Palladium/Zinc Co-Catalyzed Asymmetric Hydrogenation of γ-Keto Carboxylic Acids

Article abstract of DOI:10.1002/asia.202100244

A palladium-catalyzed asymmetric hydrogenation of levulinic acid has been successful developed by using Zn(OTf)₂ as co-catalyst. The present method not only has provided a strategy in the palladium-catalyzed asymmetric hydrogenation of ketone, but also allowed the preparation of a wide range of chiral γ-valerolactones in good yields with excellent enantioselectivities.

Full text of DOI:10.1002/asia.202100244

DOI: 10.1002/asia.202100244
Communication
Palladium/Zinc Co-Catalyzed Asymmetric Hydrogenation of γ-Keto
Carboxylic Acids
Keyang Zhang+,[a] Xuexin Zhang+,[a] Jingchao Chen,*[a] Zixiu Liu,[a] Chunxiang Pan,[a]
Yuanbin Zhu,[b] Shiyuan Wu,[b] and Baomin Fan*[a]
hydrogenation of ketone is still less developed, and effective
reduction of other valuable substrates is still in demand.
Abstract: A palladium-catalyzed asymmetric hydrogenation
of levulinic acid has been successful developed by using
Zn(OTf)2 as co-catalyst. The present method not only has
provided a strategy in the palladium-catalyzed asymmetric
hydrogenation of ketone, but also allowed the preparation
of a wide range of chiral γ-valerolactones in good yields
with excellent enantioselectivities.
The γ-valerolactone (GVL) moiety is ubiquitous substructure
in natural products and biologically active moleculars, such as
harzialactone A,[8] paraconic acids,[9] steganacin,[10] cardanolide[11]
and others[12] (Figure 2). It has also been frequently used as
intermediate for the synthesis of many valuable products in this
kind.[13] Therefore, it is not strange that many effective methods
were developed for its preparation from levulinic acid (LA), a
cellulose waste used as a low cost biosourced platform
chemical.[14] However, the asymmetric hydrogenation of levu-
linic acid with palladiumcatalyst has not been explored so far.
Our group has a continuous interest in the transition metal/
Lewis acid co-catalysts, which had been proved as powerful
catalysts in many important transformations.[15] Recently, we
have reported the Pd/Zn co-catalyzed chemo-selective hydro-
genation of α-methylene-γ-keto carboxylic acids.[16] In connec-
tion with our previous investigations in the transition metal/
Lewis acid co-catalysis, we here in report a palladium/zinc co-
catalyzed asymmetric hydrogenation of levulinic acid.
Transitional metal-catalyzed asymmetric hydrogenation reaction
is one of the most fundamental reactions and widely used in
the organic synthetic industry due to its high efficiency in the
preparation of enantiomerically pure compounds. The asym-
metric hydrogenation of ketones has provided a powerful
synthetic route with 100% atom efficiency to chiral alcohols.[1]
Since the first-generation of Ru-Binap catalysts have been
developed in 1987, the ruthenium catalysts have become the
dominant choice.[2] In the past three decades, chiral Rh,[3] and
Ir[4] complexes were also extensively investigated, benefited
from the successful development of new chiral ligands. On the
contrary, although palladium is relatively cost-effective among
the noble metals and successfully used in other enantioselective
transformations, palladium-catalyzed homogeneous asymmetric
hydrogenation of ketones is relatively less developed. In this
context, the group of Zhou has reported the first example of
highly enantioselective palladium-catalyzed asymmetric hydro-
genation of functionalized ketones with (R,R)-Me-Duphos as
chiral ligand (Figure 1).[5a] They have explored this kind of
reactions thereafter by the strategies such as dynamic kinetic
resolution, desymmetrization, and the employing of Brønsted
acids.[5b–d] Zhang and co-workers have studied the palladium-
catalyzed asymmetric hydrogenation of α-acyloxy-1-aryletha-
nones and α-phthalimide ketones with excellent results.[6]
Despite the advantages,[7] the palladium-catalyzed asymmetric
[a] K. Zhang,+ X. Zhang,+ Dr. J. Chen, Z. Liu, C. Pan, Prof. B. Fan
Key Laboratory of Chemistry in Ethnic Medicinal Resources (Yunnan Minzu
University)
Figure 1. Represented Pd-catalyzed asymmetric hydrogenation of ketones.
State Ethnic Affairs Commission & Ministry of Education
Kunming, 650500 (P. R. China)
E-mail: chenjingchao84@163.com
FanBM@ynni.edu.cn
[b] Y. Zhu, S. Wu
Yunnan Tiefeng High Tech Mining Chemicals Co.Ltd
Qingfeng industrial park, Lufeng, 651200 (P. R China)
[+] These authors contributed equally.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202100244
Figure 2. Represented biologically active γ-valerolactones.
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Communication
Initially, a range of chiral ligands were investigated in the
hydrogenation of levulinic acid (1a) with Pd(OAc)2/Zn(OTf)2 co-
catalytic system (Scheme 1). By using (R)-Binap, γ-valerolactone
2a was obtained in 25% yield with 71% ee under normal
presure of hydrogen gas. Then, some other biphenylbisphos-
phine ligands were screened. Among them, (R)-DM-Segphos
performed well than the others to give 2a in excellent yield but
with moderate ee. The chiral spiro bidentate ligand (R)-Xyl-SDP
gave poor result. To our delight, (1S,1’S,2R,2’R)-DuanPhos and
(R,R)-QuinoxP* won out with excellent results in view of both
yield and enantioselectivity. (R,R)-Me-Duphos and (R,R)-iPr-
Duphos also afforded the desired product with excellent yields
albeit with inferior enantioselectivities. Although quantitative
yield was obtained by (R,S)-PPF-PtBu, the ee of the products was
low. Other chiral ligands such as (R,R)-Bdpp and (R,R)-Diop were
not suitable for the present reaction due to their poor catalytic
activities. Therefore, (R,R)-QuinoxP* was selected as the chiral
ligand for further study.
Next, the reaction conditions were studied by surveying the
Lewis acids and solvents (Table 1). The control experiment has
verified the necessary of the Lewis acid as the reaction failed to
give any product in its absence whether under normal pressure
or 2 Mpa H2 (Table 1, entries 2–3). By using other trifluoromesy-
lates instead, AgOTf failed to promote the reaction (Table 1,
entry 4), and Cu(OTf)2 led to a poor result (Table 1, entry 5).
Although Fe(OTf)2 and Fe(OTf)3 were suitable additives, the
reaction outcomes were inferior to that of Zn(OTf)2 (Table 1,
entries 6&7 vs entry 1). Other Lewis acids, such as ZnCl2,
Zn(OAc)2, and Fe(OAc)2 were not efficient (Table 1, entries 8–
10). In the solvent investigations, DCE was still the optimal
solvent despite THF and 1,4-dioxane were also suitable (Table 1,
entries 11–15).
With the optimized conditions in hand, we investigated the
scope of present protocol for different γ-keto carboxylic acids
(Scheme 2). γ-Keto carboxylic acids with fluoro and chloro
substituents on the para and meta positions of the phenyl ring
were well tolerated to give the corresponding chiral γ-
valerolactones (2b–e) in excellent results. And the substrates
with di-chloro substituents also reacted well, thus allowing the
Scheme 1. Chiral ligand screening for the asymmetric hydrogenation
reaction of 1a. Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (5 mol%),
°
Ligand* (6 mol%), and Zn(OTf)2 (10 mol%) in DCE (2.0 mL) at 70 C for the
time indicated. [a] 2a was obtained with S-configuration.
Table 1. Optimization of the reaction conditions.[a]
entry
solvent
additive
time [h]
yield[b] [%]
ee[c] [%]
1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
TFE
THF
1,4-dioxane
MeOH
Zn(OTf)2
–
–
6
98
94
–
–
2
48
48
48
48
30
18
48
48
30
12
12
36
24
24
NR
NR
Trace
19
82
93
11
21
NR
91
98
3[d]
4
AgOTf
–
5
6
7
8
Cu(OTf)2
Fe(OTf)2
Fe(OTf)3
ZnCl2
Zn(OAc)2
Fe(OAc)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
10
93
90
83
77
–
83
37
87
89
85
9
10
11
12
13
14
15
90
97
32
Scheme 2. Reaction scope investigation. Reaction conditions: 1 (0.2 mmol),
Pd(OAc)2 (5 mol%), (R,R)-QuinoxP* (6 mol%), and Zn(OTf)2 (10 mol%) in DCE
°
[a] Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (5 mol%), (R,R)-QuinoxP*
(2.0 mL) at 70 C for the time indicated. [a] Results in the brackets were
°
(6 mol%), and additive (10 mol%) in DCE (2.0 mL) at 70 C for the time
obtained by using the corresponding ethyl esters of 1 as reactant. [b]
Obtained by using 4-(4-nitrophenyl)-4-oxobutanoic acid as reactant. [c]
Reacted under normal pressure.
indicated. [b] Yield of the isolated product. [c] ees were determined by
chiral-phase HPLC. [d] Reacted under 2 Mpa.
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Communication
DCE (1 mL). After stirring 30 min, Zn(OTf)2 (7.3 mg, 0.02 mmol) and
4-oxo-4-phenylbutanoic acid (35.6 mg, 0.2 mmol) were added, then
dry DCE (1.0 mL) was added to the reaction mixture by using a
syringe. Then after replacing nitrogen with hydrogen for three
times, hydrogen was continuously injected into the reaction in
further elaborations of the product via the cross coupling
reactions. The reaction performed well with CF3 group on the
phenyl ring (2h–i), but only 48% ee was observed by that on
the ortho position (2j). The present protocol is effective for the
hydrogenation of nitro group on the phenyl ring as indicated
by 2k. Moreover, the present methodology is applicable for the
alkyl levulinic acids to afford the chiral γ-valerolactones (2l–n)
in good yields with excellent optical purities. And the
corresponding ethyl ester of 1l was hydrogenated smoothly.
°
0.1 MPa. Finally, after stirred at 70 C (oil bath) for 6 h, the reaction
mixture was purified by silica gel chromatography (PE/EA=6:1) to
give product 2a (98%).
Besides, the γ-keto carboxylic acids with naphthyl and biphe- Acknowledgements
nylyl groups were also applicable (2p–q).
According to the related literatures of transitional metal
catalyzed hydrogenation of γ-keto carboxylic acids,[14b,17]
We are grateful to the National Natural Science Foundation of
a
China (21961045, 21572198, 22061048), the Applied Basic
Research Project of Yunnan Province (2017FA004, 2018FB021),
Yunnan Provincial Key Laboratory Construction Plan Funding of
Universities, Yunnan Provincial Engineering Research Center
Construction Plan Funding of Universities for their financial
support.
proposed reaction mechanism is shown in Scheme 3. Firstly, the
reaction of chiral palladium complex with hydrogen affords the
chiral palladium dihydride, which coordinates with 1 to give
intermediate A. Subsequently, A is transferred to B by migratory
insertion of the PdÀ H into the keto group. Then, B has attracted
a proton to generate intermediate C. Next, C is hydrogenated
and depronated to give intermediate D. And the ligand-
exchange reaction of intermediate D with the 1 affords E and Conflict of Interest
regenerates A. Finally, the lactonization of E results chiral γ-
valerolactone 2.
The authors declare no conflict of interest.
In summary, a powerful asymmetric hydrogenation method
of various γ-keto carboxylic acids was developed successfully.
The catalytic system constituted of Pd(OAc)/(R,R)-QuinoxP*
complex and Zn(OTf)2 as Lewis acid co-catalyst, which allowed
the preparation of a wide range of chiral γ-valerolactones.
Further synthetic applications of this methodology for the
valuable molecules are ongoing in our laboratory.
Keywords: palladium · hydrogenation · ketone · valerolactone ·
levulinic acid
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Manuscript received: March 10, 2021
Revised manuscript received: April 12, 2021
Accepted manuscript online: April 14, 2021
Version of record online: April 26, 2021
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