Highly Chemo- And Enantioselective Hydrogenation of 2-Substituted-4-oxo-2-alkenoic Acids

Article abstract of DOI:10.1021/acs.orglett.0c01618

The highly chemo- and enantioselective hydrogenation of (E)-2-substituted-4-oxo-2-alkenoic acids was established for the first time using the Rh/JosiPhos complex, affording a series of chiral α-substituted-γ-keto acids with excellent results (up to 99% yield and >99% ee) and high efficiency (up to 3000 TON). In addition, the importance of this methodology was further demonstrated by a concise and gram-scale synthesis of the anti-inflammatory drug (R)-flobufen.

Full text of DOI:10.1021/acs.orglett.0c01618

pubs.acs.org/OrgLett
Letter
Highly Chemo- and Enantioselective Hydrogenation of
2‑Substituted-4‑oxo-2-alkenoic Acids
Xian Liu, Jialin Wen, Lin Yao, Huifang Nie, Ru Jiang,* Weiping Chen,* and Xumu Zhang*
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ABSTRACT: The highly chemo- and enantioselective hydrogenation of (E)-2-substituted-4-oxo-2-alkenoic acids was established
for the first time using the Rh/JosiPhos complex, affording a series of chiral α-substituted-γ-keto acids with excellent results (up to
99% yield and >99% ee) and high efficiency (up to 3000 TON). In addition, the importance of this methodology was further
demonstrated by a concise and gram-scale synthesis of the anti-inflammatory drug (R)-flobufen.
Scheme 1. Representative Approaches to Chiral α-
Substituted-γ-Keto Acids
hiral α-substituted-γ-keto acids are common motifs found
in many chiral drugs and natural products. Important
C
examples of this family molecules include (R)-(+)-flobufen,1a
(R)-tanomastat,1b (R)-esonarimod,1c ganoderic acids,1d bisde-
hydrostemoninine A,1e (+)-applanatumol S,1f and fornicin C
(Figure 1).1g This motif could also play an important role as a
chiral backbone for the synthesis of bioactive compounds such
as human neutrophile elastase inhibitors2a and angiotensin-
converting enzyme inhibitors2b and the total synthesis of
natural products.2c
Intrigued by the great importance, significant efforts have
been made to develop synthetic approaches toward the
enantioselective construction of chiral α-substituted-γ-keto
acids. There have been several representative methods for the
synthesis of chiral α-substituted-γ-keto acids, including the
alkylation reaction or the coupling reaction using chiral
Received: May 12, 2020
Figure 1. Representative chiral drugs and natural products with an α-
substituted-γ-keto acid motif.
https://dx.doi.org/10.1021/acs.orglett.0c01618
Org. Lett. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Organic Letters
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Letter
Table 1. Screening Ligands for the Asymmetric
Table 2. Optimization of the Reaction Conditions for the
Asymmetric Hydrogenation of (E)-2a
a
Hydrogenation of (E)-2-Methyl-3-benzoylpropenoic Acid
a
2a
b
c
entry
solvent
MeOH
EtOH
i-PrOH
CF3CH2OH
EtOAc
DCM
metal precursor
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
[Rh(NBD)2]BF4
[Rh(NBD)2]BF4
[Rh(NBD)2]BF4
[Rh(NBD)2]BF4
[Rh(NBD)2]BF4
[Rh(NBD)2]BF4
[Rh(NBD)2]BF4
[Rh(NBD)2]BF4
[Ir(COD)Cl]2
>99
>99
>99
>99
>99
96
95
>99
36
97
97
98
97
90
79
95
78
NA
NA
95
THF
MTBE
MeOH
MeOH
MeOH
9
10
11
[Rh(COD)Cl]2
[Rh(NBD)Cl]2
53
>99
a
Reaction conditions: 0.2 mmol scale, [substrate] = 0.2 mol·L−1,
solvent = 1.0 mL, 1.0 mol % of catalyst (metal/SL-J404-1 1:1.1).
b
c
1
Conversions were determined by H NMR analysis. Enantiomeric
excesses were determined by chiral HPLC analysis using a chiral
column after the products were converted to the corresponding
amides.
b
c
entry
ligand
Trifer
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
>99
>99
>99
>99
>99
>99
80
89
76
96
97
90
96
−63
87
ChenPhos
SL-J005-1
SL-J404-1
SL-J008-1
SL-J418-1
(R)-BINAP
DuPhos
because of the lack of a coordinating group at the β-position of
the double bond, the enantiocontrol in the asymmetric
hydrogenation of (E)-2 might also be a problem. Therefore,
we are focused on the highly chemo- and enantioselective
hydrogenation of internal conjugate acid (E)-2 (Scheme 1d).
Our investigation was initiated by using (E)-2-methyl-3-
benzoylpropenoic acid 2a as the model substrate. When TriFer
and ChenPhos were used as ligands,9 the Rh-catalyzed
hydrogenation gave excellent chemoselectivities (100%) but
moderate enantioselectivities (89 and 76% ee, respectively)
(Table 1, entries 1 and 2). Then, the ferrocene-based
bisphosphine ligand JosiPhos family was screened. To our
delight, better results were obtained (entries 3−6), and the
ligand SL-J404-1 afforded the best results (>99% conversion
and 97% ee) (entry 4). Other well-known diphosphine ligands,
such as (R)-BINAP, Duphos, and (R)-SegPhos, showed less
attractive catalytic results (entries 7−9). The absolute
configuration of 3a was assigned by a comparison of its
optical rotation with the reported value.5d
>99
>99
(R)-SegPhos
−76
a
Reaction conditions: 0.2 mmol scale, [substrate] = 0.2 mol·L−1,
solvent = 1.0 mL, 1.0 mol % of catalyst [Rh(NBD)2]BF4/ligand 1:1.1,
b
9 h. Conversions were determined by 1H NMR analysis.
c
Enantiomeric excesses were determined by chiral HPLC analysis
using a chiral column after the products were converted to the
corresponding amides.
precursors (Scheme 1a),3 the organometallic-catalyzed enan-
tioselective Friedel−Crafts alkylation (Scheme 1b),4 and the
asymmetric hydrogenation of α-methylene-γ-keto-carboxylic
acids (Scheme 1c).5
It is well known that catalytic asymmetric hydrogenation6 is
one of the most efficient, environmentally friendly, and cost-
effective approaches to various chiral compounds. Among
these reported methods, the chemo- and enantioselective
hydrogenation of α-methylene-γ-keto-carboxylic acid 1 has
been one of the most efficient and straightforward approaches
to chiral α-substituted-γ-keto acids. However, the terminal C
C bond undergoes rapid isomerization, shifting to the
thermodynamically more stable internal conjugate acid (E)-
2.7 Therefore, it might be more practical to synthesize chiral α-
substituted-γ-keto acids by the chemo- and enantioselective
hydrogenation of this internal conjugate acid (E)-2.
α-Methylene-γ-keto-carboxylic acid 1, which bears a
coordinating carbonyl group at the β-position of the CC
double bond, enables efficient enantioinduction in hydro-
genation due to the secondary coordination.8 Unlike terminal
olefin 1, the conjugate groups make internal olefin in (E)-2
more challenging for asymmetric hydrogenation. In addition,
Next, the solvent and metal precursors for the hydro-
genation were investigated with the ligand SL-J404-1 (Table
2). Among polar solvents, the enantioselectivities enhanced
with the increase in the bulkiness of the alcohols, whereas the
conversions remained excellent (entries 1−4, Table 2). i-PrOH
was highly beneficial in terms of enantioselectivity and catalytic
activity (>99% conversion, 98% ee) (entry 3, Table 2). Polar
aprotic solvents such as EtOAc, MTBE, THF, and DCM gave
less attractive results. Cationic [Rh(NBD)2]BF4 was superior
to the neutral precursor [Rh(NBD)Cl]2 with respect to
enantioselectivity (97 vs 95% ee) (entry 1 vs 11, Table 2).
Other metal precursors [Rh(COD)Cl]2 and [Ir(COD)Cl]2
showed poor catalytic activity under the reaction conditions
(entries 9 and 10, Table 2).
With the optimized conditions in hand ([Rh(NBD)2]BF4/
SL-J404-1 in i-PrOH under 15 atm hydrogen pressure at room
temperature), we turned our attention to explore the substrate
scope. A variety of 2-methyl-4-oxo-2-alkenoic acids (E)-2 were
B
https://dx.doi.org/10.1021/acs.orglett.0c01618
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pubs.acs.org/OrgLett
Letter
as well as the locations of substituents on the fused benzene
ring had little influence on this asymmetric hydrogenation.
Impressive results were also obtained with heteroaromatic
substrates (3p−q), affording the hydrogenated products with
excellent results (99% yield, 96 → 99% ee). Moreover, it is
noteworthy that the nonsteroidal anti-inflammatory drug (R)-
flobufen 3s10 was obtained in 98% yield with 99% ee.
To our delight, substrate (E)-2a could be hydrogenated well
with an S/C ratio of 3000 for an extended time with the
retention of high enantioselectivity, which highlighted the high
efficiency of this catalytic system (Scheme 2a). The practicality
of our methodology was further demonstrated by the gram-
scale synthesis of (R)-flobufen 3s (Scheme 2b). Applying the
rhodium/bisphosphine catalytic system, (R)-flobufen was
obtained in 95% yield with 98% ee.
Table 3. Scope of Substrates for the Asymmetric
Hydrogenation of (E)-2-Methyl-4-oxo-2-alkenoic Acids 2
a
In conclusion, a novel and straightforward synthetic method
for the valuable chiral α-methyl-γ-keto acid scaffold through
the asymmetric hydrogenation of the challenging (E)-2-
methyl-4-oxo-2-alkenoic acid substrates utilizing the rhodi-
um/bisphosphine catalytic system has been successfully
established. A series of chiral α-methyl-γ-keto acids were
obtained in almost perfect yields and with almost perfect
chemo- and enantioselectivities (up to 99% yield, 100%
chemoselectivity, and up to >99% ee). This synthetic system
has been demonstrated to be highly efficient, with a TON of
3000. Moreover, the synthetic utility of this method was also
highlighted in the gram-scale preparation of (R)-flobufen with
98% ee.
ASSOCIATED CONTENT
* Supporting Information
■
sı
a
Reaction conditions: 0.2 mmol scale, [substrate] = 0.2 mol·L−1,
solvent = 1.0 mL, 1.0 mol % of catalyst [Rh(NBD)2]BF4/SL-J404-1
1:1.1. Yield of product was obtained after isolation from flash column
chromatography. Enantiomeric excesses were determined by chiral
HPLC analysis using a chiral column after the products were
converted to the corresponding amides.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01618.
General information, preparation of 2-substituted-4-oxo-
2-alkenoic acids (E)-2, asymmetric hydrogenation of 2-
substituted-4-oxo-2-alkenoic acids (E)-2, procedures for
evaluation of S/C ratio, procedures for the gram-scale
synthesis of (R)-flobufen, references, NMR spectra, and
HPLC spectra (PDF)
Scheme 2. S/C Evaluation and Gram-Scale Synthesis of (R)-
Flobufen
AUTHOR INFORMATION
Corresponding Authors
■
Ru Jiang − School of Pharmacy, Fourth Military Medical
University, Xi’an 710032, China; orcid.org/0000-0003-
2583-5672; Email: jiangru@fmmu.edu.cn
Weiping Chen − School of Pharmacy, Fourth Military Medical
University, Xi’an 710032, China; Email: wpchen@
fmmu.edu.cn
Xumu Zhang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0001-5700-
0608; Email: zhangxm@sustech.edu.cn
Authors
Xian Liu − School of Pharmacy, Fourth Military Medical
University, Xi’an 710032, China
Jialin Wen − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0003-3328-
3265
synthesized and hydrogenated under the optimized reaction
conditions (Table 3). The reaction proceeded well in all cases,
affording the corresponding α-substituted-γ-keto acids in
excellent yields with excellent enantioselectivities (97−99%
yield, 95 →> 99% ee). The substrates (3a−o) were
hydrogenated well to give the desired products with excellent
results, which indicated that the electronic and steric properties
Lin Yao − School of Pharmacy, Fourth Military Medical
University, Xi’an 710032, China
C
https://dx.doi.org/10.1021/acs.orglett.0c01618
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Crafts Reaction of Activated Phenols and 4-Oxo-4-arylbutenoates.
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Synth. Catal. 2019, 361, 3632−3638.
Huifang Nie − School of Pharmacy, Fourth Military Medical
University, Xi’an 710032, China; orcid.org/0000-0002-
6388-8620
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01618
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ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(21272271, 21472240).
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