Quinidine thiourea-catalyzed aldol reaction of unactivated ketones: Highly enantioselective synthesis of 3-alkyl-3-hydroxyindolin-2-ones

Article abstract of DOI:10.1002/anie.201004161

New catalysis mechanism! The asymmetric aldol reaction of unactivated ketones and activated carbonyl compounds is realized with a quinidine-derived thiourea catalyst (see scheme), and involves an enolate mechanism instead of the widely used enamine mechan

Full text of DOI:10.1002/anie.201004161

Communications
DOI: 10.1002/anie.201004161
Organocatalysis
Quinidine Thiourea-Catalyzed Aldol Reaction of Unactivated
Ketones: Highly Enantioselective Synthesis of 3-Alkyl-3-hydroxy-
indolin-2-ones**
Qunsheng Guo, Mayur Bhanushali, and Cong-Gui Zhao*
The aldol reaction is one of the most important carbon–
carbon bond formation reactions[1] and, therefore, many
asymmetric variants of this reaction have been developed in
the past.[1] Since List and Barbas discovered the proline-
catalyzed cross-aldol reaction of ketones and aldehydes,[2]
many amine derivatives, mainly proline derivatives, have
been developed for asymmetric cross-aldol reactions.[3]
Mechanistically, these catalysts activate the ketones or
enolizable aldehydes through the formation of an enamine
intermediate (Scheme 1, upper equation).[3] The mechanism
formation of an enamine is difficult. During our study of using
activated ketone compounds as the enamine acceptors for
organocatalyzed aldol reactions,[8] we envisioned that such an
organocatalyzed enolate-mediated aldol reaction should be
possible if the enolate acceptor is sufficiently activated,
because the equilibrium favors the formation of the product
with such a substrate. Herein, we report the first enantiose-
lective aldol reaction of unactivated ketones involving the
enolate mechanism, which may be used for the highly
enantioselective synthesis of 3-alkyl-3-hydroxyindolin-2-
ones.[9]
The enamine-mediated aldol reactions of isatins and
ketones or enolizable aldehydes have been used in recent
years for the synthesis of 3-alkyl-3-hydroxyindolin-2-ones,[10]
which are important biologically active natural products and
medicinal compounds.[11] Since isatin contains an activated
ketone group, we tested our hypothesis with isatin (10a) and
acetone (11a) as the model substrates, and some tertiary
amines (1–8) as the catalysts (Scheme 2). The results of the
catalyst screening and optimizations are presented in Table 1.
Scheme 1. Aldol reactions involving the enamine or enolate intermedi-
ates.
is usually a combination of both covalent and noncovalent
catalyses, since most of these catalysts also contain a hydro-
gen-bonding moiety to direct the approach of the enamine
acceptor. In contrast, although enol and enolate (Scheme 1,
lower equation) are the active intermediates in the original
aldol reactions,[4] organocatalyzed enantioselective direct
aldol reaction of unactivated ketones through the enolate
mechanism is very difficult, because the acidity of the
a proton in these ketones is very low. To our knowledge,
there has been no such report.[5–7] Nevertheless, the enolate
mechanism does have certain advantages, especially when the
[*] Dr. Q. Guo, Dr. M. Bhanushali, Prof. Dr. C.-G. Zhao
Department of Chemistry, University of Texas at San Antonio
One UTSA Circle, San Antonio, TX 78249 (USA)
Fax: (+1)210-458-7428
E-mail: cong.zhao@utsa.edu
Homepage: http://www.utsa.edu/chem/zhao.html
[**] The generous financial support of this project from the NSF (Grant
no. CHE-0909954) and the Welch Foundation (Grant No. AX-1593)
is gratefully acknowledged. We also thank Dr. William Haskins and
the RCMI Proteomics Core (NIH G12 RR013646) at UTSA for
assistance with the HRMS analysis of the products.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004161.
Scheme 2. Catalysts screened for the cross-aldol reaction of isatin and
acetone [Ar=3,5-(CF3)2C6H3].
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Chemie
Table 1: Catalyst screening and reaction conditions optimization.[a]
enolate mechanism. If this is the case, the reaction must be a
complete noncovalent catalysis. With the best catalyst 4,
further optimizations (Table 1, entries 10–20) identified THF
as the best solvent for this reaction, in which the ee value was
improved to 82% (Table 1, entry 12). All the other solvents
screened led to less satisfactory results. The product yield
could be improved to 98% by using more acetone (30 equiv,
Table 1, entry 21). The ee value was improved to 86% when
the reaction was carried out at 58C, at the cost of the
reactivity (Table 1, entry 22).[13] Luckily, the lost reactivity
could be remedied by employing more acetone (70 equiv) and
prolonging the reaction time to 6 days, without affecting the
enantioselectivity (Table 1, entries 23 and 24).
Next the scope of this reaction was studied and the results
are summarized in Tables 2 and 3. As shown in Table 2, with
acetone as the substrate, various substituted isatins may be
applied in this reaction. Excellent yields and high ee values
(ꢀ79% ee) of the expected products were obtained (Table 2,
entries 1–6). The electronic nature of the substituent and its
position on the isatin phenyl ring show some influences on the
enantioselectivities. For example, the ee value of 4-bromoisa-
tin 12c (Table 2, entry 3) is much higher than that of 6-
bromoisatin 12e (Table 2, entry 5). Acetophenone (11b) is a
tough substrate for the enamine mechanism because of its low
electrophilicity[14] and it has never been used in the asym-
metric aldol reaction with isatin. However, as is evident from
the results in Table 2, 11b is even more reactive than acetone
under our conditions (only 10 equiv ketone is necessary), and
Entry
Catalyst
Solvent
10a
[equiv]
Time
[days]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
9
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
benzene
CH2Cl2
THF
–
–
–
–
–
–
–
–
–
7
7
7
7
7
7
7
7
7
7
7
30
30
70
70
1
1
1
1
1
1
1
1
1
4
4
4
4
4
4
4
4
4
4
4
4
4
4
6
78
84
80
98
99
98
trace
98
0
56
–
2
61
68
57[d]
57[d]
–
40
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
56
53
82
76
70
67
–
46
58
60
64
Et2O
dioxane
CH3CN
AcOEt
DMSO
hexane
DME
MeOH
THF
THF
22
trace
trace
trace
15
49
98
23
73
97
–
–
77
31
80
86[e]
86[e]
85[e]
THF
THF
Table 2: Cross-aldol reaction of isatins and ketones.[a]
[a] Unless otherwise indicated, all reactions were carried out with isatin
(0.10 mmol), acetone, and the catalyst (0.01 mmol, 10 mol%) in the
specified solvent (1.0 mL for acetone; 2.0 mL for THF and other
solvents) at room temperature. [b] Yield of the isolated product after
column chromatography. [c] Determined by HPLC analysis. Absolute
configuration was assigned according to reference [10c]. [d] The S en-
antiomer was obtained. [e] Carried out at 58C. DMSO=dimethyl
sulfoxide, DME=dimethoxyethane.
Entry R1/10
R2/11
Time [days] 12/Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
H/a
Me/a
Me/a
Me/a
Me/a
Me/a
6
4
4
5
4
5
6
5
5
4
5
5
6
5
6
4
3
a/97
b/98
c/99
d/99
e/99
f/99
g/75
h/98
i/98
j/99
k/98
l/98
m/70
n/98
o/76
p/98
q/82[d]
85
87
91
85
79
83
90
95
97
86
84
92
86
90
87
91
73[e]
4-Cl/b
4-Br/c
5-F/d
6-Br/e
5,7-Br2/f Me/a
H/a
4-Cl/b
4-Br/c
5-F/d
6-Br/e
With acetone as the solvent, the reaction catalyzed by
quinuclidine (1) gave a good yield of the desired 12a (Table 1,
entry 1). Quinidine (2) is similarly reactive, but the ee value
obtained was poor (Table 1, entry 2). In contrast, quinidine-
derived thioureas[12] 3 and 4 gave much improved ee values for
the R enantiomer (61 and 68%, respectively; Table 1,
entries 3 and 4). As expected, quinine thiourea (5) and
cinchonidine thiourea (6) led to the formation of the
S enantiomer (57% ee, Table 1, entries 5 and 6). High yields
of 12a were also obtained for these four catalysts. Nonethe-
less, with thiourea 7, only a trace amount of 12a was formed
(Table 1, entry 7). This was probably because of the lower
basicity of 7. Takemoto thiourea 8 is more reactive, but the
ee value obtained was lower (Table 1, entry 8). However, a
simple thiourea 9 that has no basic moiety does not catalyze
the reaction (Table 1, entry 9). This result excludes the
possibility of the involvement of an enol intermediate in
this reaction.
Ph/b
Ph/b
Ph/b
Ph/b
Ph/b
9
10
11
12
13
14
15
16
17
4,7-Cl2/g Ph/b
H/a
H/a
H/a
H/a
H/a
1-Np/c
2-Np/d
E-MeCH CH/e
E-PhCH CH/f
H/g
=
=
[a] All reactions were carried out with 10 (0.10 mmol), the ketone 11
(7.0 mmol for acetone and 1.0 mmol for acetophenone), and catalyst 4
(0.01 mmol, 10 mol%) in THF (2.0 mL) at 58C. [b] Yield of isolated
product after column chromatography. [c] Determined by HPLC analy-
ses. [d] Yield of the corresponding diol after reduction of the primary
product with NaBH4. [e] Determined by HPLC analysis of the corre-
sponding diol.
Since the reaction is catalyzed by 1 (Table 1, entry 1) and
not by 9 (Table 1, entry 9), it most likely works through the
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Table 3: Cross-aldol reaction of activated carbonyl compounds and
respectively. The ee values of these two products were
determined to be 61 and 76% ee, respectively (Table 3,
entries 2 and 3). The lower ee value obtained with 13b
(Table 3, entry 3) relative to 13a (Table 3, entry 1) was most
likely due to the steric effects of the N-methyl group in 13b,
which may be easily rationalized with our proposed mecha-
nism in Scheme 3.
ketones.[a]
Entry
1
13
11
b
14/Yield [%][b] ee [%][c]
/a
/b
a/60
90
2
3
a
b
b/90
c/78
61
76
4
/c b[d]
d/41
e/46[f]
74
56
5
6
PhCOCHO·H2O /d a[e]
PhCOCHO·H2O /d
/h f/54[g,h]
93[i]
[a] Unless otherwise indicated, all reactions were carried out with 13
(0.10 mmol), 11 (7.0 mmol for 11a and 1.0 mmol for 11b), and catalyst 4
(0.01 mmol, 10 mol%) in THF (2.0 mL) at 58C for 6 days. [b] Yield of
isolated product after column chromatography. [c] Determined by HPLC
analyses. [d] The reaction was carried out at room temperature. [e] The
reaction was carried out for 4 days with THF (0.2 mL) as the solvent.
[f] The product of this reaction is 2-hydroxy-1-phenylpentane-1,4-dione
(14e). [g] The reaction was carried out in cyclohexanone (11h, 1.0 mmol)
as the solvent for 2 days; the product of this reaction is 2-(1-hydroxy-2-
oxo-2-phenylethyl)cyclohexanone (14 f). [h] Total yield of two inseparable
diastereomers; the diastereomeric ratio (anti/syn) was determined to be
Scheme 3. Proposed transition states for the aldol reaction of isatin
and acetone.
1
86:14 according to H NMR analysis of the crude product. The relative
stereochemistry of these products was assigned according to refer-
ence [15]. [i] Value of the major anti diastereomer.
Other active carbonyl derivatives, such as 4,4-dimethyldi-
hydrofuran-2,3-dione (13c) and phenylglyoxal hydrate (13d),
may also be applied in this reaction. The reaction of 13c with
11b leads to the desired product 14d in 41% yield and 74% ee
(Table 3, entry 4). Compound 13d has both a ketone and an
aldehyde group; nonetheless, only the aldehyde group reacts
in the cross-aldol reactions with acetone (11a) and cyclo-
hexanone (11h). With acetone (11a) as the substrate, the
product 2-hydroxy-1-phenylpentane-1,4-dione (14e) was
obtained in 46% yield and 56% ee (Table 3, entry 5). When
cyclohexanone (11h) was used as the substrate, the reaction
gave 14 f as a mixture of anti and syn diastereomers[15] in 54%
yield, with an anti/syn ratio of 86:14. The major anti
diastereomer was obtained in a high ee value of 93%
(Table 3, entry 6). To our knowledge, this is first example of
an enantioselective cross-aldol reaction of phenylglyoxal
hydrate that yields the anti diastereomer as the major
product.[16]
the ee values obtained for the products are also higher than
those of the corresponding acetone products (Table 2,
entries 7–12). The observed higher reactivity is in accord
with the increased acidity of the acetophenone a proton.
Other aryl methyl ketones, such as acetonaphthones 11c and
11d, also give very good results (Table 2, entries 13 and 14).
Excellent results were also obtained for a,b-unsaturated
ketones (E)-3-penten-2-one (11e) and (E)-4-phenyl-3-buten-
2-one (11 f) (Table 2, entries 15 and 16). Besides ketones,
acetaldehyde (11g) may also be applied in this reaction. Since
the corresponding aldol product 12q is not very stable, it was
reduced in situ with NaBH4 to give the corresponding diol in
82% yield. The ee value of this diol was determined to be
73% (Table 2, entry 17).
In addition to isatins, other activated carbonyl compounds
may also be used as the substrates in this reaction. As is
evident from the results collected in Table 3, the aldol
reaction of 7-azaisatin (13a) with acetophenone (11b) gives
the expected 14a in 60% yield and 90% ee (Table 3, entry 1).
These results are comparable to those of isatin (Table 2,
entry 7). Similarly, the aldol reaction of 1-methyl-7-azaisatin
(13b) with acetone (11a) and acetophenone (11b) yields the
desired products 14b and 14c in 90 and 78% yields,
A plausible mechanism of this reaction is proposed to
account for the observed enantioselectivity in the isatin–
acetone cross-aldol reaction. As shown in Scheme 3, acetone
is deprotonated by the tertiary amine in the quinidine
thiourea catalyst backbone. After deprotonation, the enolate
associates closely with the catalyst through ionic interactions.
On the other hand, two hydrogen bonds are formed between
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time given in the tables. The solvent was then removed under reduced
the isatin carbonyl groups and the thiourea moiety of the
quinidine thiourea catalyst. Besides activating the ketone
group for the enolate attack, these hydrogen bonds also direct
the approach of isatin. Among the two possible orientations
of isatin, the re face orientation (Scheme 3, top left) is favored
since the unfavorable interaction between the isatin benzene
ring and the enolate is avoided. Attacking of the enolate to
the si face of the isatin ketone group leads to the observed
major R enantiomer. These proposed transition states predict
that an increase of the steric bulkiness at position 1 of isatin
will lead to lower enantioselectivity, while an increase of the
steric bulkiness at position 4 will lead to higher enantioselec-
tivity. As shown by the results (Table 3, entry 3 versus entry 1;
Table 2, entries 2 and 3 versus entry 1), this is indeed the case,
which lends some support to this mechanism.
To show the utility of the current method, we developed
the first enantioselective synthesis of 3-hydroxyindolin-2-one
12r, which is the lead compound for treating Ewingꢀs sarcoma
discovered most recently by Toretsky and co-workers.[17] As
shown in Scheme 4, when isatin 10g and 4’-methoxyaceto-
phenone (11i, 20 equiv) were allowed to react in the presence
of catalyst 4 (20 mol%) under optimized conditions, the
desired product 12r was obtained in 85% yield and 91% ee.[18]
pressure and the mixture was purified by flash column chromatog-
raphy on silica gel (1:1 hexane/ethyl acetate) to give the desired aldol
product.
Received: July 7, 2010
Published online: October 29, 2010
Keywords: aldol reaction · enantioselectivity · ketones ·
.
organocatalysis · reaction mechanisms
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Scheme 4. Enantioselective synthesis of 3-hydroxyindolin-2-one (12r).
In summary, we have developed the first organocatalyzed
asymmetric aldol reaction of unactivated ketones and acti-
vated carbonyl compounds on the basis of a new noncovalent
catalysis mechanism involving the enolate intermediate by
using quinidine thiourea as the catalyst. The method is
complementary to the enamine-based organocatalyzed aldol
reactions and works well in cases where the enamine
mechanism has difficulties. The reaction may be utilized for
the highly enantioselective synthesis of biologically significant
3-alkyl-3-hydroxyindolin-2-ones.
Experimental Section
General procedure for the aldol reaction of isatins with ketones: The
organocatalyst
4 (5.9 mg, 0.01 mmol, 10 mol%) and isatin 10
(0.10 mmol) were stirred in THF (2.0 mL) for 10 min at 58C. The
corresponding ketone 11 (7.0 mmol for acetone or 1.0 mmol for other
methyl ketones) was added and the mixture was stirred at 58C for the
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www.angewandte.org 9463

Communications
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[18] The ee value may be increased to > 99.5% ee by a single
recrystallization with a 65% recovery.
[13] The ee value of 12a could be improved to 89% by further
dropping the reaction temperature to À158C, but the yield
obtained was impractical.
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