Ferrocenyl chiral bisphosphorus ligands for highly enantioselective asymmetric hydrogenation via noncovalent ion pair interaction

Article abstract of DOI:10.1039/c6sc01845a

A new class of ferrocenyl chiral bisphosphorus ligand, Wudaphos, was developed, and exhibits excellent ee and activity (ee up to 99%, TON up to 20000) for the asymmetric hydrogenation of both 2-aryl and 2-alkyl acrylic acids through ion pair noncovalent interaction under base free and mild reaction conditions. Well-known anti-inflammatory drugs such as naproxen and ibuprofen together with the intermediate for the preparation of Roche ester and some bioactive compounds were also efficiently obtained with excellent ee. Control experiments were conducted and revealed that the ion pair noncovalent interaction and chain length played important roles.

Full text of DOI:10.1039/c6sc01845a

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DOI: 10.1039/C6SC01845A
Journal Name
ARTICLE
Ferrocenyl
chiral
bisphosphorus
ligands
for
highly
enantioselective asymmetric hydrogenation via the noncovalent
Received 00th January 20xx,
Accepted 00th January 20xx
ion pair interaction
Caiyou Chen,a Heng Wang,a Zhefan Zhang,a Shicheng Jin,a Songwei Wen,a Jianjian Ji,a Lung Wa
DOI: 10.1039/x0xx00000x
Chung,b Xiu-Qin Dong,a* and Xumu Zhang a, b
*
www.rsc.org/
A new class of ferrocenyl chiral bisphosphorus ligands, Wudaphos, was developed, which exhibits excellent
ee and activity (ee up to 99%, TON up to 20, 000) for the asymmetric hydrogenation of both 2-aryl and 2-alkyl
acrylic acids through the ion pair noncovalent interaction under base free and mild reaction conditions. Well-
known anti-inflammatory drugs such as Naproxen and Ibuprofen together with the intermediate for the
preparation of Roche ester and some bioactive compounds were also efficiently obtained with excellent ee.
Control experiments were conducted that revealed the ion pair noncovalent interaction and chain length
played important roles.
noncovalent interactions are responsible for many of the
remarkable rate accelerations and stereoselectivity
improvements by lowering the kinetic barrows through the
Introduction
Since 1960s, exploration of new efficient chiral phosphine ligands
remains continuous work for transition-metal catalyzed
stabilization of the transition state and suppressing the degree
of the freedom in the transition state.3 Consequently, intensive
research efforts have been directed toward the development
of new efficient catalytic system utilizing attractive
noncovalent interactions.4 As summarized by Jacobson et al.
(Table 1),3 among the three representative noncovalent
interactions, the steric repulsion is highly distance dependent
(1/r12) wherein weak interaction was observed with long
distance. H-bond interaction (1/r2) and ion pair interaction (1/r)
are relatively less distance dependent and the ion pair
interaction showed the strongest interaction. We anticipated
that the strong ion pair noncovalent interaction can be utilized
in the development of new efficient catalytic system for
asymmetric hydrogenation (AH), wherein the substrates can
interact with the catalyst strongly, accelerating the reaction
rate to a large extent. However, few examples have been
reported concerning of the strong ion pair noncovalent
interaction and the substrate scope was limited.5
a
asymmetric reactions.1 Development of new asymmetric reactions
largely relies on the exploration of new efficient chiral phosphine
ligands.2 As a result, the research of developing more efficient and
practical phosphine ligands in terms of excellent enantioselectivity
and activity, good air stability, ease of preparation, remains highly
desirable in asymmetric catalysis.
Table 1 Distance dependencies of the representative noncovalent
interactions.
Entry
Noncovalent interaction
Steric repulsion
H-bond
Energy dependence
on distance
1
2
3
1/r12
Complicated ~ 1/r2
1/r
Ion pair
Attractive noncovalent interactions play a key role in the
design of catalysis. Similar to the enzymatic catalysis, attractive
Scheme 1. The new ferrocenyl ligands and the corresponding model of the three
hindered quardrants. L = large substitutent, S = small substitutent, Ferr =
ferrocene.
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With regard to the utilization of the strong ion pair noncovalent neutralize the free acid.19 This method is non-direct and needs
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DOI: 10.1039/C6SC01845A
interaction in the development of new chiral catalysts for AH, we additional procedure to remove the base. Herein we report a
found the Ugi’s amine is a privileged motif in which the dimethyl ferrocenyl catalytic system that can finely utilize the free acid
amine moiety can play as a proton acceptor which can interact with via the attractive noncovalent ion pair interaction to realize
the acid substrates strongly through the noncovalent ion pair this valuable transformation in a direct and concise way
interaction (Scheme 1). Moreover, the Ugi’s amine motif can without any base with ee (enantiomeric excess) up to 99% and
conveniently incorporate planar chirality, C-chirality and P-chirality TON up to 20, 000 (Scheme 3).
into the catalytic system as exemplified by many efficient chiral
ligands such as Josiphos,6 Walphos,7 Taniaphos,8 Bophoz,9
Mandyphos,10 TRAP,11 Trifer5a and Chenphos5b. Herein, we report a
new class of bisphosphorus ligands incorporating the Ugi’s amine
motif (Scheme 1). This type of bisphosphorus ligands possesses one
chiral phosphine and the chiral Ugi’s amine moiety. Two large
substituents of the non-chiral phosphine together with the ferrocene
backbone block three quadrants and the small substituent of the
Scheme 3. AH of 2-substituted acrylic acids.
chiral phosphine makes the remaining quadrant open. This three
blocked quadrant model is believed to have good chiral induction.12
Results and discussion
Furthermore, the dimethyl amine unit in the ligand can be a proton
acceptor thus can interact with the acid substrates through the
noncovalent ion pair interaction. According to the above hypothesis,
this catalytic system is believed to exhibit excellent
enantioselectivity and activity in the AH of unsaturated acid
substrates.
Scheme 2. Representative drugs and chemicals featuring the -substituted
propanoic acid moiety.
AH of 2-substituted acrylic acids will generate chiral
-
substituted propanoic acids which are important units that
widely exist in pharmaceuticals and fine chemicals (Scheme 2).
Good examples are the well-known non-steroid anti-
inflammatory and analgesic drugs such as naproxen, ibuprofen
and flurbiprofen,13 the esterification potent inhibitors
4
against the inflammatory phenotype of the cystic fibrosis (CF)
Scheme 4. Synthesis of the ferrocenyl new bisphosphorus ligands.
lung disease,14 the bioactive natural product
5
isolated from
The new ferrocenyl bisphosphorus ligands we report herein
can be easily synthesized in two-pot with very high
diastereoselectivity (dr > 99:1) (Scheme 4). Starting from (S)-
the Fusarium oxysporum which shows cytotoxicity against
three human cancer cell lines PC-3, PANC-1 and A549,15 and
artemisnin16 which is a famous drug against Plasmodium
falciparum malaria that won the 2015 Nobel Prize in medicine.
Ugi’s amine, one pot sequential reaction gave
1
efficiently.
single
Importantly, compound was obtained as
1
a
Furthermore, -substituted propanoic acid can also be used to
diastereomer as determined by NMR which makes the
synthesis to be very simple and practical. The subsequent
lithiation followed by treating with different chlorophosphines
prepare the synthetically important Roche ester, a well-known
synthon in total synthesis.17 Although AH of 2-substituted
acrylic acids was previously realized by chiral Ru catalysts,18
the reactions were limited by the generally required high
pressure. Chiral Rh and Ir catalysts have also recently been
reported to realize this valuable transformation.19 However,
most of these catalytic systems need an equivalent base to
afforded the desired ligands L1-L5 in good yields. Moreover,
the absolute configuration of L1 was determined by X-ray
spectrum analysis as (Sc, RFC, Sp).20 Importantly, ligands L1-L5
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are all highly air stable even storing under air for more than (Table 3, 3a-3e), electron withdrawing (Table 3, 3h), or halogen
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one year.
(Table 3, 3f-3h). 2-Alkyl acrylic acids DwOIe:r1e0.10a3ls9o/C6sSmC0o1o8t4h5lAy
With ligands L1-L5 in hand, AH of 2-substituted acrylic acids was hydrogenated with high ee (Table 3, 3i, 3j, 3m). Thus, the
initiated by evaluating ligand effects using 2-phenyl acrylic acid 2a intermediate for the preparation of Roche ester was conveniently
as a model substrate (Table 2). We are pleased to find that the obtained in high ee (Table 3, 3m). Furthermore, the well-known
substrate was all smoothly converted except when using L5 as the anti-inflammatory drugs ibuprofen and naproxen were also easily
ligand (Table 2, entry 5) in the absence of any base. The obtained in excellent ee under mild conditions (Table 3, 3k, 3l). Our
hydrogenation results highly depended on the ligand structure. catalyst system shows clear advance compared with the previous
With L1, good ee was obtained (Table 2, entry 1). Changing the systems owing to its high enantioselectivity and base free
phenyl group in L1 into cyclohexyl group (L2, Table 2, entry 2), the conditions.
ee significantly increased to 98%. However, to our surprise, further
changing the phenyl group into the steric bulky t-butyl group
resulted in a very low ee and the product configuration was
changed from (S) to (R) (L3, Table 2, entry 3). This is probably due to
the much too big steric hindrance of the t-butyl group which
influences the noncovalent ion pair interaction between the ligand
and substrate. Further changing the phenyl group into the p-tolyl
group resulted in decreased ee (L4, Table 2, entry 4). Using L5 as
ligand with a phenyl group instead of a methyl group attached to
the chiral phosphine, the ee dropped significantly (L5, Table 2, entry
5). This result corresponds to the hypothesis we made that the
ligand should have three blocked quadrants and make the
remaining quadrant open in order to get good enatioselectivities
(Scheme 1). In terms of the reactivity and enantioselectivity, L2 was
selected as the optimum ligand for the further investigation. Due to
the remarkable performance, herein we name L2 as Wudaphos.
Table 3 Substrate scope using Wudaphos as the ligand. a
Table 2 Ligand effects in the asymmetric hydrogenation of 2-phenyl acrylic
acids.a
Entry
Ligand
Conv.% b
> 99
Ee% c
84
Configurationd
1
2
3
4
5
L1
(S)
(S)
(R)
(S)
(S)
a
The reaction was conducted in 0.1 mmol scale in 1 mL of EtOH, [Rh(NBD)2]BF4
Wudaphos
> 99
98
(NBD = norbornadiene) was used as metal precursor, wudaphos was used as
ligand, S/C = 100, L/Rh = 1.1:1, temperature = rt, H2 pressure = 1 bar, reaction
time = 6 h, the configuration of all the product was determined as (S) by
comparing the optical rotation data with those reported by the literature, ee was
determined by chiral HPLC after esterification with CH2N2, conversion of the
substrates was determined by 1H NMR.
L3
L4
L5
> 99
33
> 99
74
67
57
Asymmetric hydrogenation of 2-substituted acrylic acids was also
conducted with low catalyst loading using 2a as a model substrate
under 50 bar H2 atmosphere. Satisfyingly, our catalyst system
showed excellent activity under very mild condition in the absence
of any base when the catalyst loading was 0.02 mol% (S/C = 5, 000)
without any decrease of ee (Table 4, entry 1). Moreover, the
hydrogenation also proceeded smoothly with full conversion and
high ee when lowering the catalyst loading to 0.01 mol% (S/C = 10,
000, Table 4, entry 2) or 0.005 mol% (S/C = 20, 000, Table 4, entry 3)
albeit with slight drop of ee. As shown in scheme 5, the potent
inhibitors 418 and the bioactive natural product 519 can be readily
synthesized following literature procedures starting from the
hydrogenation product 3a.
a
The reaction was conducted in 0.1 mmol scale in 1 mL of EtOH, [Rh(NBD)2]BF4
(NBD = norbornadiene) was used as metal precursor, S/C = 100, L/Rh = 1.1:1,
temperature = rt, H2 pressure = 1 bar, reaction time = 6 h. b Substrate conversion,
determined by 1H NMR. enantiomeric excess of 3a, determined by chiral HPLC
c
after treating 3a with CH2N2. d Configuration of 3a, determined by comparing the
optical rotation data with those reported by the literature.
Subsequently, substrate scope of the AH of 2-substituted acrylic
acids was investigated using the optimum ligand Wudaphos under
the best reaction conditions (For the screening of the reaction
conditions and the discussion of the solvent effects, see supporting
information). As listed in Table 3, 2-aryl acrylic acids were efficiently
hydrogenated with excellent enantioselectivities under mild
reaction conditions in the absence of any base regardless of
whether the substituents on the phenyl ring were electron donating
In order to gain more insights into this catalyst system, several
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Table 4 TON experiment with Wudaphos as the ligand. a
ion pair noncovalent interaction between ligand and acid substrates
is critical (Scheme 6).
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DOI: 10.1039/C6SC01845A
On the basis of the observed (S)-enantioselectivity, the X-ray
crystal structure of ligand L1 (Scheme 1) and previous
computational studies,21 3D models were built to account for the
important roles of the ion pair interaction and the small substituent
on the phosphine ligand (Scheme 7). The favorable ionic pair
interaction is present and the phenyl group on the substrate
experience a less repulsion with the phosphine ligand for the (S)-
hydrogenation. Whereas, such ionic pair interaction cannot form
and the phenyl group on the substrate has a larger repulsion with
the ferrocenyl group for the (R)-hydrogenation. These 3D models
also correspond to the hypothesis we made that the good
enantiomeric control of the Wudaphos is based on the three
hindered quadrant model.
Entry
S/C
Time (h)
Conv.% b
> 99
Ee% c
98
1
2
3
5, 000
10, 000
20, 000
6
12
24
> 99
97
> 99
96
a The reaction was conducted in EtOH, [Rh(NBD)2]BF4 (NBD = norbornadiene) was
used as metal precursor, wudaphos was used as ligand L/Rh = 1.1:1, temperature
= rt, H2 pressure = 50 bar. Substrate conversion, determined by 1H NMR.
b
c
enantiomeric excess of 3a, determined by chiral HPLC after esterification with
CH2N2.
Scheme 5. Synthesis of the potent inhibitors 4 and the bioactive natural product
5.
control experiments were also conducted. The effect of chain
length between the olefin and the acid moiety was first investigated.
It was found that chain length played an important role in
determining the ee. Although hydrogenation of compounds 6, 7 and
2a all proceeded smoothly, the ee obtained in the hydrogenation of
6 and 7 was very low (Scheme 6), which indicated that excellent
enantiomeric control was based on a matched chain length.
Subsequently, the effect of the ion pair noncovalent interaction was
also investigated. Hydrogenation of the ester substrate 8 didn’t
occur at all. The ee of the hydrogenation of 2a also dropped
evidently when adding 0.5 equivalent of Cs2CO3. Moreover, only
racemic product was observed when one equivalent amount of
triethylamine was added. It is probably due to the reason that the
ion pair interaction between the ligand and substrate was
interrupted by the additional base. These results suggested that the
Scheme 7. 3D models and the predicted enantiomeric control
Conclusions
In summary, a new class of ferrocenyl chiral bisphosphorus
ligands, Wudaphos, was developed. The Wudaphos type
ligands are highly air stable and exhibit excellent ee and
activity (ee up to 99%, TON up to 20, 000) for the asymmetric
hydrogenation of both 2-aryl and 2-alkyl acrylic acids.
Importantly, the hydrogenation reaction was efficiently
realized through the attractive ion pair noncovalent
interaction in base free and mild reaction conditions, which
shows clear advance compared with the previous catalytic
system. Well-known anti-inflammatory drugs such as naproxen
and ibuprofen together with the intermediate for the
preparation of Roche ester and some bioactive compounds
were efficiently obtained with excellent ee. Control
experiments were conducted that revealed the ion pair
noncovalent interaction played an important role and the
excellent enantiomeric control was based on the matched
chain length between the olefin and the acid moiety.
Scheme 6. Control experiments for the investigation of chain length effect and
the ion pair noncovalent interaction effect.
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16 (a) Y. Tu, M. Ni, Y. Zhong, L. Li, S. Cui, M. Zhang, X. Wang, X.
Acknowledgements
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DOI: 10.1039/C6SC01845A
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We are grateful for financial support by the grant from Wuhan
University (203273463, 203410100064), “111” Project of the
Ministry of the Education of China and the National Natural Science
Foundation of China (Grant No. 21372179, 21432007, 21502145).
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The new ferrocenyl bisphosphorus ligand, Wudaphos, was developed for highly enantioselective asymmetric hydrogenation based
on the noncovalent ion pair interaction.
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