An Atropos Chiral Biphenyl Bisphosphine Ligand Bearing Only 2,2′-Substituents and Its Application in Rh-Catalyzed Asymmetric Hydrogenation

Article abstract of DOI:10.1002/adsc.201701281

An atropos chiral biphenyl bisphosphine ligand bearing only 2,2′-substituents was rationally designed and easily synthesized utilizing a bulky chiral t-butylmethylphosphino block. Computational results showed a large difference in the free energies betwee

Full text of DOI:10.1002/adsc.201701281

Title: An <i>Atropos</i> Chiral Biphenyl Bisphosphine Ligand Bearing
Only 2,2’-Substituents and Its Application in Rh-Catalyzed
Asymmetric Hydrogenation
Authors: Jia Jia, Zheng Ling, Zhenfeng Zhang, Ken Tamura, Ilya
Gridnev, Tsuneo Imamoto, and Wanbin Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701281
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10.1002/adsc.201701281
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
An Atropos Chiral Biphenyl Bisphosphine Ligand Bearing Only
2,2’-Substituents and Its Application in Rh-Catalyzed
Asymmetric Hydrogenation
Jia Jia,a Zheng Ling,a Zhenfeng Zhang,b* Ken Tamura,c Ilya D. Gridnev,d Tsuneo
Imamoto,a,c† and Wanbin Zhanga,b*
a
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai
200240, P. R. China. Fax: +86-21-54743265. E-mail: wanbin@sjtu.edu.cn.
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
Organic R&D Department, Nippon Chemical Industrial Co., Ltd., Kameido, Koto-ku, Tokyo 136-8515, Japan.
Department of Chemistry, Graduate School of Science, Tohoku University, Aramaki 3-6, Aoba-ku, Sendai 980-8578,
b
c
d
Japan.
†
Visiting professor of Shanghai Jiao Tong University from Chiba University (Japan).
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An atropos chiral biphenyl bisphosphine ligand
bearing only 2,2’-substituents was rationally designed and
easily synthesized utilizing bulky chiral t-
Keywords: Atropos; Biphenyl; Bisphosphine ligand; Rh-
catalyzed; Asymmetric hydrogenation
a
butylmethylphosphino block. Computational results showed
a large difference in the free energies between the two
diastereomers (7.8 kcal/mol) and attainable rotational energy
barriers from one diastereomer to another (27.7 kcal/mol and
reverse 19.9 kcal/mol). This ligand avoids the time-
consuming optical resolution generally needed for the
preparation of axially chiral ligands and shows high
reactivity and enantioselectivity in Rh-catalyzed asymmetric
hydrogenations.
Since 1997, we have developed a series of tropos
ligands bearing an unfixed biphenyl axis with only
two chiral 2,2’-substituents (Figure 1). Due to the
chiral substituents at the 2,2’-positions, the
bis(oxazoline) ligand BiphBOX showed an unequal
diastereoisomeric ratio (29:71) according to NMR
spectra. Interestingly, only one of these two reversal
diastereoisomers was able to form a stable complex
with Cu or Pd, thus no resolution step for the axial
chirality is needed.[4] This phenomenon can be
explained by the large differences in coordinating
energy barriers (dynamics) and free energies
(thermodynamics) between the two diastereomeric
complexes. Subsequently, the biphenyl phosphine-
oxazoline ligands BiphPHOX and their Pd- and Ir-
complexes were also developed by us using the same
strategy and showed high efficiency in asymmetric
catalysis.[5] The preparation of these ligands has an
obvious synthetic advantage over the preparation of
the binaphthyl phosphine-oxazoline ligand, which
requires separation of the diastereoisomers before
coordination with Pd.[6] In 2015, Trapp and
coworkers developed a new biphenyl bisphosphine
ligand 3,3’-Biphep with C-stereogenic (S-
Introduction
Chiral ligands play a key role in defining the
efficiency and applicability of metal-catalyzed
asymmetric reactions.[1] The biaryl group, particularly
the biphenyl group, is undoubtedly the most widely
used backbone for the construction of versatile
axially chiral ligands. Generally, these types of
ligands, e.g. BINAP, BINOL, BIPHEP and SegPhos,
require at least three substituents at the 2,2’- and 6,6’-
positions to create a chiral biphenyl axis possessing
an adequate rotational energy barrier.[2] In order to
minimize the torsion angle imposed by the steric
repulsion between the substituents at the 2,2’- and
6,6’-positions, we previously designed and
synthesized a new type of chiral biphenyl ligand
(such as 5,5'-BridgePhos shown in Figure 1) without
substituents at the 6,6’-positions.[3] The rotational
energy barrier in these ligands is alternatively
produced by introduction of bridged substituents at
the 5,5’-positions. However, the atropos property of
the aforementioned ligands requires an indispensable
resolution of the enantiomers.
1
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10.1002/adsc.201701281
Advanced Synthesis & Catalysis
configuration) substituents at the 3,3’-positions
(Figure 1).[7] This ligand also exhibits an atropos-to-
tropos property but only when its Rh-complex is
18.4 kcal/mol). These results indicate that a ligand
possessing a chiral axis could be produced due to the
presence of the P-stereogenic (R-configuration
depicted) tert-butylmethylphosphino group and a
single diastereoisomer could be obtained without the
need for further resolution. This finding represents
the first synthesis of an atropos chiral biphenyl ligand
bearing only 2,2’-substituents and would bring
inspiration for the design of new axially chiral
ligands and organocatalysts.
o
heated at high temperature (70 C) for a certain
period of time (300 min). At room temperature, a
61:39 diastereoisomeric mixture was detected and
completely retained after coordination with Rh. We
considered that the rotational energy barrier was
markedly increased by the 3,3’-substituents and the
relatively fixed biphenyl axis reduced the
epimerization rate of the biphenyl axis so that the
rotation rate was much slower than the coordination
rate at room temperature. Therefore, to use
bisphosphine ligands with strong coordinating ability
in dynamic kinetic way is difficult, especially at low
temperature. Nevertheless, since the chiral 3,3’-
substituents are remote from the chiral biphenyl axis
and active metal center, bulky groups are always
demanded in order to obtain satisfactory stereocontrol.
Results and Discussion
The preparation of the ligand BipheP* required only
a few simple steps (Scheme 1). The starting material
(R)-2-bromophenyl(tert-butyl)(methyl)phosphane-
borane (1) could be easily synthesized from (S)-tert-
butylmethylphosphane-borane
dibromobenzene according
and
a
1,2-
to
literature
procedure.[8c,d] Compound 1 was then treated with s-
BuLi
and
transformed
to
(RP,RP)-2,2'-
bis(boranoto(tert-butyl)(methyl)phosphino)biphenyl
(2) via a Cu-promoted homocoupling in a relatively
low yield of 27% due to the formation of a
debrominated byproduct. Judging from the 31P NMR
spectrum, only one of the two diastereoisomers was
obtained. The borane protecting group was easily
removed by the reaction with DABCO and the free
ligand
(RP,RP)-2,2'-bis((tert-
butyl)(methyl)phosphino)biphenyl (3, BipheP*) was
obtained by recrystallization from methanol. It is
worth to mention that this ligand is an air-stable
crystalline solid. The rhodium complex
4
[Rh(BipheP*)(cod)]SbF6 was crystallized from
THF/Et2O after coordination with [Rh(cod)2]SbF6 in
THF.
Figure 1. Design of Ligand BipheP*.
To overcome these problems, we proposed to
introduce bulky chiral 2,2’-substituents exclusively
on the biphenyl skeleton to increase the rotational
energy barrier and to provide a more well-defined
chiral environment. Furthermore, the presence of
suitable chiral groups at the 2,2’-positions will also
increase the free energy difference between the two
diastereoisomers and make it possible to obtain the
ligand, as a single enantiomer, without requiring a
resolution step. In continuation of our research
concerning P-stereogenic ligands bearing a tert-
butylmethylphosphino group,[8] we designed a new
ligand named BipheP* with the aid of theoretical
calculations (Figure 1). The calculated results
Scheme 1. Synthesis of Ligand BipheP* and Its Rh-
Complex.
31P NMR experiments carried out at different
temperatures showed presence of
a
single
diastereomer of 3; no dynamic effects were detected
in the temperature range from -50 to 25 °C (Figure 2).
obtained
using
a
theoretical
method of
The
more
detailed
computation
showed
B3LYP/6311G+(d,p) showed a great difference in the
free energies between the two diastereomers (5.0
kcal/mol) and considerable rotational energy barriers
that must be overcome to convert from one
diastereomer to the other (23.4 kcal/mol and reverse
(wB97XD/6311G+(d,p)/SMD(methanol))
that the RP,RP,Sa-isomer is thermodynamically
favoured for 7.8 kcal/mol (Figure 3). In the same
fashion, the 31P NMR and calculated results of the
2
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10.1002/adsc.201701281
Advanced Synthesis & Catalysis
rhodium complex 4 also indicated a single RP,RP,Sa-
isomer with an energy difference of 9.7 kcal/mol
((wB97XD/631G(d,p)/SMD(methanol)), Figure 4 and
Figure 5), hence that the axial chirality of the
biphenyl backbone did not change during the
coordination process. Unfortunately, attempts to
obtain good crystals of either 3 or 4 for X-ray
analysis were unsuccessful.
Figure 5. Computed Structure of 4 (Left: RP,RP,Sa-isomer,
0.0 kcal/mol. Right: RP,RP,Ra-isomer, 9.7 kcal/mol.
Coordinated COD is not shown for clarity).
To get insight into the reasons of the significant
difference in the stabilities of two conformations of 3,
we have scanned the changes of the relative energy
and molecular structure during the rotation around the
internal bond of the biphenyl backbone (Figure 6).
The
energy
scan
(wB97XD/631G(d,p)/SMD(methanol)) demonstrated
the presence of two conformations separated by
significant activation barrier (the full scan contains
another relatively unstable minimum that was not
accounted in the further analysis). Despite the
relatively small size of a molecule of 3, a significant
number of interatomic distances in the range of 2-3 Å
is detected in either of the conformations. To find the
crucial intramolecular interactions characteristic for
each conformation and making it a minimum in
Figure 2. The 31P NMR of Compound 3 (2-1: 223 K; 2-2:
233 K; 2-3: 250 K; 2-4: 298 K).
energy, we considered that
a
stabilizing
intramolecular interaction must be conserved even
when the configuration is removed from the
minimum one by changing the dihedral angle. We
have found four such interatomic distances
(corresponding to the C-H…π interactions) for the
RP,RP,Sa-isomer, and only two C-H…H-C interactions
of that kind for another diastereomer. From the
Figure 6 (down) one can see that these interatomic
distances are keeping the same value in a wide range
of the dihedral angles that is a clear indication of their
attractive character. We concluded therefore that
RP,RP,Sa-conformation is stabilized by C-H…π
interactions of a tert-butyl group and corresponding
phenyl ring, since they overcome in number the
attractive C-H…H-C interactions in the other
diastereomer. Apparently, essentially the same
intramolecular interactions affect the structure of the
Rh complex 4. As a result, a strong difference in the
dihedral angled P-Rh—P-C for the methyl and tert-
butyl groups is observed, thus making the methyl
groups quasi-equatorial substituents that is usually
not observed in other Rh complexes of this kind
(Figure 5, left).
Figure 3. Computed Structure of 3 (Left: RP,RP,Sa-isomer,
0.0 kcal/mol. Right: RP,RP,Ra-isomer, 7.8 kcal/mol).
Figure 4. The 31P NMR of Compound 4 (4-1: 223 K; 4-2:
298 K).
3
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10.1002/adsc.201701281
Advanced Synthesis & Catalysis
To our delight, the meta,para-disubstituted substrate
5o gave its corresponding product with the highest
enantioselectivity of 97% ee. When the S/C was
increased to 4000, the hydrogenation of 5a was
completed within 8 hours and with 86% ee.
Figure 6. Up: section plot of the computed energy scan of
the rotation around the C-C single bond in the biphenyl
unit. Down: spheres, changes of interatomic distances
H…C shown in the Figure 3 (left); stars, changes of
interatomic distances H…H shown in the Figure 3 (right).
Scheme 2. Substrate Scope. Conditions: 5 (0.2 mmol),
[Rh(BiPheP*)(cod)]SbF6 (1 mol %), H2 (3 bar), MeOH (2
mL), rt, 2 h; Isolated yields were obtained after
chromatography; The ee values were determined by HPLC.
To test the activity and enantioselectivity of this
rhodium complex, methyl (Z)-2-acetamido-3-
arylacrylates were chosen as prochiral substrates and
their asymmetric hydrogenations were performed
under standard reaction conditions.[9] Firstly, solvent
screening showed that polar protic solvents are better
than less polar solvents (see Supporting Information
Conclusion
In conclusion, we have prepared the first example of
atropos chiral biphenyl bisphosphine ligands bearing
only two chiral groups at 2,2'-positons. Both the
theoretical calculations and experimental data verify
that only one axial isomer exists. Its Rh-complex
showed high activity and enantioselectivity in the
asymmetric hydrogenation of α-dehydroamino acid
esters (up to 97% ee and 4000 S/C). Other catalytic
asymmetric reactions using BipheP* are currently
being developed in our laboratory and similar ligands
utilizing the same tactic are being prepared.
for
details).
Catalyst
[Rh((RP,RP,Sa)-
BipheP*)(cod)]SbF6 in MeOH solvent provides
promising enantioselectivity for the hydrogenation of
5a (91% ee). Then, various substrates bearing
different substituents on the phenyl ring were tested
and high enantioselectivities were obtained (82-97%
ee) (Scheme 2). The para-substituted substrates, such
as 5b, 5e, 5g-k, and 5n, gave their corresponding
products with approximately 90% ees. For substrates
bearing electron-donating methoxy groups, ortho-
substituted 5d gave a better enantioselectivity than
meta-substituted 5c, while the electron-withdrawing
fluoro group showed an opposite trend (5l and 5m).
Experimental Section
General information
4
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10.1002/adsc.201701281
Advanced Synthesis & Catalysis
All air- and moisture-sensitive manipulations were carried
out with standard Schlenk techniques under nitrogen. All
hydrogenation reactions were performed in autoclave
under an atmosphere of hydrogen. Solvents were dried and
distilled by standard procedures. All commercially
available reagents were used as received. 1H, 13C, 31P NMR
spectra were obtained using a Varian MERCURY plus-400
spectrometer with an internal standard. Melting points
were measured with SGW X-4 micro melting point
apparatus. Enantioselectivities were determined by high
performance liquid chromatography (HPLC) using Daicel
CHIRALPAK AD-H or OD-H columns with
hexane/iPrOH as eluent. Optical rotations were measured
on a Rudolph Research Analytical Autopol VI automatic
polarimeter using a 50 mm path-length cell at 589 nm.
High Resolution Mass Spectrometry (HRMS) analysis was
carried out using an electrospray spectrometer Waters
Micromass Q-TOF Premier Mass Spectrometer.
0.61 (m, 6H). 31P NMR (162 MHz, CDCl3) δ 25.46 (br s).
13C NMR (101 MHz, CDCl3) δ 146.84 (d, J = 16.1 Hz),
133.66 (s), 132.82 (d, J = 8.8 Hz), 129.43 (s), 127.85 (d, J
= 45.9 Hz), 127.19 (d, J = 6.3 Hz), 30.73 (d, J = 32.2 Hz),
26.64 (s), 9.12 (d, J = 39.0 Hz). HR-MS (ESI) m/z
calculated for C22H39B2P2 [M-BH3+H]+ 373.2380, found
373.2387.
(RP,RP,Sa)-2,2'-Bis((tert-
butyl)(methyl)phosphino)biphenyl (3): A solution of
compound 2 (151.6 mg, 0.39 mmol) and DABCO (133.1
mg. 1.19 mmol) were heated to reflux temperature in THF
under nitrogen for 3 h. The solvent was removed under
reduced pressure and the residue was extracted with
degassed hexane (5 mL × 3). The combined solution was
removed under reduced pressure and the residue was
recrystallized in hot degassed MeOH to give compound 3
as a white solid (104.5 mg, 74% yield). Mp 106-109 °C.
1
[α]25 +48.6 (c 0.53, CHCl3). H NMR (400 MHz, CDCl3)
D
Preparation of ligand and its Rh-complex
δ 7.50 (t, J = 3.6 Hz, 2H), 7.34 (dd, J = 5.6, 3.3 Hz, 4H),
7.18-7.14 (m, 2H), 1.26 (t, J = 2.4 Hz, 6H), 0.74 (t, J = 6.0
Hz, 18H). 31P NMR (162 MHz, CDCl3) δ -23.39 (s). At
223 K, δ -26.11 (s). A slight amount of partially oxidation
product was detected at 18.70 (d, P(O)) and -25.10 (d, P).
13C NMR (101 MHz, CDCl3) δ 149.49 (s), 137.56 (s),
131.31 (s), 130.98 (s), 128.15 (s), 126.34 (s), 29.81 (d, J =
24.8 Hz), 27.63 (t, J = 7.5 Hz), 5.86 (t, J = 9.5 Hz). HR-
MS (ESI) m/z calculated for C22H33P2 [M+H]+ 359.2052,
found 359.2056.
(R)-2-Bromophenyl(tert-butyl)(methyl)phosphane-
borane (1):[8c,d] n-BuLi (8.5 mL, 1.3 M in hexane, 11
mmol, 1.1 eq) was added dropwise into a solution of
borano (S)-tert-butyl(methyl)phosphane (1.17 g, 10 mmol)
in THF (10 mL) at -78 °C under the atmosphere of
nitrogen. The solution was stirred for 1 hour followed by
the slow addition of a solution of 1,2-dibromobenzene
(3.54 g, 15 mmol, 1.5 eq) in THF (5 mL). The temperature
was gradually elevated up to 0 °C. The reaction was stirred
for 6 hours and quenched with water. The mixture was
extracted with EtOAc and then the combined organic
phases were dried over Na2SO4 and filtered. The solvent
was evaporated and the residue was purified by column
chromatography on silica gel using petroleum ether/EtOAc
(10:1) as the eluent. The product was recrystallized from
((RP,RP,Sa)-2,2'-Bis((tert-
butyl)(methyl)phosphino)biphenyl)(1,5-
cyclooctadiene)rhodium(I)
hexafluoroantimonate
([Rh(3)(cod)]SbF6, 4): A solution of compound 3 (68.7
mg, 0.19 mmol) in THF (0.5 mL) was added dropwise to a
solution of [Rh(cod)2]SbF6 (96.7 mg, 0.17 mmol) in THF
(0.5 mL) under nitrogen. The solution was stirred for 40
min under room temperature and then for 20 min under
0 °C. The solution was concentrated under reduced
pressure to 0.5 mL followed by the addition of diethyl
ether (about 5 mL). The precipitated solid was collected
via filtration and washed with a small amount of diethyl
ether to give compound 4 as an orange solid (142.0 mg,
1
hexane to give white needles (1.54 g, 56% yield). H NMR
(400 MHz, CDCl3) δ 8.05 (ddd, J = 12.8, 7.8, 1.8 Hz, 1H),
7.63 (ddd, J = 7.9, 2.4, 1.3 Hz, 1H), 7.39 (tt, J = 7.7, 1.4
Hz, 1H), 7.34-7.28 (m, 1H), 1.90 (d, J = 10.0 Hz, 3H), 1.19
(d, J = 14.4 Hz, 9H), 1.04-0.37 (br m, 3H). 31P NMR (162
MHz, CDCl3) δ 39.01 (dd, J = 119.0, 52.5 Hz).
1
(RP,RP)-2,2'-Bis(boranoto(tert-
92% yield). H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 7.4
butyl)(methyl)phosphino)biphenyl (2): To a solution of
compound 1 (0.82 g, 3.0 mmol) in cyclopentyl methyl
ether (CPME) (10 mL) was added s-BuLi (3.2 mL of 1 M
hexane solution, 3.2 mmol) under nitrogen at -78 °C. The
reaction was stirred for 45 min before Cu(OTf)2 (1.63 g,
4.5 mmol) was added and the temperature was gradually
elevated to room temperature. The reaction was quenched
with ammonium hydroxide after the starting material was
expended. The mixture was extracted with ethyl acetate
twice. The combined organic phases were dried over
Na2SO4. TLC check and 31P NMR analysis indicate that
only one of the two diastereoisomers was obtained in the
reaction. The volatiles were evaporated and the residue
was purified by chromatography on silica gel using petrol
ether/ethyl acetate (50:1) as the eluent to give compound 2
Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.45 (t, J = 7.4 Hz, 2H),
7.20 (d, J = 7.3 Hz, 2H), 5.38 (br s, 2H), 4.73 (br s, 2H),
2.47 (br s, 4H), 2.24 (br s, 4H), 1.62 (d, J = 4.7 Hz, 6H),
0.84 (d, J = 13.9 Hz, 18H). 31P NMR (162 MHz, CDCl3) δ
17.54 (d, J = 140.5 Hz). 13C NMR (101 MHz, CDCl3) δ
146.54 (t, J = 7.1 Hz), 135.87 (t, J = 3.5 Hz), 131.67 (s),
130.95 (s), 129.32 (t, J = 2.9 Hz), 128.80 (s), 101.55-
101.22 (m), 91.56 (dd, J = 12.5, 6.3 Hz), 37.27-36.93 (m),
33.68 (s), 29.85-29.57 (m), 28.36 (s), 7.00-6.65 (m). HR-
MS (ESI) m/z calculated for C30H44P2Rh [M-SbF6]+
569.1968, found 569.1997.
General procedure for asymmetric hydrogenation
Substrate (0.2 mmol), rhodium catalyst (0.002 mmol), and
a magnetic stir bar were charged in a hydrogenation bottle
and autoclave. The system was evacuated and filled with
hydrogen. After repeating this operation three times,
as a white powder (157 mg, 27% yield). Mp 152-153 °C.
1
[α]25 +72.6 (c 0.50, CHCl3). H NMR (400 MHz, CDCl3)
D
δ 7.59-7.52 (m, 2H), 7.48-7.37 (m, 4H), 7.25-7.20 (m, 2H),
1.67 (d, J = 9.2 Hz, 6H), 1.07 (d, J = 13.4 Hz, 18H), 0.36--
5
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10.1002/adsc.201701281
Advanced Synthesis & Catalysis
degassed solvent (2 mL) was added and the vessel was
filled with hydrogen (3 bar). Vigorous stirring was
[5] For representative examples: a) W. Zhang, F. Xie, H.
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continued for
2 hours. The reaction mixture was
evaporated under reduced pressure and the residue was
passed through a short column of silica gel. The solvent
was removed under reduced pressure and the product was
dried in vacuum. The enantiomeric excess was determined
by HPLC.
Acknowledgements
This work was partially supported by the National Natural
Science Foundation of China (Nos. 21232004, 21572131 and
21620102003), Shanghai Municipal Education Commission (No.
201701070002E00030) and Science and Technology Commission
of Shanghai Municipality (No. 15JC1402200). We thank the
Instrumental Analysis Center and the High Performance
Computing Center of Shanghai Jiao Tong University.
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Büthe, Angew. Chem. Int. Ed. 1968, 7, 942; l) W. S.
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10.1002/adsc.201701281
Advanced Synthesis & Catalysis
FULL PAPER
An Atropos Chiral Biphenyl Bisphosphine Ligand
Bearing Only 2,2’-Substituents and Its Application
in Rh-Catalyzed Asymmetric Hydrogenation
Adv. Synth. Catal. Year, Volume, Page – Page
Jia Jia, Zheng Ling, Zhenfeng Zhang,* Ken
Tamura, Ilya D. Gridnev, Tsuneo Imamoto, and
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