Chiral phosphoric acid catalyzed enantioselective decarboxylative alkylation of β-keto acids with 3-hydroxy-3-indolyloxindoles

Article abstract of DOI:10.1021/acs.orglett.5b00159

A chiral phosphoric acid catalyzed enantioselective decarboxylative alkylation of β-keto acids with 3-hydroxy-3-indolyloxindoles is described in this context. This method tolerates a series of aromatic and aliphatic β-keto acids as well as substituted 3-hydroxy-3-indolyloxindoles, affording the corresponding chiral 3-functionalized 3-indolyloxindoles in high yields (up to 98%) and enantioselectivities (up to 99% ee).

Full text of DOI:10.1021/acs.orglett.5b00159

Letter
pubs.acs.org/OrgLett
Chiral Phosphoric Acid Catalyzed Enantioselective Decarboxylative
Alkylation of β‑Keto Acids with 3‑Hydroxy-3-indolyloxindoles
Xiao-Dong Tang, Shen Li, Ran Guo, Jing Nie, and Jun-An Ma*
Department of Chemistry, Key Laboratory of Systems Bioengineering (the Ministry of Education), Tianjin University, and
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. of China
S
* Supporting Information
ABSTRACT: A chiral phosphoric acid catalyzed enantiose-
lective decarboxylative alkylation of β-keto acids with 3-
hydroxy-3-indolyloxindoles is described in this context. This
method tolerates a series of aromatic and aliphatic β-keto acids
as well as substituted 3-hydroxy-3-indolyloxindoles, affording
the corresponding chiral 3-functionalized 3-indolyloxindoles in
high yields (up to 98%) and enantioselectivities (up to 99% ee).
he 3,3′-bisindoline unit bearing an all-carbon quaternary
Scheme 1. Catalytic Asymmetric Alkylation of 3-Hydroxy-3-
indolyloxindoles
T
stereocenter (Figure 1, highlighted in red) is a privileged
alkylation of acyclic alkyl ketones with 3-hydroxy-3-indolylox-
indoles still suffers from unsatisfactory results.
The utility of β-keto acids as ketone enolate equivalents in the
catalytic asymmetric decarboxylative transformations4 has been
well established by our group5 and others.6 Many electrophilic
partners, including nitroalkenes, carbonyl compounds, alkyl
halides, and imines, have been successfully employed in the
enantioselective decarboxylative reactions of β-keto acids.
However, the use of alcohols as electrophiles for the asymmetric
decarboxylative alkylation of β-keto acids remains elusive.
Recently, we found that chiral phosphoric acids could facilitate
the asymmetric alkylation of β-keto acids with 3-hydroxy-3-
indolyloxindoles under mild reaction conditions, delivering the
corresponding oxindoles bearing an all-carbon quaternary
stereocenter in high yields (up to 98%) and enantioselectivities
Figure 1. 3,3′-Bisindoline-based alkaloids bearing an all-carbon
quaternary stereocenter.
substructure which is present in a large family of alkaloids with
important biological and pharmaceutical activities.1,2 Catalytic
asymmetric transformation of 3-hydroxy-3-indolyloxindoles
represents one of the feasible methods for the construction of
3,3′-bisindoline frameworks. In this context, Gong and co-
workers developed an enantioselective nucleophilic substitution
of 3-hydroxy-3-indolyloxindoles with enamides of aromatic
methylketones for the synthesis of 3-functionalized 3- indolylox-
indoles and the cyclotryptamine alkaloid (+)-folicanthine
(Scheme 1a),3a whereas the group of Guo and Peng disclosed
an organocatalytic asymmetric alkylation of 3-hydroxy-3-
indolyloxindoles with unmodified ketones (Scheme 1b).3b
While these publications are excellent, the enantioseletive
Received: January 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
(up to 99% ee). Herein, we report our preliminary results on this
subject.
Table 1. Catalyst Screening and Condition Optimization
Our studies were initiated with the reaction between 3-oxo-3-
phenylpropanoic acid 1a and racemic 3-hydroxy-3-indolyl-
oxindole 2a7 by using phosphoric acid catalysts.8,9 The results
are shown in Table 1. Under the room temperature conditions,
the simplest catalyst 4a was able to catalyze this reaction slowly to
give the desired product 3a in a moderate yield (entry 1).
Employment of anhydrous Na2SO4 as a dehydration agent
significantly improved reaction rate, giving a quantitative yield,
but without any enantioselectivity (entry 2). Subsequent
screening of chiral phosphoric acids 4b−h revealed that the
aryl group at the 3,3′-position of the BINOL backbone had a
significant effect on catalytic activity as well as enantioselectivity
(entries 3−9). Among them, (S)-4h was identified as the optimal
catalyst in terms of chiral induction ability (entry 9). Further
improvement in enantioselectivity was achieved by decreasing
reaction temperature with a prolonged reaction time (entries
10−12). Subsequent attempts to conduct the reaction at −50 °C
failed (entry 13). Following these evaluations of chiral catalyst
and reaction temperatures, a solvent screen was undertaken
(entries 14−17). Among the solvents tested, dichloromethane
was found to be the best with respect to reaction activity and
enantioselectivity. Reducing the catalyst loading from 10 to 5 mol
% was also acceptable, giving a comparable result under standard
reaction conditions (entry 18). Finally, it was found that an
excess of β-keto acid 1a was necessary to get the maximum yield,
since an undesired decarboxylation process cannot be excluded
(entries 19 and 20). It is worth noting that the presence of the N-
protecting group at the oxindolyl moiety proved to be essential
for the reaction activity and asymmetric induction (entries 21−
24). N-Boc- and N-benzylisatin-derived 3-hydroxyoxindoles 2b
and 2c were also found to be suitable substrates, providing the
chiral 3-functionalized 3-indolyloxindoles 3b and 3c with high
yields (86% and 88%, respectively) and enantioselectivities (89%
ee and >99% ee, respectively) (entries 21 and 22). However, no
reaction was observed for substrates 2d and 2e (entries 23 and
24) wherein the N-protecting group at the oxindolyl moiety was
absent.
b
c
temp
time
(h)
yield
ee
entry
4/3
solvent
(°C)
(%)
(%)
d
1
(S)-4a/3a CH2Cl2
(S)-4a/3a CH2Cl2
(S)-4b/3a CH2Cl2
(S)-4c/3a CH2Cl2
25
12
12
12
12
12
30
99
60
66
61
0
0
2
3
4
5
25
25
25
25
0
17
8
(S)-4d/
3a
CH2Cl2
6
7
8
9
(S)-4e/3a CH2Cl2
(S)-4f/3a CH2Cl2
(S)-4g/3a CH2Cl2
25
25
25
25
12
12
12
12
73
70
54
52
21
6
60
63
(S)-4h/
3a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CHCl3
10
11
12
13
14
15
16
17
(S)-4h/
3a
0
−20
−35
−50
−35
−35
−35
−35
−35
−35
−35
−35
24
24
36
36
36
36
36
36
36
36
36
36
93
92
90
0
82
84
93
--
(S)-4h/
3a
(S)-4h/
3a
(S)-4h/
3a
(S)-4h/
3a
50
82
40
0
41
60
35
(S)-4h/
3a
(S)-4h/
3a
toluene
THF
(S)-4h/
3a
e
After determination of the optimal conditions, the scope of
this decarboxylative alkylation was investigated, and the results
are summarized in Scheme 2. We first tested the reaction of four
3-hydroxy-3-indolyloxindoles with 3-oxo-3-phenylpropanoic
acid 1a under the established conditions. The corresponding
alkylation products 3f−i were obtained in high yields (83−94%)
with excellent enantioselectivities (90−94% ee). Next, the
substrate scope of β-keto acids was explored by the reaction
with 3-hydroxy-3-indolyloxindole 2a under the optimal con-
ditions. We were pleased to find that a broad range of phenyl-
substituted β-keto acids with substituents in the ortho-, meta-, or
para-position of phenyl ring proceeded well to furnish the
desired products 3j−q in good to excellent levels of yield (71−
98%) and enantioselectivity (86−99% ee). Other aryl-
substituted β-keto acids such as 3-(naphthalen-2-yl)-3-oxopro-
panoic acid and 3-(furan-2-yl)-3-oxopropanoic acid could also be
successfully employed in this decarboxylative alkylation reaction,
delivering the desired products (3r and 3s) in good to high yields
and enantioselectivities. In addition, alkyl-substituted β-keto
acids participated in this reaction to afford the corresponding
products 3t−v in 65−71% yield with 88−93% ee.
18
(S)-4h/
3a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
87
78
90
86
90
93
f
19
(S)-4h/
3a
g
20
(S)-4h/
3a
93
21
(S)-4h/
3b
89
22
23
(S)-4h/3c CH2Cl2
−35
25 or 0
36
36
88
0
>99
(S)-4h/
3d
CH2Cl2
24
(S)-4h/
3e
CH2Cl2
25 or 0
36
0
a
General reaction conditions: 1a (0.15 mmol), 2 (0.1 mmol), Na2SO4
(100 mg), and catalyst 4 (10 mol %) in solvent (2 mL) at the given
temperature for the stated time. Isolated yield. Determined by
HPLC analysis on a chiral stationary phase. The absolute stereo-
chemistry was assigned by comparison of the optical rotation with
literature reported data (ref 3a). The reaction was performed in the
absence of Na2SO4. 5 mol % of catalyst was used. 0.1 mmol of 1a was
b
c
d
e
f
g
used. 0.2 mmol of 1a was used.
indolyloxindole 2f under the established conditions. This
substrate 2f was readily synthesized from commercially available
N-methylisatin and N-methylindole7b and then was proved to be
suitable for our protocol to produce 3-functionalized 3-
The tolerance of N-methyl on the indole moiety encouraged
us to carry out the enantioselective decarboxylative alkylation of
3-(4-methoxyphenyl)-3-oxopropanoic acid with 3-hydroxy-3-
B
DOI: 10.1021/acs.orglett.5b00159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a c
−
Scheme 2. Scope of the Decarboxylative Alkylation of β-Keto Acids 1 with 3-Hydroxyoxindoles 2
a
Reaction conditions: 1 (0.15 mmol), 2 (0.1 mmol), Na2SO4 (100 mg), and chiral phosphoric acid (S)-4h (10 mol %) in CH2Cl2 (2 mL) at −35 °C
b
c
for 36−72 h. Isolated yield. ee value was determined by HPLC analysis on a chiral stationary phase.
indolyloxindole 3w in almost quantitative yield with 93% ee
(Scheme 3). The compound 3w is a known intermediate in the
Scheme 3. Preparation of the Key Intermediate 3w for Access
to Alkaloid (+)-Folicanthine (PMP = 4-Methoxyphenyl)
Figure 2. Structure of intermediate 5.
indolyloxindole under our standard conditions. These results
clearly indicate that the alkylation occurs prior to the
decarboxylation step in this asymmetric decarboxylative reaction.
On the basis of our experimental results and previous
studies,3a,b the reaction is proposed to begin with the formation
of a chiral iminium phosphate ion pair upon treatment of 3-
hydroxyoxindole 2 with the phosphoric acid catalyst, followed by
a conjugate addition with the β-keto acid and subsequent
decarboxylation (Figure 3). The stereochemistry could be
ascribed to the hydrogen-bond interaction between the catalyst
and the carboxylic acid group of the β-keto acid, allowing the enol
of β-keto acid to only attack the iminium species from the Re face
and thus giving the R-configured alkylation product.
In summary, we have developed a chiral phosphoric acid
catalyzed enantioselective decarboxylative alkylation of β-keto
acids with 3-hydroxy-3-indolyloxindoles. This method tolerates a
series of aryl- and alkyl-substituted β-keto acids, affording the
corresponding 3-functionalized 3-indolyloxindoles bearing an
all-carbon quaternary stereocenter in high yields (up to 98%) and
enantioselectivities (up to 99% ee). With our protocol, a key
synthesis of cyclotryptamine alkaloid (+)-folicanthine (created
by Gong and co-workers),3a and our methodology complements
Gong’s elegant approach to this ketone.
To cast some light on the mechanism, the electrospray
ionization mass spectrometry (ESI-MS) method was used to
study this decarboxylative alkylation reaction. An ESI-MS
measurement of a mixture of 3-(4-fluorophenyl)-3-oxopropa-
noic acid, 3-hydroxy-3-indolyloxindole 2a, and the catalyst (S)-
4h in dichloromethane displayed a base peak at m/z 541.1540,
pertaining to the existence of the alkylation intermediate 5
[HRMS (ESI) calcd for C32H23FN2NaO4+ (5 + Na+) 541.1534]
(Figure 2). Nevertheless, isolation of this intermediate was not
successful by chromatography on silica gel due to rapid
decomposition. In the control experiment, we found that the
corresponding acetophenone could not react with 3-hydroxy-3-
C
DOI: 10.1021/acs.orglett.5b00159
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Figure 3. Proposed reaction pathway.
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readily obtained. A mass spectroscopy analysis indicated that the
alkylation of β-keto acids with 3-hydroxy-3-indolyloxindoles
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investigations focused on other variants of enantioselective
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectral data of all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: majun_an68@tju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China, the National Basic Research Program of
China (973 Program, 2014CB745100), and Tianjin Municipal
Science & Technology Commission (14JCZDJC33400).
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DOI: 10.1021/acs.orglett.5b00159
Org. Lett. XXXX, XXX, XXX−XXX