Enantioselective synthesis of 3-hydroxy oxindoles by ytterbium-catalysed decarboxylative addition of β-ketoacids to isatins

Article abstract of DOI:10.1039/c3ob41460d

A ytterbium(iii)-indapybox catalysed enantioselective decarboxylative addition reaction of β-ketoacids to isatins is described. The biologically important 3-hydroxy oxindoles were obtained in high yields and excellent enantioselectivities.

Full text of DOI:10.1039/c3ob41460d

Organic &
Biomolecular Chemistry
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Enantioselective synthesis of 3-hydroxy oxindoles by
ytterbium-catalysed decarboxylative addition of
β-ketoacids to isatins†
Cite this: Org. Biomol. Chem., 2013, 11,
6456
Received 16th July 2013,
Accepted 2nd August 2013
Zhiqiang Duan,a Jianlin Han,a,b Ping Qian,a Zirui Zhang,a Yi Wang*a,c and Yi Pana,c
DOI: 10.1039/c3ob41460d
www.rsc.org/obc
A ytterbium(III)-indapybox catalysed enantioselective decarboxyla-
tive addition reaction of β-ketoacids to isatins is described. The
biologically important 3-hydroxy oxindoles were obtained in high
yields and excellent enantioselectivities.
Fig. 1 Bioactive 3-hydroxy-3-substituted oxindoles.
Introduction
decarboxylative aldol sequence, which involves the generation
of the nucleophile in situ using an Yb(OTf)3–pybox catalytic
system. Recently, Lu and co-workers13 reported a tertiary
amine–thiourea catalysed aldol reaction between β-ketoacids
and isatins. 3-Hydroxy oxindoles with different substituents at
C5 and C7 were afforded with good enantioselectivities.
However, oxindoles with substituents at C4 and C6, which are
the precursors of bioactive convolutamydines and flustrami-
nols, were not recorded,13,14 probably due to the steric and
electronic resistance of the organocatalyst with the corres-
ponding isatin substrate. Herein, we document our successful
development of a new ytterbium-catalysed enantioselective
decarboxylative addition of β-ketoacids to isatin, generating
biologically important 3-hydroxy-3-substituted oxindoles in
excellent yields and enantioselectivities, especially with
different substituents at C4 and C6.
Oxindole motifs bearing C3-quaternary structures are widely
distributed in many natural products and pharmaceutical
molecules.1 Recent interest has focused on the study of
3-hydroxy oxindoles possessing different substituents at the
3-position due to their significant biological activities.2 For
example, the convolutamydines can inhibit human promyelo-
cytic leukemia cells, and flustraminol B is a potential antagon-
ist of cholecystokinin (Fig. 1).3 The biological activities of
these compounds are greatly affected by the configuration of
the hydroxyl group and the substituents at the C3 position
of the oxindole.4 Thus far, several efficient and facile methods
have been developed for the preparation of functionalised
3-hydroxy oxindoles. Carbonyls,5–7 arenes,8 alkenes,9 nitro-
alkanes10 and oxindoles11 were successfully installed on the
oxindole framework with good enantioselective control.
However, the development of other highly functionalised
3-hydroxyoxindoles is still desirable.
In recent years, the enantioselective decarboxylative
additions of β-ketoacids as surrogates of ketones have received
much attention.12 Our interest in ytterbium-catalysed reactions
Results and discussion
We started our investigation by examining the decarboxylative
aldol reaction between β-ketoacid 1a and N-benzyl isatin 2a in
the presence of ytterbium(III)-pybox catalysts in toluene. A
number of pybox ligands were evaluated. They all furnished
the desired decarboxylative products in high yields (Table 1,
entries 1–4). Pybox ligands L1, L2 and L3 showed remarkable
catalytic effects, and excellent enantioselectivities were
achieved. L3 (indapybox) was chosen as it gave the best results
(Table 1, entry 3). L4 led to low ee’s (Table 1, entry 4). The
addition of 4 Å molecular sieves was able to accelerate the reac-
tion without compromising the enantioselectivity (Table 1,
led to the discovery that β-ketoacids can undergo
a
aSchool of Chemistry and Chemical Engineering, Nanjing University, Nanjing,
210093, China. E-mail: yiwang@nju.edu.cn; Fax: +86-25-83309123;
Tel: +86-25-83593153
bInstitute for Chemistry & Biomedical Sciences, Nanjing University, Nanjing, 210093,
China
cState of Key Laboratory of Coordination, Nanjing University, Nanjing, 210093,
China
†Electronic supplementary information (ESI) available. CCDC 949412. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob41460d
6456 | Org. Biomol. Chem., 2013, 11, 6456–6459
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Table 1 Reaction optimisationa
Entry
Ligand
Additive
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L3
L3
L3
L3
L3
L3
L3
No
No
No
No
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CH3Cl
CH3CN
THF
CH3CN
CH3CN
91
93
90
91
91
95
93
98
—
94
95
88
−87
91
32
91
97
95
99
9
10
11
—
98d
97e
Scheme 1 Substrate scope of enantioselective decarboxylative addition of
β-ketoacids to isatins.
a Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), Yb(OTf)3
(10 mol%), and ligand (12 mol%). b Isolated yield after column
chromatography. c Determined by HPLC analysis using Chiralcel IA
column. d Yb(OTf)3 (5 mol%), ligand (6 mol%). e Yb(OTf)3 (2 mol%),
ligand (2.4 mol%).
showed a crucial influence on the reactivity of the electrophiles
(Table 2, entries 1–5). Without any protecting group, isatin
could provide the desired product in a similar yield but much
lower enantioselectivity compared with the benzyl substituted
isatin (Table 2, entries 1 and 2). 93% ee was obtained with
a methyl group (Table 2, entry 3). More sterically hindered
protecting groups such as triphenylmethyl and tert-butyl-
carbonyl (Boc) also led to low enantioselectivities (Table 2,
entries 4–5).
Table 2 Effect of protecting groups on the isatinsa
Based on these results, isatins with different substituents
on the aromatic ring were also investigated (Scheme 1). Substi-
tution at the 6-position with electron-donating and electron-
withdrawing groups afforded consistently high yields and
excellent enantioselectivities. When 4-bromo isatin was
employed, the ee dropped to 65%, suggesting that the nucleo-
philic addition was inhibited by steric interference between
the substituent at C4 and the metal–ligand complex. Further-
more, the scope of β-ketoacid substrates for nucleophilic
addition to isatins was investigated, and the substituents on
the phenyl rings with electron-donating and electron-
withdrawing groups afforded high yields and excellent
enantioselectivities. When a 2-chloro β-ketoacid was used, the
ee dropped slightly (3l). Notably, the reaction proceeded
smoothly with aliphatic β-ketoacids, affording the hydroxy
oxindoles in excellent yields and good enantiomeric excesses
(3n). The absolute configurations of the products were
assigned by comparing the optical rotation with the
value reported in the literature and confirmed by
crystallography.
Entry
R1
Product
Time
Yieldb (%)
eec (%)
1
2
3
4
5
Bn
H
Me
Boc
CPh3
3a
3o
3p
3q
3r
12
24
24
24
24
98
90
91
99
93
99
27
93
0
33
a Reaction conditions: 1a (0.2 mmol),
2 (0.1 mmol), Yb(OTf)3
(10 mol%), and ligand (12 mol%). b Isolated yield after column
chromatography. c Determined by HPLC analysis using chiralcel
column.
entry 5). Subsequent solvent screening showed that CH3CN
was the more suitable solvent (Table 1, entry 8). The reaction
efficiency was maintained when the catalyst loading was as low
as 2 mol% (Table 1, entry 11).
To test the scope of the optimised reaction conditions, a
variety of isatin derivatives with different substituents were
examined (Table 2). The protecting group on the nitrogen
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In conclusion, we have successfully developed the highly
enantioselective catalytic decarboxylative addition of β-keto-
acids to isatins catalysed by ytterbium(III)-indapybox. A series
of biologically valuable 3-hydroxy oxindoles were obtained in
up to 98% yield and up to 99% ee. Further investigation of
other decarboxylative addition reactions of β-ketoacids is in
progress.
Acknowledgements
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (no. 21102071)
and the Fundamental Research Funds for the Central Univer-
sities (no. 1107020522 and no. 1082020502). The Jiangsu 333
program (for Pan) and Changzhou Jin-Feng-Huang program
(for Han) are also acknowledged.
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