Ni(II)-Catalyzed Enantioselective Synthesis of β-Hydroxy Esters with Carboxylate Assistance

Article abstract of DOI:10.1021/acs.orglett.9b02297

A Ni-oxazoline complex-catalyzed asymmetric decarboxylative aldol reaction between malonic acid half-oxyesters and various carbonyls with carboxylate assistance was developed, affording structurally diverse β-hydroxy esters with good yields and enantioselectivities under mild conditions. Importantly, the broad substrate scope of this methodology enabled rapid accesses to several natural products and their analogues as exemplified by phenylpropanoid, phaitanthrin B, and phthalide.

Full text of DOI:10.1021/acs.orglett.9b02297

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ni(II)-Catalyzed Enantioselective Synthesis of β‑Hydroxy Esters with
Carboxylate Assistance
Na Wang, Hongxin Liu,* Hang Gao, Jiafeng Zhou, Longzhangdi Zheng, Juan Li, Hong-Ping Xiao,
Xinhua Li, and Jun Jiang*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
S
* Supporting Information
ABSTRACT: A Ni−oxazoline complex-catalyzed asymmetric decarbox-
ylative aldol reaction between malonic acid half-oxyesters and various
carbonyls with carboxylate assistance was developed, affording
structurally diverse β-hydroxy esters with good yields and enantiose-
lectivities under mild conditions. Importantly, the broad substrate scope
of this methodology enabled rapid accesses to several natural products
and their analogues as exemplified by phenylpropanoid, phaitanthrin B,
and phthalide.
nantioenriched β-hydroxy esters, especially α-nonsubsti-
In this context, silyl ketene acetals were always employed as
actual nucleophiles in the Mukaiyama aldol reaction (Figure
1b)8 due to the difficulty of direct catalytic activation of esters
(for butyl acetate, pKa = 30.3 in DMSO).9 Despite these
achievements, the constructions of β-tertiary hydroxy esters
and multifunctional ones are still very challenging, while the
multistep preparation of corresponding reactants (β-keto esters
and silyl ketene acetals) or extra post-treatment of products in
these transformations has always limited the substrate scope,
product diversity, and synthetic efficiency. Thus, the develop-
ment of catalytic, asymmetric, and direct addition of ester to
carbonyls, which would provide a facile access to structurally
diverse β-hydroxy esters from simple starting materials, is a
very challenging but attractive target. Inspired by our previous
experience with the synthesis of enantioenriched carboxylic
acid10 and given the importance of chiral α-nonsubstituted β-
hydroxy esters in the synthesis of natural products and
pharmaceutical compounds, we began to think about the
possibility of exploring a versatile nucleophilic precursor
through which rapid synthesis of various β-hydroxy esters
could be achieved. A simple retrosynthetic analysis clearly
indicated that malonic acid half-oxyesters (MAHOs), which
can release CO2 by decarboxylation to produce ester species
under mild conditions, would be ideal nucleophiles in the
synthesis of β-hydroxy esters. However, compared with active
malonic acid half-thioesters (MAHTs), the indirect ester
sources that have received a great deal of attention10,11 since
the pioneering work of Shair in this field,11b MAHOs always
exhibit poorer nucleophilic ability12 due to weaker acidity of
E
tuted ones, are important building blocks1 for the
synthesis of various biologically active natural products and
pharmaceutical compounds as exemplified by juglomycin A,2
phenylpropanoid,3 fluoxetine,4 duloxetine,5 and atomoxetine6
(Figure 1a). Accordingly, entries to optically active β-hydroxy
Figure 1. Chiral β-hydroxy ester-derived bioactive compounds and
catalytic asymmetric synthesis of β-hydroxy esters.
esters are of widespread interest in the past few decades. For
example, great achievements have been made in the catalytic
synthesis of chiral β-hydroxy esters by asymmetric hydro-
genation of β-keto esters, in which a large number of chiral
ligands have been employed and afforded β-hydroxy esters
with excellent enantioselectivities (Figure 1b).7 Alternatively, a
different approach to this target is the enantioselective
introduction of the nucleophilic ester motif into carbonyls.
Received: July 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02297
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
their methylene protons. As a result, even though Shair et al.
achieved the asymmetric decarboxylative aldol reaction
between methylmalonic acid half-thioester and aldehydes
with high enantioselectivity in 2005,11b MAHOs remain largely
unexplored and unexploited in catalytic asymmetric decarbox-
ylative additions despite their great synthetic potential. In the
first report of two related transformations, Ma and co-workers
reported an asymmetric decarboxylative aldol reaction of 3-
oxo-3-phenoxypropanoic acid and 2,2,2-trifluoroacetophenone
with 68% ee13 while Takemoto et al. described a highly
reactive α-Boc-amino MAHO that participated decarboxylative
aldol reaction, and an adduct with the highest enantioselec-
tivity of 90% ee was obtained when 2-nitrobenzaldehyde was
employed as an electrophile.12 Thus, the efficient activation of
unmodified, less active MAHOs with good enantiocontrol is
still very challenging and in high demand. Herein, we report
our preliminary research result on this topic (Figure 1c). A
Ni(II)−oxazoline complex-promoted decarboxylative aldol
reaction of simple MAHOs was developed, in which a wide
range of carbonyls such as aldehydes, Phenylgly oxals,
tryptanthrins, 2-acetylpyridines, α-keto amide, α-diketones,
and isatins were all successfully employed as electrophiles and
afforded desired products with good yields and enantiose-
lectivities; it was shown that various unsaturated groups, even
extra carbonyls on electrophiles, were well tolerated.
Importantly, with this methodology, rapid access to optically
active phenylpropanoid, phthalide, phaitanthrin B, 4-hydroxy-
5-phenyldihydrofuran-2(3H)-one, and an (R)-duloxetine in-
termediate was also achieved.
Considering the great synthetic utility of β-aryl-β-hydroxy
esters and pushed by our failure to employ aldehyde
electrophiles in the synthesis of carboxylic acid,10 we started
our studies by exploring a proper catalytic system for the
decarboxylative aldol reaction of 4-nitrobenzaldehyde and 3-
methoxy-3-oxopropanoic acid. The reaction condition re-
ported by shair’s group11c was first examined. Unfortunately,
no desired product was observed within 24 h. Subsequently, a
careful screening of metal salts was carried out, which revealed
that Ni(OAc)2·4H2O was a good catalyst, affording the desired
methyl 3-hydroxy-3-(4-nitrophenyl)propanoate 3a in 60%
yield at 80 °C (Table 1, entry 1; for the full evaluation of
metal salts, see the Supporting Information). With this catalyst
in hand, the effects of different chiral ligands were next studied
(entries 2−9). It was shown that an oxazoline L7-derived
catalyst exhibited best catalytic activity and enantiocontrol,
resulting in desired product 3a in 60% yield and 60% ee (entry
8). To improve the enantioselectivity, various solvents as well
as reaction temperatures were subsequently evaluated (see the
Supporting Information). However, the highest optical purity
of 77% ee accompanied by a moderate yield was obtained
when the reaction was carried out in THF at 20 °C with the
promotion of anhydrous Ni(OAc)2 (entry 11). To further
optimize reaction conditions, different nickel salts were fully
evaluated. Unfortunately, some nickel catalysts failed to
promote the reaction, probably because of their poor solubility
in THF that caused the bad coordination with ligands (entry
12; full evaluation in the Supporting Information). These
failures inspired us to systematically study the influence of
anion species of nickel salts. Considering the limited nickel
salts that are commercially available, an anion-exchange
strategy was employed by simply mixing nickel salts with
different acid salts before coordinating. For this purpose,
different sodium salts of aliphatic or aromatic acids were
Table 1. Screening Results of Catalysts
additive (o-
NO2−
t
yield
ee
b
c
entry
catalyst
ligand
PhCO2M)
(°C/h) (%)
(%)
1
Ni(OAc)2·
4H2O
−
−
80/24
80/12
80/12
80/12
80/12
80/12
80/12
80/12
80/12
20/24
60
45
45
27
45
56
60
60
32
49
54
−
2
Ni(OAc)2·
L1
L2
L3
L4
L5
L6
L7
L8
L7
−
−
−
−
−
−
−
−
−
2
4H2O
3
Ni(OAc)2·
4H2O
Ni(OAc)2·
4H2O
Ni(OAc)2·
4H2O
Ni(OAc)2·
4H2O
Ni(OAc)2·
4H2O
Ni(OAc)2·
4H2O
Ni(OAc)2·
4H2O
Ni(OAc)2·
4H2O
9
4
9
5
9
6
1
7
21
60
19
77
8
9
10
11
12
Ni(OAc)2
NiX2 (X = F,
Cl, or Br)
L7
L7
−
−
20/24
20/48
77
−
trace
13
14
15
16
17
18
19
20
21
22
23
24
Ni(OAc)2
NiCl2
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
Na
Na
Na
Li
20/24
20/24
20/24
20/24
20/24
20/24
20/24
20/24
20/24
20/24
20/36
15/60
53
47
54
trace
56
54
54
trace
74
89
80
75
88
−
89
84
85
−
91
90
90
92
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
K
Rb
Cs
Mg
K
K
K
d
d
d
d
,e
,e
,e
,
f
80
89
K
a
General reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), ligand (22
mol %), additive (45 mol %), and catalyst (20 mol %) in 2 mL of
solvent at a specific temperature. Isolated yield. Determined by
chiral HPLC analysis. o-NO2-PhCO2K (60 mol %) was used. With
100 mg of 5 Å molecular sieves. NiCl2·6H2O (10 mol %) was used.
b
c
d
e
f
carefully examined under standard conditions (see the
Supporting Information). Encouragingly, sodium 2-nitro-
benzoate was proven to be the optimal additive that afforded
desired product 3a in 80% ee (entry 13). With this information
in hand, various nickel salts were investigated again in the
presence of sodium 2-nitrobenzoate (see the Supporting
Information). Interestingly, previously inactive NiCl2 exhibited
good catalytic activity and enantiocontrol under modified
conditions, while NiCl2·6H2O was found to be the best choice
B
DOI: 10.1021/acs.orglett.9b02297
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
for a catalyst (entry 15, 88% ee). Further optimizations of
reaction conditions revealed that the cation types of acid salts,
molecular sieves (M.S.), and temperature had obvious
influences on the result (entries 15−24). For example, 60
mol % potassium 2-nitrobenzoate was found to be necessary to
improve the catalytic ability as well as enantiocontrol. Finally,
the best result was obtained when the reaction was catalyzed
by a NiCl2·6H2O−L7 complex in the presence of 60 mol %
potassium 2-nitrobenzoate and 5 Å M.S. at 15 °C (entry 24,
89%, 92% ee).
substituted aldehydes were employed as electrophiles (3n−
3p, 3s, 3t, and 3ac), and the resulting β-hydroxy esters bearing
an extra carbonyl group that cannot be obtained from
traditional asymmetric hydrogenation reactions could be
versatile chiral building blocks in enantioselective synthesis.
In addition, the reaction between 2a and 2-thiophenecarbox-
aldehyde afforded an efficient way to construct the key
intermediate of (R)-duloxetine 3af (76% yield, 94% ee).
Importantly, 2-oxopropanal and aliphatic aldehydes that were
capable of self-condensation were also smoothly converted into
desired products 3ag−3ai in good yields and 80−93% ee. The
absolute configurations of products in Scheme 1 were assigned
by comparing their rotation values with literature data.
Using the conditions described in Table 1, the generality of
the protocol was first demonstrated by evaluating a variety of
MAHOs with 4-nitrobenzaldehyde 1a. As shown in Scheme 1,
Inspired by the good results obtained above and our ongoing
interest in exploring new catalytic processes for the
construction of enantioenriched indoloquinazoline alka-
loids,10,14 we subsequently investigated the possibility of the
asymmetric synthesis of phaitanthrin B15 and its derivatives via
decarboxylative aldol reaction of tryptanthrin. To the best of
our knowledge, there is no example exit for the direct catalytic
construction of enantioenriched phaitanthrin B. However, very
low enantioselectivity (19% ee) was obtained when the
reaction of 2a and tryptanthrin was carried out under standard
conditions. Fortunately, a careful evaluation of reaction
conditions revealed that the desired product phaitanthrin B
5a can be obtained in excellent enantioselectivity with the
promotion of the Ni(OAc)2−L1 complex in CH3CN (for the
details of the evaluation conditions, see the Supporting
Information). Encouraged by this result, we employed a
variety of tryptanthrin derivatives as electrophiles under
modified conditions. As shown in Scheme 2, different
functional groups were well tolerated and good to excellent
yields and optical purities were obtained in most cases (5a−5i,
up to >99% ee). Subsequently, different MAHOs were also
successfully employed in this reaction, affording the desired
products in high enantioselectivities of up to >99% ee, albeit
with lower yields (5j−5p). Additionally, this methodology was
also compatible with various ketone type electrophiles under
modified reaction conditions (for the details of evaluation
conditions, see the Supporting Information). For example, 2-
acylpyridines and 2-oxo-N,2-diphenylacetamide reacted with
2a smoothly to afford corresponding β-hydroxy esters 5q−5s
and 5v with a quaternary stereocenter in good enantioselectiv-
ities of 82−92% ee. In addition, isatins were also found to be
good participants in this transformation. It was shown that the
substituent group on the nitrogen or aromatic ring of isatin had
little influence on the reactivity and enantiocontrol; free isatin,
N-methyl isatin, and isatin with either electron-withdrawing or
electron-donating group were all tolerated well and led to the
desired products with good results (5w−5z). Additionally, α-
diketones exhibited good reactivity and were converted into
enantioenriched γ-carbonyl β-hydroxy esters (5t and 5u) with
high yields and 92%−98% ee in 12 h. Noticeably, when 1H-
indene-1,2(3H)-dione was employed as an electrophile,
excellent regioselectivity and enantioselectivity were observed
(5t), and the catalyst loading can be decreased to 0.5 mol %
without a loss of yield or enantioselectivity (72 h, 90%, 98%
ee). The absolute configuration of product 5a was assigned by
comparing its rotation value with our previous report.10
Scheme 1. Catalytic Asymmetric Decarboxylative Addition
of Malonic Acid Half-Oxyesters and Aldehydes
a,b
a
General reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), ligand
(22 mol %), catalyst (20 mol %), o-NO2-PhCO2K (60 mol %), and
100 mg of 5 Å molecular sieves in 2 mL of THF at the corresponding
temperature for a specific time; isolated yield; determined by chiral
b
c
d
HPLC analysis. At 15 °C for 96 h. At 30 °C for 120 h. At 20 °C for
e
f
g
144 h. At 50 °C for 48 h. At −40 °C for 144 h. With 10 mol %
h
i
j
catalyst. At 25 °C for 48 h. With 5 mol % catalyst. In THP
(tetrahydropyran) at 30 °C for 36 h and then at 80 °C for 16 h.
MAHOs with different ester groups all result in desired
products with good yield and enantioselectivity (3a−3f). In
addition, other decarboxylative candidates were also tested.
Encouragingly, 2-cyanoacetic acid reacted smoothly with 1a
under standard reaction conditions, affording the desired
product with good yield and moderate enantioselectivity (3g).
Subsequently, the expansion of the protocol to a variety of
aromatic aldehydes was also proven to be successful, and high
enantioselectivities were achieved with either electron-donat-
ing or electron-withdrawing substituents under standard
reaction conditions (24 examples, ≤94% ee). It was shown
that carbonyls, cyano, and double and triple bonds on the
aromatic ring were well tolerated and afforded the desired
product in good to excellent enantioselectivity (3n−3p, 3s, 3t,
3x, 3ac, 3ad, and 3ag). Noticeably, good chemoselectivities
were observed even when cyano-, formyl-, or benzoyl-
To demonstrate synthetic utilities of our methodology with
enantioenriched β-hydroxy esters, a two-step synthesis of
phenylpropanoid,3a,16 which was isolated from Peperomia
tetraphylla with cytotoxicity against the A549, HeLa, and
C
DOI: 10.1021/acs.orglett.9b02297
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Scheme 2. Catalytic Asymmetric Decarboxylative Addition
of Malonic Acid Half-Oxyesters and Ketones
Scheme 4. Asymmetric Synthesis of 3-Hydroxyl Butyrol-
Actone and Phthalide Derivatives
a
phenylbutanoate 3ad could be reduced by NaBH4 in MeOH,
producing chiral 4-hydroxy-5-phenyldihydrofuran-2(3H)-one,
the key structure of juglomycin A and B, in good yield and
optical purity. In addition, methyl 2-formylbenzoate could
proceed via a decarboxylative aldol-transesterification cascade
with 2a under standard conditions and afforded methyl 2-(3-
oxo-1,3-dihydroisobenzofuran-1-yl)acetate, an analogue of
soochracinic acid II and herbaric acid III, in moderate yield
and enantioselectivity.17
To demonstrate the synthetic utility of our protocol, a 1
mmol-scale catalytic procedure was performed. As shown in
Scheme 5, by treatment of 1H-indene-1,2(3H)-dione (1
Scheme 5. One Millimole-Scale Catalytic Procedure
a
General reaction conditions: 2 (0.4 mmol), 4 (0.2 mmol), ligand L1
(22 mol %), catalyst Ni(OAc)2 (20 mol %) in 2 mL of CH3CN at the
corresponding temperature for a specific time; isolated yield;
b
determined by chiral HPLC analysis. NiF2·4H2O (20 mol %), L7
(25 mol %), 50 mg of 5 Å molecular sieves in 2 mL of THF under a
c
nitrogen atmosphere at 10 °C for 48 h. Ni(OAc)2·4H2O (5 mol %),
mmol) with 2a (2 mmol) in the promotion of 0.5 mol %
catalyst, desired product 5t was obtained in high yield and
enantioselectivity (88% yield, 98% ee).
On the basis of the results presented above, a nickel-
catalyzed aldol-decarboxylation mechanism was proposed. As
shown in Figure 2, a nickel−MAHO complex was first formed
by interaction of the chiral nickel complex and MAHO;
subsequently, enolization and deprotonation of the nickel−
MAHO complex generated a nucleophilic intermediate II,
which was capable of enantioselectively attacking aldehydes/
L5 (6 mol %) in 2 mL of CPME (cyclopentyl methyl ether) at 10 °C
d
for 12 h. Ni(OAc)2·4H2O (10 mol %), L5 (11 mol %) in 2 mL of
e
THF at 10 °C for 12 h. NiCl2·6H2O (10 mol %), L6 (11 mol %) and
o-NO2-PhCO2K (60 mol %) in 2 mL of CPME at 25 °C for 96 h.
f
NiCl2·6H2O (10 mol %), L6 (11 mol %) in 2 mL of THF at 10 °C
g
for 96 h. NiCl2·6H2O (10 mol %), L6 (11 mol %) in 2 mL of THP at
10 °C for 96 h.
HepG2 cell lines, was first carried out. As shown in Scheme 3,
commercially available myristicin aldehyde can be smoothly
Scheme 3. Asymmetric Synthesis of Phenylpropanoid
converted into corresponding β-hydroxy ester ent-3y in 71%
yield and 90% ee under standard conditions; subsequently,
treatment of ent-3y with a simple esterification afforded
phenylpropanoid in 67% overall yield and 90% ee.
In addition, the high functional group tolerance of this
method also allowed further transformations to access diverse
valuable chiral building blocks such as 3-hydroxyl butyr-
olactone and phthalide with simple operations (Scheme 4),
which are wildly found in many bioactive natural products. For
example, enantioenriched product methyl 3-hydroxy-4-oxo-4-
Figure 2. Proposed mechanism of the aldol-decarboxylation reaction.
D
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02297.
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Corresponding Authors
■
*E-mail: junjiang@wzu.edu.cn.
*E-mail: hongxin-107@163.com.
ORCID
Hongxin Liu: 0000-0001-5401-2953
Jun Jiang: 0000-0001-5815-1600
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors gratefully acknowledge the National Natural
Science Foundation of China (21472141 and 21571144), the
Zhejiang Provincial Natural Science Foundation of China
(LY18B020011 and LQ19B020004), and the Foundation of
Zhejiang Educational Committee (Y201430852 and
Y201839490).
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