Organocatalytic enantioselective cross-aldol reactions of aldehydes with isatins: Formation of two contiguous quaternary centered 3-substituted 3- hydroxyindol-2-ones

Article abstract of DOI:10.1002/asia.200900243

Good neighbors: Cross-aldol reactions of isatins with aldehydes, catalyzed by (S)-pyrrolidine tetrazole are developed. In the process, two contiguous quaternary centers and one chiral carbon are created simultaneously with good efficiency.

Full text of DOI:10.1002/asia.200900243

COMMUNICATION
DOI: 10.1002/asia.200900243
Organocatalytic Enantioselective Cross-Aldol Reactions of Aldehydes with
Isatins: Formation of Two Contiguous Quaternary Centered 3-Substituted 3-
Hydroxyindol-2-ones
Fei Xue,[a] Shilei Zhang,[a] Lu Liu,[a] Wenhu Duan,[a] and Wei Wang*[a, b]
Efficient catalytic asymmetric methods with the ability to
create a chiral quaternary center in biologically significant
molecular frameworks are of considerable importance and
challenge in organic synthesis.[1] The 3-hydroxyindol-2-one
structure constitutes a core unit of a number of natural
products and pharmaceuticals (see Figure 1).[2] Among them
er, the use of aldehydes as nucleophiles for cross-aldol reac-
tions has not been reported.[5] In this communication, we
wish to disclose an organocatalytic enantioselective aldol re-
action of a-branched aldehydes with isatins. Significantly,
two adjacent quaternary centers are created simultaneously
with high efficiency.
Aldol reactions are one of the most general and versatile
À
methods for the formation of C C bonds in organic synthe-
sis.[6] The plethora of reagents, catalysts, and protocols have
been developed for the synthesis of structurally diversified
building blocks and targets. In recent years, significant ef-
forts have focused on developing organocatalytic asymmet-
ric aldol reactions.[7,8] We envision that the application of
enolizable aldehydes as aldol donors and a-ketoamide isa-
tins as acceptors in the presence of a chiral amine organic
catalyst will generate 3-substituted 3-hydroxyindol-2-ones.
To demonstrate the working hypothesis, we carried out a
model reaction of isatin (1a) with isobutyraldehyde (2a) in
the presence of a chiral amine under neat conditions
(Table 1). It was found that under the reaction conditions,
the reaction efficiency varied significantly. l-Proline (I)[8a]
and diaryl prolinol TMS ether (II),[9] both are the effective
promoters in iminium/enamine catalysis, failed to catalyze
the reaction (entries 1 and 2). The same result was observed
for bisthiourea (VII) (entry 7).[10] Primary amine thioureas
V and VI[11] could catalyze the reaction, but the product was
racemic (entries 5 and 6). Among the catalysts probed, only
(S)-pyrrolidine tetrazole (III)[12] exhibited 20% enantiose-
lectivity in 18% yield (entry 3).
We then turned our attention to the optimization of III-
catalyzed reaction conditions aimed at improving the cross-
aldol reaction efficiency. Screening of solvents revealed that
protic solvents were better than aprotic ones. Low reaction
yields and poor ees were obtained when the reaction was
conducted in CH3CN (entry 8), CHCl3 (entry 9), and DMSO
(entry 10). Among the protic solvents surveyed (entries 11–
15), the best result was achieved in iPrOH. The process pro-
ceeded fast (2 h) to give the product 3a in 70% yield and
with 40% ee (entry 11).
Figure 1. 3-Hydroxyindol-2-one structure.
are convolutamydines,[3a] maremycins,[3b] diazonamide A,[3c]
leptosin D,[3d] o-hydroxyglucoisatisin,[3e] witindolinone C,[3f]
TMC-95A-D,[3g] and celogentin K,[3h] arundaphine,[3i] paratu-
namides A–D,[3j] and neuroprotectins A and B.[3k] The reac-
tion of readily available isatins as electrophile with an ap-
propriate nucleophile affords a straightforward access to the
chiral quaternary centered molecular architectures. The
studies in this field have received increasing interest recent-
ly.[1] Notably, Malkov, Bella, and Kocovsky, and Nakamura
and Toru have independently reported organocatalytic
asymmetric aldol reaction of isatins with acetone.[4] Howev-
ˇ
´
[a] F. Xue, Dr. S. Zhang, L. Liu, Prof. Dr. W. Duan, Prof. Dr. W. Wang
School of Pharmacy
East China University of Science and Technology,
130 Mei-Long Road, Shanghai 200237 (China)
[b] Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico
MSC03 2060, Albuquerque, NM 87131-0001 (USA)
Fax : (+1)505-277-2609
E-mail: wwang@unm.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900243.
1664
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 1664 – 1667

Table 1. Exploratory study of chiral amine catalyzed aldol reaction of
reaction yield (92%) and enantioselectivity (73%) were im-
proved dramatically. Lowering the reaction temperature re-
sulted in a further improvement of the enantioselectivity
(84%) without sacrificing the yield although with an exten-
sion of the reaction time (24 h, entry 6). In addition, it was
noted that slow addition of isatin (1a) was necessary for ob-
taining a higher ee without affecting the yield. These studies
provided the optimal reaction conditions: addition of isatin
(1a) to a solution of isobutyraldehyde (2a) in iPrOH in the
presence of 15 mol% III, 100 mol% water, and 15mol%
phosphoric acid at 08C.
isatin (1a) with isobutyraldehyde (2a).[a]
Having established the optimal reaction conditions, we
determined the scope of the reaction with a variety of isatins
(1) and aldehydes (2) (Table 3). In general, the III-catalyzed
Table 3. Scope of III-catalyzed cross-aldol reactions of isatins (1) with al-
dehydes (2).[a]
Entry
Cat
Solvent
t [h]
Yield [%][b]
ee[c]
[d]
1
2
3
4
5
6
7
8
I
II
III
IV
V
VI
VII
III
III
III
III
III
III
III
III
–
–
–
–
–
–
–
2
<5
<5
18
20
73
89
<5
55
<5
20
70
nd[e]
nd[e]
20
0
0
[d]
24
24
24
4
[d]
[d]
[d]
Entry
X, R1, R2, R3, 3
t [h]
Yield [%][b]
ee [%][c]
dr[d]
[d]
4
0
[d]
nd[e]
27
1
2
3
4
5
6
7
8
H, H, Me, Me, 3a
4-Me, H, Me, Me, 3b
5-F, H, Me, Me, 3c
5-Cl, H, Me, Me, 3d
7-Cl, H, Me, Me, 3e
6-Br, H, Me, Me, 3 f
H, H, -(CH2)4-, 3g
H, Bn, Me, Me, 3h
H, H, H, Me, 3i
24
48
26
29
72
120
40
52
3
92
50
74
83
46
69
86
92
80
69
86
70
84
75
60
80
49
79
G
–
–
–
–
–
–
–
–
3:2
7:5
8:1
7:1
24
24
24
24
2
24
2
2
CH3CN
CHCl3
DMSO
iPrOH
H2O
9
nd[e]
50
10
11
12
13
14
15
40
<5
91
68
nd[e]
30
EtOH
G
33
19
9
98[g]
90[g]
90
U
1.5
68
10
11
12
H, H, H, nBu, 3j
4-Br, H, H, Me, 3k
4, 6-Br2, H, H, Me, 3l
3
3
3
[a] Reaction conditions: unless specified, see Experimental Section.
[b] Yields of isolated product. [c] Determined by chiral HPLC analysis.
[d] Under neat conditions. [e] Not determined.
93[g]
[a] Reaction conditions: unless specified, see Experimental Section and
Supporting Information. [b] Yields of isolated product. [c] Determined by
1
chiral HPLC analysis. [d] Determined by H NMR. [e] After recrystaliza-
tion. [f] Determined by converting to corresponding alcohol. [g] 2 equiv
of aldehyde used.
Further optimization of reaction conditions using iPrOH
as solvent was carried out next. A survey of additives re-
vealed that they played a certain role in governing reaction
yields and enantioselectivity (Table 2). Water as an additive
was beneficial to the process in terms of enantioselectivity
(entry 1). Among the acids probed (entries 2–5), it was ob-
served that phosphoric acid was the best (entry 5) and both
asymmetric cross-aldol reactions proceeded smoothly to
generate products with the formation of two contiguous
quaternary centers, which are otherwise very difficult to
construct. It appears that the
Table 2. Effect of additives on the III-catalyzed cross-aldol reaction of isatin (1a) and isobutyraldehyde (2a)
in iPrOH.[a]
electronic effect and steric hin-
drance have an influence on
the reaction yield and enantio-
selectivity (entry 1 vs 2–6). The
steric effect slowed down the
reaction (entry 5) and also af-
fected the enantioselectivity.
The substitution pattern also
had roles in the reaction yield
and enantioselectivity (en-
tries 2–6), indicative of the sen-
sitive nature of the substrate
structures. A cyclic aldehyde
could engage in the process ef-
Entry
Additives
t [h]
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
100 mol% H2O
4
5
4
4
4
24
RT
RT
RT
RT
RT
0
72
68
75
85
92
92
50
60
76
65
73
84
15 mol% HOAc+100 mol% H2O
15 mol% TFA+100 mol% H2O
15 mol% H3BO3+100 mol% H2O
15 mol% H3PO4 (85%)+100 mol% H2O
15 mol% H3PO4 (85%)+100 mol% H2O
[a] Reaction conditions: unless specified, see Experimental Section. [b] Yields of isolated product. [c] Deter-
mined by chiral HPLC analysis.
Chem. Asian J. 2009, 4, 1664 – 1667
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www.chemasianj.org
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W. Wang et al.
COMMUNICATION
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sign.[5] It was realized that the ee value could be readily im-
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thetic utility.
In conclusion, we have a (S)-pyrrolidine tetrazole cata-
lyzed cross-aldol reactions of isatins with aldehydes. In the
process, two highly hindered contiguous quaternary centers
and one chiral carbon are created with good efficiency. The
protocol, which is applicable for both a-branched and linear
aldehydes as aldol donors, is complementary to that report-
ed recently by Nakamur, Toru, and co-workers, which is
only effective for linear aldehydes.[5] Further investigations
of the valuable catalytic asymmetric aldol reactions aimed
at improving yields and enantioselectivity are currently
being pursued in our laboratory.
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reactions of aldehydes with isatins: N. Hara, S, Nakamura, K.
Kubo, N. Shibata, T. Toru, Chem. Eur. J. 2009, 15, 6790. It is noted
that the catalytic system is not applicable to the a-branched alde-
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Experimental Section
Typical procedure for the aldol reaction using 3a as an example (Table 3,
entry 1): To a mixture of III (15mol%, 4.3 mg), isobutyraldehyde (2a)
(1.0 mmol, 90 mL), and water (0.20 mmol, 3.6 mL), and 85% phosphoric
acid (15mol%, 1.6 mL) in iPrOH (0.5 mL) was added isatin (1a) (30 mg,
0.20 mmol) over 1 h in portions at 08C. After stirring for 24 h, the solvent
was removed under reduced pressure to give a residue that was directly
purified by column chromatography (hexane/ethyl acetate=3:1) giving
3a (41 mg, 92%). Single recrystallization of 3a from hexane/ethyl acetate
afforded >97% ee.
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Acknowledgements
Financial support of this research is supported by the School of Pharma-
cy, East China University of Science and the China 111 Project (Grant
No. B07023).
Keywords: aldehydes · aldol · isatins · organocatalysis
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