Chiral bisphosphine ligands based on quinoline oligoamide foldamers: application in asymmetric hydrogenation

Article abstract of DOI:10.1039/c9ob01649j

A series of chiral bisphosphine ligands were designed and synthesized based on single-handed quinoline oligoamide foldamers. The bisphosphine ligands can coordinate with Rh(cod)₂BF₄ in a 1 : 1 stoichiometry and the resulted chiral Rh(i) catalysts were applied in the asymmetric hydrogenation of α-dehydroamino acid esters, in which excellent conversions and promising levels of enantioselectivity were achieved.

Full text of DOI:10.1039/c9ob01649j

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Chiral bisphosphine ligands based on quinoline
oligoamide foldamers: application in asymmetric
hydrogenation†
Cite this: Org. Biomol. Chem., 2019,
17, 9573
Received 26th July 2019,
Lu Zheng,a,b,c Dan Zheng,d Yanru Wang,d Chengyuan Yu,d Kun Zhang*a,b and
Accepted 28th October 2019
a,b,d
DOI: 10.1039/c9ob01649j
Hua Jiang
*
rsc.li/obc
A series of chiral bisphosphine ligands were designed and syn- increasing attention is being paid to catalysts whose enantio-
thesized based on single-handed quinoline oligoamide foldamers. discrimination relies on the main chain chirality because it
The bisphosphine ligands can coordinate with Rh(cod)2BF4 in a only requires the introduction of a simple achiral ligand or
1 : 1 stoichiometry and the resulted chiral Rh(I) catalysts were catalyst. Recently, Suginome has developed several chiral poly
applied in the asymmetric hydrogenation of α-dehydroamino acid (quinoxaline-2,3-diyl)-based phosphines (PQXphos) as helical
esters, in which excellent conversions and promising levels of macromolecular ligands for some asymmetric reactions and
enantioselectivity were achieved.
excellent conversions and enantioselectivities have been
observed.15–19 Some helical-shaped small molecules such as
helicenes and their derivatives, some octahedral metal com-
plexes and certain axially chiral biaryl systems are also used as
asymmetric catalysts,20,21 but the asymmetric catalysis based
on foldamers is still a huge challenge.22
The functions of biopolymers highly rely on their structures,
such as the helical structure of DNA, peptides and proteins. A
lot of well-defined folded structures have been developed in
recent years to mimic the conformation of helical biopolymers
but the reports that mimic the function of helical structures is
rather few.1 Inspired by the high catalytic activity and selecti-
vity of enzyme catalysis under mild conditions,2,3 foldamer-
based catalysis is considered as a promising area that has the
advantage of enzyme catalysis and a wide scope of application,
but it is still at an infant stage. Huc4,5 and Moore6,7 have
reported several prominent examples that foldamers enhance
reaction rates but the reports about foldamer-based asym-
metric catalysis are rather limited.8 Artificial helical structures
have been developed in recent years to mimic the properties of
DNA and peptides2,9,10 and some helical polymer-based struc-
tures have been used as scaffolds for asymmetric catalysis
because they are expected to have a huge steric hindrance com-
pared with small-molecule-based chiral structures and the
enantioselectivity of this kind of catalyst mainly originates
from the main chain chirality or the chiral pendants such as
the chiral active sites or metal-binding sites.11–14 By contrast,
Quinoline oligoamide foldamers (QOFs) composed of
achiral repeating units exhibit interconvertible equilibrium
between the left (M)-handed and right (P)-handed enantio-
mers.23 Attaching a chiral moiety to the terminus of the folda-
mer is one of the major methods to achieve absolute control of
the helix sense, which leads to potential applications in chiral
recognition and chiral electro-optical devices. Huc and our
group have reported several chiral moieties that can absolutely
bias QOFs to a one-handed helix with high fidelity which
renders QOFs to be good chiral scaffolds for asymmetric
catalysis.24–26 The crystal structure of quinoline oligoamide fol-
damers shows that the helical structure comprises 2.5 repeat
units per turn and the C-terminus and the side chain of the
third monomer (from the C-terminus) are on the same face of
the foldamer, which bring them in close proximity and thus
provide a chance to be locked through a covalent bond.23,27 In
this work, we propose to modify the C-terminus and the side
chain of single-handed quinoline oligoamide foldamers with
phosphorus groups to provide several bisphosphine ligands
and to investigate whether these ligands can be used as a cata-
lytic platform for metal-catalyzed asymmetric reactions
(Fig. 1). For the asymmetric reaction, we chose rhodium-cata-
lyzed asymmetric hydrogenation of α-dehydroamino acid
esters as the model.
aSchool of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China.
E-mail: jiangh@bnu.edu.cn, kzhang@gdut.edu.cn
bInternational Healthcare Innovation Institute (Jiangmen), Jiangmen, China
cSchool of Chemical Engineering and Light Industry, Guangdong University of
Technology, Guangzhou, China
dCollege of Chemistry, Beijing Normal University, Beijing, China
†Electronic supplementary information (ESI) available. CCDC 1939544 and
1939549. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c9ob01649j
Phosphine ligands, such as chiral diphosphines, P- and
N-ligands, and monodentate phosphorus ligands, are one of
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Fig. 1 Illustration of the chiral catalyst based on the chiral quinoline oli-
goamide foldamer.
the most commonly used ligands that asymmetric catalysts are
highly dependent on and have attracted huge attention and
made great progress in recent years.28–30 Chiral phosphine
ligands bearing three aryl substituents are an important class
of structures for transition metal catalysts and have been
applied in a number of asymmetric reactions because of their
high levels of enantioselectivity and stability.31 Hence, we
designed and synthesized several bidentate phosphorus
ligands bearing three aryl substituents based on quinoline oli-
goamide foldamers in which the (−)-camphanyl moiety was
used as the chiral motif at the N-terminus of the foldamer
because of its absolute induction of the P helix for quinoline
oligoamide foldamers and commercial availability.26 We
expected that the bidentate ligands could coordinate with
Rh(cod)2BF4 in a 1/1 ratio to form a cyclic Rh-complex which can
be used for the asymmetric hydrogenation of α-dehydroamino
acid esters with good conversions and enantioselectivities.
Initially, two achiral bidentate phosphorus ligands L1 and
L2 bearing monomer 6 at the N-terminus and a 1,3-phenylene-
diphenylphosphino group at the C-terminus (Scheme 1 and
the ESI†) of the foldamers were prepared to verify whether this
kind of bidentate phosphorus ligand can coordinate with Rh
(cod)2BF4. X-ray crystallographic analyses show that the struc-
tures of L1 and L2 span more than one helical turn with the
Fig. 2 Top view and side view of the crystal structures of ligands L1 (a)
and L2 (b). All isobutyl side chains were omitted for clarity. C, gray; N,
blue; O, red; H, white and P, orange.
two phosphorus groups located on the same face of the helices
(Fig. 2). After the addition of one equivalent of Rh(cod)2BF4 to
the solution of L1 or L2 in CDCl3, 1H NMR experiments
showed that the original signals of L1 and L2 completely dis-
appeared with the concomitant appearance of a set of new
signals respectively, hinting at the formation of L1[Rh] (L[Rh]
is short for RhL(Cod)BF4, e.g., L2[Rh], Fig. 3a) and L2[Rh] com-
plexes (Fig. 3b). The upfield shifts of the amide hydrogens
were observed for both L1[Rh] and L2[Rh], indicating the
different shielding effects as a result of the formation of cyclic
structures. Besides, the 31P-signal patterns are one set of
doublet of doublet peaks for L1[Rh] and two sets of doublet of
doublet peaks for L2[Rh] (Fig. 3c), which are the characteristic
P–P and P–Rh coupling constants (e.g., L2[Rh], JP–P = 29.16 Hz,
JP–Rh = 140.9, 143.4 Hz) that reveal the successful coordination
between the phosphine ligands and the rhodium atoms that
further illustrates the formation of the cyclic structures.32
ESI-MS confirmed that the L1[Rh] and L2[Rh] complexes were
obtained in a 1 : 1 stoichiometry according to the peaks of
[L[Rh]-BF4−]+ (Fig. S13 and S14†).
Then we attempted to investigate whether the two L[Rh]
complexes can be used as active catalysts for the hydrogen-
ation of α-dehydroamino acid esters and the hydrogenation
reactions using L2[Rh] as the catalyst were performed under
different conditions (Table S1†). The results showed that mod-
erate conversions were detected when 2 mol% of L2[Rh] was
used under 1 atm of H2 for 1a–1g in CDCl3. Increasing the
pressure to 10 atm enhanced the conversions for 1a–1g from
20%–80% to 72%–98%. Complete conversions for 1a–1g could
be obtained by using 4 mol% of L2[Rh] as the catalyst under 7
atm of H2 at room temperature. The hydrogenations of 1a–1g
in two other solvents, THF and toluene, were also conducted
using 4 mol% of L2[Rh] as the catalyst under 7 atm of H2 at
room temperature and complete conversions were observed
Scheme 1 The structures of the foldamer-based ligands L1–L6.
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the (−)-camphanyl moiety for L4. The coordination of L3 and
L4 with Rh(cod)2BF4 was studied by 1H NMR, 31P NMR and
ESI-MS (Fig. S5–8, S15 and S16†), which were similar to those
of L1 and L2, indicating the successful coordination of the
phosphorus atoms and the rhodium atom and the formation
of the cyclic structures. The CD spectra of L3, L4, L3[Rh] and
L4[Rh] were obtained in DCM (Fig. S18 and S19†) and strong
positive signals can be observed in the absorption region of
quinoline rings between 250 and 500 nm for all the ligands
and L[Rh] complexes, which demonstrate the chiral induction
of (−)-camphanyl for these compounds.
In order to investigate the ability of L3 and L4 to induce the
enantioselectivity in Rh(I)-catalyzed asymmetric hydrogen-
ation, the hydrogenation reactions of α-dehydroamino acid
ester 1a were performed under 7 atm of H2 in CDCl3, toluene
and THF. The ligand L3, in which the 1,3-phenylenediphenyl-
phosphino group at the C-terminus was connected to QOFs by
an ester bond, displays full conversions in the three men-
tioned solvents but with low ee values (Table 1, entries 1–3,
4%–12%, Fig. S43–47†). However, the ligand L4 connecting the
1,3-phenylenediphenylphosphino group at the C-terminus by
an amide bond exhibits an increase in enantioselectivity up to
49% in CDCl3 and 42% in toluene but only 10% in THF
(Table 1, entries 4–6, Fig. S48–51†). These results not only
revealed that the enantioselectivity greatly depends on the
solvent used but also demonstrated that the amide bond at the
C-terminus is beneficial for the enantioselectivity in asymmetric
hydrogenation, which may be because the hydrogen bond
between the amide hydrogen and the nitrogen atom in the adja-
cent quinoline ring enhanced the chiral transmission efficiency
from the chiral foldamer to the produced metal complex that
determined the enantioselectivity of hydrogenation.
Table 1 Optimization for asymmetric hydrogenation of methyl (Z)-2-
acetamido-3-phenylacrylatea
Fig. 3 (a) Coordination structure of L2[Rh], and (b) 1H NMR and (c) 31P
NMR spectra of compounds L1 and L2, and the produced metal com-
plexes L1[Rh] and L2[Rh] in CDCl3 at 298 K.
(Table S1 and Fig S22–42†). These results demonstrated that the
L2[Rh] complex could be used as an efficient catalyst for the
hydrogenation of α-dehydroamino acid esters. L1[Rh] was also
evaluated under the same conditions mentioned above and the
results of the hydrogenation revealed that L1[Rh] is also an
effective catalyst for the hydrogenation reactions (Table S2†).
With these results in hand, we began to introduce the
(−)-camphanyl moiety that can induce a complete P helix even
for trimeric QOFs into the N-termini of L1 and L2, and the
chiral ligands L3 and L4 were synthesized (Scheme 1 and S1†).
To clarify whether the large side chain can alter the chiral
induction ability of the (−)-camphanyl group in the chiral
Entry
Ligand
Solvent
Conv. (%)
ee (%)
1
2
3
4
5
6
7
8
L3
CDCl3
THF
Toluene
CDCl3
THF
Toluene
CDCl3
THF
Toluene
CDCl3
THF
>98
>98
>98
>98
76
>98
10
6
5
>98
>98
>98
8
4
12
49
10
42
—
—
—
0
L4
L5b
L6
9
10
11
12
3
11
Toluene
1
a [Rh(cod)2]BF4 : ligand : substrate = 4/4/100, 7 atm of H2, room temp-
erature, 12 h. The conversions were determined by 1H NMR spec-
troscopy and the ee values were determined by chiral GC using a
Varian Chirasil-L-Val column CP7495 (25 m × 0.25 mm). b The hydro-
genation was performed under 15 atm of H2 for L5.
ligands, the variable temperature (VT) H NMR experiments of
L4 were carried out from 25 to −80 °C in CD2Cl2 and only one
set of signals can be detected in the whole range of tempera-
tures (Fig. S12†), hinting at the absolute helical sense bias of
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Table 2 Asymmetric hydrogenation of α-dehydroamino acid estersa
Given that the structure and steric conformation of the reac-
tive site in catalysts play an important role in the enantio-
selectivity of transition metal complex catalyzed asymmetric
reactions,12 we proposed to modulate the steric hindrance of
the metal-binding site by changing the substituted position of
the phenylenediphenylphosphino group to improve the
enantioselectivity of the asymmetric hydrogenation. We
expected that the ortho-substituted amino-phenylenediphenyl-
phosphino group would increase the steric hindrance, which
would enhance the enantioselectivity of the asymmetric hydro-
genation of α-dehydroamino acid ester 1a; however, the para-
Entry
Substrate (R)
Conv. (%)
ee (%)
1
2
3
4
5
6
7
1a (H)
>98
>98
>98
>98
>98
>98
>98
49
47
49
39
1b (2-OMe)
1c (3-OMe)
1d (4-OMe)
1e (2-Me)
1f (4-F)
48
53 (51)b
54 (48)b
substituted
amino-phenylenediphenylphosphino
group
1g (3-Cl)
decreased the steric hindrance resulting in lower enantio-
selectivity of the hydrogenation. To verify our concept, com-
pounds L5 and L6 were designed and synthesized (Scheme 1
and S1†). The coordination ability of L5 and L6 with Rh
a [Rh(cod)2]BF4 : L4 : substrate = 4/4/100, 7 atm of H2, room tempera-
ture, 12 h. The conversions were determined by 1H NMR spectroscopy
and the ee values were determined by GC using a Varian Chirasil-L-Val
column CP7495 (25 m × 0.25 mm). b The catalyst loading for the ee
values in parentheses is 2 mol%.
1
(cod)2BF4 was tested in CDCl3 and monitored by H NMR and
ESI-MS, which showed that the corresponding cyclic Rh-
complex was formed for L5 when 1.0 equivalent of Rh
(cod)2BF4 was added (Fig. S9, S10 and S17†). The 1H NMR
spectra of L6 and L6[Rh] showed that the signals of L6 dis-
appeared with the emergence of complex patterns of peaks
(Fig. S11†), which revealed that maybe more than one kind of
Rh-complex was formed in the solution. The CD spectra of L5,
L6, L5[Rh] and L6[Rh] showed the chiral amplification of
(−)-camphanyl to cyclic Rh-complexes (Fig. S20 and S21†).
The hydrogenation reaction of α-dehydroamino acid ester
1a using L5[Rh] and L6[Rh] as the catalysts was conducted
under the same conditions mentioned above to assess their
reactivities and enantioselectivities. It is surprising that the
steric hindrance of L5[Rh] is so large that the double bond in
1a cannot coordinate with the catalytically active site, which
resulted in the catalytic activity of L5[Rh] being lowered to a
certain extent, even increasing the pressure of H2 to 15 atm
regardless of the solvent used (Table 1, entries 7–9,
Fig. S52–54†). Complete conversions were obtained in the
three solvents when L6[Rh] was used as the catalyst, but they
were accompanied by rather low ee values of the hydrogenated
product of 1a probably because of the weak steric hindrance
(Table 1, entries 10–12, Fig. S55–57†). The modification of the
substituted position of the amino-phenylenediphenylpho-
sphino group produced tremendous changes in enantio-
selectivities and conversions of asymmetric hydrogenation,
which was indicative of the significance of the steric hindrance
effect.
values (39%–54%). High ee values were provided by the elec-
tron-deficient substrates (Table 2, entries 6 and 7) compared
with the electron-efficient substrates (Table 2, entries 1–5).
Reducing the dosage of L4[Rh] to 2 mol% for 1f and 1g did not
affect the ee values of the hydrogenation products (Table 2,
entries 6 and 7).
Conclusions
In conclusion, we have synthesized a series of chiral bidentate
phosphoric ligands based on single-handed quinoline oligoa-
mide foldamers, which can coordinate with Rh(cod)2BF4 in a
1 : 1 stoichiometry and the produced rhodium complex can be
used for asymmetric hydrogenations. The enantioselectivity
and reactivity of the hydrogenation reaction is highly depen-
dent on the chirality of the metallocycle that is transferred
from the helical chirality and the structure and microenvi-
ronment of the catalytically active site. Complete conversions
and moderate enantioselectivity were obtained in the hydro-
genation of α-dehydroamino acid esters when L4[Rh] was used
as the catalyst, which demonstrated that the chiral foldamers
can be used as a platform for the asymmetric reaction. This
work is expected to trigger further investigation of aromatic
foldamers for the development of chiral ligands for asym-
metric catalysis.
The results summarized in Table 1 show clearly that L4
exerted the best enantioselectivity in the four chiral foldamer-
based ligands and CDCl3 was the best solvent used in which
100% conversion and 49% ee value can be obtained for the
hydrogenation product of 1a. Therefore, some other electron-
efficient or electron-deficient α-dehydroamino acid esters were
applied in the asymmetric hydrogenation under 7 atm of H2 in
the presence of 4 mol% L4[Rh] to further assess the reactivity
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
and enantioselectivity of L4[Rh] and the results are shown in We acknowledge the financial supports from the 973 Program
Table 2 (Fig. S58–69†). All the hydrogenation reactions pro- (2015CB856502) and the National Natural Science Foundation
ceeded smoothly with complete conversions and moderate ee of China (21672026).
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