Enantioselective hydrogenation of N-acetyldehydroamino acids over supported palladium catalysts

Article abstract of DOI:10.1002/adsc.200600304

The enantioselective hydrogenation of two N-acetyldehydroamino acids over Cinchona alkaloid-modified, supported palladium catalysts has been studied. Moderate enantioselectivities, up to 36%, were obtained in the hydrogenation of 2-acetamidocinnamic acid over cinchonidine-modified Pd/TiO₂ under low hydrogen pressure. Increase in the pressure or use of benzylamine as additive led to a gradual decrease in the enantiomeric excess and eventually inversion of the sense of the enantioselectivity. On the contrary, the optical purity of the product resulting from the hydrogenation of 2-acetamidoacrylic acid was significantly increased by addition of benzylamine to the reaction mixture. Enantiomeric excess values up to 58% and 60% were obtained over Pd/Al ₂O₃ modified by cinchonidine and cinchonine, respectively. These optical purities are the best obtained in the hydrogenation of dehydroamino acid derivatives over chirally modified heterogeneous metal catalysts.

Full text of DOI:10.1002/adsc.200600304

FULL PAPERS
DOI: 10.1002/adsc.200600304
Enantioselective Hydrogenation of N-Acetyldehydroamino Acids
over Supported Palladium Catalysts
a,
b
a,b
Gyçrgy Szçll o˝ si, * Emese Szabó, and Mihµly Bartók
a
Organic Catalysis Research Group of the Hungarian Academy of Sciences, University of Szeged, Department of Organic
Chemistry, 6720 Szeged, Dóm tØr 8, Hungary
Fax : (+36)-62-544-200; e-mail: szollosi@chem.u-szeged.hu
University of Szeged, Department of Organic Chemistry, Dóm tØr 8, 6720 Szeged, Hungary
b
Received: June 26, 2006
Abstract: The enantioselective hydrogenation of two acid was significantly increased by addition of ben-
N-acetyldehydroamino acids over Cinchona alkaloid- zylamine to the reaction mixture. Enantiomeric
modified, supported palladium catalysts has been excess values up to 58% and 60% were obtained
studied. Moderate enantioselectivities, up to 36%, over Pd/Al O modified by cinchonidine and cincho-
2
3
were obtained in the hydrogenation of 2-acetamido- nine, respectively. These optical purities are the best
cinnamic acid over cinchonidine-modified Pd/TiO2 obtained in the hydrogenation of dehydroamino acid
under low hydrogen pressure. Increase in the pres- derivatives over chirally modified heterogeneous
sure or use of benzylamine as additive led to a grad- metal catalysts.
ual decrease in the enantiomeric excess and eventu-
ally inversion of the sense of the enantioselectivity. Keywords: N-acetyldehydroamino acid; Cinchona al-
On the contrary, the optical purity of the product re- kaloids; enantioselectivity; heterogeneous catalysis;
sulting from the hydrogenation of 2-acetamidoacrylic hydrogenation; palladium catalyst
Introduction
cently, special attention has been paid to the enantio-
selective hydrogenation of the C=C group in dehy-
The enantioselective catalytic hydrogenations of pro- droamino acid derivatives, due to the high importance
[11–14]
chiral unsaturated carboxylic acids are among the of the production of optically pure amino acids.
simplest methods for the production of optically en- The hydrogenation of 2-acetylaminocinnamic acid
[
1]
riched chiral carboxylic acids and their derivatives.
and 2-benzoylaminocinnamic acid led to nearly race-
Although, for these purposes the most widely used mic product over cinchonidine-modified, supported
[
1,2]
[11]
catalysts are chiral homogeneous metal complexes,
Pd catalysts, and only low ee, up to 24%, were ob-
the recent developments published on the heteroge- tained in the hydrogenation of dehydroamino acid
[
12,13]
neous enantioselective hydrogenation of some substi- esters.
tuted a-phenylcinnamic acids over Cinchona alkaloid- In a recent report the enantioselective hydrogena-
modified, supported palladium catalysts makes this tion of several N-benzoyldehydroamino acids has
[
3,4]
latter method an attractive potential alternative.
been attempted and for the first time the effect of
Over 90% enantiomeric excess (ee) could be obtained equivalent amounts of an achiral base additive such
[
14]
by a proper choice of the catalyst and use of benzyla- as triethylamine has been studied.
mine (1) as additive. However, both the ee
Although, in
[
4]
[5,6]
and most of these reactions low substrate/modifier molar
the effect of 1 were found to be highly dependent on ratios were used, an ee of 26% has been reached only
the substrate structure, the largest increase in the ee in the hydrogenation of N-benzoyl-2-cyclohexylidene-
induced by the use of 1 was observed in the hydroge- glycine, in the case of the other substrates lower
[
7]
[14]
nation of itaconic acid.
values were obtained. The successful use of 1 as ad-
Following the early results obtained in the hydroge- ditive in the enantioselective hydrogenation of a-phe-
[
15]
nation of a,b-unsaturated acids, several attempts were nylcinnamic acid, several aliphatic a,b-unsaturated
[
7]
published on the extension of the scope of the Cin- acids and itaconic acid, encouraged us to attempt
chona-modified, supported palladium catalytic the application of this method of increasing the enan-
[8,9]
system.
These attempts also included hydrogena- tioselectivity in the hydrogenation of two N-acetylde-
tions of the C=N group leading to amino acid deriva- hydroamino acids, that is, 2-acetamidocinnamic acid
[
10]
tives, however, only low ee could be obtained. Re- (2) and 2-acetamidoacrylic acid (3). The results of
Adv. Synth. Catal. 2007, 349, 405 – 410
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
405

Gyçrgy Szçll o˝ si et al.
FULL PAPERS
these hydrogenations are summarized in the present
report.
Results and Discussion
The hydrogenation of 2 has already been studied over
Pd catalysts in presence of Cinchona alkaloids, how-
[
11]
ever, only without basic additives. As a second test
molecule we used the a-substituted acrylic acid 3,
which has not yet been studied in this catalytic system
and has a terminal olefinic bond, similar to itaconic
acid. The hydrogenation of 2 and 3 results in the for-
mation of the corresponding N-acetyl-a-amino acids:
N-acetylphenylalanine (4) and N-acetylalanine (5), as
shown in Scheme 1.
The ee values obtained in the hydrogenation of 2
over cinchonidine (6)-modified Pd/Al O under differ-
2
3
ent pressures in the absence and in presence of an
equivalent amount of 1 are presented in Figure 1. In
[
11]
contrast to the published results, we have obtained
enantioselection even in the absence of 1, yet the
highest ee value under atmospheric H pressure was
2
Figure 1. Enantiomeric excesses in the hydrogenation of 2-
acetamidocinnamic acid (2) over Pd/Al O . Reaction condi-
only 13% in favour of the R enantiomer. By increas-
ing the pressure the ee decreased and interestingly
under higher pressure (5MPa) a small, but reproduci-
ble excess of the S enantiomer was obtained. An even
2
3
tions: 25 mg catalyst, 3 mL methanol, 0.05 mmol modifier 6,
.5 mmol 2, 295 K; white columns: without addition of 1;
dark columns: using 0.5 mmol 1 (initial rates under the col-
0
more striking effect of the H pressure was observed umns).
2
when the hydrogenations were carried out in the pres-
ence of one equivalent of 1. Thus, in the hydrogena-
tion under 0.1MPa the ee was slightly increased by enantioselectivity in the heterogeneous catalytic hy-
[13]
the presence of 1, while under higher pressures again drogenation of the C=C bond has been described.
the opposite enantiomer was formed in excess, reach- In the hydrogenation of the methyl ester of 2 over
ing an ee of 8% in favour of (S)-4. As shown by the Cinchona-modified Pd/Al O an increase in the con-
2
3
values in Figure 1, the initial rates decreased as an centration of the modifier led to an inversion of the
effect of the addition of 1.
enantioselectivity.
Several examples of inversion of the enantioselec-
Our present study is the first that reports such in-
tivity have been reported in the hydrogenation of ac- version in the hydrogenation of an a,b-unsaturated
tivated ketones over Cinchona-modified Pt catalysts. carboxylic acid. Furthermore, it has never been re-
These reports showed that the extent of the hydroge- ported that changes in the H pressure may lead to in-
2
[
16]
nation, a change in the substituents on the C-9 of version of the enantioselectivity, which may be even
[17]
[18]
the modifier
or a simple change in the solvent
more amplified by the presence of an equivalent
may cause changes in the direction of the enantiose- amount of an achiral additive such as 1. One should
lection. Inversion was also observed over palladium not neglect that this phenomenon was observed only
catalysts in the hydrogenation of pyruvic acid in the case of a-acetamidocinnamic acid (present
[19]
[13]
esters. Recently, the first report on inversion of the work) and its methyl ester, although the H pres-
2
sure dependence has been studied for a,b-unsaturated
[
6,20,21]
carboxylic acids of various structures.
In a first
approach, this shows that the a-acetamido group of
the unsaturated acid is necessary to observe this
effect.
Using a 5% Pd/TiO catalyst successfully applied in
2
[22]
the hydrogenation of a-phenylcinnamic acid,
we
have obtained the results presented in Table 1.
The hydrogenation under 0.1MPa H2 pressure
Scheme 1. Hydrogenation of N-acetyldehydroamino acids using 6 as modifier led to the highest ee (36%) in the
over palladium catalyst.
hydrogenation of an a-acetamido-a,b-unsaturated car-
406
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Enantioselective Hydrogenation of N-Acetyldehydroamino Acids
FULL PAPERS
[a]
[a]
Table 1. Hydrogenation of 2 over 5% Pd/TiO catalyst.
Table 2. Hydrogenation of 3 over 6-modified Pd/Al O .
2
2
3
[
b]
[c]
[b]
ꢀ1 ꢀ1
[c]
Entry Modifier Additive p H2
Ri
ee
Entry Additive pH [MPa] Ri [mol h g ] ee [%]
2
ꢀ
1
ꢀ1
[
MPa] [mmolh g ] [%]
1
2
3
4
5
6
7
-
-
-
-
1
1
1
0.1
2
5
5
0.1
2
0.26
1.61
3.45
4.21
0.19
1.23
2.70
2 (S)
6 (S)
9 (S)
-
1
2
3
4
5
6
7
8
9
1
1
-
-
-
-
1
1
-
-
1
-
0.1
0.1
5
0.1
5
0.1
0.1
0.1
0.1
0.1
0.1
36.0
2.1
5.3
1.5
4.4
5.9
2.8
1.1
4.3
4.9
2.2
-
6
6
6
6
6
7
7
8
9
6
36 (R)
5 (S)
5 (R)
6 (S)
5 (R)
10 (S)
4 (R)
2 (R)
0
[d]
29 (S)
54 (S)
[e]
[
d]
5
56, 58 (S)
[a]
Reaction conditions: 25 mg catalyst, 3 mL methanol,
.05 mmol 6, 0.5 mmol 3, 0.5 mmol 1.
Initial rate (see Experimental Section).
Configuration of the excess enantiomer in parenthesis.
Hydrogenation without modifier.
0
[
[
[
b]
c]
d]
0
1
-
-
[
e]
35 (R)
[
a]
[e]
Reaction conditions: 50 mg catalyst, 3 mL methanol,
0.05 mmol modifier, 0.5 mmol 2, 0.5 mmol 1.
b]
Hydrogenation at 275 K.
[
[
[
[
Initial rate (see Experimental Section).
c]
d]
e]
Configuration of the excess enantiomer in parenthesis.
DMF (2.5 vol% water) was used as solvent.
00 mg catalyst, 5 mL methanol, 0.1 mmol 6, 2 mmol 2, enced in the hydrogenation of 2 we then chose 3 (see
interesting inversion of the enantioselectivity experi-
1
9
5% conversion.
Scheme 1) as the next substrate.
Hydrogenation of 3 over 6-modified Pd/Al O in
2
3
the absence of 1 led to poor ee values, a small in-
crease in the ee was obtained by increasing the H2
boxylic acid over a supported metal catalyst, and a pressure, however, even under 5MPa H only 9% ee
2
more than one magnitude decrease in the initial rate. was obtained in favour of (S)-5 (see Table 2). As ex-
The ee value decreased significantly on changing the pected the initial hydrogenation rate of 3 was three
solvent from methanol to N,N-dimethylformamide orders of magnitude larger than that of 2, due mainly
(
DMF) or by using 1 as additive. A lower ee value to the bulky b-substituent of the latter. Only a small
was also obtained with cinchonine (7) as modifier, in decrease in the initial rate was observed as an effect
accordance with the results usually obtained in the of the modification with 6, contrary to the high de-
enantioselective hydrogenations over Cinchona-modi- crease of more than one magnitude detected in the
[23,24]
fied catalysts.
As expected the major enantiomer hydrogenation of 2. Thus, the lack of substituents in
formed in presence of 7 had the opposite absolute the b position of a-acetamido-a,b-unsaturated acids
configuration as obtained in presence of 6, and the leads to only a small decrease in the hydrogenation
addition of 1 also resulted in inversion of the enantio- rate in the presence of Cinchona alkaloids and to
selectivity. Significantly decreased values were ob- poor ee values. Using molar amounts of 1 as achiral
tained when the C-6’-methoxy-substituted Cinchona additive led to a surprisingly high increase in the ee,
alkaloids quinine (8) or quinidine (9) were used; in up to 58% under 5MPa H at 275 K. The use of 1
2
the presence of the latter the racemic product was ob- was also accompanied by a moderate decrease in the
tained. Decreased ee values were also obtained in the initial rate. Even more intriguing were the results ob-
hydrogenation of a-phenylcinnamic acid using 8 or 9 tained in the hydrogenation of 3 over 7-modified cata-
[24]
as chiral source, possibly due to the steric hindrance lysts, shown in Table 3.
of the C-6’-methoxy group.
The presence of 7 reduced even less the rate of hy-
To sum up, the highest ee value in the hydrogena- drogenation than 6 (see Entries 1 and 2, Table 3) and
tion of 2 was obtained in methanol over Pd/TiO2 the obtained ee was very low even under 5MPa H2
under low (0.1MPa) H pressure using 6 as modifier pressure. As expected, the opposite enantiomer was
2
and without addition of 1. We have also carried out formed in excess compared to the reaction over the 6-
the reaction by increasing four times the substrate modified catalyst. In presence of 1 the ee was even
amount and the results were similar with that ob- slightly higher when modifier 6 was replaced with 7.
tained on the smaller scale (see Entry 11, Table 1). Thus, it was possible to obtain the unnatural R enan-
Refluxing this product overnight in methanol in pres- tiomer of 5 in 60% ee, a value which exceeds any
ence of concentrated H SO resulted in the formation result published on the enantioselective hydrogena-
2
4
of (R)-phenylalanine methyl ester isolated in 90% tion of dehydroamino acid derivatives over chirally
yield and 35% optical purity. modified heterogeneous metal catalysts. A similar ee
Intrigued by the still open question as to whether (55%) result from the hydrogenation over Pd/TiO2
solely the a-acetylamino group is responsible for the under otherwise identical reaction conditions, while
Adv. Synth. Catal. 2007, 349, 405 – 410
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407

Gyçrgy Szçll o˝ si et al.
FULL PAPERS
Table 3. Hydrogenation of 3 over 7-, 8- or 9-modified cata-
lysts.
The role of 1 in the enantioselective hydrogenation
of unsaturated a,b-unsaturated carboxylic acids over
Cinchona-modified palladium is still unclear. The
only substrate for which hydrogenation in presence of
1 has been studied in more detail was a-phenylcin-
[a]
[b]
ꢀ1 ꢀ1
[c]
Entry Modifier Additive Ri [mol h g ] ee [%]
1
2
3
4
5
6
7
8
9
1
-
-
-
4.21
4.08
3.34
2.03
n.d.
0.79
n.d.
2.31
2.51
n.d.
-
[
15]
7
7
7
7
7
7
8
9
7
3 (R)
60 (R)
55 (R)
35 (R)
12 (R)
8 (R)
12 (S)
5 (R)
56 (R)
namic acid. Thus, the results obtained in our pres-
ent work complement the few observations published
until now. The results of our present study showed
that the effect of 1 on the hydrogenation of a-acetam-
ido-a,b-unsaturated acids was different as compared
with that on the hydrogenation of a-phenylcinnamic
acid. Furthermore, though increase in the ee was
found in the hydrogenation of several aliphatic a,b-
1
1
1
-
1
1
1
1
[
[
[
[
d]
e]
f]
f]
[
g]
0
[
7]
unsaturated carboxylic acids, up to now this increase
was high only in the reaction of two compounds bear-
[
a]
Reaction conditions: 25 mg Pd/Al O , 3 mL methanol,
2
3
0
.05 mmol modifier, 0.5 mmol 3, 0.5 mmol 1, pH 5MPa.
[7]
2
ing a terminal C=C group, that is, itaconic acid and
[
b]
Initial rate (see Experimental Section), n.d.=not deter-
mined.
Configuration of the excess enantiomer in parenthesis.
Hydrogenation over Pd/TiO2.
Reaction under 10MPa H pressure.
DMF (2.5 vol% water) was used as solvent.
2-acetamidoacrylic acid (present work).
[
[
[
[
[
c]
d]
e]
f]
Conclusions
2
g]
5
2
0 mg catalyst, 5 mL methanol, 0.2 mmol 7, 2 mmol 3, The first example of the heterogeneous catalytic hy-
mmol 1.
drogenation of an N-acylated dehydroamino acid with
good enantioselectivity over a chirally modified metal
catalyst has been described. The hydrogenation of 2-
acetamidocinnamic acid resulted in (R)-N-acetylphe-
increase in the H pressure to 10MPa brought down nylalanine of 36% optical purity over cinchonidine-
2
the ee to 35%. Although, in the absence of 1 a prom- modified Pd/TiO under low H pressure. Increasing
2
2
ising increase in the ee was obtained by changing the the pressure led to an interesting inversion in the
solvent to DMF (2.5 vol% H O), the use of the addi- sense of the enantioselectivity which was more pro-
2
tive 1 had an opposite effect as in methanol, decreas- nounced if benzylamine was used as additive. In the
ing the ee to 8%. The good enantioselectivity was hydrogenation of 2-acetamidoacrylic acid the enantio-
also maintained at the 2 mmol scale, proving that the selectivities were significantly increased by using ben-
method may be used on a larger scale (see Entry 10, zylamine as achiral base under elevated H pressures.
2
Table 3). This product was transformed in (R)-N-ace- Thus, it was possible to obtain (R)-N-acetylalanine in
[
10b]
tylalanine methyl ester using SOCl in methanol,
60% optical purity using cinchonine as chiral modifier
2
the ester isolated in 94% yield and 55% optical and 5MPa H pressure. The results presented in this
2
purity.
report broaden the range of unsaturated carboxylic
In the hydrogenations of 3 over 6- or 7-modified acid derivatives which can be hydrogenated enantio-
catalysts, no inversion in the enantioselectivity occur- selectively with the Cinchona-modified palladium cat-
red as an effect of changes in the H pressure, this alytic system.
2
phenomenon seems to be a special case, characteristic
of a-acetamido-b-phenyl-a,b-unsaturated carboxylic
acids and esters. Obviously the inversion is related
with the presence of the a-acetamido group comple-
mented with the steric effect of the b-phenyl substitu-
Experimental Section
ent. Interestingly the configurations of the products
obtained in excess in the hydrogenation of 2 and 3
Materials
Benzylamine (1, ꢁ99.5%), 2-acetamidocinnamic acid (2,
using the same modifier under low H pressures were
2
ꢁ
99%), 2-acetamidoacrylic acid (3, ꢁ99%), cinchonidine
opposite. This observation is in accordance with our
suggestion on the role of the b-substituents in deter-
mining the sense of the chiral induction in the hydro-
genation of a,b-unsaturated acids over Cinchona-
(
6, ꢁ98%), cinchonine (7, ꢁ98%), quinine (8, ꢁ98%) and
quinidine (9, ꢁ98%) were commercial products (Fluka) and
were used as received. The catalysts used were: commercial
alumina-supported Pd catalyst (5% Pd/Al O , Engelhard
2
3
[
6]
modified palladium. Modifiers 8 and 9 gave low ee
[25]
4
0692, 0.21 Pd dispersion ) and 5% Pd/TiO (TiO , Degus-
2 2
in the presence of 1 and the initial hydrogenation rate
sa P-25) prepared by a deposition-precipitation method ac-
[26]
of 3 decreased as compared with the rates obtained cording to a described procedure. Commercial high purity
over 6- and 7-modified catalysts. solvents were used without purification.
408
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Adv. Synth. Catal. 2007, 349, 405 – 410

Enantioselective Hydrogenation of N-Acetyldehydroamino Acids
FULL PAPERS
Catalytic Hydrogenations and Product Analysis
Acknowledgements
Hydrogenations were carried out using a conventional glass
hydrogenation apparatus or a stainless steel autoclave
equipped with a glass liner and an automatic pressure re-
corder. In a typical run the catalyst was pretreated by stir-
ring the given amount of catalyst in the solvent for 0.5 h
Financial support by the Hungarian National Science Foun-
dation (OTKA Grants TS 044690 and T 048764) is highly ap-
preciated. Gy. Sz. is grateful for the financial support of HAS
through Bolyai Jµnos Research grant.
under H at 297 K followed by addition of the modifier, ben-
2
zylamine (when used) and the substrate. The reactor was
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1
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