylpropyl)acetamide (2c). The reaction
was performed according to method A using 1.25 mol % of Pd-AmP-
MCF. The product was isolated after column chromatography (SiO2,
pentane/EtOAc 100:0 → 0:100) to give 120 mg (97%) as a white
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(14) Balkenhohl, F.; Ditrich, K.; Hauer, B.; Ladner, W. J. Prakt. Chem.
1997, 339, 381.
(15) See the Supporting Information.
(16) Running the same reaction at 70 °C for 36 h gave 2a with only
92% ee.
(17) Varma, R.; Kasture, S. M.; Gaikwad, B. G.; Nene, S.; Kalkote, U.
R. Asian J. Biochem. 2007, 2, 279−283.
(18) Elemental analysis of the reaction mixture for the first three
cycles revealed that the leaching of palladium in the first two cycles
was negligible (<0.2 ppm) and in the third cycle it was 1.8 ppm. The
latter number is still very low and corresponds to only 0.15% of the
total palladium amount used in the reaction.
REFERENCES
■
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(2) (a) Polaina, J.; McCabe, A. P. Industrial Enzymes Structure,
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