Synthesis of bempedoic acid through electrochemical decarboxylation of dialkylated malonic acid

Article abstract of DOI:10.1055/a-1482-9822

Bempedoic acid is a small-molecule inhibitor of adenosine triphosphate-citrate lyase (ACL) that is effective in the treatment of hypercholesterolemia and hypertension. In this paper, a new, six-step synthesis of bempedoic acid with 42% overall yield is reported. Ketone formation by electrochemical decarboxylation of dialkylated malonic acid is introduced as the key step of this process. This method uses mild conditions and its high efficiency makes it potentially suitable for industrial production.

Full text of DOI:10.1055/a-1482-9822

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–E
paper
A
en
Z. Xu et al.
Paper
Synthesis
Synthesis of Bempedoic Acid through Electrochemical Decarb-
oxylation of Dialkylated Malonic Acid
Zhimin Xu
Electrochemical Decarboxylative
Ketone Formation
Yue Zheng
Lifang Tian*
Yahui Wang*
EtO2C
CO2Et
EtO2C
CO2Et
HO2C CO2H
O
Technical Institute of Fluorochemistry (TIF), Institute
of Advanced Synthesis (IAS), School of Chemistry and
Molecular Engineering, Nanjing Tech University,
Nanjing 211816, P. R. of China
tianlifang@njtech.edu.cn
ias_yhwang@njtech.edu.cn
Dialkylation
Reduction & Hydrolysis
HO2C
CO2H
CO2Et
+
Br
BnO2C
CO2Bn
OH
Bempedoic acid
YLTNeiMeaafchanahnujiCinglinotiWTgcairaisr2anl_e1nyIlsni1gphfsa8owtn1niatg6dun@,itngPen@g.joRtnAef.jucFtohetlfuhc.Ceohodhr.reuoisndc.cauhn.ecmn istry (TIF), Institute of Advanced Synthesis (IAS), School of Chemistry and Molecular Engineering, Nanjing Tech University,
Received: 28.01.2021
Accepted after revision: 15.04.2021
Published online: 15.04.2021
Therefore, bempedoic acid is not anticipated to induce the
adverse effects associated with inhibition of biological in-
termediates within the cholesterol biosynthesis pathway in
skeletal muscle. Bempedoic acid is found to be effective in
lowering LDL-C both when used as a monotherapy and in
combination with statins and/or ezetimibe, and it is also
well tolerated in patients with statins intolerance.
DOI: 10.1055/a-1482-9822; Art ID: ss-2021-g0168-op
Abstract Bempedoic acid is a small-molecule inhibitor of adenosine
triphosphate-citrate lyase (ACL) that is effective in the treatment of hy-
percholesterolemia and hypertension. In this paper, a new, six-step syn-
thesis of bempedoic acid with 42% overall yield is reported. Ketone for-
mation by electrochemical decarboxylation of dialkylated malonic acid
is introduced as the key step of this process. This method uses mild con-
ditions and its high efficiency makes it potentially suitable for industrial
production.
Dasseux et al. reported a synthetic process for obtaining
bempedoic acid in a patent (WO2004067489) which is out-
lined in the following five steps in Scheme 1.4 Using ethyl
isobutyrate (1) and 1,5-dibromopentane (2) as starting ma-
terials, the ethyl 7-bromo-2,2-dimethylheptanoate (3) was
obtained upon treatment with lithium diisopropylamide
(LDA) at low temperature. Compound 3 was used as alkyla-
tion reagent to prepare the addition compound 5 with p-
methylbenzene sulfonyl methyl isocyanide (4) catalyzed by
tetrabutyl ammonium iodide under strong alkaline condi-
tions. After hydrolyzing 5 under acidic conditions to un-
mask the carbonyl group, diethyl 2,2,14,14-tetramethyl-8-
oxopentadecanedioate (6) was isolated in 66% yield over
two steps. Saponification of 6 in ethanol gave diethyl 8-
hydroxy-2,2,14,14-tetramethylpentadecanedioate (7). The
last step of the synthesis was the reduction of compound 7
with 10 equivalents of NaBH4 to give bempedoic acid (8) as
a very viscous oil with a yield of 60%. However, the p-meth-
ylbenzene sulfonyl methyl isocyanide used in the second
step is highly toxic, and after hydrolysis in the third step,
potentially genotoxic impurities (p-methyl benzene sulfo-
nyl derivatives) are generated, which are not conducive to
the quality control of API (Active Pharmaceutical Ingredi-
ent). In addition, the required amount of NaBH4 is more
than 10 times that of the substrate, resulting in high reac-
tion risk. Therefore, this synthetic process has low efficien-
cy, high loss, high potential risk, and is not ideal for indus-
trial production.
Key words bempedoic acid, electrochemical synthesis, decarboxyl-
ation, malonic acid, high efficiency
Cardiovascular disease (CVD) is one of the worldwide
leading causes of death, and tremendous efforts have been
made to treat it. Statins, as reductase inhibitors of 3-hy-
droxy-3-methylglutaryl coenzyme A (HMG-CoA), are cur-
rently clinically effective drugs for reducing low-density li-
poprotein cholesterol (LDL-C) and reducing the risk of car-
diovascular diseases. However, many people at high risk of
cardiovascular disease cannot reach the target value of LDL-
C after taking statins. Although the level of LDL-C can be
significantly reduced by increasing the dose to several
times the conventional levels, adverse drug reactions will
also increase accordingly.1 Bempedoic acid is a small-mole-
cule inhibitor of adenosine triphosphate-citrate lyase (ACL)2
and is used to lower endogenous cholesterol and to reduce
elevated LDL-C levels by upregulating LDL receptors, reduc-
ing musculose-related side effects. Bempedoic acid-coen-
zyme A can inhibit ACL to reduce LDL-C in the same way
that statins inhibit HMG-CoA reductase. An important dis-
tinguishing feature of bempedoic acid is that, unlike statins,
it does not inhibit cholesterol synthesis in skeletal muscle.3
The enzyme needed to convert bempedoic acid into bempe-
doic acid-coenzyme A is not present in skeletal muscle.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Z. Xu et al.
Paper
Synthesis
Ts
NC
CO2Et
LDA,THF
60%
4
EtO2C
CO2Et
Br
Br
Br
+
CO2Et
Ts NC
n-Bu4NI/THF
NaH/DMSO
2
1
3
5
HO2C
CO2H
EtO2C
CO2Et
HCI/DCM
KOH/EtOH
79%
O
66%, over two steps
O
6
7
HO2C
CO2H
NaBH4/MeOH
60%
OH
Bempedoic Acid (8)
Scheme 1 Previous synthesis of bempedoic acid described in patent WO2004067489
Organic reactions are often accompanied by side path-
ways, complex technological process and sometimes heavy
environmental pollution. Therefore, in recent years, the de-
velopment of more environmentally friendly technologies
has become critical for the chemical industry. Among the
approaches being considered, organic electrochemical syn-
thesis, as a clean and effective synthetic method, has at-
tracted increasing attention.5 Organic electrochemical reac-
tions can be realized either directly or indirectly by the gain
and loss of electrons on the surface of the electrodes, and
thus avoid the use of toxic and harmful redox reagents.
Therefore, we waned to develop a new method of preparing
biologically active bempedoic acid by electrochemical syn-
thesis of ketones through decarboxylation of malonic acid
derivatives as a key step.
treatment of the crude reaction mixture after electrolysis
with 1 M aq HCl enabled the transformation of initially gen-
erated ketals into the corresponding ketones in a single ves-
sel operation (Scheme 2). Compared with the traditional
oxidative decarboxylation of malonic acids with lead
tetraacetate,7 this electrochemical process is carried out un-
der mild reaction conditions and avoids the use of toxic and
harmful chemical oxidants.
Inspired by this electrochemical decarboxylative meth-
od with disubstituted malonic acids, we envisioned that
malonic acids could be applied as a masked carbonyl group
and should be readily available through a much more so-
phisticated double alkylation step. In the retrosynthetic
analysis of bempedoic acid (Scheme 3), we proposed an ap-
proach to access the key intermediate 7 through this elec-
trochemical decarboxylation method from tetracarboxylic
acid (9), which would be easily prepared through a dial-
kylation from the reported ethyl 7-bromo-2, 2-dimethyl-
heptanoate (3).
In 2015, Markò et al. reported an efficient and chemose-
lective electrochemical oxidative methodology for the con-
version of disubstituted malonic acids into ketals under
mild reaction conditions in the presence of NH3.6 Direct
The originally designed synthetic path is shown in
Scheme 4. Ethyl 7-bromo-2,2-dimethylheptanoate (3) was
first prepared in 76% yield by a monoalkylation of ethyl
isobutyrate (1) with commercially available 1,5-dibro-
mopentane (2) in the presence of lithium diisopropyl-
amide, according to a reported procedure.8 Reaction tem-
perature (–40 °C) was found to be a key factor for con-
O
HO2C CO2H
MeO OMe
R1 R2
NH3, MeOH
– e–
HCl, H2O
R1 R2
R1 R2
readily available
Scheme 2 Ketone formation by electrochemical decarboxylation of
malonic acids
HO2C
CO2H
HO2C
CO2H
HO2C CO2H
O
7
9
Electrochemical Decarboxylative
Ketone Formation
Dialkylation
CO2Et
Br
Br
+
RO2C
CO2R
Br
+
CO2Et
Alkylation
1
2
3
Scheme 3 Retrosynthetic analysis of bempedoic acid
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–E

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Z. Xu et al.
Paper
Synthesis
trolling the desired monoalkylation. Diethyl malonate (10)
was successfully dialkylated with ethyl 7-bromo-2,2-di-
methylheptanoate (3) in the presence of sodium hydride to
form tetraester compound 11 in 95% yield. After hydrolyz-
ing with potassium hydroxide, 2,14-dimethylpentadecane-
2,8,8,14-tetracarboxylic acid (9) was isolated in 76% yield.
However, when tetracarboxylic acid 9 was dissolved in a
solution of methanol and ammonia and subjected to the re-
ported electrolysis conditions, the desired ketone 7 was not
detected. Instead, a small amount of decarboxylative etheri-
sation (12a) and elimination product (12b) were generated
under these conditions.9 Apparently, the terminal carboxyl
groups of compound 7 also underwent a process of decar-
boxylation by anodic oxidation following a Hofer–Moest
process.10 To avoid these competing side reactions, the car-
boxylic ester groups instead of carboxylic acids at terminal
positions were then proposed, which could be more stable
under the electrochemical conditions. Dibenzyl malonate
(13) was introduced in the dialkylation step to distinguish
these carboxyl groups, and the desired tetraester 14 was
obtained in 87% yield (Scheme 5). Benzyl groups were se-
lectively removed to give 15 in 98% yield with Pd/C and hy-
drogen, and two terminal ethyl ester groups were un-
touched. To our delight, the desired ketone 6 was obtained
in 75% yield by electrochemical decarboxylation of 15 in an
undivided cell equipped with a graphite anode and a graph-
ite cathode in a solution of methanol and ammonia at room
temperature. After reduction with sodium borohydride and
saponification with potassium hydroxide, the final bempe-
doic acid (8) was isolated in excellent yield. In comparison
to the overall yield (42.0%) of the previous method by
Dasseux et al. (18.8%),4 the synthetic efficiency has been
significantly increased by this electrochemical decarboxyl-
ative process. Moreover, it is worth noting that by switching
the order of the last two steps, only 1 equivalent of NaBH4
was sufficient (more than 10 equivalents were required in
the previous route),4 which is beneficial to scale-up production.
In conclusion, we have developed a mild and efficient
method for the preparation of bempedoic acid with an
overall yield of 42% through an electrochemical oxidative
decarboxylation as the key step. The approach is potentially
suitable for industrial production with environmentally
friendly electro-organic conditions and mild reaction pro-
tocol. We believe that our approach might open the door to
more cost-effective bempedoic acid.
LDA
EtO2C
Br
O
Br
+
Br
CO2Et
THF, –40 °C
76%
2
3
1
EtO
OEt
10
EtO2C
CO2Et
COOH
O
EtO2C CO2Et
NaH, DMF:toluene = 1:1
0 °C, 1 h, 100 °C, 36 h, 95%
11
KOH
HOOC
EtOH:H2O = 4:1
reflux, 8 h
76%
HOOC COOH
9
C(+) | C(-) : I = 15 mA
NH3 in MeOH
HOOC
COOH
OMe
MeOH, rt, 8 h
undivided cell
O
7
MeO
O
12a
O
12b
Scheme 4 Synthetic route 1 to bempedoic acid
BnO
OBn
13
O
O
EtO2C
EtO2C
EtO2C
CO2Et
CO2Et
CO2Et
3
BnO2C CO2Bn
NaH, DMF:toluene = 1:1
0 °C, 1 h, 100 °C, 36 h,
87%
14
Pd/C, H2
HOOC COOH
EtOAc
rt, 4 h, 98%
15
C(+) | C(-) : I = 15 mA
NH3 in MeOH
MeOH, rt, 8 h
undivided cell
75%
O
6
EtO2C
HO2C
CO2Et
CO2H
NaBH4
MeOH, 0 °C, 4 h
96%
OH
16
KOH
EtOH:H2O = 4:1
reflux, 6 h
90%
OH
Bempedioc acid (8)
Reagents of the highest commercial quality grade were purchased
and used without further purification, unless otherwise stated. Yields
refer to chromatographically and spectroscopically (1H NMR) homo-
geneous material, unless otherwise stated. Reactions were monitored
by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck
silica plates (60F-254), using UV light (254 nm) and TLC stain with
anisaldehyde–sulfuric acid for visualization. Flash chromatography
columns were packed with 200–300 mesh silica gel in petroleum (bp
60–90 °C). 1H and 13C NMR data were recorded with Bruker (400
Scheme 5 Synthetic route 2 to bempedoic acid
MHz) or Jeol (400 MHz) spectrometers with tetramethylsilane as in-
ternal standard. All chemical shifts () are reported in ppm and cou-
pling constants (J) in Hz. All chemical shifts are reported relative to
tetramethylsilane (0 ppm for 1H), CDCl3 (77.0 ppm for 13C).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–E

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Z. Xu et al.
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Synthesis
Ethyl 7-Bromo-2,2-dimethylheptanoate (3)
Diethyl 2,2,14,14-Tetramethyl-8-oxopentadecanedioate (6)
To a 250 mL round-bottom flask was added ethyl isobutyrate (4.2 g,
36 mmol) and THF (40 mL) at –40 °C and the mixture was stirred for
10 min at this temperature under a N2 atmosphere. Lithium diisopro-
pylamide (2.0 M in THF/Hexane, 18 mL, 36 mmol) was added drop-
wise and the mixture was stirred at –40 °C for 1 h before addition of
1,5-dibromopentane (11.8 g, 51.6 mmol). The reaction mixture was
stirred at –40 °C for 0.5 h then at r.t. for 8 h before being poured into
ice water. The solution was extracted with EtOAc (3 × 50 mL) then the
combined organics were washed with water and dried over magne-
sium sulfate, filtered and evaporated in vacuo. The crude product was
purified by column chromatography (petroleum ether/EtOAc = 100:1)
to afford the title compound as a light-yellow oil in 76% yield (7.2 g).
1H NMR (400 MHz, CDCl3):  = 4.11 (q, J = 7.1 Hz, 2 H), 3.45–3.35 (m, 2
H), 1.92–1.80 (m, 2 H), 1.55–1.46 (m, 2 H), 1.46–1.35 (m, 2 H), 1.28–
1.20 (m, 5 H), 1.15 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 177.9, 60.2, 42.0, 40.4, 33.8, 32.5, 28.5,
25.1, 24.0, 14.2.
The electrolysis was carried out in the electrolysis cell of IKA® Electra-
Syn 2.0. The anodic electrode and the cathodic electrode were both
carbon electrodes (3.0 cm × 0.8 cm × 0.2 cm). 2,2-Bis(7-ethoxy-6,6-
dimethyl-7-oxoheptyl)malonic acid (142 mg, 0.3 mmol), NH3 (MeOH)
(90 L, 0.63 mmol) and MeOH (4 mL) were added to an oven-dried
undivided cell (5 mL) equipped with a stirring bar (the order of the
addition did not affect the results). The reaction mixture was stirred
for 15 minutes before being electrolyzed at a constant current of 15
mA at r.t. for 8 h. Then, 1 M HCl (1.6 mL) was added to the reaction
mixture (pH 5–6), and the resulting solution was stirred at r.t. for an
additional 6 h. The solution was extracted with EtOAc (3 × 10 mL),
then the combined organics were washed with water and dried over
magnesium sulfate, filtered and evaporated in vacuo. The crude prod-
uct was purified by column chromatography (petroleum ether/EtOAc
= 20:1) to afford the title compound as a colorless oil in 75% yield (90
mg).
1H NMR (400 MHz, CDCl3):  = 4.07 (q, J = 7.1 Hz, 4 H), 2.33 (t, J = 7.4
Hz, 4 H), 1.57–1.41 (m, 8 H), 1.27–1.14 (m, 14 H), 1.10 (s, 12 H).
13C NMR (100 MHz, CDCl3):  = 211.2, 177.8, 60.0, 42.6, 42.0, 40.4,
29.5, 25.0, 24.6, 23.5, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H22BrO2: 265.0798; found:
265.0798.
HRMS (ESI): m/z [M + H]+ calcd for C23H43O5: 399.3105; found:
399.3104.
8,8-Dibenzyl 14,2-Diethyl 2,14-dimethylpentadecane-2,8,8,14-
tetracarboxylate (14)
A 100 mL round-bottom flask containing a solution of dibenzyl
malonate (1.42 g, 5 mmol) in 30 mL of DMF/toluene (1:1) was stirred
at 0 °C for 5 minutes before the addition of NaH (60%, 360 mg, 12
mmol) portionwise. After stirring for 1 h, ethyl 7-bromo-2, 2-dimethyl-
heptanoate (2.78 g, 10.5 mmol) was added via syringe in one portion.
The resulting reaction mixture was heated to 100 °C and stirred for 36
h before being poured into water. The solution was extracted with
EtOAc (3 × 30 mL), then the combined organics were washed with wa-
ter and dried over magnesium sulfate, filtered and evaporated in vac-
uo. The crude product was purified by column chromatography (pe-
troleum ether/EtOAc = 5:1) to afford the title compound as a colorless
oil in 87% yield (2.85 g).
Diethyl 8-Hydroxy-2,2,14,14-tetramethylpentadecanedioate (16)
To a solution of diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedio-
ate (680 mg, 1.7 mmol) in MeOH (5 mL) was added NaBH4 (65 mg, 1.7
mmol) and the resulting mixture was stirred at 0 °C for 4 h before be-
ing poured into water. The solution was extracted with EtOAc (3 × 10
mL) then the combined organics were washed with water and dried
over magnesium sulfate, filtered and evaporated in vacuo. The crude
product was purified by column chromatography (petroleum
ether/EtOAc = 9:1) to afford the title compound as a colorless oil in
96% yield (650 mg).
1H NMR (400 MHz, CDCl3):  = 4.10 (q, J = 7.1 Hz, 4 H), 3.61–3.48 (m, 1
H), 1.53–1.46 (m, 4 H), 1.45–1.34 (m, 6 H), 1.32–1.18 (m, 16 H), 1.14
(s, 12 H).
13C NMR (100 MHz, CDCl3):  = 178.0, 71.8, 60.1, 42.1, 40.6, 37.3, 30.1,
25.4, 25.1, 24.8, 14.2.
1H NMR (400 MHz, CDCl3):  = 7.35–7.16 (m, 10 H), 5.09 (s, 4 H), 4.09
(q, J = 7.1 Hz, 4 H), 1.92–1.77 (m, 4 H), 1.49–1.36 (m, 4 H), 1.26–1.13
(m, 12 H), 1.15 (s, 12 H), 1.10–0.97 (m, 6 H).
13C NMR (100 MHz, CDCl3):  = 177.9, 171.4, 135.5, 128.3, 128.1,
128.0, 66.6, 60.0, 57.5, 42.0, 40.4, 32.1, 30.2, 25.0, 24.6, 23.7, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C39H57O8: 653.4048; found:
HRMS (ESI): m/z [M + H]+ calcd for C23H45O5: 401.3262; found:
401.3262.
653.4049.
Bempedoic Acid (8)
2,2-Bis(7-ethoxy-6,6-dimethyl-7-oxoheptyl)malonic Acid (15)
A mixture of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecane-
dioate (650 mg, 1.6 mmol) and KOH (2 mL, 20%) in EtOH (8 mL) was
heated to reflux for 6 h. The solvent was removed in vacuo, and the
residue was acidified with 2 M HCl to pH 1. After saturation with
brine, the product was extracted with EtOAc (3 × 20 mL) then the
combined organics were washed with water and dried over magne-
sium sulfate, filtered and evaporated in vacuo. The crude product was
purified by column chromatography (petroleum ether/EtOAc = 1:2) to
afford the title compound as a white solid in 90% yield (495 mg).
To a solution of 8,8-dibenzyl 14,2-diethyl 2,14-dimethylpentadecane-
2,8,8,14-tetracarboxylate (1.5 g, 2.3 mmol) in EtOAc (40 mL) was add-
ed Pd/C (Wako, 5%W, 200 mg, 0.23 mmol) and the mixture was placed
under a hydrogen atmosphere (balloon, 1 atm). The resulting mixture
was stirred for 4 h, then degassed, filtered over Celite and evaporated
in vacuo to afford the title compound as a colorless oil in 98% yield
(1.068 g), which was used for the next step without further purifica-
tion.
1H NMR (400 MHz, CDCl3):  = 8.92–7.93 (br, 2 H), 4.10 (q, J = 7.1 Hz, 4
H), 1.99–1.81 (t, J = 7.7 Hz, 4 H), 1.52–1.40 (m, 4 H), 1.36–1.15 (m, 18
H), 1.13 (s, 12 H).
1H NMR (400 MHz, CDCl3):  = 8.49–7.31 (br, 2 H), 3.65–3.49 (m, 1 H),
1.58–1.47 (m, 4 H), 1.47–1.34 (m, 6 H), 1.34–1.21 (m, 10 H), 1.17 (s,
12 H).
13C NMR (100 MHz, CDCl3):  = 178.6, 176.8, 60.5, 57.4, 42.1, 40.4,
13C NMR (100 MHz, CDCl3):  = 184.5, 71.7, 42.1, 40.5, 37.0, 29.7, 25.2,
35.8, 29.9, 25.0, 24.7, 24.4, 14.1.
25.0, 24.7.
HRMS (ESI): m/z [M + H]+ calcd for C25H45O8: 473.3109; found:
HRMS (ESI): m/z [M + H]+ calcd for C19H37O5: 345.2636; found:
473.3106.
345.2637.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–E

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Z. Xu et al.
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Synthesis
Conflict of Interest
(3) Pinkosky, S. L.; Newton, R. S.; Day, E. A.; Ford, R. J.; Lhotak, S.;
Austin, R. C.; Birch, C. M.; Smith, B. K.; Filippov, S.; Groot, P. H.;
Steinberg, G. R.; Lalwani, N. D. Nat. Commun. 2016, 7, 13457.
(4) Dasseux, J. H.; Oniciu, D. C. PCT Int. Appl WO 2004067489,
2004.
The authors declare no conflict of interest.
Funding Information
(5) (a) Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117,
13230. (b) Yang, Q.-L.; Fang, P.; Mei, T.-S. Chin. J. Chem. 2018, 36,
338. (c) Möhle, S.; Zirbes, M.; Rodrigo, E.; Gieshoff, T.; Wiebe, A.;
Waldvogel, S. R. Angew. Chem. Int. Ed. 2018, 57, 6018. (d) Lin, D.-
Z.; Huang, J.-M. Org. Lett. 2018, 20, 2112. (e) Zhao, Y.; Xia, W.
Chem. Soc. Rev. 2018, 47, 2591. (f) Kärkäs, M. D. Chem. Soc. Rev.
2018, 47, 5786. (g) Yoshida, J.-i.; Shimizu, A.; Hayashi, R. Chem.
Rev. 2018, 118, 4702. (h) Jiang, Y.; Xu, K.; Zeng, C. Chem. Rev.
2018, 118, 4485. (i) Yuan, Y.; Lei, A. Acc. Chem. Res. 2019, 52,
3309. (j) Xiong, P.; Xu, H.-C. Acc. Chem. Res. 2019, 52, 3339.
(k) Ackermann, L. Acc. Chem. Res. 2020, 53, 84. (l) Leech, M. C.;
Lam, K. Acc. Chem. Res. 2020, 53, 121. (m) Zheng, Y.; Shao, X.;
Ramadoss, V.; Tian, L.; Wang, Y. Synthesis 2020, 52, 1357.
(n) Shao, X.; Zheng, Y.; Ramadoss, V.; Tian, L.; Wang, Y. Org.
Biomol. Chem. 2020, 18, 5994. (o) Ramadoss, V.; Zheng, Y.; Shao,
X.; Tian, L.; Wang, Y. Chem. Eur. J. 2021, 27, 3213. (p) Gale-Day,
Z. J. Synthesis 2021, 53, 879.
We thank the National Natural Science Foundation of China
(21702105) for funding.
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Acknowledgment
We thank Prof. Haihua Lu at Westlake University for valuable discus-
sions.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1482-9822.
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orti
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