Enantioselective Hydrogenation of Tetrasubstituted α,β-Unsaturated Carboxylic Acids Enabled by Cobalt(II) Catalysis: Scope and Mechanistic Insights

Article abstract of DOI:10.1002/anie.202016705

Chiral carboxylic acids are important compounds because of their prevalence in pharmaceuticals, natural products and agrochemicals. Asymmetric hydrogenation of α,β-unsaturated carboxylic acids has been widely recognized as one of the most efficient synthetic approaches to afford such compounds. Although related asymmetric hydrogenation of di- and trisubstituted unsaturated acids with noble metals is well established, asymmetric hydrogenation of challenging tetrasubstituted α,β-unsaturated carboxylic acids is rarely reported. We demonstrate enantioselective hydrogenation of cyclic and acyclic tetrasubstituted α,β-unsaturated carboxylic acids via cobalt(II) catalysis. This protocol showed broad substrate scope and gave chiral carboxylic acids in good yields with excellent enantiocontrol (up to 98 % yield and 99 % ee). Combined experimental and computational mechanistic studies support a Co^II catalytic cycle involving migratory insertion and σ-bond metathesis processes. DFT calculations reveal that enantioselectivity may originate from the steric effect between the phenyl groups of the ligand and the substrate.

Full text of DOI:10.1002/anie.202016705

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11384–11390
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doi.org/10.1002/anie.202016705
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Asymmetric Hydrogenation
Enantioselective Hydrogenation of Tetrasubstituted a,b-Unsaturated
Carboxylic Acids Enabled by Cobalt(II) Catalysis: Scope and
Mechanistic Insights
Xiaoyong Du+, Ye Xiao+, Yuhong Yang+, Ya-Nan Duan, Fangfang Li, Qi Hu, Lung Wa Chung,*
Gen-Qiang Chen,* and Xumu Zhang*
Dedicated to the 10th anniversary of Southern University of Science and Technology
Abstract: Chiral carboxylic acids are important compounds
because of their prevalence in pharmaceuticals, natural prod-
ucts and agrochemicals. Asymmetric hydrogenation of a,b-
unsaturated carboxylic acids has been widely recognized as
one of the most efficient synthetic approaches to afford such
compounds. Although related asymmetric hydrogenation of di-
and trisubstituted unsaturated acids with noble metals is well
established, asymmetric hydrogenation of challenging tetra-
substituted a,b-unsaturated carboxylic acids is rarely reported.
We demonstrate enantioselective hydrogenation of cyclic and
acyclic tetrasubstituted a,b-unsaturated carboxylic acids via
cobalt(II) catalysis. This protocol showed broad substrate
scope and gave chiral carboxylic acids in good yields with
excellent enantiocontrol (up to 98% yield and 99% ee).
Combined experimental and computational mechanistic stud-
ies support a CoII catalytic cycle involving migratory insertion
and s-bond metathesis processes. DFT calculations reveal that
enantioselectivity may originate from the steric effect between
the phenyl groups of the ligand and the substrate.
by some noble metals such as ruthenium,[4] rhodium,[5] and
iridium[6] has been successfully and extensively investigated
and applied. However, due to their high steric hinderance and
low reactivity, limited successes have been achieved for the
challenging tetrasubstituted substrates so far,[7] especially for
the more challenging cyclic tetrasubstituted ones (Sch-
eme 1a).[8] Notably, the asymmetric hydrogenation of tetra-
substituted a,b-unsaturated carboxylic acids has drawn the
attention of many synthetic chemists, due to the wide
existence of the resulting products in chiral drugs, natural
products and organocatalysis (Figure 1).[9]
Due to their low cost, high abundance in the earthꢀs crust
and good biological compatibility, the development of earth-
abundant 3d transition metal alternatives to noble-metal
catalysts has attracted increasing interest in homogeneous
catalytic hydrogenation.[10] Especially, catalysts based on
cobalt are highly attractive for asymmetric hydrogenation,[11]
and appreciable progress has been made in recent years.[12]
Very recently, we and the Chirik group independently
reported cobalt-catalyzed enantioselective hydrogenation of
a,b-unsaturated carboxylic acids.[12a,b] The catalytic system
worked well for both di- and trisubstituted unsaturated acids
(Scheme 1b). However, hydrogenation of tetrasubstituted
a,b-unsaturated carboxylic acids is still challenging, and to the
best of our knowledge, asymmetric hydrogenation of cyclic
tetrasubstituted substrates enabled by cobalt or other 3d
Introduction
Chiral carboxylic acids and their derivatives are important
and valuable synthetic intermediates for a wide range of
pharmaceuticals,[1] bioactive compounds[2] and natural prod-
ucts.[3] Transition metal-catalyzed asymmetric hydrogenation
of a,b-unsaturated carboxylic acids is one of the most direct
and efficient protocols for the preparation of chiral carboxylic
acids. During the last few decades, the asymmetric hydro-
genation of di- and trisubstituted unsaturated acids enabled
[*] X. Du,[+] Y. Xiao,[+] Y. Yang,[+] Y.-N. Duan, F. Li, Q. Hu, L. W. Chung,
G.-Q. Chen, X. Zhang
Shenzhen Grubbs Institute and Department of Chemistry
Southern University of Science and Technology
Shenzhen, 518000 (China)
E-mail: oscarchung@sustech.edu.cn
chengq@sustech.edu.cn
zhangxm@sustech.edu.cn
G.-Q. Chen
Academy for Advanced Interdisciplinary Studies
Southern University of Science and Technology
Shenzhen, 518000 (China)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016705.
Scheme 1. Previous works, and the research reported herein, describ-
ing the asymmetric hydrogenation of unsaturated carboxylic acids.
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Table 1: Optimization for CoII-catalyzed asymmetric hydrogenation of
tetrasubstituted a,b-unsaturated carboxylic acids.[a]
Entry
Ligand
X
T [8C] Conv. [%][b] ee [%][c]
[mol%]
1
2
3
4
5
6
7
8
9
10
11
12[d]
13[d]
14[d]
15[e]
16[e]
(Rc,Sp)-DuanPhos
(S)-QuinoxP*
(R)-BenzP*
(S)-Binapine
(S,S)-Me-DuPhos
(S,S)-iPr-DuPhos
(S,S)-Ph-BPE
(R,S)-JosiPhos
(S)-SegPhos
(S)-Ph-O-SDP
(S,S)-Ph-BPE
(S,S)-Ph-BPE
(S,S)-Ph-BPE
(S,S)-Ph-BPE
(S,S)-Ph-BPE
(S,S)-Ph-BPE
10
10
10
10
10
10
10
10
10
10
5
50
50
50
50
50
50
50
50
50
50
50
50
35
rt
84
47
ND
77
56
95
>98
61
ND
ND
82
>98
86
62
3
12
–
58
À18
À44
90
73
–
–
90
90
92
Figure 1. Potential synthetic applications of the asymmetric hydrogena-
tion of tetrasubstituted unsaturated carboxylic acids.
5
5
5
5
metal catalysis is still underexplored. Herein, we reported
a highly efficient and enantioselective CoII-catalyzed hydro-
genation of tetrasubstituted a,b-unsaturated carboxylic acids.
In particular, the first asymmetric hydrogenation of challeng-
ing cyclic tetrasubstituted a,b-unsaturated carboxylic acids
via cobalt(II) catalysis (Scheme 1c).
92
92
91
35
40
95
>98
5
Results and Discussion
Condition optimization. Considering the challenges in
asymmetric hydrogenation of cyclic tetrasubstituted a,b-
unsaturated carboxylic acids, we initiated our investigation
on the asymmetric hydrogenation of the model substrate 1b
by using 10 mol% cobalt(II) catalyst. After screening of
various cobalt(II) precursors and solvents, cobalt(II) stearate
and tBuOH were found to be the best choice, respectively (for
details, see the Supporting Information). It should be noted
that cobalt precursors played a crucial role in the efficiency
and selectivity of current reaction. Furthermore, Zn was not
necessary for the activation the CoII precursor in the current
reaction (Supporting Information, Table S1). Ligand screen-
ing was then investigated and the reactions were conducted
under 80 atm H2 pressure at 508C in tBuOH, in the presence
of 10 mol% of cobalt(II) stearate and 10 mol% of a chiral
ligand as the catalyst. Electron-rich diphosphine ligands
(Rc,Sp)-DuanPhos[13] and (S)-Binapine,[14] which were previ-
ously developed by our group, could not give satisfactory
results (Table 1, entries 1 and 4). P-chiral diphosphine
QuinoxP* and BenzP* gave 2b in very low conversion and
enantioselectivity (entries 2–3). Although moderate to good
conversion were obtained by the Me-DuPhos and iPr-
DuPhos, the ee values were poor (entries 5–6). Notably, the
Ph-BPE was found to be the best one, which afforded the
desired product 2b in > 98% conversion with 90% ee
(entry 7). The reaction using (R,S)-JosiPhos afforded 2b in
61% conversion with 73% ee (entry 8). No desired product
was detected when employing (S)-SegPhos or (S)-Ph-O-SDP
as the ligand (entries 9–10). To further improve the enantio-
control, temperature effect was then investigated in the
[a] Reaction conditions: 1 (0.05 mmol), [Co] (10 mol%), (S,S)-Ph-BPE
(10 mol%) in tBuOH (0.6 mL) under 80 atm H2 pressure at 508C for
24 h. [b] Determined by 1H NMR spectroscopy. [c] Determined by HPLC
analysis. [d] 48 h. [e] 72 h.
presence of 5 mol% of catalyst. 86% conversion of 2b was
achieved at 358C after 48 h (entry 13) and the conversion
could increase to 95% after 72 h (entry 15). The ee value
increased to 92% at rt while the conversion dropped to 62%
(entry 14). To our delight, 2b was obtained in nearly
quantitative conversion with 91% ee under 80 atm H2 at
408C over 72 h (entry 16).
Substrate scope. With the optimized reaction condition in
hand, the substrate scope of cobalt(II)-catalyzed asymmetric
hydrogenation was investigated, and the results were sum-
marized in Scheme 2. (The absolute configuration of the
products was established by comparison of its optical rotation
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a,b,b-Trisubstituted acrylic acids were also subjected to
our [Co]/BPE system due to the corresponding hydrogena-
tion products are key structural component in numerous
bioactive molecules.[15] To our delight, the [Co]/BPE system is
active for the asymmetric hydrogenation of 3a, giving 4a in
96% yield with 90% ee. A wide range of acyclic tetrasub-
stituted a,b-unsaturated carboxylic acids were hydrogenated
smoothly to give chiral a-phenyl isopentyl carboxylic acids in
good to excellent yields and enantioselectivities (Scheme 3).
Substrates with electron-donating (3a–3c, 3 f, 3g) or electron-
withdrawing group (3d, 3e) on the phenyl group were
hydrogenated smoothly to give the desired chiral carboxylic
acids in 85–98% yield and 87–94% ee. Multi-substituted 3h
and 3i bearing 3,4-disubstituted methoxy and methyl groups
also provided excellent results (92% ee, respectively). Exo-
cyclic substrate 3j was also a suitable substrate for the current
reaction, and 93% yield with 97% ee was obtained. The
substrate 3k containing two different substituents at the
b-position were also synthesized and subjected to the [Co]/
BPE system, and 4k with two contiguous stereocenters was
obtained in 90% yield with 80% ee and > 20/1 dr.
Mechanism study. To elucidate the detailed mechanism of
this cobalt(II)-catalyzed asymmetric hydrogenation, a control
experiment and a series of deuterium-labelling experiments
were conducted, and the results were summarized in
Scheme 4. In sharp contrast to the high efficiency exhibited
in the hydrogenation of 1b (85% yield and 91% ee), no
reaction occurred for the corresponding ester 1b’ under the
standard conditions (Scheme 4a). In addition, additives such
Scheme 2. Cobalt-catalyzed asymmetric hydrogenation of cyclic tetra-
substituted a,b-unsaturated carboxylic acids. [a] Reaction conditions:
1 (0.1 mmol), cobalt(II) stearate (5 mol%), (S,S)-Ph-BPE (5 mol%) in
tBuOH (0.6 mL) under 80 atm H2 pressure at 408C for 72 h. Yield of
isolated products, unless noted otherwise. The ee values were deter-
mined by HPLC analysis. [b] With 10 mol% of catalyst.
with previous reports.) Most of the reactions proceeded
smoothly with 5 mol% of the catalyst under 80 atm H2
pressure at 408C, providing the desired products in high
isolated yields and enantioselectivities (90–99% ee). Sub-
strates bearing both electron-donating and electron-with-
drawing groups on the phenyl group were suitable for the
reaction to give the hydrogenation products 2a–2j in good to
excellent yields and enantioselectivities (85–98% yield, 89–
99% ee). Furthermore, the phenyl-deuterated substrate 1k
was efficiently hydrogenated to give the desired product 2k in
92% isolated yield with 90% ee. Compared to b-phenyl-
substituted unsaturated acids, b-naphthyl-substituted sub-
strates generally exhibited better enantioselectivities to give
the desired products 2l–2n (96–97% ee). In addition, the
method also works efficiently for substrates bearing bicyclic
heterocyclic rings, furnishing the chiral acids products 2o and
2p in 95% and 90% isolated yield with 96% and 91% ee,
respectively. The reaction also tolerates substrates bearing
seven- or five-membered ring (1q–1s). 2q and 2r were
obtained in 91% and 94% yield with 82% and 93% ee,
respectively. Moreover, 1s was hydrogenated smoothly to
give 2s in 89% yield with 60% ee.
Scheme 3. Cobalt-catalyzed asymmetric hydrogenation of acyclic tetra-
substituted a,b-unsaturated carboxylic acids. [a] Reaction conditions: 3
(0.1 mmol), cobalt(II) stearate (5 mol%), (S,S)-Ph-BPE (5 mol%) in
tBuOH (0.6 mL) under 80 atm H2 pressure at 408C for 72 h. Yield of
isolated products, unless noted otherwise. The ee values were deter-
mined by HPLC analysis. [b] With 10 mol% of catalyst.
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as Zn have no effect on the asymmetric hydrogenation (for
favorable transition state 2ATS1S leading to the desired
details, see the Supporting Information). These results
revealed that the carboxyl group was essential in this
[Co]/BPE system. It is possibly involved in both the activation
of the pre-catalyst and the control of activity and enantio-
selectivity.
(S)-form final product PS was computed to be lower in free
energy than 2ATS1R forming the (R)-form product PR by
about 2.1 kcalmolÀ1 in solution.[19,20a] This computational
result (equivalent to 94.4% ee) is qualitatively consistent
with the experimental result (90% ee, Scheme 2). Metalla-
2
2
In the presence of D2, 1b was hydrogenated smoothly to
give deuterated product 2b-d2 in > 98% conversion (Sch-
eme 4b). Furthermore, no deuterated product was detected
when the solvent was replaced by tBuOD (Scheme 4c). The
results demonstrated that protonation of the Co-alkyl inter-
mediate was probably not involved in this transformation and
the hydrogen source was H2. The hydrogenation of 1b with
H2/D2 mixture was also conducted, and some mono-deuter-
ated product 2b-d1 was observed, indicating that the hydro-
gen atoms in the product may origin from two molecules of
hydrogen gas (for details, see the Supporting Information).
Besides, a series of CoII-catalyzed asymmetric hydrogenation
of 1b were conducted with (S,S)-Ph-BPE with different
enantiopurities as the ligand under the standard reaction
conditions. A linear effect was observed in this asymmetric
reduction, indicating a 1: 1 binding pattern between (S,S)-Ph-
BPE and cobalt(II) stearate (Supporting Information, Fig-
ure S6).[16] EPR experiments were also conducted to monitor
the process of asymmetric hydrogenation using 1b as model
substrate. Our EPR results suggested that a paramagnetic
CoII species could be involved in the catalytic cycle (Figur-
es S7–S9).
cycle intermediates A2S and A2R can be formed after this
2
insertion. Coordination of one hydrogen molecule to A2S
2
2
2
and A2R then takes place to form A3S and A3R before s-
2
2
bond metathesis via ATS2S and ATS2R to afford the final
products and CoII-hydride species. Alternatively, more stable
intermediates 4A2S and 4A3S can be formed after spin
4
transition prior to ATS2S. Such spin crossing is supported
by our PCM B3LYP-D3//B3LYP-D3, PCM PBE0-D3//PBE0-
D3 and PCM M06-L//M06-L methods (Table S7). Finally,
ligand exchange of the product PS or PR by another substrate
molecule completes the catalytic cycle and regenerates the
4
active species A1S or 4A1R.[20b]
(Relative) distortion/interaction analysis[5b, 21] further sug-
2
gests that, compared to favorable ATS1S, a larger distortion
2
energy in ATS1R plays the dominant role in the enantiose-
lectivity (Figure 3b). In this connection, the phenyl group of
the substrate is oriented into a close (top left) quadrant of the
2
catalyst in ATS1S, in which one phenyl group of the chiral
ligand adapts to stack with the phenyl group of the substrate
(Figure 3a). Whereas, owing to the CoII-carboxylate chela-
tion, the phenyl group of the substrate is forced to be
2
positioned into the two right quadrants in ATS1R, in which
DFT study. On the basis of the previous computational
studies on asymmetric hydrogenation employing 3d metal
catalysts[12f,17] and our control experiments (Scheme 4), sys-
tematic density functional theory (B3LYP-D3 (mainly))
calculations were conducted to understand the origin of the
enantioselectivity.[18] Our computational results suggest that
the active CoII-carboxylate hydride intermediates (A1R or
A1S) preferentially undergo hydrogen insertion into C1 atom
of the substrate (Figure 2) via 2ATS1S and 2ATS1R, which
were computed to be the rate-, regio- and stereo-determining
step with the barriers of about 15.8–17.9 kcalmolÀ1 in solution
by the PCM B3LYP-D3//B3LYP-D3 method. The most
the two phenyl groups have a poor geometric complemen-
tarity. The steric map can also show the steric hindrance of the
chiral ligand in 4A1R, 2ATS1S and 2ATS1R (Figure 3c).[22]
Indeed, the steric repulsion can be partly attributed to
a shorter H-H distance between the substrate and ligand in
2
2ATS1R (1.96 Š vs. 2.12 Š in ATS1S; Figure 3a). Moreover,
their free energy difference was slightly increased by 0.2 kcal
molÀ1 in the absence of dispersion correction (Table S18).
These computational results and our additional calculations
(replacement of the phenyl groups by a smaller methyl
group(s) and its substitution effect evaluated by isodesmic-
reaction approach;[23] Figure S13) support that the steric
effect between phenyl groups of the ligand and the substrate
should play a more critical role in the observed enantio-
selectivity.
Based on our combined mechanistic and DFT (Figure 2)
investigations, a plausible mechanism of cobalt(II)-catalyzed
asymmetric hydrogenation of tetrasubstituted a,b-unsaturat-
ed carboxylic acids was proposed (Scheme 5). After ligand
exchange and heterolytic cleavage of hydrogen, the cobalt(II)
monohydride species 4A1S is formed and then enters the
catalytic cycle.[12b] Metallacycle intermediates 2A2S can be
formed after the migratory insertion of cobalt(II) monohy-
dride 4A1S via transition state 2ATS1S. The migratory insertion
is suggested to be the rate-, regio- and stereo-determining
2
step. Coordination of one hydrogen molecule to A2S then
4
takes place to form A3S. Subsequently, CoII-hydride species
4A4S is produced via s-bond metathesis (4ATS2S). The ligand
exchange of 4A4S with another unsaturated carboxylate
substrate 1a releases the less acidic hydrogenation product
2a and regenerates the cobalt(II) hydride species 4A1S.
Scheme 4. Mechanistic studies for cobalt(II)-catalyzed asymmetric
hydrogenation.
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Figure 2. Free energy profile for the most favorable path (Path A) of the CoII-catalyzed enantioselective hydrogenation with the initial hydrogen
insertion into the C1 atom to form PS and PR products in doublet (red line) and quartet (black line) states in tBuOH solvent by the PCM B3LYP-
D3//B3LYP-D3 (in bold), PCM PBE0-D3//PBE0-D3 (in parentheses) and PCM B3LYP-D3 (in bold purple, in parentheses) methods.
Scheme 5. Proposed catalytic cycle.
Conclusion
Figure 3. a) The optimized key rate-, regio- and enantio-determining
In conclusion, we have developed a highly efficient and
enantioselective hydrogenation of tetrasubstituted unsaturat-
ed a,b-unsaturated carboxylic acids (up to 98% yield and
99% ee) employing an earth-abundant cobalt(II)-catalyst.
The [Co]/BPE system not only works well for challenging
endocyclic substrates, but also shows comparable results with
noble metal-catalyzed hydrogenations in the case of acyclic
tetrasubstituted substrates. Mechanistic investigations were
conducted through combined control experiment, deuterium-
transition states in doublet state in the gas phase by the B3LYP-D3
method. The key distances (Š), key angles (8), and dihedral angles (8)
are given. Unimportant hydrogen atoms are not shown for clarity.
b) Relative distortion-interaction energy analysis on the two key
transition states with relative distortion energy for the metal hydride
and ligand (E°dist,LMH), relative distortion energy for the substrate
(E°dist,sub) and relative interaction energy (E°int) using 2ATS1S as the
reference point by the PCM B3LYP-D3//B3LYP-D3 method. c) Steric
2
map for 4A1R, 2ATS1S and ATS1R (more bulky (red), less bulky
(green)).
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b) G.-Q. Chen, J.-M. Huang, B.-J. Lin, C. Shi, L.-Y. Zhao, B.-D.
labeling experiments and DFT calculations. Our results
revealed that hydrogen was activated through s-bond meta-
thesis rather than oxidative addition (Scheme 5). In addition,
our DFT calculations suggested that the migratory insertion
serves as the rate-, regio- and stereo-determining step, and the
steric effect between phenyl groups of the ligand and the
substrate play a critical role in the enantiocontrol of this
transformation.
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Acknowledgements
This work was sponsored by Shenzhen Nobel Prize Scientists
Laboratory Project (C17213101), Southern University of
Science and Technology (start-up fund), Shenzhen Science
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and
Technology
Innovation
Committee
(Nos.
KQTD20150717103157174 and JCYJ20170817104736009),
and National Natural Science Foundation of China (Nos.
21672096, 21901107, 21991113 and 21933003). The Center for
Computational Science and Engineering at the Southern
University of Science and Technology are appreciated for
partly supporting this work.
Conflict of interest
The authors declare no conflict of interest.
Keywords: cobalt ·DFT calculations ·mechanisms ·
tetrasubstituted unsaturated carboxylic acids
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and B3LYP-D3 methods using larger basis sets. The computed
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2
the most favorable path A via ATS1S by ~ 3.3–11.1 kcalmolÀ1
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Likewise, path B also kinetically favors the formation of the
major product PS with a lower reaction barrier of 7.8 kcalmolÀ1
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Manuscript received: December 16, 2020
Cheng, X. Shen, Z. Lu, J. Am. Chem. Soc. 2017, 139, 15316 – Accepted manuscript online: February 18, 2021
15319; j) D. Zhang, E.-Z. Zhu, Z.-W. Lin, Z.-B. Wei, Y.-Y. Li, J.- Version of record online: April 7, 2021
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