Temperature-controlled bidirectional enantioselectivity in a dynamic catalyst for asymmetric hydrogenation

Article abstract of DOI:10.1002/anie.201412098

Asymmetric catalysis using enantiomerically pure catalysts is one of the most widely used methods for the preparation of enantiomerically pure compounds. The separate synthesis of both enantiomerically pure compounds requires tedious and time-consuming pr

Full text of DOI:10.1002/anie.201412098

Angewandte
Chemie
DOI: 10.1002/anie.201412098
Asymmetric Catalysis
Hot Paper
Temperature-Controlled Bidirectional Enantioselectivity in a Dynamic
Catalyst for Asymmetric Hydrogenation**
Golo Storch and Oliver Trapp*
Abstract: Asymmetric catalysis using enantiomerically pure
catalysts is one of the most widely used methods for the
preparation of enantiomerically pure compounds. The sepa-
rate synthesis of both enantiomerically pure compounds
requires tedious and time-consuming preparation of both
enantiomerically pure catalysts or chiral separation of the
racemic products. Here, we report a stereochemically flexible
diastereomeric rhodium(I) catalyst for asymmetric hydroge-
nations of prochiral (Z)-a-acetamidocinnamates and a-sub-
stituted acrylates, which changes its enantioselectivity depend-
ing on the temperature to produce each enantiomerically pure
compound in high yield with constant high enantioselectivity
over time. The same axially chiral rhodium(I) catalyst
produces (R)-phenylalanine derivatives in enantiomeric
ratios of up to 87:13 (R/S) at low temperature and up to 3:97
(R/S) of the corresponding S enantiomers after re-equilibration
of the same catalyst at elevated temperature.
of the activator controls the productꢀs chirality. Together with
the elaborate synthesis and selection of the chiral activator,
this constitutes one of the major drawbacks of this elegant
approach.
In an effort to overcome the above-mentioned limitations
we developed a catalytic system with a tropos 2,2’-bis(diphe-
nylphosphino)biphenyl (BIPHEP) ligand as a stereochemi-
cally flexible ligand core to enable switching of the catalystꢀs
enantioselectivity (Figure 1A). BINAP, the stereochemically
A
symmetric hydrogenation constitutes one of the most
widely used reactions to synthesize enantiomerically pure
compounds, for example, the Parkinsonꢀs drug l-3,4-dihy-
droxyphenylalanine (l-DOPA).[1–3] Enantiopure and stereo-
chemically rigid catalysts are used for this purpose. The
synthesis of these catalysts remains a tedious and expensive
task. In particular, pharmacological studies often require both
enantiomers to investigate potentially different activities and
side effects. One concept to facilitate this cumbersome
process is to use catalysts with stereochemically flexible
ligands,[4] for example, tropos biphenyls, in combination with
a suitable activator that forms a diastereomeric complex with
the catalyst and shifts the equilibrium to one of the ligand
enantiomers.[5–11] Upon hydrogenation, this activator is irre-
versibly removed to generate free coordination sites.[12]
Initially, this yields enantiomerically enriched hydrogenation
products, yet over the course of the reaction the racemization
of the catalyst leads to a depletion of the net enantioselec-
tivity.[13] However, the opposite activator is required to obtain
the opposite product enantiomer, because the configuration
Figure 1. Design of a bidirectional enantioselective catalyst that
switches enantioselectivity upon changing the temperature. A) A
stereochemically flexible ligand core as a chiral switching unit of the
catalyst with binding sites to allow modification with a chiral auxiliary
and coordination of metals. B) Chemical bonding of a chiral auxiliary
shifts the equilibrium as a consequence of diastereomer formation.
C) Catalyst formation by coordinating a metal precursor to the ligand
core. The equilibrium ratio of the metal-fixed diastereomeric catalysts
can be altered by changing the temperature. The asymmetric catalysis
of prochiral substrates leads to either R or S products.
rigid atropos parent ligand, is a widely used chiral ligand in
asymmetric catalysis.[14] The enantioselectivity of BINAP-
type catalysts is controlled by the torsion angle of the biaryl
and the alignment of the phenyl groups at the phosphine atom
binding to the metal center. In the present study we modified
the tropos ligand core with a homochiral auxiliary substituent
as the chiral directing group (Figure 1B).
The ligand core was modified with binding sites to attach
readily available chiral auxiliaries to form a pair of diaste-
reomeric complexes (Figure 1B). By binding the auxiliary to
the ligandꢀs core, the chiral information is continuously
transferred to the stereochemically flexible chiral axis of the
tropos biphenyl, which shifts the stereoisomeric ratio away
from the 1:1 equilibrium. The catalyst is formed by coordi-
nation of a metal precursor to the pair of diastereomeric
[*] M. Sc. G. Storch, Prof. Dr. O. Trapp
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: trapp@oci.uni-heidelberg.de
[**] This work was supported by the European Research Council under
Grant Agreements No. StG 258740. G.S. acknowledges support
from the Fonds der Chemischen Industrie for a PhD fellowship. We
thank Dr. F. Rominger for X-ray structure analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412098.
Angew. Chem. Int. Ed. 2015, 54, 1 – 7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
ligand cores, which freezes the equilibrium ratio of the
stereoisomers, provided a proper auxiliary is chosen (Fig-
ure 1C). In general, the ratio of epimerizing diastereomers
can be controlled by external parameters, for example,
temperature (Figure 1C).
The chiral auxiliary has to fulfill the following pre-
requisites: A stereogenic center close to the linking group
that maximizes stereoselective interactions, and an expanded
aryl group that aligns the adjacent phenyl rings of the metal-
bound diphenylphosphine group.[15] In addition, this auxiliary
can be the enantiomerically pure product of a catalytic
reaction, thereby making self-amplifying asymmetric process-
es possible.[16,17]
In a previous study[18] we investigated the stereodynamic
properties of BIPHEP ligands depending on the substituents
in the ortho or para position to the diphenylphosphine group.
The rotational barrier DG° of the biphenyl structure is
adjustable between 86 and 101 kJmolꢀ1, which makes such
compounds ideally suited as tropos ligand cores. Rotational
barriers between 95 and 97 kJmolꢀ1 were measured for
simple alkoxy-substituted BIPHEPs. This allows rapid epi-
merization of the ligand at elevated temperature while
maintaining the de novo isomer ratio by cooling below
room temperature. Furthermore, we could previously dem-
onstrate that chirality transfer to the stereogenic axis by
selector–selectand interactions in the backbone of the
BIPHEP ligand leads to partial deracemization and enantio-
selectivity in asymmetric catalysis.[19]
Figure 2. Synthesis of the bidirectional enantioselective catalyst 3.
A) The interconverting tropos 2,2’-bis(diphenylphosphino)-[1,1’-
biphenyl]-3,3’-diol (3,3’-BIPHEPOH, 1) as the chiral ligand core is
treated with (S)-naproxen as the chiral auxiliary to afford the diastereo-
meric ligand 3,3’-BIPHEPONap* (2). Tropos ligand 2 is converted into
the diastereomeric 3,3’-BIPHEPONap*RhI catalysts (RaxSS)-3 and (SaxSS)-
3 by using the rhodium precursor [Rh(cod)2](BF4). The diastereomeric
ratio of the ligands 2 is retained in the catalysts 3. B) Molecular
structure of (SaxSS)-2 (ellipsoids are shown at the 50% probability
level; chloroform molecules and hydrogen atoms are omitted for
clarity).[34]
through the ester group (Figure 2A) yields the modified
With the objective of a higher rotational barrier DG° of
the tropos ligand and a facilitated central-to-axial chirality
transfer, which improves the enantioselectivity in the
intended catalytic transformation, we introduced hydroxy
groups in positions 3 and 3’ of the BIPHEP ligand core by
a phospho-Fries rearrangement[13] of 3-bromophenyl diphe-
nylphosphinate. Protection of the hydroxy groups, followed
by Ullmann coupling, deprotection, and finally reduction of
the phosphine oxides gives stereolabile 2,2’-bis(diphenylphos-
phino)-[1,1’-biphenyl]-3,3’-diol (3,3’-BIPHEPOH, 1) as the
ligand core (Figure 2A, see the Supporting Information for
experimental details). This compound exists as a 1:1 mixture
of interconverting axially chiral enantiomers (Rax/Sax) and
hence is racemic. Chemical modification of the tropos ligand
core 3,3’-BIPHEPOH (1) can be performed in a late synthetic
step, which allows convergent large-scale synthesis of the
unmodified chiral core and facile preparation of various
derivatives.
We chose the anti-inflammatory drug (S)-naproxen as the
auxiliary, which is attached to the phenolic binding sites of
3,3’-BIPHEPOH (1). Enantiopure (S)-naproxen has an
extended aryl moiety and a stereogenic center close to the
linking carboxy group. It is readily available in large amounts,
thus allowing to easily scale-up the synthesis of the targeted
catalyst. This 2-aryl propionic acid can be synthesized by
enantioselective hydrogenation and exhibits fascinating prop-
erties in relation to deracemization, for example, (S)-nap-
roxen can be readily obtained in enantiomerically pure form
by Ostwald ripening.[20–22]
diastereomeric ligands 3,3’-BIPHEPONap
* (RaxSS)-2 and
(SaxSS)-2. This also results in a shift of the ligands equilibrium
ratio (RaxSS)-2 and (SaxSS)-2 from 50:50 to 61:39 as a result of
a central-to-axial chirality transfer of the chiral auxiliary to
the axially chiral biphenyl core.
To determine the barriers for the epimerization of the
tropos diastereomers (RaxSS)-2 to (SaxSS)-2 and vice versa,
the single diastereomers were isolated by preparative chiral
high-performance liquid chromatography (Chiralpak-IB,
separation factor a = 1.35). The elution order of (RaxSS)-2
before (SaxSS)-2 was assigned by determining the absolute
configuration by X-ray diffraction crystallography (Fig-
ure 2B). The epimerization process was followed by
31P{1H} NMR and 1H NMR spectroscopy of (RaxSS)-2 and
(SaxSS)-2 dissolved in CDCl3 under heating to 708C (Figures
S4–S8). This resulted in rapid re-equilibration to a (RaxSS)-
2/(SaxSS)-2 ratio of 61:39, with reaction rate constants and
epimerization barriers of k(RaxSS!SaxSS) = 1.06 ꢁ 10ꢀ4 sꢀ1
and DG° = 110.6 kJmolꢀ1, and k(SaxSS!RaxSS) = 1.66 ꢁ
10ꢀ4 sꢀ1 and DG° = 109.3 kJmolꢀ1 (correlation factor R2 =
0.986), respectively. This corresponds to half-lifes t of 55
and 35 min at 708C, respectively. These extended half-lifes of
ligands (RaxSS)-2 and (SaxSS)-2 compared to previously
reported BIPHEPs[18,19] will already reduce degradation of
the enantioselectivity as a result of ligand epimerization
during the course of catalysis.
To investigate the catalytic properties of the tropos ligand
(RaxSS)-2/(SaxSS)-2, we prepared the rhodium(I) catalysts
(RaxSS)-3 and (SaxSS)-3 (Figure 2A) to perform asymmetric
hydrogenations of prochiral olefins. Thus, the equilibrated
ligand mixture (RaxSS)-2/(SaxSS)-2 (61:39) was treated with
Covalently binding the (S)-naproxen auxiliary to the
stereochemically flexible ligand core 3,3’-BIPHEPOH (1)
2
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
the rhodium(I) complex [Rh(cod)2](BF4) to yield the corre-
sponding catalyst 3,3’-BIPHEPONap*RhI (RaxSS)-3/(SaxSS)-3
(Figure 2A) with a retained diastereomeric ratio of 61:39 for
(RaxSS)-3/(SaxSS)-3, as determined by 31P{1H} NMR spectros-
copy (Figure S12A). It should be mentioned that the diaste-
reomeric ratio is frozen upon complexation of the metal and
does not change at room temperature.
Surprisingly, heating the dissolved diastereomeric 3,3’-
BIPHEPONap*RhI mixture (RaxSS)-3/(SaxSS)-3 (61:39) to 708C
prior to catalysis provides the previously minor isomer
(SaxSS)-3 in a purity greater than 99% instead of the initial
major rotational diastereomer (RaxSS)-3 obtained from the
thermodynamically favored ligand (RaxSS)-2. Additional
kinetic studies were conducted to study the stereoselective
auxiliary-controlled depletion of the (RaxSS)-3 catalyst. The
diastereomeric RhI catalysts (RaxSS)-3 and (SaxSS)-3 show two
characteristic 1JP-Rh doublets for the individual diastereomers
(Figures S9–S11), which we utilized as
a
probe in
31P{1H} NMR spectroscopy to follow the shift of the diaste-
reomeric ratio (Figure 3).
Figure 4. Enantioselectivity and amplification of chirality of RhI catalyst
Figure 3. Kinetic profile of the epimerization of diastereomeric RhI
catalysts (RaxSS)-3/(SaxSS)-3 to (SaxSS)-3 upon heating at 708C. The
diastereomeric ratios were determined by 31P{1H} NMR spectroscopic
3 in the asymmetric hydrogenation of (Z)-methyl-a-acetamidocinna-
mate (4a) to N-acetylphenylalanine methyl ester (5a) depending on
the diastereomeric excess of the 3,3’-BIPHEPONap*RhI catalysts 3.
A) Blue data points: the R product is formed predominately by catalyst
(RaxSS)-3. Lowering the reaction temperature to ꢀ408C at a catalyst
ratio (RaxSS)-3/(SaxSS)-3 of 61:39 leads to an additional increase of the
enantiomeric excess from 42% to 74%. Red data points: Thermally
pretreated catalyst leading to altered catalyst ratios (RaxSS)-3/(SaxSS)-3.
A catalyst ratio (RaxSS)-3/(SaxSS)-3 greater than 45:55 leads to a reversal
of the enantioselectivity, with predominantly the S product produced.
Reaction temperature: ꢀ108C. B) Corresponding plot of the maximum
amplification of chirality achieved in the catalytic hydrogenation
depending on the diastereomeric ratio of catalyst 3.
1
analysis of the two characteristic JP-Rh doublets of the diastereomers.
The originally dominating diastereomeric catalyst (RaxSS)-3 is com-
pletely depleted after 360 min to afford (SaxSS)-3 in high purity
(>99%). The epimerization process can be stopped at any arbitrary
ratio by cooling to room temperature.
Indeed, a reversal of the diastereomeric ratio is achieved
at 708C within 100 min and complete de-epimerization within
360 min, which suggests a bidirectional enantioselectivity
solely controlled by temperature. The epimerization process,
which follows a sigmoidal function (Figure 3), can be stopped
at any arbitrary ratio, here at ratios of 58:42, 45:55, 26:74,
14:86, 12:88, and < 1:99 for (RaxSS)-3/(SaxSS)-3, by cooling to
room temperature. Shifting the diastereomeric ratio back to
the initial 61:39 ratio would require de-complexation, ligand
re-equilibration, and re-complexation, because the diastero-
merically pure catalyst remains at a ratio of < 1:99 upon
cooling.
We comprehensively studied several diastereomeric ratios
of the 3,3’-BIPHEPONap*RhI catalyst (RaxSS)-3 and (SaxSS)-3
in the asymmetric hydrogenation of (Z)-methyl-a-acetami-
docinnamate (MAC, 4a) as a prochiral substrate (Figure 4).
The reactions were performed at temperatures between ꢀ40
and ꢀ108C and under an initial hydrogen pressure of 10 atm
at different (RaxSS)-3/(SaxSS)-3 catalyst ratios by utilizing
high-pressure tube autoclaves. These reactors are charged
with NMR tubes as an inert reaction inlet to directly
determine the stereoisomeric ratio and detect potential
epimerization of the diastereomeric catalysts by comparing
NMR measurements before and after catalysis. The conver-
sion of the substrate was measured by NMR spectroscopy,
and the absolute configurations and the enantiomeric ratio of
the hydrogenation products N-acetylphenylalanine methyl
ester (5a) were determined by HPLC by comparison to
known standards directly after each catalytic run. To ascertain
the upper and lower limits of the catalystꢀs enantioselectivity,
Angew. Chem. Int. Ed. 2015, 54, 1 – 7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
we also determined the enantiomeric ratios e.r. in the
hydrogenation catalysis by using the RhI complexes of the
ligand isomers, which were separated by preparative HPLC
on a chiral stationary phase. For these stereoisomerically pure
catalysts we obtained enantiomeric ratios of the N-acetyl-
phenylalanine methyl ester (5a) of 98:2 ((R)-5a/(S)-5a,
96% ee) with (RaxSS)-3 and 2:98 ((R)-5a/(S)-5a, 96% ee)
with (SaxSS)-3. This is a remarkable result, since diastereo-
meric complexes typically exhibit matched or mismatched
behavior and therefore the enantioselectivity is decreased for
one of the product enantiomers.
origin and principle of nonlinear effects in catalysis using
diastereomeric ligand mixtures has been reported in the
literature, for example, for asymmetric dihydroxylation,[25]
asymmetric additions of terminal alkynes,[26] and enantiose-
lective CuI-catalyzed three-component reactions.[27] Nonlin-
ear effects in asymmetric hydrogenations were observed in
catalysts built from (mixed) pairs of monophosphorus ligands,
for example, phosphonites, phosphites, and phosphorami-
dites.[28–31] The distinct kinetics of the hydrogenation of the
cod spectator ligand from the two diastereomeric precatalysts
can additionally contribute to the nonlinear effect.[32]
Next, we investigated the catalysts with the frozen original
isomer ratio of 61:39 (RaxSS)-3/(SaxSS)-3 in the same asym-
metric hydrogenation reaction. At ꢀ108C we observed
a slight nonlinear amplification of the enantiomeric ratio of
71:29 ((R)-5a/(S)-5a) instead of the expected maximum
enantiomeric ratio of 61:39 (R/S; Figure 4A, blue data
points). This corresponds to an amplification factor famp of
1.9. The amplification factor famp is defined as the ratio of the
enantiomeric excess of the reaction product and the diaste-
reomeric excess of the 3,3’-BIPHEPONap*RhI catalyst (RaxSS)-
3/(SaxSS)-3 (famp = eeprod/decat). Investigation of this nonlinear
chiral amplification at lower reaction temperatures (ꢀ308C
and ꢀ408), which did not change the isomeric ratio of the
catalyst 3, confirmed that (RaxSS)-3 catalyzes the kinetically
favored formation of (R)-N-acetylphenylalanine methyl ester
((R)-5a). By decreasing the reaction temperature to ꢀ408C,
the enantiomeric ratio even increased to 87:13 ((R)-5a/((S)-
5a; Figure 4A). Kinetic evaluation of these data yields an
acceleration of 4.3 for the kinetically favored reaction and
a difference in enantioselectivities DDH° of 18.4 kJmolꢀ1 and
DDS° of 67 JKꢀ1 molꢀ1 between the 3,3’-BIPHEPONap*RhI
catalysts (RaxSS)-3 and (SaxSS)-3. This is a significant result
in terms of the mechanism of chiral amplification since it
proves that even small deviations from a 1:1 equilibrium are
sufficient to generate high selectivity just by varying the
external conditions, such as the reaction temperature.
We extended the here-reported novel concept of bidirec-
tional enantioselectivity to (Z)-methyl-a-acetamidocinna-
mate derivatives 4 bearing either electron-withdrawing or
-donating substituents at the phenyl group, dimethyl itaconate
(6), and methyl-a-acetamidoacrylate (8). Hydrogenations
were performed first with the temperature-depleted < 1:99
(RaxSS)-3/(SaxSS)-3 catalyst mixture at ꢀ108C and second
with the original 61:39 (RaxSS)-3/(SaxSS)-3 mixture at ꢀ408C
(Table 1). In all cases, significant nonlinearities were
observed, with the 61:39 catalyst mixture giving enantiomeric
ratios of up to 87:13 (R product/S product) for the N-
acetylphenylalanine methyl ester derivatives 5, up to 20:80
(R product/S product) for dimethyl-2-methyl succinate (7),
and up to 82:18 (R product/S product) for the N-acetylalanine
methyl ester (9). The > 99% (SaxSS)-3 catalyst was found to
be highly enantioselective for the opposite enantiomer in all
cases, thereby leading to enantiomeric ratios of up to 3:97
(R product/S product) for the N-acetylphenylalanine methyl
ester derivatives 5, up to 98:2 (R product/S product) for
dimethyl-2-methylsuccinate (7), and up to 1:99 (R product/
S product) for the N-acetylalanine methyl ester (9). Scale up
of the asymmetric hydrogenation of methyl-a-acetamidoa-
crylate (8) at a low catalyst loading of only 0.2 mol% yielded
(S)-N-acetylalanine methyl ester ((S)-9) with an enantiomeric
ratio of 1: > 99 (R product/S product) and a turnover number
(TON) of > 460.
3,3’-BIPHEPONap*RhI catalyst mixtures (RaxSS)-3/(SaxSS)-
3 with ratios of 58:42, 45:55, 26:74, 14:86, 12:88, and < 1:99
were studied in the asymmetric hydrogenation of (Z)-methyl-
a-acetamidocinnamate (4a, Figure 4). All the diastereomeric
catalyst mixtures were highly active and converted the
substrate into (S)-N-acetylphenylalanine methyl ester ((S)-
5a) in enantiomeric excesses of up to 4:96 ((R)-5a/(S)-5a,
92% ee) for catalyst mixtures with a dominating (SaxSS)-3
epimer. This demonstrates that temperature-controlled bidir-
ectional enantioselectivity in a stereodynamically flexible
3,3’-BIPHEPONap*RhI catalyst (RaxSS)-3/(SaxSS)-3 is possible
without any separation of the diastereomers. Amplification of
the chirality[23,24] famp was plotted as a function of the
diastereomeric excess of the catalyst (Figure 4B). A signifi-
cant positive nonlinear effect of up to famp = 3.4 (at a diaste-
reomeric excess of only 22% of the catalyst) in amplification
of the enantioselectivity is observed for the 3,3’-BI-
PHEPONap*RhI catalyst (RaxSS)-3 (Figure 4B). It has to be
noted that complete stereocontrol corresponds only to
a linear transmission of the chirality, in which the amplifica-
tion factor converges to 1.0, as is seen in the right branch of
the plot depicted in Figure 4B. A detailed discussion of the
In summary, we demonstrated the first example of an
easily accessible catalytic system that provides access to both
enantiomers of an asymmetric hydrogenation reaction solely
by changing the applied temperature. Key features are the
stereolabile tropos ligand core in combination with a remotely
bound auxiliary. Synergy of highly selective asymmetric
deactivation, nonlinearity, and stereodynamics result in
a catalytic system that provides high enantioselectivities in
both directions depending on the applied temperature. This
bidirectional 3,3’-BIPHEPONap*RhI catalyst shows excellent
results in asymmetric hydrogenations to yield d- and l-
phenylalanine derivatives, which are pharmaceutically rele-
vant, for example, in the Parkinsonꢀs drug l-DOPA,
dimethyl-2-methylsuccinate, and N-acetylalanine methyl
ester. We assume that the underlying fundamental principle
of this concept is directly transferable to other catalyzed
reactions. The here-presented approach allows decoupling
kinetic and thermodynamic control according to the Curtin–
Hammett principle of enantiomeric catalysts (Figure S2). The
discovery of temperature-controlled bidirectional enantiose-
lectivity and chiral amplification as demonstrated herein is
not only interesting in asymmetric synthesis but could be
4
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Table 1: Enantioselectivity of the bidirectional RhI catalyst 3 in the asymmetric hydrogenation of (Z)-
[1] R. Noyori, Science 1990, 248, 1194 –
methyl-a-acetamidocinnamate derivatives, dimethyl itaconate (6), and methyl-a-acetamidoacrylate
(8).[a]
1199.
[2] R. Noyori, Angew. Chem. Int. Ed.
2002, 41, 2008 – 2022; Angew.
Chem. 2002, 114, 2108 – 2123.
[3] W. S. Knowles, Angew. Chem. Int.
Ed. 2002, 41, 1998 – 2007; Angew.
Chem. 2002, 114, 2096 – 2107.
[4] S. Zahn, J. W. Canary, Science 2000,
288, 1404 – 1407.
Substrate
R Product
S Product
Product enantiomeric
ratio R/S [%]
catalyst ratio
(RaxSS)-3/(SaxSS)-3
61:39
<1:99
87:13
4:96
[5] K. Mikami, S. Matsukawa, Nature
1997, 385, 613 – 615.
[6] K. Mikami, T. Korenaga, M.
Terada, T. Ohkuma, T. Pham, R.
Noyori, Angew. Chem. Int. Ed.
1999, 38, 495 – 497; Angew. Chem.
1999, 111, 517 – 519.
[7] K. Mikami, T. Korenaga, K.
Ohkuma, R. Noyori, Angew.
Chem. Int. Ed. 2000, 39, 3707 –
3710; Angew. Chem. 2000, 112,
3854 – 3857.
[8] P. J. Walsh, A. E. Lurain, J. Balsells,
Chem. Rev. 2003, 103, 3297 – 3344.
[9] J. W. Faller, A. R. Lavoie, J. Parr,
Chem. Rev. 2003, 103, 3345 – 3368.
[10] K. Mikami, M. Yamanaka, Chem.
Rev. 2003, 103, 3369 – 3400.
[11] K. T. Barrett, A. J. Metrano, P. R.
Rablen, S. J. Miller, Nature 2014,
509, 71 – 75.
[12] K. Aikawa, Y. Takabayashi, S.
Kawauchi, K. Mikami, Chem.
Commun. 2008, 5095 – 5097.
[13] T. Punniyamurthy, M. Mayr, A. S.
Dorofeev, C. J. R. Bataille, S.
Gosiewska, B. Nguyen, A. R.
Cowley, J. M. Brown, Chem.
Commun. 2008, 5092 – 5094.
[14] R. Noyori, H. Taakaya, Acc. Chem.
Res. 1990, 23, 345 – 350.
[15] P. J. Donoghue, P. Helquist, P.-O.
Norrby, O. Wiest, J. Am. Chem.
Soc. 2009, 131, 410 – 411.
4a
4b
4c
(R)-5a
(R)-5b
(R)-5c
(S)-5a
(S)-5b
(S)-5c
80:20
79:21
81:19
75:25
3:97
10:90
5:95
4d
(R)-5d
(S)-5d
6:94
98:2
4e
6
(R)-5e
(R)-7
(R)-9
(S)-5e
(S)-7
(S)-9
20:80
82:18
1:99
[16] K. Soai, T. Shibata, H. Morioka, K.
Choji, Nature 1995, 378, 767 – 768.
[17] T. Kawasaki, Y. Matsumura, T.
Tsutsumi, K. Suzuki, M. Ito, K.
Soai, Science 2009, 324, 492 – 495.
[18] F. Maier, O. Trapp, Angew. Chem.
Int. Ed. 2012, 51, 2985 – 2988;
Angew. Chem. 2012, 124, 3039 –
3043.
<1:99 (S)[b]
8
[a] Reaction conditions: 0.1 mmol substrate, 5 mol% 3 or 2 mol% 3 for dimethyl itaconate (6) and
methyl-a-acetamidoacrylate (8), 10 atm hydrogen in chloroform. The absolute configurations of the
hydrogenation products were obtained by chiral HPLC or GC by comparison to known standards.
[b] Scale-up: 1.15 mmol 8, 2.51 mmol 3 (0.2 mol%), 5 atm hydrogen, TON>460.
[19] F. Maier, O. Trapp, Angew. Chem.
Int. Ed. 2014, 53, 8756 – 8760;
Angew. Chem. 2014, 126, 8901 –
8905.
a key mechanism to trigger homochirality by temperature
[20] W. L. Noorduin, P. van der Asdonk, H. Meekes, W. J. P.
van Enckevort, B. Kaptein, M. Leeman, R. M. Kellogg, E.
Vlieg, Angew. Chem. Int. Ed. 2009, 48, 3278 – 3280; Angew.
Chem. 2009, 121, 3328 – 3330.
[21] W. L. Noorduin, E. Vlieg, R. M. Kellogg, B. Kaptein, Angew.
Chem. Int. Ed. 2009, 48, 9600 – 9606; Angew. Chem. 2009, 121,
9778 – 9784.
gradients, as was identified in the (spontaneous) polymeri-
zation of RNA.[33]
Received: December 17, 2014
Published online: && &&, &&&&
Keywords: asymmetric amplification · asymmetric synthesis ·
hydrogenation · ligand design · tropos biaryls
[22] W. L. Noorduin, W. J. P. van Enckevort, H. Meekes, B. Kaptein,
R. M. Kellogg, J. C. Tully, J. M. McBride, E. Vlieg, Angew.
.
Angew. Chem. Int. Ed. 2015, 54, 1 – 7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Chem. Int. Ed. 2010, 49, 8435 – 8438; Angew. Chem. 2010, 122,
8613 – 8616.
Henderickx, J. G. de Vries, Adv. Synth. Catal. 2003, 345, 308 –
323.
[29] M. T. Reetz, X. Li, Angew. Chem. Int. Ed. 2005, 44, 2959 – 2962;
Angew. Chem. 2005, 117, 3019 – 3021.
[23] C. Girard, H. B. Kagan, Angew. Chem. Int. Ed. 1998, 37, 2922 –
2959; Angew. Chem. 1998, 110, 3088 – 3127.
[30] M. T. Reetz, Angew. Chem. Int. Ed. 2008, 47, 2556 – 2588;
Angew. Chem. 2008, 120, 2592 – 2626.
[31] F. G. Terrade, M. Lutz, J. N. H. Reek, Chem. Eur. J. 2013, 19,
10458 – 10462.
[32] T. Schmidt, W. Baumann, H.-J. Drexler, D. Heller, J. Organomet.
Chem. 2011, 696, 1760 – 1767.
[33] C. B. Mast, S. Schink, U. Gerland, D. Braun, Proc. Natl. Acad.
Sci. USA 2013, 110, 8030 – 8035.
[34] CCDC 1043639 [(Rax)-1] and CCDC 1043640 [(SaxSS)-2] contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[24] T. Satyanarayana, S. Abraham, H. B. Kagan, Angew. Chem. Int.
Ed. 2009, 48, 456 – 494; Angew. Chem. 2009, 121, 464 – 503.
[25] S. Y. Zhang, C. Girard, H. B. Kagan, Tetrahedron: Asymmetry
1995, 6, 2637 – 2640.
[26] P. Zarotti, T. F. Knçpfel, P. Aschwanden, E. M. Carreira, ACS
Catal. 2012, 2, 1232 – 1234.
[27] N. Gommermann, C. Koradin, K. Polborn, P. Knochel, Angew.
Chem. Int. Ed. 2003, 42, 5763 – 5766; Angew. Chem. 2003, 115,
5941 – 5944.
[28] M. van den Berg, A. J. Minnaard, R. M. Haak, M. Leeman, E. P.
Schudde, A. Meetsma, B. L. Feringa, A. H. M. de Vries, C. E. P.
Maljaars, C. E. Willans, D. Hyett, J. A. F. Boogers, H. J. W.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric Catalysis
G. Storch, O. Trapp*
Temperature switches enantioselectivity!
A stereochemically flexible diastereo-
meric rhodium(I) catalyst has been
designed for the asymmetric hydrogena-
tion of prochiral (Z)-a-acetamidocinna-
mates and a-substituted acrylates. The
catalyst changes its enantioselectivity
depending on the temperature to pro-
duce each single enantiomer in high yield
and a constant high enantioselectivity.
&&&& — &&&&
Temperature-Controlled Bidirectional
Enantioselectivity in a Dynamic Catalyst
for Asymmetric Hydrogenation
Angew. Chem. Int. Ed. 2015, 54, 1 – 7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!