Temperature-Controlled Bidirectional Enantioselectivity in Asymmetric Hydrogenation Reactions Utilizing Stereodynamic Iridium Complexes

Article abstract of DOI:10.1055/s-0036-1588861

Stereochemically flexible 2,2(-bis(diphenylphosphino)biphenyl (BIPHEP) ligands were modified with chiral α-substituted carboxylic acid auxiliaries in the 3- and 3′-position. The resulting central-to-axial chirality transfer to the stereochemically flexible chiral axis of the BIPHEP core was investigated as well as complexation of these diastereomeric ligands to iridium(I). Solid-state structures of both ligand diastereomers and a diastereomerically pure iridium(I) BIPHEP complex were obtained. Thermal equilibration of the resulting iridium(I) complexes was studied to investigate the stereodynamic properties of the BIPHEP ligands. The iridium(I) complexes without and after pre-catalysis warming in solution - which induces a shift of the diastereomeric ratio - were applied for asymmetric hydrogenation of a prochiral α-substituted acrylic acid, resulting in temperature-controlled bidirectional enantioselectivity of iridium catalysts for the first time. In both cases, enantioenriched (R)-naproxen as well as (S)-naproxen - after re-equilibration of the catalyst at elevated temperatures - was obtained by using the same catalyst.

Full text of DOI:10.1055/s-0036-1588861

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–J
paper
A
en
Synthesis
M. Siebert et al.
Paper
Temperature-Controlled Bidirectional Enantioselectivity in Asym-
metric Hydrogenation Reactions Utilizing Stereodynamic Iridium
Complexes
Max Sieberta
Golo Storcha
Frank Romingerb
OH
O
O
Oliver Trapp*a
0
0
0
0
0-
0
0
2
3-
5
9
4
5-
1
8
1
(
S)
a
Department Chemie, Ludwig-Maximilians-Universität
München, Butenandtstr. 5-13, 81377 München, Germany
Organisch-Chemisches Institut, Ruprecht-Karls-Universität
Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,
Germany
OH
b
Δ
O
O
oliver.trapp@cup.uni-muenchen.de
(
R)
This contribution is dedicated to Prof. Dr. Herbert Mayr on the
occasion of his 70th birthday.
OH
O
O
Received: 09.05.2017
Accepted: 11.05.2017
Published online: 20.06.2017
DOI: 10.1055/s-0036-1588861; Art ID: ss-2017-z0312-op
Previous Work
A
PRODUCT
ACT
(
S)-CAT
(S)-CAT
(S)-ACT
(S)-ACT
kACT (x % ee)
(
S( RS ))-- cA aC tT
Abstract Stereochemically flexible 2,2(-bis(diphenylphosphino)biphe-
nyl (BIPHEP) ligands were modified with chiral α-substituted carboxylic
acid auxiliaries in the 3- and 3′-position. The resulting central-to-axial
chirality transfer to the stereochemically flexible chiral axis of the
BIPHEP core was investigated as well as complexation of these diaste-
reomeric ligands to iridium(I). Solid-state structures of both ligand dias-
tereomers and a diastereomerically pure iridium(I) BIPHEP complex
were obtained. Thermal equilibration of the resulting iridium(I) com-
plexes was studied to investigate the stereodynamic properties of the
BIPHEP ligands. The iridium(I) complexes without and after pre-catalysis
warming in solution — which induces a shift of the diastereomeric ratio
(
R(R))-- cC aA tT
(R)-CAT
(S)-CAT
B
C
PRODUCT
(
S)-CAT
kACT
(x % ee)
ACT
(S( RS ))-- cA aC tT
(
R(R))-- cC aA tT
(R)-CAT
(S)-CAT
(S( RS ))-- cA aC tT
T<Tiso
PRODUCT
(
S)-CAT
C O( RSN ) T- cR a Ot L
(S)-CAT
(x% ee)
k
T>Tiso
C O( RSN ) T- cR a Ot L
C O( RSN ) T- cR a Ot L
(
R(R))-- cC aA tT
(R)-CAT
C O( RSN ) T- cR a Ot L
—
were applied for asymmetric hydrogenation of a prochiral α-substi-
tuted acrylic acid, resulting in temperature-controlled bidirectional en-
antioselectivity of iridium catalysts for the first time. In both cases, en-
This Work
D
CATALYSIS PRODUCT
ENANTIOMER B ENRICHED
antioenriched (R)-naproxen as well as (S)-naproxen
— after re-
equilibration of the catalyst at elevated temperatures — was obtained
by using the same catalyst.
(S)-CAT
Aux-(S)-CAT
Aux-(R)-CAT
Aux-(S)-CAT
T<Tiso
T>Tiso
(
RSA ) U- cX at
Key words asymmetric catalysis, bidirectional enantioselectivity,
chiral auxiliaries, stereodynamic catalysts, supramolecular chemistry,
tropos ligands
(
R)-CAT
Aux-(R)-CAT
CATALYSIS PRODUCT
ENANTIOMER A ENRICHED
The synthesis of enantiopure catalysts is often cumber-
some and expensive. Most commonly, the ligands used are
synthesized by using asymmetric synthetic procedures. If
an achiral synthetic procedure is applied instead, racemic
intermediates have to be optically resolved by using tedious
preparative methods. A concept to reduce these expendi-
tures is to use racemic catalysts with stereochemically flex-
ible ligands in combination with suitable chiral activators.
This results in the formation of diastereomeric complexes
Figure 1 Schematic overview of chiral activation utilizing racemic
tropos ligands and chiral additives. All cases represent ideal cases of asym-
metric activation. (A) Selective formation of a diastereomeric adduct.
(
B) Nonselective formation of diastereomeric adducts, with only one
adduct being catalytically active. (C) Nonselective formation of diaste-
reomeric adducts and enrichment of one enantiomer of the racemic
catalyst prior to catalysis. (D) Nonselective formation of diastereomeric
adducts and enrichment of either diastereomer depending on the reac-
tion conditions.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

B
Synthesis
M. Siebert et al.
Paper
and a shift out of the 1:1 equilibrium.1 Enantioenriched
products are obtained if only one enantiomer is activated
by addition of the additive (Figure 1A), if one of the formed
diastereomers is catalytically more active (Figure 1B) or if
one enantiomer of the racemic catalyst is enriched prior to
catalysis (Figure 1C). In previously reported examples, the
chiral additives were cleaved upon pre-catalyst activation
In 2015, Trapp et al. used a catalytic system that provid-
ed access to both enantiomers of an asymmetric hydroge-
nation reaction solely by changing the applied temperature
4
(Figure 1D). The stereochemically flexible diastereomeric
rhodium(I) catalyst showed excellent results in the asym-
metric hydrogenation of several substrates. The catalytic
system was based on a tropos 2,2′-bis(diphenylphosphi-
no)biphenyl (BIPHEP) ligand modified with a covalently
bound homochiral auxiliary as chiral directing group. Inde-
pendently from our work, Leitner and Franciò recently de-
scribed a catalytic system that showed temperature-
controlled bidirectional enantioselectivity in rhodium-
2
to generate free coordination sites.
However, this potentially results in racemization of the
remaining catalyst over the course of the reaction, leading
to a progressive reduction of the net enantioselectivity.
Brown et al. used a chiral diene to resolve rhodium(I)
BIPHEP complexes prior to catalysis, thereby allowing the
subsequent asymmetric hydrogenation of dehydroamino
acid derivatives with high enantioselectivities. To retain the
stereoinformation of the catalyst and the enantioselectivity
during the course of the catalysis, enantiomerically pure di-
5
catalyzed hydrogenations. Beside the tropos BIPHEP ligand,
an enantiomerically pure (S)-proline derivative was used as
chiral selector. In both cases, the key factor of the catalytic
systems was the stereochemically flexible ligand core,
which enabled switching of the enantioselectivity of the
catalyst.
3
ene had to be added in excess (Figure 2).
Furthermore, only one enantiomer of the product can
be obtained by using a certain activator because the config-
uration of the chiral activator determines the product con-
figuration. Another remaining challenge is the necessity for
enantiomerically pure chiral activators, which themselves
often require elaborate and cumbersome preparation.
In the present study, we expanded the concept of tem-
perature-controlled bidirectional enantioselectivity from
rhodium to iridium, which extends the spectrum of catalyt-
ic transformations. Furthermore, we evaluated the influ-
ence of different, easily accessible chiral auxiliaries with re-
gard to their importance in subsequent catalytic reactions.
i
i
OPr
OPr
Ph2
P
Ph2
P
Rh
P
Rh
P
Ph2
Ph2
OTf
OTf
i
i
OPr
OPr
(
Sax,S,S)
(Rax,S,S)
O
O
O
2 mol% [Rh] complex
H2, MeOH, 5 h, rt
O
N
N
H
H
O
a) 84% ee
b) 10 mol% additional
S,S)-diene: 95% ee
(
addition of chiral diene
to retain stereoinformation is
necessary
P
chiral auxiliary is removed:
loss of chiral information
Rh
*
P
H2
P
P
Solv
Solv
Rh
*
O
O
degradation of
calatyst's enantiomeric excess
due to ligand's stereolability
O
N
H
O
O
N
H
O
H2
P
P
NH
Rh
E
O
*
decreasing enantioselectivity
over course of reaction
2
E = CO Me
Figure 2 Catalytic system reported by Brown et al. and schematic catalytic cycle of the asymmetric hydrogenation of a dehydroamino acid derivate
showing the necessity for an excess of enantiomerically pure chiral diene3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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Synthesis
M. Siebert et al.
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In line with our ongoing interest in stereodynamic li-
gands and their use in asymmetric catalysis, we chose a
,3′-disubstituted BIPHEP ligand as a stereochemically flex-
6
4,7
A
B
C
3
ible ligand core and starting point for further modifications.
To covalently attach chiral carboxylic acid auxiliaries, the
BIPHEP ligand core was modified with suitable phenolic
binding sites (Figure 3A). Ester formation led to the forma-
tion of a pair of diastereomeric ligands. Due to the perma-
nent central-to-axial chirality transfer from the chiral aux-
iliaries to the stereochemically flexible chiral axis of the
BIPHEP core, the stereoisomeric ratio was shifted out of the
1
:1 equilibrium (Figure 3B). Upon complexation utilizing a
suitable precursor, the equilibrium ratio of the resulting di-
astereomeric complex species was frozen at room tempera-
ture. Epimerization of the dissolved complex was induced
by warming the solution under inert conditions. During
this process, the initial minor isomer was subsequently en-
riched while the initial major isomer was thermally deplet-
ed. It has to be noted that this led to an inversion of the dia-
stereomeric ratio of the catalyst (Figure 3C). The resulting
diastereomeric complex species were used for asymmetric
catalysis (Figure 3D).
shift of
diastereomeric ratio
at elevated
D
temperatures
(R)-product
(S)-product
The hydroxy groups in the 3,3′-position were intro-
duced by a phospo-Fries rearrangement of 3-bromophenyl
diphenylphosphinate. After protection of the hydroxy
OH
OH
OH
O
O
O
O
O
O
3
groups, two aryl moieties were homo-coupled by Ullmann
coupling. Deprotection of the hydroxy groups and final
reduction of the phosphine oxides yielded the tropos
selector binding site
chiral selector
metal coordination site
metal
Figure 3 Design of a bidirectional enantioselective catalyst. The enan-
tioselectivity is solely controlled by temperature. (A) Stereochemically
flexible BIPHEP core with binding sites for the coordination to a metal
center and for the modification with chiral auxiliaries. (B) Shifted equi-
librium towards one diastereomer due to binding of chiral auxiliaries.
2
,2′-bis(diphenylphosphino)-[1,1′-biphenyl]-3,3′-diol (3,3′-
OH
4
BIPHEP , 1) ligand core.
The desired modification with chiral auxiliaries is per-
formed in a late-step synthesis, thereby enabling facile
scale-up and convergent synthesis of the final 3,3′-disubsti-
tuted ligands (Figure 4A). To induce optimal central-to-axial
chirality transfer, the chiral auxiliaries should possess ste-
reogenic centers close to the linking group. Furthermore, an
aryl moiety within the chiral auxiliary aligns the adjacent
phenyl groups of the metal-bound diphenylphosphino
group. Consequently, we chose (S)-phenylpropionic acid,
(
C) Catalyst formation with a suitable metal precursor. The resulting
stereoisomeric ratio may be changed by epimerization above the isom-
erization temperature. (D) The enantioselectivity of the diastereomeric
complex species is inverse and they give either (R)- or (S)-products, for
instance (R)- or (S)-naproxen, respectively.
Intriguingly, it was possible to separate the two diaste-
OPh
reomers (R ,S,S) and (S ,S,S) of 3,3′-BIPHEP (2a) through
ax
ax
(
S)-ibuprofen, and (S)-naproxen as chiral auxiliaries. Inves-
precipitation from DCM/n-pentane. Assignment of the ab-
tigation of the resulting ligands in subsequent metal-cata-
lyzed reactions was expected to give insights into the role
of the auxiliary, especially with regard to the relevance of
steric factors. Covalent binding of the chiral auxiliaries to
solute configuration was achieved by X-ray diffraction crys-
tallography for the isolated isomers (Figure 4B/4C). Given
8
that enantiomerically pure (S)-phenylpropionic acid was
used as chiral auxiliary, the axial chirality of the crystal-
lized isomers was unambiguously determined. Examining
the molecular structure of the two diastereomers, the
alignment of the aromatic moieties is noteworthy. Whereas
OH
the stereochemically flexible ligand core 3,3′-BIPHEP (1)
OPh
OIbu
yielded ligand 3,3′-BIPHEP (2a), 3,3′-BIPHEP
(2b), and
ONap
3,3′-BIPHEP
(2c). The ligands were obtained as mixtures
of the (R ,S,S)- and (S ,S,S)-diastereomers with an equilib-
for (S ,S,S)-2a one phenyl group of each PPh2 group is
ax
ax
ax
rium ratio of 61:39 in all cases as a result of central-to-axial
chirality transfer. It is astonishing that the equilibrium dias-
tereomeric ratio is insignificantly influenced by steric ef-
fects of the auxiliary.
aligned with the opposite phenyl group of the biphenyl
core, a significant alignment of aromatic moieties in
(R ,S,S)-2a was not found in a similar manner. Another in-
ax
teresting difference between the molecular structures is
the different biphenyl torsion angle between the PPh2
groups. Whereas these angles were –90.7° and –98.7° for
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

D
Synthesis
M. Siebert et al.
Paper
A
(Sax)-1
(
SaxSS)-2a–c
(SaxSS)-3a–c
Aux =
BF4
Ir
+
Ir
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
HO
P
P
OH
OH
Aux
O
O
P
P
O
O
Aux
Aux
O
O
P
P
P
O
Aux
a
Aux-Cl
[Ir(COD)2]BF4
b
c
P
P
Aux
P
P
Aux
Aux
P
O
Aux
O
HO
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
BF4
(
Rax)-1
(RaxSS)-2a–c
(RaxSS)-3a–c
B
C
D
O18
O17
O17
O18
P1
O17
O48
O47
P2
O18
Ir1
P2
P2
P1
P1
(
SaxSS)-3a
O57
O57
O58
O58
(
RaxSS)-2a
(SaxSS)-2a
Figure 4 Synthetic overview of the modification and subsequent complexation of the BIPHEP ligand as well as molecular structures of a pair of diaste-
reomeric ligands and the resulting complex of one of these ligands. (A) Modification of the BIPHEP core with auxiliaries and complexation of an iridium
precursor. (B) Molecular structure of (R ,S,S)-2a. (C) Molecular structure of (S ,S,S)-2a. (D) Molecular structure of (S ,S,S)-3a. For (B)+(C) only one of
ax
ax
ax
two obtained crystallographically independent molecules is depicted. For (B)+(C)+(D) ellipsoids are shown at the 50% probability level. Hydrogen at-
oms, solvent molecules, and the counter-ion are omitted for clarity.
the two crystallographically independent molecules of
R ,S,S)-2a, respectively, the angles for (S ,S,S)-2a were sig-
[Ir(COD) ]BF . Complexation was achieved at –15 °C to re-
2 4
tain the equilibrium ratio of the ligands. Astonishingly, the
(
ax
ax
nificantly smaller with 78.9° and 80.2°, respectively.
diastereomeric ratio between (R ,S,S) and (S ,S,S) of the
ax
ax
The epimerization kinetics of 2a were then investigated.
Both diastereomers were separated and the epimerization
process was followed by NMR spectroscopy for the isolated
diastereomers (R ,S,S)-2a and (S ,S,S)-2a in CDCl at 70 °C
complexes differed from the expected ratio with 54:46 dr
for 3a, 55:45 dr for 3b, and 59:41 dr for 3c. During the com-
ax
ax
3
(
Figure 5). The resulting reaction constants and the respec-
= 2.39 × 10–4
s
–1
tive epimerization barriers were k
and ΔG
and ΔG
RaxSS→SaxSS
‡
–1
–4 –1
= 108.2 kJ mol , and k
= 3.74 × 10
s
3
43 K
SaxSS→RaxSS
‡
–1
= 107.0 kJ mol . In comparison to our results
3
43 K
ONap
on the epimerization kinetics of 3,3′-BIPHEP
(2c), which
had higher epimerization barriers and consequently
showed lower epimerization rates, the present results in-
5
0:50 er
2
dicate that the smaller aryl moiety of the chiral auxiliaries
OPh
in 3,3′-BIPHEP
(2a) has a considerable impact on the ki-
netics of the epimerization process. It is noteworthy that
steric effects of the auxiliary do not seem to influence the
relative thermodynamic stability of the ligands. The equi-
librium ratio of the two diastereomers (R ,S,S) and (S ,S,S)
ax
ax
was observed to be 61:39 in both cases.
To investigate the catalytic properties of the tropos li-
gands 2a–c, we prepared the respective iridium(I) complex-
OPh/OIbu/ONap
es 3,3′-BIPHEP
Ir(I) 3a–c (Figure 4A). The com-
Figure 5 The epimerization process of the isolated diastereomers
1
(
R ,S,S)-2a and (S ,S,S)-2a in CDCl was followed by H NMR spectros-
plexes 3a–c were obtained by using equilibrated mixtures
of the ligands 2a–c and the iridium(I) precursor
ax
ax
3
copy at a constant temperature of 70 °C
©
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E
Synthesis
M. Siebert et al.
Paper
plexation, epimerization is apparently facilitated through a
mechanism that has not yet been elucidated, leading to
small deviations from the equilibrium ratio 61:39 of the li-
gands. The assignment of the diastereomers was realized by
complexation of a small sample of diastereomerically pure
was followed over time. After 12.5 days, the diastereomeric
ratio between (R ,S,S) and (S ,S,S) was 11:89 dr for 3a,
ax
ax
10:90 dr for 3b and 11:89 dr for 3c.
We studied the asymmetric hydrogenation of the
prochiral α-substituted acrylic acid 4 to naproxen 5 using
catalysts 3a–c before and after warming in solution for 12.5
days (Figure 7, Table 1). The catalytic reactions were per-
formed at room temperature under an initial hydrogen
pressure of 5 bar utilizing high-pressure tube autoclaves.
The catalysts 3a–c were used with diastereomeric ratios
derived at the two conditions noted above. The conversion
of the substrate was measured by 1H NMR spectroscopy,
whereas the absolute configuration and the enantiomeric
ratio of the hydrogenation products were determined by
enantioselective HPLC analysis. Screening of the catalytic
conditions revealed the necessity for a base (namely DIPEA)
to deprotonate the acrylic acid. The high epimerization bar-
riers of the tropos ligands 2a–c ensured reduced degrada-
tion of enantioselectivity based on ligand epimerization
during the course of catalysis.
(
S ,S,S)-2a with [Ir(COD) ]BF . The absolute configuration
ax 2 4
of the resulting iridium complex (S ,S,S)-3a with retained
ax
stereoinformation was determined by X-ray diffraction
9
crystallography (Figure 4D). In the solid state, the complex
adopts a C -symmetric conformer, which is, inter alia, illus-
1
trated by the different Ir-P distances: dIr–P1 = 2.309(2) Å and
dIr–P2 = 2.385(2) Å. The biphenyl torsion angle between the
PPh groups of 66.3° is significantly smaller than the afore-
2
mentioned torsion angles for the two crystallographically
independent molecules of (S ,S,S)-2a (78.9° and 80.2°, re-
ax
spectively). In analogy to the molecular structure of the
free ligand (S ,S,S)-2a, the ligand shows a significant align-
ax
ment of aromatic moieties in the molecular structure of the
complex. Again, one phenyl group of each PPh2 group is
aligned with the opposite phenyl group of the biphenyl
core.
Considering the very strong coordination of diphos-
phine ligands to iridium, we were pleased to find that heat-
ing the dissolved diastereomeric complex mixture 3b led to
a shift and finally to an inversion of the diastereomeric ratio
OH 5 mol% 3a–c
OH
Ar
Ar
*
Ar =
O
O
DIPEA
O
5
atm H2
DCM
4
5
based on the dominating epimerization of the (R ,S,S) to
ax
Figure 7 Asymmetric hydrogenation of a prochiral α-substituted
the (S ,S,S) complex species. Screening of various solvents
and temperatures revealed CDCl3 and a temperature of
acrylic acid utilizing the diastereomeric complex mixtures 3a–c upon
complexation and upon epimerization after 12.5 days
ax
6
0 °C to be the combination of choice for the epimerization
conditions to enrich the previously minor complex species
Sax,S,S) (Figure 6). Heating the complex mixture of 3b for
several days yielded (R ,S,S)-3b and (S ,S,S)-3b with a dias-
Table 1 Asymmetric Hydrogenation of Prochiral α-Substituted Acrylic
Acid 4 Utilizing the Diastereomeric Complex Mixtures 3a–c Upon Com-
(
ax
ax
a,b
plexation and Upon Epimerization after 12.5 Days
tereomeric ratio of 8:92. Subsequently, an aliquot of all
three diastereomeric complex mixtures 3a–c was heated in
Catalyst
Catalyst dr (Rax,S,S/Sax,S,S)
Product er (R/S)
CDCl to 60 °C for several days and the diastereomeric ratio
3
3
a
b
c
54:46
56:44
41:59
53:47
38:62
58:42
41:59
1
1:89
55:45
0:90
59:41
1:89
3
1
3
1
CDCl3
a
C D6
The reactions were performed using Ir(I) complex (5 mol%), DIPEA (1.0
6
equiv) as base, anhydrous, degassed DCM as solvent and 5 bar hydrogen
pressure.
All data are the average of two runs.
C D Cl
4
2
2
b
5
0:50 dr
First, we investigated hydrogenations with the catalysts
with the initial diastereomeric ratios obtained after com-
plexation. The product enantiomers (R)-5 and (S)-5 were
obtained with 56:44 er (3a), 53:47 er (3b) and 58:42 er
(
3c); thus, the (R)-enantiomer was formed in excess. Inter-
Figure 6 The epimerization process of the dissolved diastereomeric
complex mixture 3b in CDCl (black triangles), C D (red dots) and
3
6
6
estingly, the complexes 3a and 3c, with chiral auxiliaries
that have mainly a rigid aryl moiety, gave a slightly higher
percentage of the (R)-enantiomer than complex 3b, with
31
1
C D Cl (blue triangles) was followed by P{ H} NMR spectroscopy at a
2
2
4
constant temperature of 60 °C
©
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F
Synthesis
M. Siebert et al.
Paper
the additional conformationally flexible isobutyl group in
the backbone of the auxiliary. By using the catalysts that
were warmed in solution prior to catalysis, we were able to
obtain the opposite product enantiomer of 5 in excess and
observed enantiomeric ratios of 41:59 er (R/S) (3a),
were purchased from manufacturing and trading companies (Abcr
GmbH, Acros Organics b.v.b.a., Sigma–Aldrich Co. LLC., Strem Chemi-
cals Inc. and TCI Europe N.V.) and stored according to the respective
instructions. Isolated compounds were stored under argon and, if
needed, at 5 or –20 °C.
NMR spectra were recorded with Bruker Avance III spectrometers
38:62 er (3b), and 41:59 er (3c), all in favor of the (S)-enan-
(300, 400, 500 and 600) or with a Bruker Avance DRX 300 spectrome-
tiomer. Comparing these results, the temperature-
controlled bidirectional enantioselectivity is apparent even
though the enantiomeric ratios are not particularly high.
The absolute change in enantiomeric excess was Δee = 30%
for the catalysts 3a and 3b and Δee = 34% for catalyst 3c.
In summary, the influence of chiral α-substituted car-
boxylic acid auxiliaries on the central-to-axial chirality
transfer to the stereochemically flexible chiral axes of
BIPHEP cores was elucidated by showing that the equilibri-
um diastereomeric ratio is insignificantly influenced by ste-
ric effects which, in turn, strongly influence the rate of epi-
merization. We investigated the complexation of novel
BIPHEP ligands to iridium and studied the stereodynamic
properties of both the ligands and the resulting complexes.
The iridium(I) complexes upon complexation and after in-
ducing a shift of the diastereomeric ratio by warming in
solution, were used for asymmetric hydrogenation of a
prochiral α-substituted acrylic acid. By using the same cata-
lyst in both cases, (R)-naproxen as well as (S)-naproxen (af-
ter re-equilibration of the catalyst at elevated tempera-
tures) was obtained in excess. This synthetic procedure of-
fers an elegant way to synthesize both enantiomers of α-
substituted propionic acids, which include several pharma-
ceutically relevant compounds, for instance the anti-
inflammatory drugs ibuprofen and naproxen.
ter. NMR spectra of air- and moisture-sensitive compounds were
measured with J. Young NMR tubes. The solvent residual signals were
used as internal standards. Chemical shifts are given in ppm relative
to TMS. The different multiplicities are defined as s (singlet), d (dou-
blet), t (triplet), q (quartet) and m (multiplet) or by combinations of
these. In a few cases, the peak shape is specified by br (broad) in addi-
13
tion to the description of the multiplicity. The assignments in C and
3
1
P NMR spectra refer to proton-decoupled experiments. The assign-
ment of all signals was realized by two-dimensional NMR spectrosco-
1
1
1
13
1
13
py ( H- H-COSY, H- C-HSQC-ME and H- C-HMBC experiments)
13
and, if appropriate, supported by C-DEPT-135 NMR experiments or
31
P decoupling.
Mass spectrometric measurements were performed with a JEOL JMS-
700 magnetic sector (EI, FAB, LIFDI), a JEOL AccuTOF GCx time-of-
flight (EI) and a Bruker ApexQe Hybrid 9.4 T FT-ICR (ESI). If isotopic
patterns are pronounced, the most intense peak is indicated. In the
case of EI and LIFDI analyses, fragments are given in ascending order
with regard to their m/zvalue. Regarding ESI and FAB analyses, the
most abundant peak or the peak referring to the molecular ion is giv-
en in comparison to the calculated m/zvalue. Molecular ions are ab-
breviated as M.
IR spectra were recorded with a Thermo Scientific Nicolet 700 ATR-
FT-IR spectrometer using the purified products without further mod-
ification. The background transmission was measured before the
sample measurement and subtracted.
X-ray crystallographic analyses were performed with a Bruker APEX
or a Bruker APEX-II Quazar diffractometer equipped with a CCD area
detector. The data sets were recorded at 200(2) K using Mo Kα
Concluding, we were able to control the enantioselec-
tivity of stereochemically flexible iridium(I) catalysts solely
by changing the temperature, thereby successfully expand-
ing the concept of temperature-controlled bidirectional en-
antioselectivity to iridium(I) catalysts and broadening the
spectrum of catalytic transformations. The described con-
cept does not seem to be limited to certain transition met-
als; therefore, it can be envisioned that the underlying prin-
ciple is transferable to a variety of other metals and differ-
ent types of enantioselective transformations.
(
λ = 0.71073Å) radiation. Intensities were corrected for Lorentz and
polarization effects. Empirical absorption corrections were applied
using SADABS based on the respective Laue symmetry of the recip-
rocal space. The structures were refined against F with a full-matrix
least-squares algorithm using the SHELXL-2014/7 software. Hydro-
gen atoms were treated using appropriate riding models. The graphi-
cal visualization of the crystal structures was performed by using OR-
10
2
11
12
TEP-3.
HPLC measurements were carried out with an Agilent Technologies
200 HPLC system equipped with a binary solvent pump, an au-
1
tosampling unit, a membrane solvent degasser, a DAD detector and a
quadrupole mass spectrometer Agilent 6120 using an APCI or ESI
source, respectively. The performed separations were controlled with
Agilent ChemStation software. All HPLC solvents were obtained from
Sigma–Aldrich Co. LLC. in HPLC-grade quality. Monitoring of reactions
was, inter alia, realized with an UPLC-MS system (Waters Acquity
SQD2). Preparative purification by flash column chromatography was
performed using silica gel (technical grade, pore size: 60Å, particle
size: 63–200 μm, 70–230 mesh) or aluminum oxide (activated, neu-
tral, Brockmann Acitivity I). Thin-layer chromatography was per-
formed using pre-coated polyester sheets (0.2 mm silica gel or alumi-
num oxide with fluorescent indicator).
A detailed description of all experiments and the assignment for 1H
13
and C NMR spectra can be found in the Supporting Information. Air-
and moisture-sensitive syntheses were carried out within an argon
atmosphere (Ar 5.0) under exclusion of air and moisture. The argon
was used without further purification. All glassware was flame-dried
prior to use and standard Schlenk techniques were applied. Reactions
at NMR scale were performed in J. Young NMR tubes. Solvents (ACN,
DCM, Et O, THF and toluene) were dried with a MB SPS-800 system
2
and stored under argon. Other anhydrous solvents were bought and
directly used or stored under exclusion of air and moisture. Degassing
was accomplished by at least three freeze-pump-thaw cycles. The an-
hydrous and degassed solvents were stored under argon over molecu-
lar sieve (3Å or 4Å, respectively). All other solvents and chemicals
The ligand core 2,2′-bis(diphenylphosphino)-[1,1′-biphenyl]-3,3′-diol
OH
(3,3′-BIPHEP , 1) was synthesized in a six-step reaction starting with
3,4
3
-bromophenol and diphenylphosphinic chloride. The acid chlo-
rides (S)-2-phenylpropanoyl chloride and (S)-2-(4-isobutylphe-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

G
Synthesis
M. Siebert et al.
Paper
1
H NMR (CDCl , 600 MHz): δ = 0.88 (B, d, 3J
20
nyl)propanoyl chloride were synthesized by adding oxalyl chloride to
the respective carboxylic acids. The acid chloride (S)-2-(6-me-
thoxynaphthalen-2-yl)propanoyl chloride was purchased from
Sigma–Aldrich (>97.0% purity).
= 6.7 Hz, 12 H, H ),
3
H–H
3
3
20
13
0.90 (A, d, J
1.05 (B, d, J
= 6.7 Hz, 12 H, H ), 1.04 (A, d, J
= 7.1 Hz, 6 H, H ),
H–H
H–H
3
13
19
= 7.1 Hz, 6 H, H ), 1.77–1.89 (A+B, m, H ), 2.41 (B, d,
H–H
3
18
3
18
JH–H = 7.2 Hz, 4 H, H ), 2.44 (A, d, J
= 7.2 Hz, 4 H, H ), 2.65 (A, q,
= 7.1 Hz, 2 H, H ), 6.69 (A, m,
H, H ), 6.84–6.87 (B, m, 6 H, H ), 6.96 (A, m, 4 H, H ), 6.98–7.03
H–H
3J
= 7.1 Hz, 2 H, H ), 2.75 (B, q, J
12
3
12
H–H
H–H
2
4,15
15
2
2,2′-Bis(diphenylphosphino)-1,1′-biphenyl-3,3′-diyl (2S,2′S)-Bis-
4
2,16
16
(A, m, 2 H, H + B, m, 6 H, H ), 7.05 (A, m, 4 H, H ), 7.09–7.32 (A+B,
(2-phenylpropanoate) (2a)
3,8,9,10
10
8
m, H
), 7.36 (A, m, 2 H, H ), 7.50 (A, m, 4 H, H ).
Compound 1 (500 mg, 902 ꢀmol, 1.00 equiv) was dissolved in anhy-
13
, 151 MHz): δ = 17.4 (B, 2C, C ), 17.8 (A, 2C, C13), 22.5
13
drous, degassed DCM (8 mL) and freshly powdered K CO3 (2.49 g,
C NMR (CDCl
3
2
20
20
19
19
1
8.0 mmol, 20.0 equiv) was added. Subsequently, a freshly degassed
solution of (S)-2-phenylpropanoyl chloride (1.14 g, 6.76 mmol,
.50 equiv) in anhydrous, degassed DCM (12 mL) was added drop-
(B, 4C, C ), 22.6 (A, 4C, C ), 30.3 (B, 2C, C ), 30.3 (A, 2C, C ), 44.0 (A,
2C, C ), 44.0 (B, 2C, C ), 45.2 (B, 2C, C ), 45.2 (A, 2C, C ), 122.6 (A,
2C, C ), 122.9 (B, 2C, C ), 126.4 (B, m, 2C, C ), 126.8 (A, m, 2C, C ), 126.9
(A, 2C, C ), 127.3 (B, 4C, C ), 127.4 (A, 4C, C ), 127.5 (B, 2C, C ),
127.9 (A, m, 2C, C ), 127.9 (B, 2C, C ), 128.0 (B, m, 4C, C ), 128.3 (A, m,
4C, C ), 128.4 (B, m, 2C, C ), 128.5 (A, m, 4C, C ), 128.5 (B, m, 4C, C ),
128.8 (A, 2C, C ), 129.4 (B, 4C, C ), 129.5 (A, 4C, C ), 129.6 (A, 2C, C ),
130.0 (B, 2C, C ), 130.4 (A, m, 4C, C ), 132.0 (B, m, 4C, C ), 132.1 (B, m,
4C, C ), 134.5 (A, m, 4C, C ), 135.1 (A, m, 2C, C ), 136.4 (B, m, 2C, C ),
1
2
(B, m, 2C, C ), 153.3 (A, m, 2C, C ), 153.8 (B, m, 2C, C ), 171.9 (A, 2C,
C
31P NMR (CDCl
12
12
18
18
4
4
6
6
7
10
15
15
10
wise. The reaction mixture was stirred for an additional 64 h. The
crude product was concentrated in vacuo and purified by flash col-
umn chromatography (Al O , DCM, R = 0.90 (DCM)). Compound 2a
2
10
9
9
2
9
9
2
3
f
10
16
16
3
was isolated as a colorless microcrystalline solid (767 μmol, 85%). The
product was obtained as a mixture of two diastereomers featuring
two signal patterns - A: major isomer, B: minor isomer.
3
8
8
8
8
7
7
7
14
14
36.6 (B, m, 2C, C ), 136.9 (B, 2C, C ), 137.5 (A, 2C, C ), 139.2 (A, m,
C, C ), 140.6 (A, 2C, C ), 140.7 (B, 2C, C ), 151.4 (A, m, 2C, C ), 151.7
IR (neat): 3056, 3027, 2977, 2933, 1750, 1584, 1557, 1479, 1433,
7
17
17
5
1
8
1
377, 1325, 1259, 1217, 1194, 1130, 1110, 1091, 1058, 1027, 908,
5
1
1
–1
72, 832, 795, 770, 743, 693 cm
.
11
11
), 172.4 (B, 2C, C ).
3
= 7.1 Hz, 6 H, H13), 1.07
H NMR (CDCl , 600 MHz): δ = 1.06 (A, d, J
3
H–H
3
13
3
12
3
, 243 MHz): δ = –17.08 (B), –16.02 (A).
(B, d, J
= 7.1 Hz, 6 H, H ), 2.66 (A, q, J
= 7.1 Hz, 2 H, H ), 2.77
H–H
H–H
3
12
2
4
HRMS (FAB): m/z [M + H]+ calcd for C62 +: 931.4040; found:
931.4053.
(B, q, J
= 7.1 Hz, 2 H, H ), 6.67 (A, m, 2 H, H ), 6.85 (B, m, 2 H, H ),
H O P
61 4 2
H–H
15
4
2
6
.96 (B, m, 4 H, H ), 7.00 (A, m, 2 H, H ), 7.01 (B, m, 2 H, H ), 7.06 (A,
m, 4 H, H15), 7.09–7.33 (A+B, m, H
3,8,9,10,16,17
), 7.37 (A, m, 2 H, H ), 7.48
10
(
A, m, 4 H, H8).
2,2′-Bis(diphenylphosphino)-[1,1′-biphenyl]-3,3′-diyl (2S,2′S)-
Bis(2-(6-methoxynaphthalen-2-yl)propanoate) (2c)
4
1
3
C NMR (CDCl , 151 MHz): δ = 17.4 (B, 2C, C13), 17.8 (A, 2C, C13), 44.4
3
12
12
4
4
(A, 2C, C ), 44.4 (B, 2C, C ), 122.6 (A, 2C, C ), 122.8 (B, 2C, C ), 126.4
Compound 1 (225 mg, 406 μmol, 1.00 equiv) was dissolved in anhy-
drous, degassed DCM (5 mL) and freshly powdered K CO3 (1.12 g,
6
6
10
17
(B, m, 2C, C ), 126.8 (A, m, 2C, C ), 126.9 (A, 2C, C ), 127.2 (A, 2C, C ),
2
17
10
15
1
C
27.3 (B, 2C, C ), 127.5 (B, 2C, C ), 127.6 (B, 4C, C ), 127.7 (A, 4C,
8.11 mmol, 20.0 equiv) was added. Subsequently, (S)-2-(6-me-
thoxynaphthalen-2-yl)propanoyl chloride (505 mg, 2.03 mmol,
5.00 equiv) was added. The reaction mixture was stirred for an addi-
tional 64 h. The crude product was concentrated in vacuo and puri-
fied by flash column chromatography (Al O , DCM, R = 0.90 (DCM)).
Compound 2c was isolated as a colorless microcrystalline solid
(345 μmol, 85%). The product was obtained as a mixture of two dias-
tereomers featuring two signal patterns - A: major isomer, B: minor
isomer.
1
5
2
10
9
), 128.0 (A, m, 2C, C ), 128.0 (B, 2C, C ), 128.1 (B, m, 4C, C ), 128.3
9
2
9
(A, m, 4C, C ), 128.5 (B, m, 2C, C ), 128.5 (A, m, 4C, C ), 128.5 (B, m, 4C,
9
16
16
10
C ), 128.7 (B, 4C, C ), 128.8 (A, 4C, C ), 128.9 (A, 2C, C ), 129.6 (A, 2C,
C ), 130.0 (B, 2C, C ), 130.4 (A, m, 4C, C ), 132.0 (B, m, 4C, C ), 132.1 (B,
m, 4C, C ), 134.5 (A, m, 4C, C ), 135.1 (A, m, 2C, C ), 136.4 (B, m, 2C,
C ), 136.6 (B, m, 2C, C ), 139.3 (A, m, 2C, C ), 139.8 (B, 2C, C ), 140.3
3
3
8
8
2
3
f
8
8
7
7
7
7
14
14
5
5
(A, 2C, C ), 151.4 (A, m, 2C, C ), 151.6 (B, m, 2C, C ), 153.2 (A, m, 2C,
1
1
11
11
C ), 153.7 (B, m, 2C, C ), 171.7 (A, 2C, C ), 172.3 (B, 2C, C ).
3
1
P NMR (CDCl , 243 MHz): δ = –17.08 (B), –16.00 (A).
IR (neat): 3052, 2962, 2935, 2840, 1751, 1633, 1605, 1583, 1558,
1506, 1480, 1462, 1433, 1391, 1375, 1323, 1261, 1215, 1127, 1066,
3
HRMS (FAB): m/z [M + H]+ calcd for C54H45O4P2+: 819.2788; found:
8
–1
1026, 926, 883, 849, 789, 741, 693 cm .
19.2760.
1
3
= 7.1 Hz, 6 H, H13), 1.13
H NMR (CDCl , 600 MHz): δ = 1.12 (A, d, J
3
H–H
3
13
3
12
(B, d, J
= 7.1 Hz, 6 H, H ), 2.79 (A, q, J
= 7.1 Hz, 2 H, H ), 2.90
2
,2′-Bis(diphenylphosphino)-[1,1′-biphenyl]-3,3′-diyl (2S,2′S)-
H–H
H–H
3
12
24
24
(B, q, J
= 7.1 Hz, 2 H, H ), 3.89 (B, s, 6 H, H ), 3.90 (A, s, 6 H, H ),
Bis(2-(4-isobutylphenyl)propanoate) (2b)
H–H
2
4
4
6
.63 (A, m, 2 H, H ), 6.82 (B, m, 2 H, H ), 6.97 (A, m, 2 H, H ), 7.00 (B,
Compound 1 (225 mg, 406 μmol, 1.00 equiv) was dissolved in anhy-
drous, degassed DCM (2 mL) and freshly powdered K CO (1.12 g,
2
3,8,9,10,15,18,20,23
15
m, 2 H, H ), 7.04–7.33 (A+B, m, H
), 7.40 (A, br s, 2 H, H ),
2
3
8
3
22
3
7
8
8
.45 (A, m, 4 H, H ), 7.59 (B, d, J
= 8.6 Hz, 2 H, H ), 7.61 (B, d, J
= 8.6 Hz, 2 H, H ), 7.65 (A, d, J
=
=
H–H
H–H
8
.11 mmol, 20.0 equiv) was added. Subsequently, a freshly degassed
solution of (S)-2-(4 isobutylphenyl)propanoyl chloride (684 mg,
.04 mmol, 7.50 equiv) in anhydrous, degassed DCM (3 mL) was add-
17
3
22
3
.9 Hz, 2 H, H ), 7.64 (A, d, J
H–H
H–H
.9 Hz, 2 H, H17).
3
1
3
, 151 MHz): δ = 17.3 (B, 2C, C ), 17.7 (A, 2C, C13), 44.3
13
ed dropwise. The reaction mixture was stirred for an additional 64 h.
The crude product was concentrated in vacuo and purified by flash
column chromatography (Al O , DCM, R = 0.90 (DCM)). Compound 2b
was isolated as a colorless microcrystalline solid (349 μmol, 86%). The
product was obtained as a mixture of two diastereomers featuring
two signal patterns - A: major isomer, B: minor isomer.
C NMR (CDCl
3
(A, 2C, C12), 44.3 (B, 2C, C ), 55.4 (B, 2C, C ), 55.5 (A, 2C, C ), 105.6 (B,
2C, C ), 105.7 (A, 2C, C ), 119.0 (B, 2C, C ), 119.1 (A, 2C, C ), 122.6
(A, 2C, C ), 122.8 (B, 2C, C ), 126.2 (B, 2C, C ), 126.2 (A, 2C, C ), 126.3
(B, 2C, C ), 126.4 (A, 2C, C ), 126.4 (B, m, 2C, C ), 126.7 (A, m, 2C, C ),
126.9 (A, 2C, C ), 127.2 (B, 2C, C ), 127.3 (A, 2C, C ), 127.5 (B, 2C,
C
12
24
24
20
20
18
18
2
3
f
4
4
23
23
15
15
6
6
10
22
22
1
0
10
2
9
), 127.9 (B, 2C, C ), 127.9 (A, m, 2C, C ), 128.0 (B, m, 4C, C ), 128.3
IR (neat): 3052, 2954, 2926, 2867, 1753, 1584, 1558, 1512, 1480,
1
9
9
9
2
(A, m, 4C, C ), 128.4 (B, m, 4C, C ), 128.4 (B, m, 2C, C ), 128.5 (A, m, 4C,
464, 1433, 1375, 1366, 1330, 1218, 1196, 1176, 1127, 1063, 1021,
98, 906, 884, 869, 847, 789, 740, 693 cm
9
10
21
21
–1
C ), 128.8 (A, 2C, C ), 128.9 (B, 2C, C ), 129.1 (A, 2C, C ), 129.4 (B, 2C,
C
.
1
7
17
3
3
), 129.4 (A, 2C, C ), 129.6 (A, 2C, C ), 130.0 (B, 2C, C ), 130.4 (A, m,
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

H
Synthesis
M. Siebert et al.
Paper
C, C ), 132.0 (B, m, 4C, C ), 132.1 (B, m, 4C, C ), 133.8 (B, 2C, C16),
8
8
8
Iridium(I) Complex of Ligand 2b with BF4– Counterion (3b)
4
1
2
1
16
8
14
33.8 (A, 2C, C ), 134.4 (A, m, 4C, C ), 134.9 (B, 2C, C ), 135.0 (A, m,
Compound 2b(52.1 mg, 56.0 μmol, 1.00 equiv) was dissolved in anhy-
drous, degassed DCM (2 mL). The solution was cooled to –15 °C and
7
14
7
7
C, C ), 135.4 (A, 2C, C ), 136.3 (B, m, 2C, C ), 136.7 (B, m, 2C, C ),
7
5
5
39.4 (A, m, 2C, C ), 151.4 (A, m, 2C, C ), 151.7 (B, m, 2C, C ), 153.3 (A,
m, 2C, C ), 153.7 (B, m, 2C, C ), 157.7 (B, 2C, C ), 157.8 (A, 2C, C ),
71.8 (A, 2C, C ), 172.3 (B, 2C, C ).
[
Ir(COD) ]BF (27.7 mg, 56.0 μmol, 1.00 equiv) was added. The reac-
2 4
1
1
19
19
tion mixture was stirred at –15 °C for an additional 18 h. The reaction
mixture was warmed to r.t. and stirred for an additional 1 h. The
crude product was concentrated in vacuo to approximately 0.5 mL
and precipitation of the complex was induced by addition of anhy-
drous, degassed n-pentane (3 mL). The supernatant solution was sep-
arated by using a filter cannula. The washing procedure was repeated
two more times. The resulting red solid was dried in vacuo for 16 h.
Compound 3bwas isolated as a red solid (43.7 μmol, 78%). The com-
plex was obtained as a mixture of two diastereomers featuring two
signal patterns - A: major isomer, B: minor isomer.
11
11
1
31
P NMR (CDCl , 243 MHz): δ = –17.12 (B), –16.01 (A).
HRMS (FAB): m/z [M + H]+ calcd for C64H53O6P2+: 979.3312; found:
79.3292.
3
9
Iridium(I) Complex of Ligand 2a with BF – Counterion (3a)
4
Compound 2a(49.1 mg, 60.0 μmol, 1.00 equiv) was dissolved in anhy-
drous, degassed DCM (2 mL). The solution was cooled to –15 °C and
Ir(COD) ]BF (29.7 mg, 60.0 μmol, 1.00 equiv) was added. The reac-
[
2 4
IR (neat): 3054, 2951, 2923, 2868, 1756, 1586, 1564, 1511, 1479,
tion mixture was stirred at –15 °C for an additional 18 h. The reaction
mixture was warmed to r.t. and stirred for an additional 1 h. The
crude product was concentrated in vacuo to approximately 0.5 mL
and precipitation of the complex was induced by addition of anhy-
drous, degassed n-pentane (3 mL). The supernatant solution was sep-
arated by using a filter cannula. The washing procedure was repeated
two more times. The resulting red solid was dried in vacuo for 16 h.
Compound 3awas isolated as a red solid (45.6 μmol, 76%). The com-
plex was obtained as a mixture of two diastereomers featuring two
signal patterns - A: major isomer, B: minor isomer.
1
9
1
464, 1436, 1381, 1331, 1315, 1224, 1180, 1107, 1086, 1048, 997,
–1
11, 868, 784, 724, 693 cm
.
H NMR (CDCl , 600 MHz): δ = 0.87–0.90 (A+B, m, H20), 0.97 (B, d, 3J
3
H–
13
3
13
=
7.1 Hz, 6 H, H ), 1.44 (A, d, J
= 7.1 Hz, 6 H, H ), 1.62 (B, m, 2 H,
H
H–H
2
2
2
1
3/24
), 1.65 (A, m, 2 H, H23/24), 1.78–1.89 (A+B, m, H ), 1.80 (B, m, 2 H,
19
H
3/24
3/24
8
23/24
23/24
3
H
H
H
), 1.86 (A, m, 2 H, H
), 2.17 (B, m, 2 H, H
), 2.35 (B, m, 2 H,
= 7.2 Hz, 4 H,
3
18
), 2.42 (A, d, J
= 7.2 Hz, 4 H, H ), 2.47 (B, d, J
H–H
H–H
23/24
23/24
), 2.83 (A, q, 3J
), 2.47 (A, m, 2 H, H
), 2.57 (A, m, 2 H, H
=
H–H
.1 Hz, 2 H, H 2), 2.84 (B, q, JH–H = 7.1 Hz, 2 H, H ), 3.77 (A, m, 2 H,
1
3
12
7
2
1/22
21/22
21/22
H
H
), 4.28 (B, m, 2 H, H
), 5.07 (B, m, 2 H, H
), 5.36 (A, m, 2 H,
IR (neat): 3060, 2977, 2922, 2879, 2836, 1752, 1585, 1564, 1479,
21/22
4
2
4
), 6.20 (A, m, 2 H, H ), 6.30 (B, m, 2 H, H ), 6.39 (B, m, 2 H, H ),
1
7
1
435, 1376, 1314, 1224, 1181, 1107, 1089, 1049, 995, 909, 868, 787,
2
15
3
6.57 (A, m, 2 H, H ), 6.87 (A, m, 4 H, H ), 6.94 (A, m, 2 H, H ), 6.98 (B,
–1
23, 694 cm
.
3
16
9,10,15
m, 2 H, H ), 7.04 (A, m, 4 H, H ), 7.06–7.11 (B, m, 10 H, H
(B, m, 4 H, H ), 7.19–7.26 (A, m, 6 H, H ), 7.34–7.44 (A, m, 10 H,
), 7.14
3
= 7.1 Hz, 6 H, H13), 1.47
H–H
H NMR (CDCl , 600 MHz): δ = 0.99 (B, d, J
16
9,10
3
3
= 7.1 Hz, 6 H, H ), 1.64 (B, m, 2 H, H20/21), 1.67 (A, m, 2 H,
13
(A, d, J
8,9,10
+ B, m, 6 H, H8,10), 7.46–7.53 (A, m, 4 H, H + B, m, 4 H, H ), 7.58
8
9
H–H
H
2
2
2
1
1
0/21
0/21
0/21
2
20/21
20/21
20/21
20/21
3
H
H
H
H
H
), 1.82 (B, m, 2 H, H
), 2.36 (B, m, 2 H, H
), 2.85 (B, q, J
), 3.79 (A, m, 2 H, H
), 1.87 (A, m, 2 H, H
), 2.49 (A, m, 2 H, H
= 7.1 Hz, 2 H, H ), 2.86 (A, q, J
), 2.18 (B, m, 2 H,
), 2.59 (A, m, 2 H,
B, m, 4 H, H8).
(
13
C NMR (CDCl , 151 MHz): δ = 18.2 (B, 2C, C ), 18.9 (A, 2C, C13), 22.4–
13
3
12
3
= 7.1 Hz, 2 H,
H–H
H–H
20
23/24
), 29.0 (B, 2C, C23/24), 30.2 (A, 2C,
), 35.1 (A, 2C, C
2
C
C
C
1
2.5 (A+B, m, C ), 27.2 (A, 2C, C
18/19
18/19
), 4.32 (B, m, 2 H, H
), 6.22 (A, m, 2 H, H ), 6.33 (B, m, 2 H, H ),
), 5.04 (B, m, 2 H,
1
1
2
9
19
23/24
23/24
), 30.3 (B, 2C, C ), 32.8 (B, 2C, C
), 44.7 (B, 2C,
8/19
18/19
4
2
), 5.38 (A, m, 2 H, H
2
12
18
18
), 44.8 (A, 2C, C ), 45.0 (B, 2C, C ), 45.1 (A, 2C, C ), 85.8 (B, m, 2C,
4
2
3
6.41 (B, m, 2 H, H ), 6.62 (A, m, 2 H, H ), 6.96 (A, m, 2 H, H ), 6.98 (A,
1/22
21/22
21/22
21/22
), 87.2 (A, b, 2C, C
), 88.3 (A, b, 2C, C
), 90.0 (B, b, 2C, C
),
15
3
9,10
m, 4 H, H ), 7.01 (B, m, 2 H, H ), 7.07–7.14 (B, m, 6 H, H ), 7.19–7.33
6
6
2
21.5 (A, m, 2C, C ), 122.1 (B, m, 2C, C ), 123.1 (A, 2C, C ), 123.4 (B, 2C,
9
,10,16,17
15,17
8,9,10
(A, m, 12 H, H
+ B, m, 6 H, H
), 7.37–7.46 (A, m, 10 H, H
+
2
15
15
9
C ), 127.2 (B, 4C, C ), 127.4 (A, 4C, C ), 128.8 (A, m, 4C, C ), 128.9 (B,
m, 4C, C ), 129.0 (B, m, 4C, C ), 129.3 (A, m, 4C, C ), 129.5 (A, 4C, C ),
8
,10,16
8
9
B, m, 10 H, H
4
), 7.48–7.53 (A, m, 4 H, H + B, m, 4 H, H ), 7.60 (B, m,
9
9
9
16
8
H, H ).
16
7
10
129.8 (B, 4C, C ), 130.2 (B, m, 2C, C ), 130.6 (B, 2C, C ), 130.7 (A, m,
1
3
C NMR (CDCl , 151 MHz): δ = 18.3 (B, 2C, C ), 19.0 (A, 2C, C13), 27.2
13
7
10
10
10
3
2C, C ), 130.8 (A, 2C, C ), 130.9 (B, 2C, C ), 131.0 (A, 2C, C ), 131.1 (B,
m, 2C, C ), 131.2 (A, m, 2C, C ), 132.4 (B, 2C, C ), 132.5 (A, m, 2C, C ),
20/21
20/21
20/21
20/21
(A, 2C, C
), 29.2 (B, 2C, C
), 32.6 (B, 2C, C
), 35.0 (A, 2C, C
),
4
4
3
7
12
12
18/19
4
C
1
C
4
1
C
2
1
5.0 (B, 2C, C ), 45.1 (A, 2C, C ), 85.6 (B, m, 2C, C
), 87.2 (A, b, 2C,
8
3
7
1
4
1
32.5 (A, m, 4C, C ), 132.5 (A, 2C, C ), 133.0 (B, m, 2C, C ), 133.0 (B, br,
C, C ), 135.1 (B, m, 4C, C ), 135.6 (A, m, 4C, C ), 136.1 (A, 2C, C ),
36.4 (B, 2C, C ), 141.1 (A, 2C, C ), 141.2 (B, 2C, C ), 144.1 (B, m, 2C,
1
8/19
18/19
18/19
6
), 88.3 (A, b, 2C, C
), 90.2 (B, b, 2C, C
), 121.5 (A, m, 2C, C ),
8
8
8
14
6
2
2
22.1 (B, m, 2C, C ), 123.2 (A, 2C, C ), 123.4 (B, 2C, C ), 127.5 (B, 4C,
14
17
17
1
5
17
15
17
), 127.6 (A, 2C, C ), 127.6 (A, 4C, C ), 127.8 (B, 2C, C ), 128.9 (A,
5
5
1
1
C ), 144.1 (A, m, 2C, C ), 151.7 (B, 2C, C ), 151.9 (A, 2C, C ), 173.0 (B,
16
9
9
9
C, C ), 128.9 (A, m, 4C, C ), 128.9 (B, m, 4C, C ), 129.0 (B, m, 4C, C ),
11
11
2C, C ), 173.2 (A, 2C, C ).
16
9
7
29.2 (B, 4C, C ), 129.3 (A, m, 4C, C ), 130.2 (B, m, 2C, C ), 130.7 (B, 2C,
31
P NMR (CDCl , 243 MHz): δ = 10.83 (A), 12.19 (B).
1
0
7
10
10
3
), 130.7 (A, m, 2C, C ), 130.8 (A, 2C, C ), 130.9 (B, 2C, C ), 131.0 (A,
19
F NMR (CDCl , 283 MHz): δ = –153.71 (11B), –153.66 (10B).
10
4
4
7
C, C ), 131.1 (B, m, 2C, C ), 131.2 (A, m, 2C, C ), 132.4 (A, m, 2C, C ),
3
3
8
3
HRMS (ESI): m/z [M-BF4]+ calcd for C70H72193IrO4P2+: 1231.4530;
found: 1231.4547.
32.4 (B, 2C, C ), 132.4 (A, m, 4C, C ), 132.5 (A, 2C, C ), 132.9 (B, m, 2C,
7
8
8
8
C ), 133.0 (B, b, 4C, C ), 135.0 (B, m, 4C, C ), 135.6 (A, m, 4C, C ), 138.9
14
14
5
5
(A, 2C, C ), 139.1 (B, 2C, C ), 144.1 (B, m, 2C, C ), 144.1 (A, m, 2C, C ),
1
1
11
11
1
51.6 (B, 2C, C ), 151.7 (A, 2C, C ), 172.8 (B, 2C, C ), 173.0 (A, 2C, C ).
Iridium(I) Complex of Ligand 2c with BF4– Counterion (3c)
31
P NMR (CDCl , 243 MHz): δ = 10.78 (A), 12.28 (B).
3
Compound 2c(58.2 mg, 59.4 μmol, 1.00 equiv) was dissolved in anhy-
drous, degassed DCM (2 mL). The solution was cooled to –15 °C and
19
F NMR (CDCl , 283 MHz): δ = –153.68 (11B), –153.63 (10B).
3
HRMS (ESI): m/z [M-BF4]+ calcd for C62H56193IrO4P2+: 1119.3278;
found: 1119.3295.
[Ir(COD) ]BF (29.5 mg, 59.4 μmol, 1.00 equiv) was added. The reac-
2 4
tion mixture was stirred at –15 °C for an additional 18 h. The reaction
mixture was warmed to r.t. and stirred for an additional 1 h. The
crude product was concentrated in vacuo to approximately 0.5 mL
and precipitation of the complex was induced by addition of anhy-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

I
Synthesis
M. Siebert et al.
Paper
drous, degassed n-pentane (3 mL). The supernatant solution was sep-
arated by using a filter cannula. The washing procedure was repeated
two more times. The resulting red solid was dried in vacuo for 16 h.
Compound 3cwas isolated as a red solid (51.7 μmol, 87%). The com-
plex was obtained as a mixture of two diastereomers featuring two
signal patterns - A: major isomer, B: minor isomer.
ture was partitioned between DCM (2 mL) and AcOH solution (2 mL,
4 M in H O). The organic phase was eluted with DCM (15 mL) through
2
a short pad of silica (ca. 2 cm) to remove metal residues. The volatile
compounds were removed in vacuo. The conversion of the reaction
was determined by NMR and the enantiomeric ratio of the product by
enantioselective HPLC analysis. All enantioselective HPLC analyses
were carried out using
a (S,S)-Whelk-O1 column (n-hexane/
IR (neat): 3049, 2935, 2880, 2839, 1752, 1630, 1604, 1565, 1505,
IPA/AcOH,, 80:20:0.1; 1.0 mL min−1; 20 °C; λ = 230 nm).
1
8
1
481, 1436, 1391, 1323, 1263, 1223, 1161, 1106, 1049, 996, 906, 855,
09, 784, 723, 693 cm–
1
.
3
13
H NMR (CDCl , 600 MHz): δ = 1.05 (B, d, J
= 7.1 Hz, 6 H, H ), 1.50
3
7/28
H–H
2
3
= 7.1 Hz, 6 H, H13), 1.67 (A, m, 2 H,
Funding Information
(B, m, 2 H, H
), 1.53 (A, d, J
H–H
27/28
27/28
27/28
12
), 1.81 (B, m, 2 H, H27/28), 1.89 (A, m, 2 H, H
27/28
H
H
H
H
), 2.06 (B, m, 2 H,
), 2.57 (A, m, 2 H,
Generous financial support by the European Research Council (ERC)
for a Starting Grant (No. 258740, AMPCAT) is gratefully acknowl-
edged. G.S. acknowledges the Fonds der Chemischen Industrie for a
27/28
27/28
3
), 2.30 (B, m, 2 H, H
), 2.46 (A, m, 2 H, H
3
12
), 2.96 (B, q, J
= 7.1 Hz, 2 H, H ), 3.00 (A, q, J
= 7.1 Hz, 2 H,
H–H
H–H
25/26
), 3.89 (A, 6 H, H24), 3.91 (B, 6 H, H24), 4.40
), 3.83 (A, m, 2 H, H
Ph.D. fellowship
E
u
or
p
e
a
n
Reseacrh
C
o
u
n
lc
i
N(
o
.
2
5
8
7
4
0
,
A
M
P
C
A
T)
2
5/26
25/26
25/26
(B, m, 2 H, H
), 4.92 (B, m, 2 H, H
), 5.34 (A, m, 2 H, H
), 6.17
4
2
4
(A, m, 2 H, H ), 6.28 (B, m, 2 H, H ), 6.36 (B, m, 2 H, H ), 6.62 (A, m, 2 H,
2
3
3
10
H ), 6.91 (A, m, 2 H, H ), 6.94 (B, m, 2 H, H ), 6.95 (B, m, 2 H, H ),
7
7
Supporting Information
2
3
9
20
.04–7.09 (A, m, 2 H, H + B, m, 4 H, H ), 7.11 (A, m, 2 H, H ), 7.13–
9,10,18
18,20
15
.25 (A, m, 8 H, H
+ B, m, 4 H, H
), 7.28–7.30 (A, m, 2 H, H + B,
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588861.
23
8,9,10
8,10
m, 2 H, H ), 7.31–7.45 (A, m, 10 H, H
+ B, m, 6 H, H ), 7.46–7.54
S
u
p
p
o
nrtogI
i
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
8
9
15
8
(A, m, 4 H, H + B, m, 4 H, H ), 7.58 (B, m, 2 H, H ), 7.61 (B, m, 4 H, H ),
17,22
17,22
7.65–7.69 (A, m, 4 H, H
), 7.76–7.79 (B, m, 4 H, H
).
1
3
C NMR (CDCl , 151 MHz): δ = 18.1 (B, 2C, C ), 19.0 (A, 2C, C13), 27.4
13
References
3
27/28
27/28
27/28
27/28
(A, 2C, C
), 29.6 (B, 2C, C
), 32.1 (B, 2C, C
), 34.9 (A, 2C, C
),
5.0 (B, 2C, C12), 45.1 (A, 2C, C ), 55.4 (A, 2C, C ), 55.4 (B, 2C, C ),
5.1 (B, m, 2C, C
12
24
24
(1) (a) Mikami, K.; Matsukawa, S. Nature 1997, 385, 613.
(b) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.;
Noyori, R. Angew. Chem. Int. Ed. 1999, 38, 495. (c) Mikami, K.;
Korenaga, T.; Ohkuma, T.; Noyori, R. Angew. Chem. Int. Ed. 2000,
39, 3707. (d) Korenaga, T.; Aikawa, K.; Terada, M.; Kawauchi, S.;
Mikami, K. Adv. Synth. Catal. 2001, 343, 284. (e) Mikami, K.;
Korenaga, T.; Yusa, Y.; Yamanaka, M. Adv. Synth. Catal. 2003,
345, 246. (f) Walsh, P. J.; Lurain, A. E.; Balsells, J. Chem. Rev.
2003, 103, 3297. (g) Faller, J. W.; Lavoie, A. R.; Parr, J. Chem. Rev.
2003, 103, 3345. (h) Mikami, K.; Yamanaka, M. Chem. Rev. 2003,
103, 3369. (i) Schmitkamp, M.; Chen, D.; Leitner, W.;
Klankermayer, J.; Francio, G. Chem. Commun. 2007, 4012.
(j) Aikawa, K.; Mikami, K. Chem. Commun. 2012, 11050.
(2) Aikawa, K.; Takabayashi, Y.; Kawauchi, S.; Mikami, K. Chem.
Commun. 2008, 5095.
4
8
2
5/26
25/26
25/26
), 87.1 (A, b, 2C, C
), 88.4 (A, b, 2C, C
), 90.5
25/26
20
20
18
(B, b, 2C, C
), 105.7 (A, 2C, C ), 105.7 (B, 2C, C ), 119.3 (A, 2C, C ),
1
8
6
6
1
2
2
19.5 (B, 2C, C ), 121.5 (A, m, 2C, C ), 122.0 (B, m, 2C, C ), 123.2 (A,
C, C ), 123.5 (B, 2C, C ), 125.7 (B, 2C, C ), 125.8 (A, 2C, C ), 126.5 (B,
C, C ), 126.5 (A, 2C, C ), 127.5 (A, 2C, C ), 127.8 (B, 2C, C ), 128.8
2
2
23
23
15
15
22
22
16
9
9
(A, 2C, C ), 128.9 (A, m, 4C, C ), 128.9 (B, m, 4C, C ), 128.9 (B, m, 4C,
9
16
17
9
C ), 129.0 (B, 2C, C ), 129.2 (A, 2C, C ), 129.3 (A, m, 4C, C ), 129.3 (B,
2
1
C ), 131.2 (A, m, 2C, C ), 132.3 (B, 2C, C ), 132.4 (A, b, 4C, C ), 132.4 (A,
m, 2C, C ), 132.5 (A, 2C, C ), 133.0 (B, m, 2C, C ), 133.0 (B, b, 4C, C ),
1
2
1
C
17
7
10
7
C, C ), 130.1 (B, m, 2C, C ), 130.5 (B, 2C, C ), 130.7 (A, m, 2C, C ),
10
10
10
30.8 (A, 2C, C ), 130.9 (B, 2C, C ), 131.0 (A, 2C, C ), 131.1 (B, m, 2C,
4
4
3
8
7
3
7
8
1
4/21
14/21
14/21
33.9 (A, 2C, C
C, C
), 133.9 (A, 2C, C
), 133.9 (B, 2C, C
), 134.1 (B,
14/21
8
8
5
), 134.9 (B, m, 4C, C ), 135.5 (A, m, 4C, C ), 144.1 (B, m, 2C, C ),
5
1
1
44.1 (A, m, 2C, C ), 151.5 (B, 2C, C ), 151.7 (A, 2C, C ), 157.9 (A, 2C,
1
9
19
11
11
(3) Punniyamurthy, T.; Mayr, M.; Dorofeev, A. S.; Bataille, C. J. R.;
Gosiewska, S.; Nguyen, B.; Cowley, A. R.; Brown, J. M. Chem.
Commun. 2008, 5092.
(4) Storch, G.; Trapp, O. Angew. Chem. Int. Ed. 2015, 54, 3580.
(5) Oczipka, P.; Müller, D.; Leitner, W.; Francio, G. Chem. Sci. 2016,
), 158.0 (B, 2C, C ), 172.9 (B, 2C, C ), 173.1 (A, 2C, C ).
31
P NMR (CDCl , 243 MHz): δ = 10.81 (A), 12.53 (B).
F NMR (CDCl , 283 MHz): δ = –153.55 (11B), –153.50 (10B).
3
19
3
HRMS (ESI): m/z [M-BF4]+ calcd for C72H64193IrO6P2+: 1279.3802;
found: 1279.3826.
7
, 678.
6) (a) Maier, F.; Trapp, O. Angew. Chem. Int. Ed. 2012, 51, 2985.
b) Maier, F.; Trapp, O. Chirality 2013, 25, 126. (c) Storch, G.;
Siebert, M.; Rominger, F.; Trapp, O. Chem. Commun. 2015,
5665. (d) Storch, G.; Pallmann, S.; Rominger, F.; Trapp, O. Beil-
(
(
General Procedure for Hydrogenations
The diastereomeric ratio of the used catalysts was determined by
NMR prior to the catalysis. All catalysts and small amounts of liquids
were added to the reaction mixture by using stock solutions. All stock
solutions were prepared from anhydrous, degassed DCM. The cata-
lyst, the substrate and the additive were solved in a Schlenk flask in
the same solvent used for the stock solutions. A stainless steel high-
pressure tube autoclave loaded with a NMR tube and a small stirring
bar was evacuated and flushed with argon three times before the re-
action mixture was transferred to the NMR tube. After purging the
hydrogen gas line with hydrogen gas at least seven times, the auto-
clave was pressurized with hydrogen gas (5 bar). The reaction mix-
ture was stirred for 16–20 h. After the indicated period of time, the
hydrogen gas was discharged from the autoclave. The reaction mix-
1
stein J. Org. Chem. 2016, 12, 1453. (e) Storch, G.; Maier, F.;
Wessig, P.; Trapp, O. Eur. J. Org. Chem. 2016, 5123. (f) Storch, G.;
Deberle, L.; Menke, J.-M.; Rominger, F.; Trapp, O. Chirality 2016,
2
8, 744.
7) (a) Maier, F.; Trapp, O. Angew. Chem. Int. Ed. 2014, 53, 8756.
b) Storch, G.; Trapp, O. Nat. Chem. 2017, 9, 179.
(
(
(
8) The X-ray crystallographic data for (Rax,S,S)-2a and (Sax,S,S)-2a
are deposited at the Cambridge Crystallographic Data Centre
(
1
(
CCDC) under deposition numbers CCDC 1517247 and CCDC
517248. These data can be obtained free of charge
http://www.ccdc.cam.ac.uk/data_request/cif).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

J
Synthesis
M. Siebert et al.
Paper
(
9) The X-ray crystallographic data for (Sax,S,S)-3a is deposited at
(10) Sheldrick G. M., SADABS, version 2012/1, Bruker Analytical X-
ray Division, Madison, Wisconsin, USA.
(11) Sheldrick, G. M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun.
2015, 71, 3.
the Cambridge Crystallographic Data Centre (CCDC) under
deposition numbers CCDC 1517249. This data can be obtained
free of charge ( http://www.ccdc.cam.ac.uk/data_request/cif).
(12) Farrugia, L. J. J. Appl. Crystallogr. 2012, 45, 849.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J