Enantioselective construction of 3-hydroxy oxindoles via decarboxylative addition of β-ketoacids to isatins

Article abstract of DOI:10.1021/ol301855w

The first highly enantioselective decarboxylative addition of β-ketoacids to isatins mediated by a bifunctional tertiary amine-thiourea catalyst has been developed, allowing facile synthesis of biologically important 3-hydroxy oxindoles in good yields and excellent enantioselectivities. The method reported represents a valuable approach of utilizing β-ketoacids as synthetic equivalents of aryl/alkyl methyl ketone enolates.

Full text of DOI:10.1021/ol301855w

ORGANIC
LETTERS
2012
Vol. 14, No. 15
4018–4021
Enantioselective Construction of
3‑Hydroxy Oxindoles via Decarboxylative
Addition of β‑Ketoacids to Isatins
Fangrui Zhong, Weijun Yao, Xiaowei Dou, and Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Republic of Singapore, 117543
chmlyx@nus.edu.sg
Received July 6, 2012
ABSTRACT
The first highly enantioselective decarboxylative addition of β-ketoacids to isatins mediated by a bifunctional tertiary amineꢀthiourea catalyst
has been developed, allowing facile synthesis of biologically important 3-hydroxy oxindoles in good yields and excellent enantioselectivities.
The method reported represents a valuable approach of utilizing β-ketoacids as synthetic equivalents of aryl/alkyl methyl ketone enolates.
Since the seminal work by List, Barbas, and Lerner on
the L-proline-catalyzed intermolecular aldol reaction in
2000,1 asymmetric enamine catalysis has been established
as a powerful strategy to access chiral molecules via direct
bond-forming reactions.2 Notably, pyrrolidine-based sec-
ondary amines and primary amine catalysts3 often com-
plement each other in their ability to activate different
substrates, and enable applications of a wide range of
carbonyl compounds via enamine catalysis. However,
methyl ketones, particularly aryl methyl ketones, are
difficult substrates in enamine activation.4 Thus, preacti-
vation of such less reactive ketones is often required.
For instance, silyl enol ethers5 are commonly employed.
To develop a straightforward and effective approach
for reactions involving methyl ketones as a donor, we
reasoned that decarboxylation of β-ketoacids promoted
by an amino catalyst may conveniently generate a methyl
ketone enolate, which should readily react with suitable
substrates in the following reaction step (Scheme 1).
Nature’s ability to perform organic reactions is truly
astonishing and serves as an inspiration to chemists.6
Mimicking the biosynthesis of polyketides, the decarbox-
ylative reactions of malonic acid half thioesters (MAHTs)
have drawn much attention recently.7 In the decarboxyla-
tive processes of MAHTs, various electrophiles including
aldehydes, ketones, imines, activated alkenes, and azodi-
carboxylates are used as reaction partners under either
(1) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395.
(2) For selected excellent reviews and books, see: (a) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (b)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c)
Berkessel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-VCH:
Weinheim, 2005. (d) Dalko, P. I. Enantioselective Organocatalysis: Reac-
tions and Experimental Procedures; Wiley-VCH: Weinheim, 2007. (e)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (f)
Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem.,
Int. Ed. 2008, 47, 6138.
(3) For reviews on asymmetric catalysis mediated by primary amines/
amino acids and synthetic peptides, see: (a) Xu, L.-W.; Luo, J.; Lu, Y.
Chem. Commun. 2009, 1807. (b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem.
2008, 6, 2047. (c) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J.
Chem. Rev. 2007, 107, 5759. (d) Peng, F.; Shao, Z. J. Mol. Catal. A 2008,
285, 1. (e) Chen, Y.-C. Synlett 2008, 1919.
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Angew. Chem., Int. Ed. 2004, 43, 1983. (b) Mei, K.; Zhang, S.; He, S.; Li,
P.; Jin, M.; Xue, F.; Luo, G.; Zhang, H.; Song, L.; Duan, W.; Wang, W.
Tetrahedron Lett. 2008, 49, 2681. (c) Carpenter, R. D.; Fettinger, J. C.;
Lam, K. S.; Kurth, M. J. Angew. Chem., Int. Ed. 2008, 47, 6407. (d)
Funabiki, K.; Itoh, Y.; Kubota, Y.; Matsui, M. J. Org. Chem. 2011, 76,
3545.
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Chem., Int. Ed. 2004, 43, 5590. (c) Palomo, C.; Oiarbide, M.; Garcıa,
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r
10.1021/ol301855w
Published on Web 07/25/2012
2012 American Chemical Society

we chose to study the decarboxylative aldol reaction
between β-ketoacids and isatins, since the reaction prod-
ucts, 3-hydroxy-3-substituted oxindoles,14 are important
structural motifs in medicinal chemistry (Figure 1).15
Recently, a couple of reports based on enamine catalysis
for the synthesis of 3-hydroxy oxindoles via a direct
aldol reaction between aryl methyl ketones and isatins
appeared.16 However, such direct reactions were veryslow,
requiring four to seven days to complete. Herein, we
document our successful development of enantioselective
decarboxylative addition of β-ketoacids to isatins, creating
biologically important 3-hydroxy-3-substituted oxindoles
in excellent yields and enantiomeric excesses.17
Scheme 1. Activations of Methyl Ketones in Aldol Reaction
metal8 or organocatalytic conditions.9 Surprisingly,
β-ketoacids were rarely employed in the decarboxylative
reactions,10 which may be due partly to their intrinsic
instability. To the best of our knowledge, there were only
three asymmetric examples reporting such applications.
Evans disclosed a Ni(II) complex-catalyzed Michael
addition of β-ketoacids to nitroalkenes.11 The other two
reports from the groups of Mahrwald and Tian described
stereoselective decarboxylative aldol and Mannich reac-
tions, respectively, utilizing chiral aldehydes or N-sulfinyl
R-imino esters as the substrate.12 At the outset of our
research, we questioned the possibility of generating a
methyl ketone enolate from β-ketoacids via an amine-
initiated decarboxylative process.13 To test our hypothesis,
Figure 1. Bioactive 3-hydroxy-3-substituted oxindoles.
We started our investigation by examining the reaction
between N-Boc isatin 1a and β-ketoacid 2a in chloroform
(Table 1). The noncatalyzed background reaction was
very slow, suggesting the feasibility of a catalytic approach
(entry 1). A number of bifunctional amino catalysts were
evaluated, and they all displayed good catalytic activities,
furnishing the desired decarboxylative products in high
yields. While quinidine (QD-1) and its sulfonamide-
containing derivative QD-2,18 β-ICD, and threonine-
derived thiourea L-Thr-119 led to disappointing enantios-
electivities (entries 2ꢀ5), tryptophan-derived tertiary
amineꢀthiourea Trp-120 was an excellent catalyst and 3a
was isolated with 88% ee (entry 6). Cinchona alkaloid-
derived bifunctional thioureas showed remarkable cataly-
tic effects, and excellent enantioselectivities were achieved
(entries 7ꢀ10). Among them, cinchonidine-based CD-1
gave the best results (entry 8). Subsequent solvent
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C.-H. Chem.;Eur. J. 2011, 17, 8363. (i) Bae, H. Y.; Some, S.; Lee, J. H.;
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Catal. 2011, 353, 3196. (j) Baudoux, J.; Lefebvre, P.; Legay, R.; Lasne,
M.-C.; Rouden, J. Green Chem. 2010, 12, 252. (k) Hara, N.; Nakamura,
S.; Funahashi, Y.; Shibata, N. Adv. Synth. Catal. 2011, 353, 2976.
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J.-Y.; Tian, S.-K. Chem. Commun. 2011, 47, 8343.
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Chem. 2003, 2209. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2007, 46, 8748. (c) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003,
103, 2945. (d) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352,
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(f) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20.
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Ed. 2010, 49, 9460. (b) Allu, S.; Molleti, N.; Panem, R.; Singh, V. K.
Tetrahedron Lett. 2011, 52, 4080.
(17) For our recent examples of enatioselective creation of oxindole
cores, see: (a) Zhu, Q.; Lu, Y. Angew. Chem., Int. Ed. 2010, 49, 7753. (b)
Zhong, F.; Chen, G.-Y.; Lu, Y. Org. Lett. 2011, 13, 82. (c) Zhong, F.;
Han, X.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 7837. (d)
Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Chem. Sci. 2012, 3, 1231. (e) Dou,
X.; Lu, Y. Chem.;Eur. J. 2012, 18, 8315.
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C.-F.; Shen, C.; Wang, J.-Y.; Tian, S.-K. Org. Lett. 2012, 14, 3092.
(13) During the preparation of this manuscript, Ma and co-workers
described a biscinchona alkaloid-catalyzed decarboxylative addition of
β-ketoacids to trifluoromethyl ketones; see: Zheng, Y.; Xiong, H.-Y.;
Nie, J.; Hua, M.-Q.; Ma, J.-A. Chem. Commun. 2012, 48, 4308.
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Org. Lett., Vol. 14, No. 15, 2012
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screening did not offer further imporvement, and chloro-
form remained as the best reaction medium.21 It is note-
worthy that the reaction also proceeded smoothly in protic
solvents such as methanol and water, albeit with decreased
enantioselectivities (entries 11ꢀ12). When the reaction was
carried out at 0 °C for 24 h, the desired product was
obtained in quantitative yield and with 96% ee (entry 13).
2-naphthyl, 2-thiophenyl, and vinylic group were well-
tolerated for the reaction as well (entries 13ꢀ15). Notably,
the reaction proceeded smoothly with aliphatic β-keto-
acids, affording the adducts in excellent yields and high
enantiomeric excesses (entries 16ꢀ19). In particular,
92% ee was attainable when tert-butyl β-ketoacid was
employed in the reaction (entry 19). To the best of our
knowledge, this represents the only protocol to access the
chiral aldol product with methyl tert-butyl ketone as a
donor. The activation of such a highly hindered ketone
usually requires very harsh conditions, in sharp contrast to
the mild reaction conditions utilized here. The absolute
configurations of aldol products were determined by com-
parison of the optical rotation of a 3a derivative with the
value reported in the literature.21
Table 1. Exploration of the Decarboxylative Addition of
β-Ketoacids to N-Boc Isatinsa
Table 2. Substrate Scopea
entry
R1/R2
H/C6H5
3
yield (%)b
ee (%)c
1
3a
3b
3c
3d
3e
3f
96
94
90
91
90
96
95
84
93
97
75
89
99
85
82
91
92
92
95
96
96
97
94
94
91
93
86
91
96
96
92
95
92
91
82
86
87
92
2
5-Me/C6H5
5-OMe/C6H5
5-Cl/C6H5
3
entry
cat.
solvent
time (h)
yield (%)b
ee (%)c
4
1
ꢀ
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
MeOH
H2O
24
24
24
2
<10
96
85
95
98
99
97
98
96
93
92
88
99
ꢀ
5
5-Br/C6H5
5-NO2/C6H5
7-F/C6H5
2
QD-1
L-Thr-1
β-ICD
QD-2
Trp-1
Q-1
2
6
3
50
7
3g
3h
3i
4
ꢀ20
ꢀ64
88
8
5,7-Me/C6H5
H/4-Me-C6H4
H/4ꢀF-C6H4
H/3-Cl-C6H4
H/2-OMe-C6H4
H/2-naphthyl
H/2-thiophenyl
H/(E)-PhCHdCH
H/Me
5
2
9
6
3
10
11d
12
13
14
15
16
17
18
19
3j
7
6
91
3k
3l
8
CD-1
QD-3
C-1
6
92
9
6
ꢀ87
ꢀ89
71
3m
3n
3o
3p
3q
3r
3s
10
11
12
13d
6
CD-1
CD-1
CD-1
10
12
24
65
CHCl3
96
H/n-Pr
H/i-Pr
a Reactions were performed with 1a (0.05 mmol), 2a (0.075 mmol),
and the catalyst (0.005 mmol) in the solvent specified (0.5 mL). b Isolated
yield. c Determined by HPLC analysis on a chiral stationary phase.
d Reaction was performed at 0 °C.
H/t-Bu
a Reactions were performed with 1 (0.05 mmol), 2 (0.075 mmol) and
CD-1 (0.005 mmol) in CHCl3 (0.5 mL). b Isolated yield. c Determined by
HPLC analysis on a chiral stationary phase. d Reaction was performed
in the presence of CD-1 (20 mol %) for 48 h.
The current reaction system was applicable to isatins
with different substituents on the aromatic ring, including
halogens as well as electron-donating and -withdrawing
groups, and high chemical yields and excellent enantios-
electivities were obtained (entries 2ꢀ7, Table 2). When
5,7-dimethyl isatin was used, the enantioselectivity of the
reaction dropped slightly (entry 8). Furthermore, aromatic
moieties of β-ketoacids could also be varied; high yields
and excellent enantioselectivities were achieved regardless
of the positions and electronic nature of the substituents
on the phenyl rings (entries 9ꢀ12). β-Ketoacids with a
We next tried to gain some insight into the reaction
mechanism. Notably, even though the decarboxylative
reaction of related MAHTs has been widely explored,
the reaction mechanism remains unclear. While the
decarboxylationꢀnucleophilic addition pathway is widely
accepted for enzyme-catalyzed Claisen condensation
in polyketide biosynthesis,22 the alternative additionꢀ
decarboxylation reaction sequencewas alsowellsupported
in a number of catalytic systems.8d,9e,h In our current
(22) Austin, M. B.; Izumikawa, M.; Bowman, M. E.; Udwary, D. W.;
Ferrer, J.-L.; Moore, B. S.; Noel, J. P. J. Biol. Chem. 2004, 279, 45162.
(21) See the Supporting Information for details.
4020
Org. Lett., Vol. 14, No. 15, 2012

concurrent release of CO2. The protonated ammonium
then forms an ion pair with the keto enolate. The double
hydrogen bonding interactions between the carbonyls of
isatin 1a and the thiourea group of the catalyst play a key
role in stereochemical control, giving rise to the observed
stereoisomer.
Scheme 2. Plausible Mechanism
The method described here is operationally simple and
efficient and, thus, may be valuable for practical chemical
synthesis. As an illustrative example, we carried out a gram-
scale synthesis of 3-hydroxy-3-phenacyloxindole (3a), an
anticonvulsant agent.15 When isatin 1a was treated with
β-ketoacid 2a in the presence of 5 mol % of CD-1 at 0 °C,
the decarboxylative aldol product (R)-3a was obtained in
92% yield and with 94% ee within 48 h (Scheme 3).
Scheme 3. Scaled-up Reaction with 5 mol % CD-1
system, since the β-ketoacids are highly labile for decar-
boxylation, we suspect the keto enolate is first formed
via decarboxylation, which then adds on to the isatin
substrates. To provide some evidence to our proposal,
we tested the stability of β-ketoacids under the reaction
conditions. When 2a was exposed to a catalytic amount
of QD-1 or CD-1, extensive decomposition of 2a was
observed. Acetonphenone was isolated during the decom-
position, supporting the formation of the keto enolate
species. On the other hand, had the addition step taken
place prior to the decarboxylation, a highly sterically
hindered intermediate containing adjacent quaternary
and tertiarycarbon centerswouldhavetogenerated, which
seems to be a difficult process. An analogous aldol reaction
between isatin 1a and β-ketoester 2b was carried out in
the presence of a stoichiometric amount of CD-1 or DBU
(Scheme 2, eq 1), and no desired aldol product was
detected. This experimental result suggested the difficulty
of adding ketoesters to isatins. The thiourea moiety of
catalyst CD-1 is believed to be crucial for the observed high
enantioselectivity, as evidenced from our initial catalyst
screening (Table 1). When we performed the same reaction
with isatin bearing a free NH group (1a0), the product was
obtained with only 5% ee, in stark contrast to the same
reaction with the employment of N-Boc isatin 1a as a
substrate (Scheme 2, eq 2). Based on the experimental
findings we have gathered so far, we propose a plausible
mechanism as depicted in Scheme 2. The tertiary amine
catalyst deprotonates 2a to create a keto enolate, with the
In conclusion, we have successfully developed the first
highly enantioselective catalytic decarboxylative addition
of β-ketoacids to isatins mediated by bifunctional tertiary
amineꢀthiourea catalysts. The method reported repre-
sents an efficient approach of employing β-ketoacids as
synthetic equivalents of aryl/alkyl methyl ketone enolates.
We have also demonstrated the value of our method in a
practical synthesis of biologically important 3-hydroxy-3-
phenacyloxindole. Further investigations toward a deeper
understanding of the reaction mechanism and extension of
the current method to other reactions are being pursued in
our laboratory.
Acknowledgment. We wish to thank the National Uni-
versity of Singapore (R-143-000-469-112), GSK-EDB
(R-143-000-491-592), and the Ministry of Education
(MOE) of Singapore (R-143-000-494-112) for generous
financial support.
Supporting Information Available. Representative ex-
perimental procedures, determination of absolute config-
urations of products, HPLC chromatogram, and NMR
spectra for all the compounds described. This material
is available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
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