Catalytic Hydrogenation of Chiral α-Amino and α-Hydroxy Esters at Room Temperature with Nishimura Catalyst without Racemization

Article abstract of DOI:10.1002/1615-4169(20011231)343:8<802::AID-ADSC802>3.0.CO;2-T

The hydrogenation of carboxylic acid derivatives at room temperature was investigated. With a mixed Rh/Pt oxide (Nishimura catalyst), low to medium activity was observed for various α-amino and α-hydroxy esters. At 100 bar hydrogen pressure and 10% catalysts loading, high yields of the desired amino alcohols and diols were obtained without racemization. The most suitable α-substituents were NH₂, NHR, and OH, whereas β-NH₂ were less effective. Usually, aromatic rings were also hydrogenated, but with the free bases of amino acids as substrates, some selectivity was observed. No reaction was found for α-NR₂, α-OR, and unfunctionalized esters; acids and amides were also not reduced under these conditions. A working hypothesis for the mode of action of the catalyst is presented.

Full text of DOI:10.1002/1615-4169(20011231)343:8<802::AID-ADSC802>3.0.CO;2-T

FULL PAPER
Catalytic Hydrogenation of Chiral a-Amino
and a-Hydroxy Esters at Room Temperature
with Nishimura Catalyst without Racemization
Martin Studer,* Stefan Burkhardt, Hans-Ulrich Blaser
Solvias AG, WRO-1055.617, P.O. Box, 4002 Basel, Switzerland
Fax: (+41) 61±686±6311, e-mail: martin.studer@solvias.com
Received June 18, 2001; Accepted July 31, 2001
Abstract: The hydrogenation of carboxylic acid de- drogenated, but with the free bases of amino acids
rivatives at room temperature was investigated. as substrates, some selectivity was observed. No re-
With a mixed Rh/Pt oxide (Nishimura catalyst), low action was found for a-NR2, a-OR, and unfunction-
to medium activity was observed for various a-ami- alized esters; acids and amides were also not
no and a-hydroxy esters. At 100 bar hydrogen pres- reduced under these conditions. A working hypoth-
sure and 10% catalysts loading, high yields of the de- esis for the mode of action of the catalyst is pre-
sired amino alcohols and diols were obtained sented.
without racemization. The most suitable a-substitu-
ents were NH2, NHR, and OH, whereas b-NH2 were
Keywords: 1,2-amino alcohol; a-amino ester and a-
hydroxy ester; 1,2-diol; catalytic hydrogenation
less effective. Usually, aromatic rings were also hy-
tion of malic acid to the corresponding triol,[6,7] with
little or no racemization. However, the catalyst load-
ing was very high and the catalysts are not commer-
cially available. Ru oxide was able to hydrogenate ala-
nine at 100 °C and 200 bar with moderate to good
yields but long reaction times and some racemization
(93 98.5% ee) were observed.[8] He et al.[9] modified
supported Rh, Pt, Pd, and Ru catalysts or the corre-
sponding metal salts with Mo, Re, or W carbonyls
and the resulting bimetallic catalysts were able to
reduce carboxylic acids at 145 °C/100 bar. Other
catalyst systems able to reduce carboxylic acids be-
low 200 °C were Re oxides (150 250 °C, 150
300 bar),[10,11] homogeneous Ziegler-type Ni catalysts
and Ru chloride complexes,[12] and Ru-CO-clusters
bearing P(CH2OH)3 ligands (100 130 °C and
130 bar).[13] The application of these catalysts to the
hydrogenation of chiral acids was not investigated
but we suspect that racemization would occur above
100 °C.
Esters are somewhat easier to hydrogenate than
the corresponding acids. With high loading (weight
catalyst > weight substrate!), activated Raney nickel
but also Cu chromites were claimed to be active even
at room temperature.[14] However, no follow-up re-
sults were reported by other investigators and repro-
duction might be difficult. Other systems like Cu±Al
oxides for the hydrogenation of malic acid diisopropyl
ester[15] and homogeneous Ru complexes for the hy-
Introduction
Chiral 1,2-diols and 1-hydroxy-2-amino compounds
are versatile building blocks for a variety of biologi-
cally active ingredients.[1] These products can be pre-
pared catalytically via aminohydroxylation and dihy-
droxylation of terminal C=C bonds[1,2], and via
hydrolytic kinetic resolution of terminal epoxides
using Jacobsen's methodology.[3] Another attractive
approach is obviously the reduction of a-hydroxy-
and a-amino acids or esters from the chiral pool. In
most cases, this is carried out using metal hydrides
which are reactive at low temperatures thereby guar-
anteeing the integrity of the stereogenic center.[4]
Even though such reactions can be carried out at
room temperature on a 100 150 g scale,[5] the costs
and the large amount of waste render this methodol-
ogy less attractive for technical applications. From
this point of view, catalytic hydrogenation would, in
principle, be a perfect alternative. However, car-
boxylic acids and esters are the least reactive func-
tional groups for the classical hydrogenation catalysts
and usually temperatures >200 °C are needed for effi-
cient transformations. It is thus not surprising that
under such drastic conditions the reduction of the es-
ter is often paralleled by racemization.
There are a few exceptions: for Ru oxide modified
with a second metal like Re reasonable activity even
at 60 °C and 200 bar was claimed for the hydrogena-
802
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FULL PAPER
drogenation of electron-deficient esters[16,17] also
needed T > 100 °C and high pressure, or were only ac-
tive for a very limited range of substrates.
tions, non-functionalized esters, acids, or amides
did not react (results not shown). As expected, aro-
matic rings were usually completely hydrogenated.
To summarize: all catalytic systems described ¨ Solvent and additives: The solvents giving the high-
above have drawbacks. Most of the catalysts are not
commercially available, catalysts loading is usually
high, racemization can be a problem above 100 °C
and it is not always clear whether the results are
really reproducible. Undoubtedly there is room for
improvement and in this contribution we describe a
very mild method for the hydrogenation of a variety
of chiral a-amino and a-hydroxy acid esters to the
corresponding chiral diols and amino alcohols in
good chemicals yields and with high ee.
est activities and yields were methanol or ethanol
but other polar solvents like THF, dioxane, DMF,
AcOH, or water are also suitable (> 50% yield of
the desired amino alcohol). In DMA, diglyme, tri-
glyme, or pyrrolidone conversions of > 50% but
many unidentified di- and polymers were obtained.
High conversion to polymers but no amino alcohol
was observed in hexane. The addition of bases such
as Et3N, imidazole, or p-dimethylaminopyridine
gave no improvement or lower activities; the addi-
tion of strong acids such as HCOOH or CF3COOH
blocked the reaction.
Results and Discussion
We started our investigation after a serendipitous ob-
servation. When attempting to hydrogenate the aro-
matic ring of ethyl 2-hydroxy-4-phenyl butyrate using
Nishimura's catalysts (mixed Pt/Rh oxide with the
composition 45.9% Rh, 19.9% Pt) we obtained a by-
product, identified as the corresponding diol
(Scheme 1). This finding led us to hypothesize that
Nishimura's catalyst, which is often used for ring hy-
drogenation, might also be active for ester reduc-
tions.
Scheme 2. Hydrogenation of alanine esters.
In the light of these screening results, we concen-
trated our study on the investigation of selected a-
amino and a-hydroxy esters in order to show the
scope and limitation of the Nishimura catalyst. Re-
sults are listed in Tables 2 and 3.
High yields of the amino alcohols or lactams were
obtained for all a-amino acid esters investigated (ala-
nine, glutamic acid, leucine, phenylalanine, serine,
and homophenylalanine), irrespective of the nature
and functionalization of at the a-carbon. An addi-
tional alkyl substituent on the a-carbon (entry 2.3)
and monomethylation of the amino group (entry 2.2)
were tolerated without significant loss in activity.
However, the corresponding alanine derivatives with
an N(n-Pr)2 or an NH-BOC group did not react at all
(results not shown).
Scheme 1. Ring hydrogenation and by-product formation
with Nishimura catalysts.
In a first phase we tried to confirm this hypothesis and
tested a series of different catalysts and substrates
and carried out a systematic screening with alanine
esters (Scheme 2, Table 1). We quickly found that it
is indeed possible to reduce certain esters with good
yield but that the scope of the new reaction is rather
narrow:
¨ Catalyst type: Only the Nishimura catalyst is really
suitable; while Ru and Pt oxide showed weak activ-
ity, Rh, Pd, Ir, and Re oxide as well as various sup-
ported catalysts, including a 2% Pt, 4% Rh/C were
completely inactive (results not shown). Pre-reduc-
tion of the oxide catalysts gave an almost inactive
system.
For aliphatic amino acid esters, higher conversion
and yield were obtained with the free base than with
Table 1. Screening studies: Effect of catalyst type and load-
ing, and ester group. Conditions: 1 10 mg catalyst, 100 mg
alanine ester, MeOH, 100 bar hydrogen pressure, 16 h,
25 °C.
Catalyst
Catalyst
loading (%)
R
Conversion Alaninol By-prod-
(%)[a]
(%)[a]
ucts (%)
Nishimura 10
Me
Me
Me
Me
Me
Me
Et
> 90
³ 35
30
³ 70
> 90
> 90
> 90
60
> 90
35
20
50
90
> 90
> 90
40
< 10
< 10
10
20
10
< 10
< 10
< 10
10
RuO2
PtO2
Nishimura
Nishimura
10
10
1
¨ Catalyst loading: A relatively high catalyst loading
of 10% (w/w) Nishimura catalyst was necessary.
With 1% catalyst loading, conversion was still high
but a variety of by-products (mostly dimers and oli-
gomers) was formed.
5
Nishimura 10
Nishimura 10
Nishimura 10
Nishimura 10
t-Bu
Bn
> 90
90
¨ Substrate: Only the esters of a-hydroxy and a-ami-
no acids were converted. Under the same condi-
[a] NMR results.
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Table 2. Scope of Nishimura catalyst: Effect of amino acid structure. 10 mg catalyst, 100 mg substrate, MeOH, 100 bar hy-
drogen pressure, 25 °C, 16 20 h.
Substrate
Main product
Conversion[a] (%) Yield[a] (%)
Comments
Entry
> 90
75
> 90
75
the HCl salt gave 40% conv. to
the desired amino alcohol
2.1
2.2
2.3
2.4
2.5
> 90
> 90
> 90
> 90
> 90
90
the HCl salt gave only 10%
conv.
10 mg serine, 10% byproduct;
the HCl salt gave 60% conv.
> 90
90
2.6
2.7
> 90
> 90
> 90
20
40
> 90
40
40% ring hydrogenated amino
alcohol, 20% byproducts
2.8
40% ring hydrogenated amino
alcohol, 20% byproducts
2.9
20
80% ring hydrogenated amino
ester
2.10
2.11
15
15
±
[a] NMR results.
the HCl salt (see comments in entries 2.1, 2.4, 2.5). clearly shows that a-functionalized carboxylic acid
With aromatic derivatives, the reactions of the free derivatives can be selectively hydrogenated in the
bases showed an approximately 1:1 mixture of ring presence of another ester group: The non-activated
hydrogenated and aromatic amino alcohols (en- ester function is not reduced but forms a lactam un-
tries 2.7 and 2.9). In contrast, the HCl salts always der our reaction conditions. The b-amino acid ester
gave 100% ring hydrogenation, and in the case of tested showed some conversion to the desired b-ami-
phenylalanine, the ester hydrogenation of the HCl salt no alcohol, but the reaction was much slower than
was again much slower than for the free base. These with the a-amino acids (entry 2.11).
examples show that the presence of a free amino
The scope of the catalyst system was also tested for
group slows down the rate of ring hydrogenation. a-hydroxy esters (Table 3). For a variety of deriva-
The reduction of the ester of glutamic acid (entry 2.6) tives, high conversions and yields were obtained, but
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Table 3. Variation of a-hydroxy esters. 10 mg Nishimura catalyst, 100 mg substrate, MeOH, 100 bar hydrogen pressure,
25 °C.
Substrate
Main product
Conversion[a] (%)
Yield[a] (%)
Remarks
Entry
77
77
±
3.1
> 90
> 90
±
3.2
3.3
3.4
60 (> 90)[b]
69 (> 90)[c]
45 (71)[b]
31 (> 90)[c]
15 (29)[b] % lactone
20 mg catalysts
±
< 10
< 10
R = Me, Et, i-Pr
3.5
< 10
< 10
< 10
< 10
3.6
3.7
[a] NMR results.
[b] With 30 mg catalyst.
[c] With 60 mg catalyst
Table 4. Preparative-scale experiments. 10% Nishimura catalysts (w/w), 30% substrate loading (w/v), 100 bar hydrogen
pressure, 25 °C.
Substrate
Main product
Conversion[a] (%) Yield[a] (%)
Comments
Entry
> 95
> 90
> 80
> 90
2 g substrate, 100% isolated yield,
15% di- and oligomers
4.1
6 g substrate, 91% isolated yield
4.2
[a] NMR results.
sometimes higher catalyst loadings were necessary
than for the corresponding amino esters. As expected,
phenyl groups were completely converted to cyclohex-
yl groups (entries 3.2 and 3.4). Selective hydrogenation
In order to improve the performance of the Nishi-
mura catalyst, the influence of pressure, temperature
and starting material concentration were investi-
gated in more detail using the reduction of methyl
of an a-substituted ester was possible without reducing lactate as a model reaction. Lowering the hydrogen
other ester functions but also here the cyclization prod- pressure to 10 bar resulted in very low conversions,
uct was formed (entry 3.3). No reaction was observed while there was no significant difference between
with esters of tartaric acid (entry 3.5), a-methoxy (en-
try 3.7), and b-hydroxy esters (entry 3.7).
100 and 140 bar. Figure 1 shows the effect of the start-
ing material concentration on the yield of propane-
Adv. Synth. Catal. 2001, 343, 802±808
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diol at different temperatures. Usually, the highest
i) The ease of ester reduction decreases in the se-
yields and conversions were obtained at a starting quence: a-NH2 > a-OH, NH-alkyl > b-NH2. Acids, un-
material concentration of 30% with the highest yields substituted esters or esters with an a-N(alkyl)2, a-O-
at the lowest temperature. Similar results were also alkyl, a-NH-BOC, or b-OH group are not reactive.
observed for alanine methyl ester (results not
shown). In both cases, the catalyst had a different active under these mild reaction conditions
aspect in the low temperature experiments (finely iii) The addition of acid leads to a significantly low-
divided powder instead of aggregates observed at er hydrogenation rate.
ii) Only the oxidic, bimetallic Nishimura catalyst is
higher temperatures); re-use was not possible in any
case.
iv) Pre-hydrogenation of the catalyst in absence of
substrate leads to catalysts with low activity.
Two preparative-scale experiments were carried
v) A distinct induction period and a significant de-
out with alanine methyl ester and methyl lactate un- activation of the catalyst especially at higher tem-
der optimized conditions (Table 4). In both cases, peratures are observed.
>90% conversion and >80% chemical purity of the
Based on these observations, we propose as a work-
desired alcohols were obtained without any racemi- ing hypothesis the formation of a multi-functional ac-
zation. In these experiments, a distinct induction per- tive center consisting of a basic and multi-metallic
iod of about 4 minutes was observed after hydrogen sites. On this ensemble, the substrate is adsorbed,
saturation (see Figure 2).
transformed in several steps and the desired product
is desorbed as depicted in Figure 3. We think that the
a-NH2, a-NHR, or a-OH groups act as efficient an-
choring groups by interaction with a basic (oxidic)
site situated very close to the metallic centers leading
to the strongly adsorbed and activated ester. Such an
interaction would not be possible with OR or NR2
groups and less favored with b-functions. Our model
also explains why we need an oxidic catalyst which
has to be reduced in situ and can not be re-used. From
the induction period it is obvious that the original Pt±
Rh oxide is not the active catalyst. The observed in-
duction period indicates that the active site is a re-
duced (bimetallic?) species formed in presence of hy-
drogen and stabilized by a suitable substrate. It seems
to be generated only under certain well-defined con-
ditions, which we do not completely understand. This
active form is thermally (and probably chemically)
rather unstable but is able to perform the necessary
transformations. Longer exposures to hydrogen
(pre-hydrogenation or at the end of the reaction) will
probably result in larger metallic particles where the
basic sites are no longer close to the metallic sites.
After adsorption, we propose that the C±OR bond of
the activated intermediate is cleaved by reaction with
an M-H species giving an adsorbed aldehyde and an
M±OR species. Similar reactions have been proposed
for instance by Turek et al.[12] The aldehyde can
either desorb or be hydrogenated to the desired alco-
hol. As a last step in the cycle, the active metallic cen-
ter will be restored by reaction of the M-OR species
with hydrogen (in a sort of Mars±Van Krevelen mech-
anism). If the hydrogenolysis step or the reduction of
the aldehyde is too slow, the adsorbed species and/or
the free aldehyde can react with starting material or
products to a variety of byproducts (dimers, oligo-
mers). This could explain, why two metals are neces-
sary for good activity and selectivity, one for the C±OR
cleavage (probably Rh) and for fast hydrogenation of
the aldehyde (most likely Pt).
Figure 1. Effect of substrate concentration on diol yield.
Catalyst loading 10% (w/w), for 5%, 10% and 30% substrate
concentration, 3% for 100% substrate concentration, MeOH,
16 h, 100 bar hydrogen pressure, 25 °C. NMR results.
Figure 2. Pressure drop in the reservoir with reaction time
(entry 1, Table 4). Conditions see experimental. Phase 1: no
stirring, check for leaks; phase 2: hydrogen saturation of so-
lution; phase 3: induction period/hydrogenation; phase 4:
hydrogenation.
For the discussion of a possible mode of action, we
think that the following results are pertinent:
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Figure 3. Artists view of the active site and of important stages of the reaction.
were diluted with 0.8 mL of CD3OD and analyzed directly,
to avoid problems related to the work-up. The ee of 1,2-pro-
panediol and of alaninol (derivatization with Ac2O) were de-
termined on a chiral GLC column (Beta-dex 110, Supelco
hydrogen carrier). All screening experiments were carried
out in a 50-mL autoclave, where four parallel experiments
were run at the same pressure and reaction temperature.
While this working hypothesis can rationalize
many of our observations, we still do not really under-
stand why only the Nishimura catalyst and no other
oxidic or supported bimetallic catalysts are active.
Conclusion
Typical Screening Experiment
We have shown that the Nishimura catalyst can be
used for the hydrogenation of chiral a-amino and a-
hydroxy esters to the corresponding chiral alcohols
under very mild conditions with reasonable yields.
Usually, a-amino acid esters show a higher reactivity
than the related hydroxy acid esters. No racemization
occurs, and the system does not hydrogenate unfunc-
tionalized esters. Under basic conditions, some selec-
tivity for the ester vs. aromatic ring hydrogenation is
observed. Since the Nishimura catalysts is very ex-
pensive and high loadings are necessary, this system
is only feasible for preparative but not yet for techni-
cal applications. Further investigation regarding the
nature of the active catalytic species and improve-
ment of the chemoselectivity are in progress and will
be reported in due course.
10 mg Nishimura catalysts were placed in a 2.5 mL glass vial
equipped with a small stirrer bar. 1 mL of solvent and
100 mg alanine methyl ester (liberated from the hydrochlo-
ride by extraction from a NaHCO3 solution with CH2Cl2) were
added. A total of 4 vials were placed in the autoclave. After
sealing, it was purged with argon (3 times 10 bar) and with
hydrogen (3 times 10 bar) and the pressurized to 100 bar.
Preparative-Scale Experiments for (R)-Methyl
Lactate
600 mg Nishimura catalyst were wetted with a small amount
of MeOH under inert atmosphere and placed in a 50-mL
autoclave equipped with a magnetic stirrer bar and baffles.
6 g substrate dissolved in MeOH (total volume 20 mL) were
added, and the autoclave was sealed and purged with argon
(3 times 10 bar) and hydrogen (3 times 10 bar). After pres-
surizing to 100 bar, the reaction was started by turning the
stirrer on. After 16 h, the pressure was released, and the
autoclave was purged with argon. After filtration, the solu-
tion was evaporated to dryness and analyzed by NMR and
GLC (ee determination). Yield: 4.39 g (91%, purity > 90%).
The ee values of the product was >99%.
Experimental Section
General Remarks
The Nishimura (mixed Rh/Pt oxide, composition 45.9% Rh,
19.9% Pt), the PtO2 (80.8% Pt), and the 2% Pt/4% Rh/C cata-
lyst (FG 209/RD) were supplied by Degussa, the Rh2O3 by
Engelhard (E 3867). The substrates and solvents were used
as received or prepared according to literature procedures.
Most of the analysis was done on a Bruker 300 MHz machine
equipped with an auto sampler with CDCl3 or CD3OD as sol-
vents. Usually, a few microliters of the product solutions
Acknowledgements
The authors thank Heinz Steiner of Solvias AG for helpful dis-
cussion.
Adv. Synth. Catal. 2001, 343, 802±808
807

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