Are β-acylaminoacrylates hydrogenated in the same way as α-acylaminoacrylates?

Article abstract of DOI:10.1002/anie.200461716

Five catalyst-substrate complexes of the type [Rh(chiral ligand)(β-dehydroamino acid derivative)]BF₄ were characterized for the first time by X-ray analysis (see example). Low-temperature NMR spectroscopy proved that three of these complexes ar

Full text of DOI:10.1002/anie.200461716

Angewandte
Chemie
Communications
The diastereomeric complexes of b-acylaminoacry-
lates shown do not differ much in reactivity, in contrast to intermedi-
ates in the asymmetric hydrogenation of a-dehydroamino acids. As a
result, the major intermediate determines the selectivity of the reaction
in terms of the lock-and-key principle rather than the major–minor
concept. D. Heller et al. describe the reaction mechanism in more
detail on the following pages.
1
184
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DOI: 10.1002/anie.200461716
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Angewandte
Chemie
Catalytic Hydrogenation
idea of the extreme reactivity of one intermediate is reflected,
for example, in the concept of “ligand-accelerated cataly-
[
5]
Are b-Acylaminoacrylates Hydrogenated in the
Same Way as a-Acylaminoacrylates?**
sis”. In addition to comprehensive kinetic and NMR
spectroscopic studies, three X-ray structures of major sub-
strate complexes support the mechanism, also referred to as
[
4a,6]
the “anti lock-and-key motif”.
Hans-Joachim Drexler, Wolfgang Baumann,
Thomas Schmidt, Songlin Zhang, Ailing Sun,
Anke Spannenberg, Christine Fischer,
Recently an alternative was found in studies on P,S
ligands: a catalyst–substrate complex of an a-dehydroamino
acid derivative, which was characterized by X-ray analysis,
leads to the observed major enantiomeric form of the
Helmut Buschmann, and Detlef Heller*
[
7]
product. Since, on the one hand, a C -symmetric ligand
1
Dedicated to Jack Halpern and John M. Brown
can in theory form four stereoisomeric substrate complexes
coupled by inter- and possibly intramolecular equilibria, and,
on the other hand, two sets of two substrate complexes lead to
the two enantiomers, it is not certain that the one substrate
complex detected by NMR spectroscopy and the isolated
complex are identical.
[
1]
The synthesis of amino acids is still of current interest. In
contrast to known and even industrially used homogeneously
catalyzed hydrogenations of a-dehydroamino acid deriva-
tives, the asymmetric hydrogenation of protected b-amino-
[
2]
acrylates has only lately moved into the focus of research.
First mechanistic investigations on the asymmetric hydro-
genation of b-dehydroamino acid derivatives go back to
Gridnev and Imamoto. They detected hydridoalkyl com-
plexes at À1008C after the addition of methyl (E)-3-N-
acetylamino-3-methylacrylate to the dihydrido solvent com-
plex [RhH (L)(MeOH) ]BF (L = chiral bidentate phosphine
Meanwhile, catalytic systems have been described reaching
high activities and substrate/catalyst ratios, which lead to
practically enantiomerically pure b-amino acid derivatives;
[
3]
rhodium as a transition metal seems to be most suitable.
The asymmetric hydrogenation of a-dehydroamino acids
was investigated intensively in the last decades, but there are
still only a few indications of the reaction mechanism of b-
dehydroamino acids. For the a-dehydroamino acids it is
proposed that diastereomeric substrate complexes are formed
from the solvent complex and the prochiral olefin in a
preequilibrium. The diastereomeric substrate complexes
react in a sequence of elementary steps—oxidative addition
of hydrogen, insertion, and reductive elimination—to give the
enantiomeric products. The research groups led by Halpern,
Landis, and Brown were able to show that the major substrate
complex present in distinct excess does not lead to the main
enantiomer. The source of the enantioselectivity was identi-
fied as the extreme reactivity of the minor substrate
2
2
4
[
8]
ligand). Still, it is questionable whether such species are also
stable under stationary hydrogenation conditions at room
temperature. Nevertheless, kinetic and NMR investigations
indicated that the reaction sequence of the asymmetric
hydrogenation is in principle analogous to the hydrogenation
[
9a]
of a-dehydroamino acid derivatives.
The aim of this work is the in-depth mechanistic under-
standing of the rhodium-catalyzed asymmetric hydrogenation
of b-acylaminoacrylates. The direct comparison to the known
reaction mechanism of the hydrogenation of a-acylamino-
acrylates is of special interest.
Catalyst–substrate systems particularly appropriate for
mechanistic investigations are those for which the rate of
product formation is independent of the substrate concen-
tration, that is, the hydrogenation follows a zero-order rate
law. For this borderline case of Michaelis–Menten kinetics
characterized by preequilibria, only the stable catalyst–
substrate complexes are present in the reaction solution
during the hydrogenation; this can be proved easily by
[
4]
complex. These results were generalized in the literature
as the major/minor concept, and one can certainly call it a
basic principle of homogeneous catalysis. The fundamental
[
*] Dr. H.-J. Drexler, Dr. W. Baumann, Dipl.-Chem. T. Schmidt, Dr. A. Sun,
Dr. A. Spannenberg, Dr. C. Fischer, Priv.-Doz. Dr. D. Heller
Leibniz-Institut fꢀr Organische Katalyse
31
[9]
P NMR spectroscopy. In contrast to the (E)-b-acylamino-
b-arylacrylates, which are hydrogenated in a first-order
an der Universitꢁt Rostock e.V.
[
3b]
reaction, the Z substrates show the desired kinetic behav-
ior. It should be possible to isolate and characterize such
stable catalyst–substrate complexes. We succeeded with a
complex formed from the substrate methyl (Z)-3-N-acetyl-
amino-3-phenylacrylate (1). This complex, [Rh((R,R)-Et-
Buchbinderstrasse 5/6, 18055 Rostock (Germany)
Fax: (+49)381-466-9383
E-mail: detlef.heller@ifok.uni-rostock.de
Dr. S. Zhang
College of Chemistry and Environmental Science
Henan Normal University Xinxiang
duphos)(1)]BF , is the first rhodium complex with a b-
4
453007 Henan (China)
[10]
acylaminoacrylate (see the Supporting Information).
Dr. H. Buschmann
ESTEVE
[4a,6,7]
Like the known cases with a-acylaminoacrylates,
the
Z substrate is bound as a chelate to the rhodium through the
double bond and the amide oxygen atom. This is particularly
surprising, because the enantioselectivities for the hydro-
genation of the Z isomers, which are in general lower than
those of the E isomers, were explained by the nonchelating
binding of the substrate caused by an intramolecular hydro-
gen bond in the substrate. Indeed, for several Z isomers these
Av. Mare de Deu de Montserrat 221
08041 Barcelona (Spain)
[
**] We thank the Deutsche Forschungsgemeinschaft for their generous
support as well as Prof. C. R. Landis for stimulating discussions. We
especially thank C. Pribbenow for skilled technical assistance.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
[
11]
intramolecular hydrogen bonds
were
proven by X-ray crystal structures (see
refs. [2,12] and the Supporting Information).
However, this interaction is apparently can-
celled upon complexation of the substrate to
the transition metal.
The hydrogenation of methyl (Z)-3-
N-acetylamino-3-phenylacrylate (1) with
the catalyst system Rh/(R,R)-Et-duphos
(
Et-duphos = 1,2-bis(2,5-diethylphosphol-
anyl)benzene) in methanol at 258C and
.0 bar overall pressure provides the S enan-
1
tiomer in 85% ee (59% ee in isopropyl
alcohol). In contrast, the isolated catalyst–
substrate complex leads to the R enantiomer.
Yet assigning the crystallized intermediate as
either the major or minor substrate complex
is not reasonable, since the ratio of the
complexes at room temperature in both
Figure 1. Structures of the cations in a) [Rh((S,S)-dipamp)(2)]BF and b) [Rh((S,S)-
4
dipamp)(3)]BF
determined by X-ray crystal structure analysis.
4
3
1
solvents is approximately 56:44 ( P NMR spectrum).
There are several ways to eliminate the possibility that
only the minor substrate complexes crystallize, including
complicated NOE measurements and solid-state NMR
spectroscopy. However, we chose a different, simpler variant
and tried to “freeze out” the interconversion between the
diastereomeric catalyst–substrate complexes at low temper-
atures. It is crucial to this method that both of the substrate
complexes are clearly detectable even at the lowest temper-
ature employed (Table 1, column 3) and furthermore that the
crystals are sufficiently soluble.
However, several complexes formed with the catalyst
system Rh/(S,S)-dipamp (dipamp = 1,2-ethanediylbis[(2-
methoxyphenyl)phenylphosphane]) and b-acetylamino-b-
3
1
arylacrylates show P NMR signals for one substrate complex
in great excess in methanol at room temperature (Table 1,
column 2). Here, too, we were able to analyze these catalyst–
substrate complexes by X-ray crystallography. The complexes
Table 1: [Rh((S,S)-dipamp)((Z)-b-acetylamino-b-arylacrylate)]BF in
4
The results for the substrate methyl (Z)-3-N-acetylamino-
methanol: ratios of the diastereomeric substrate complexes at different
temperatures, enantioselectivities (258C, normal pressure), and reac-
tivity ratios of the intermediates.
[
14]
3
-(p-chlorophenyl)acrylate (2) are represented in Figure 2.
When we dissolved single crystals of the substrate complex in
a sealed NMR tube at approximately À908C, only the major
substrate complex was visible in the spectrum at À838C
(Figure 2a). When we allowed the very same NMR tube to
warm over several hours to room temperature, both of the
substrate complexes were again evident in the known ratio of
8
8:12 (Figure 2b, Table 1). The spectrum recorded after
R
[Major]/[minor]
S Sel.
[% ee] (e.r.)
kmaj/kmin
recooling this NMR tube is shown in Figure 2c. The agree-
ment between the major/minor ratio determined at room
temperature and at low temperature (Figure 2, Table 1)
proves that the thermodynamic equilibrium between the
substrate complexes has been reached in both cases.
ratio (T)
1
2
3
4
C6H
90:10 (RT) 96:4 (À878C)
88:12 (RT) 93:7 (À878C)
50 (3.0)
38 (2.2)
0.33
0.30
0.35
0.39
5
p-ClC H4
6
m-NO C H 81:19 (RT) 86:14 (À848C) 20 (1.5)
2
6
4
p-MeC H4
91:9 (RT)
60 (4.0)
6
Analogous results were obtained for the substrates methyl
(Z)-3-N-acetylamino-3-phenylacrylate (1) and methyl (Z)-3-
N-acetylamino-3-(m-nitrophenyl)acrylate (3) (see the Sup-
porting Information). These findings support the unequivocal
conclusion that the major substrate complexes crystallized.
Thus, it has been proven for the first time that the substrate
complex dominant in solution controls the stereochemistry of
the product. This is in keeping with the lock-and-key
mechanism known from enzyme catalysis.
of methyl (Z)-3-N-acetylamino-3-(p-chlorophenyl)acrylate
2) and methyl (Z)-3-N-acetylamino-3-(m-nitrophenyl)acryl-
(
ate (3) are shown in Figure 1 (see the Supporting Information
for details). One peculiarity of all four substrate complexes is
that the OMe group of the dipamp ligand interacts with the
rhodium center as a hemilabile ligand. This type of coordi-
nation is often discussed but to the best of our knowledge has
The enantiomeric ratio is the result of two factors: the
ratio of the concentrations of the intermediates ([major
substrate complex]/[minor substrate complex]) as the first
level of selection in the reaction sequence and the ratio of
[
13]
never been proven by X-ray analysis.
The four isolated substrate complexes each lead to the S
enantiomer. Surprisingly, the S enantiomer is also the major
product of the asymmetric hydrogenation in methanol
[
15]
their reactivities (kmaj/kmin) as the second level of selection.
(
although the enantioselectivities are only 20–60% ee,
In case of [Rh((R,R)-Et-duphos)(1)]BF the selectivity must
4
Table 1, column 4).
arise from the difference in reactivity of the diastereomeric
1
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Angewandte
Chemie
major product of the asymmetric hydro-
[
17]
genation,
in our study three single
crystals unequivocally identified as
major substrate complexes by low-tem-
3
1
perature P NMR spectroscopy show
opposite behavior. The major intermedi-
ate determines the selectivity (lock-and-
key principle). The main cause for this
apparently lies in the slight difference in
reactivities of the diastereomeric sub-
strate complexes. The classic major/
minor concept is based on the fact that
the minor substrate complex is much
more reactive than the major substrate
complex, but this extreme difference in
reactivity is not evident in the substrate
complexes with b-acylaminoacrylates in
this work. Therefore for the examples
studied the complexation of the sub-
strate as the first level of selection plays
an even bigger role than previously
assumed.
3
1
Figure 2. P NMR spectra of a solution prepared from single crystals of [Rh((S,S)-
dipamp)(2)]BF dissolved at À908C in methanol a) immediately after dissolving (T=À838C),
4
b) after warming to 258C and equilibration ([major]/[minor]=88:12), and c) after recooling the
sample from (b) to T=À788C ([major]/[minor]=93:7).
Received: August 19, 2004
substrate complexes because their concentrations are roughly
equal at room temperature (ratio 56:44). The experimentally
determined enantiomer ratio is 12.3 in methanol (85% ee)
and 3.9 in isopropyl alcohol (59% ee), which indicates that the
difference in the reactivities of the two intermediates cannot
be very great.
Keywords: asymmetric catalysis · b-amino acids · catalyst–
substrate complexes · hydrogenation · reaction mechanisms
.
[
[
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[
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1
1
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2
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In conclusion we have determined that reaction sequence
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cationic rhodium(i) complexes is the same. For the first time
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Angew. Chem. Int. Ed. 2005, 44, 1184 –1188
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1187

Communications
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[
14] The chloro compound was chosen because the absolute config-
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X-ray structure analysis and therefore the assignment of the
[
3b]
HPLC-Chiralyser signals is definite.
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1
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