Direct Catalytic Asymmetric Synthesis of Oxindole-Derived δ-Hydroxy-β-ketoesters by Aldol Reactions

Article abstract of DOI:10.1021/acs.orglett.9b03527

Direct asymmetric synthesis of δ-hydroxy-β-ketoesters was accomplished via regio- and enantioselective aldol reactions of β-ketoesters with isatins catalyzed by cinchona alkaloid thiourea derivatives. The C-C bond formation of the reactions occurred only at the γ-position of the β-ketoesters. Reaction progress monitoring and product stability analyses under the conditions that included the catalyst indicated that the γ-position reaction products were formed kinetically. Various δ-hydroxy-β-ketoesters bearing 3-alkyl-3-hydroxyoxindole cores relevant to the development of bioactive molecules were synthesized.

Full text of DOI:10.1021/acs.orglett.9b03527

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Catalytic Asymmetric Synthesis of Oxindole-Derived
δ‑Hydroxy-β-ketoesters by Aldol Reactions
Dongxin Zhang,*,† Yan Chen,† Hu Cai,† Lei Yin,† Junchao Zhong,† Jingjing Man,† Qian-Feng Zhang,†
Venkati Bethi,‡ and Fujie Tanaka*,‡
†Institute of Molecular Engineering and Applied Chemistry, Anhui University of Technology, No. 59 Hudong Road, Ma’anshan,
Anhui 243002, China
‡Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha,
Onna, Okinawa 904-0495, Japan
S
* Supporting Information
ABSTRACT: Direct asymmetric synthesis of δ-hydroxy-β-ketoesters was
accomplished via regio- and enantioselective aldol reactions of β-ketoesters
with isatins catalyzed by cinchona alkaloid thiourea derivatives. The C−C
bond formation of the reactions occurred only at the γ-position of the β-
ketoesters. Reaction progress monitoring and product stability analyses
under the conditions that included the catalyst indicated that the γ-position
reaction products were formed kinetically. Various δ-hydroxy-β-ketoesters
bearing 3-alkyl-3-hydroxyoxindole cores relevant to the development of
bioactive molecules were synthesized.
Scheme 1. Synthesis of δ-Hydroxy-β-ketoesters
δ-Hydroxy-β-ketoesters are useful building blocks for the
synthesis of biologically important natural products and
pharmaceutical leads.1−4 Common methods to access δ-
hydroxy-β-ketoesters include reactions of dianions2 generated
from β-ketoesters by using two or more equivalents of strong
base(s) or reactions of preformed silyl dienol ethers or alkyl
dienol ether derivatives3 with carbonyl compounds (Scheme
1a and b). These methods require either severe conditions or
tedious protection and deprotection procedures. There are
only a few reports of direct use of β-ketoesters4 in aldol
reactions as nucleophiles to synthesize δ-hydroxy-β-ketoesters
under mild conditions.5,6 For example, direct aldol reactions of
β-ketoesters catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU)6 or other bases5 that form the C−C bond at the γ-
position of the β-ketoesters to provide δ-hydroxy-β-ketoester
derivatives have been reported (Scheme 1c).6a Although
enantiomerically pure δ-hydroxy-β-ketoesters were obtained
by resolutions of the aldol products using homochiral amines,6a
catalytic asymmetric processes are desired.4b Here, we report
the direct asymmetric synthesis of oxindole-derived δ-hydroxy-
β-ketoesters via regio- and enantioselective aldol reactions of β-
ketoesters with isatins catalyzed by cinchona derivatives7,8
(Scheme 1d). Isatins were used as electrophiles in the aldol
reactions because the products 3-alkyl-3-hydroxyoxindoles are
found in biologically active natural products.7a−c,9
First, we searched for catalysts and conditions suitable for
the aldol reaction of isatin (1a) with methyl acetoacetate (2a)
to afford aldol product δ-hydroxy-β-ketoester 3a (Table 1).
After a screening using various organocatalysts,8 we found that
cinchona alkaloid quinidine (I) catalyzed the aldol reaction to
give 3a with some enantioselectivity (Figure 1 and Table 1,
entry 2). Thus, we focused on the screening of cinchona
alkaloid-based organocatalysts to give 3a in high yield with
high enantioselectivity. When a quinidine derivative bearing a
primary amine (II) was used as catalyst, the reaction did not
Received: October 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03527
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
group (IV−VII) were evaluated in the aldol reaction to form
3a (Table 1, entries 5−8).
Table 1. Optimization of the Aldol Reaction of 1a and 2a To
Afford 3a
a
We found that quinidine-derived thiourea IV catalyzed the
aldol reaction efficiently; product 3a was obtained in 98% yield
with 71% ee (Table 1, entry 5). Catalysts V, VI, and VII also
catalyzed the reaction to form 3a with some enantioselectivity
(Table 1, entries 6−8). Reactions using quinine-derived
thiourea VI and cinchonidine-derived thiourea VII as catalysts
afforded the enantiomer of 3a that was the opposite to that
obtained in the reactions catalyzed by IV and V (Table 1,
entries 7 and 8 versus entries 5 and 6). After screening of some
commonly used solvents in the presence of IV, we found that
THF was optimal among those tested for catalyzing the aldol
reaction to form 3a with respect to both yield and
enantioselectivity (Table 1, entries 5 and 9−12). The ee
value of 3a was 94% when the reaction was carried out at 4 °C
rather than rt (25 °C), although the reaction took 96 h at 4 °C
to afford 3a in 95% (Table 1, entry 13). Reducing the loading
of catalyst IV or β-ketoester 2a slowed the reaction (Table 1,
entries 14 and 15). Thus, the reaction conditions using 2a (5
equiv) in the presence of IV (0.1 equiv) in THF at 4 °C
(Table 1, entry 13) were the best among those tested.
Next, with the optimized conditions, the substrate scope of
the aldol reaction in the presence of catalyst IV was studied
(Scheme 2). In general, the reactions of 1 and 2 catalyzed by
IV afforded a series of δ-hydroxy-β-ketoesters bearing the 3-
alkyl-3-hydroxyoxindole motif in high yields with high
enantioselectivities. β-Ketoesters with different ester groups,
i.e., methy, ethyl, and isopropyl ester groups, were all accepted
in the IV-catalyzed reactions to afford corresponding products
3a−c. The reactions of isatins bearing either electron-donating
or electron-withdrawing substituents at the 5-position of the
indole ring also afforded desired products 3d−j in high yields
with excellent enantioselectivities (92−98% ee). Isatins with
substituents at the 4- or 6-position of the indole also reacted
with β-ketoesters in the presence of IV to give products 3k−m
in high yields but with slightly lower enantioselectivities (79−
87% ee). The reactions of isatins with substituent at the 7-
position gave products 3n−p in high yields with good to high
enantioselectivities (79−96% ee). Reactions of isatins with two
substituents, such as 5,6-difluoro, 5,7-dimethyl, and 4-bromo-
5-methyl groups on the indole ring, also afforded products 3q−
s in high yields with high enantioselectivities (85−95% ee).
The reaction of ethyl 2-methylacetoacetate with isatin in the
presence of IV also gave 3t in 93% yield with 80% ee.
b
cd
entry
catalyst
solvent
time [h]
yield [%]
ee [%]
--
1
2
3
4
5
6
7
8
DBU
I
II
III
IV
V
VI
VII
IV
IV
IV
IV
IV
IV
IV
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
CH3CN
MeOH
PhCH3
THF
8
48
48
48
24
24
24
24
24
24
24
24
96
96
96
99
32
--
21 (R)
--
--
--
98
88
93
91
42
65
72
33
95
65
46
71 (R)
59 (R)
64 (S)
60 (S)
63 (R)
58 (R)
36 (R)
65 (R)
94 (R)
94 (R)
90 (R)
9
10
11
12
e
13
ef
14
eg
THF
THF
15
a
Conditions: 1a (0.2 mmol), 2a (1.0 mmol), and catalyst (0.02
mmol) in solvent (1.0 mL) at room temperature (25 °C), except
where noted. Catalysts are shown in Figure 1. Isolated yield of 3a.
Determined by HPLC analysis using a chiral-phase column. The
major enantiomer configuration is shown in parentheses. The
reaction was carried out at 4 °C. Catalyst (0.01 mmol) was used.
b
c
d
e
f
g
2a (0.5 mmol) was used.
Whereas reactions of 1a with 2a in the presence of IV
afforded product (R)-3a, the opposite enantiomer (S)-3a (ent-
3a) was obtained from the reaction in the presence of catalyst
VI (Table 1). Various ent-3 were synthesized in high yields
with good enantioselectivities using catalyst VI (Scheme 3).
To demonstrate the utility of the aldol reactions and to
determine the product configuration, product 3a was subjected
to reactions providing 4−6 (Scheme 4). Reduction of the
ketone group of 3a to form 4 was performed without affecting
to the enantiopurity depending on conditions (see the
Supporting Information). An acid treatment of 3a led the
formation of known compound (R)-5;7a,10 with this trans-
formation, the absolute configuration of 3a obtained from the
IV-catalyzed reaction was determined to be R. With benzyl-
amine, 3a was transformed to stable enamine 6.6a,11
Figure 1. Catalysts tested for the reaction of 1a and 2a to afford 3a;
see Table 1.
proceed at all (Table 1, entry 3). Catalyst III, in which the
hydroxy group of quinidine was protected with a benzyl group,
was also unable to catalyze the aldol reaction to give 3a (Table
1, entry 4). These results indicate that the hydroxy group of
quinidine is important for catalysis of the aldol reaction of 1a
and 2a. The hydroxy group of catalyst I may act as an acid for
the catalysis. Because it has been reported that thiourea groups
can function as acids to form hydrogen bonds with oxygen and
other atoms that have lone pairs8 and because thiourea-derived
cinchona derivatives have been used as catalysts for aldol
reactions,7 including those that use isatin derivatives as
electrophiles,7a−c cinchona derivatives bearing a thiourea
Products 3 were stable as solids stored at room temperature
(25 °C) or at 4 °C for at least 2 months. β-Aryl-substituted β-
hydroxyketones are often isomerized and/or decomposed
B
DOI: 10.1021/acs.orglett.9b03527
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 2. Direct Catalytic Asymmetric Synthesis of 3
Catalyzed by IV
Scheme 3. Direct Catalytic Asymmetric Synthesis of ent-3
Catalyzed by VI
Scheme 4. Transformation of 3a
Table 2. Analysis of the Time Course of the IV-Catalyzed
Reaction
a
Results from a 5 mmol scale reaction of 1a.
reaction time (h)
12
23
94
24
39
93
48
65
94
72
85
94
96
96
93
a
under basic or acidic conditions.12,13 For the transformations
of 3, selections of conditions were also important to retain the
enantiopurity in the products.
conversion (%)
b
ee of 3a (% ee)
a
Determined by 1H NMR analysis based on the ratio of 3a relative to
b
1a. Determined by HPLC analysis. The major enantiomer was (R)-
3a.
To understand the mechanism of the reaction catalyzed by
catalyst IV for the formation of 3a, the reaction of 1a and 2a in
the presence of IV was analyzed at various time points (Table
2). Only the formation of the γ-selective aldol product 3a was
observed by 1H NMR analysis. Even at the initial stages of the
reaction (such as at 1, 2, 4, 8, and 12 h), no product with the
bond formation at the α-position of the β-ketoester was
detected. The ee values of 3a isolated from the reaction at
reaction times from 12 to 96 h (conversion 23−96%) were
essentially the same (93−94% ee). Thus, product 3a appears to
be kinetically and directly formed in the IV-catalyzed reaction
of 1a with 2a.
Although detailed mechanisms are under investigation, a
plausible transition state (TS) for the formation of 3a from 1a
in the presence of catalyst IV is shown in Scheme 5. The
results described above suggest that the C−C bond formation
occurs directly on the γ-position of 2a to afford 3a. Once the
C
DOI: 10.1021/acs.orglett.9b03527
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Letter
Scheme 5. Plausible Pathway and Transition State
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The Supporting Information is available free of charge on the
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glett.9b03527.
Detailed experimental procedures; analytical data for all
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AUTHOR INFORMATION
Corresponding Authors
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ORCID
Dongxin Zhang: 0000-0002-2185-4692
Fujie Tanaka: 0000-0001-6388-9343
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Shuyu Zhang at Shanghai Jiaotong University
for helping us with the optical rotation measurements. This
study was supported by Anhui Provincial Natural Science
Foundation (No. 1908085MB33) (to D.Z.), by the Anhui
University of Technology (to D.Z.) and by Okinawa Institute
of Science and Technology Graduate University (to F.T.).
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