Primary amine catalyzed aldol reaction of isatins and acetaldehyde

Article abstract of DOI:10.1016/j.tetlet.2012.01.108

Several cinchona alkaloid-derived chiral primary amines were applied as the catalyst for the cross aldol reaction of isatins with acetaldehyde. With the quinine-derived amine catalyst 3, the desired aldol products were obtained in high yields and good ena

Full text of DOI:10.1016/j.tetlet.2012.01.108

Tetrahedron Letters 53 (2012) 1768–1771
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Primary amine catalyzed aldol reaction of isatins and acetaldehyde
⇑
Qunsheng Guo, John Cong-Gui Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0698, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Several cinchona alkaloid-derived chiral primary amines were applied as the catalyst for the cross aldol
reaction of isatins with acetaldehyde. With the quinine-derived amine catalyst 3, the desired aldol prod-
ucts were obtained in high yields and good enantioselectivities (up to 93% ee) under the optimized con-
ditions. Although other enolizable aldehydes and ketones may also be applied in this reaction, the ee
values obtained are usually low. A mechanism was proposed to account for the formation of the major
enantiomer in this reaction.
Received 21 November 2011
Accepted 24 January 2012
Available online 2 February 2012
Keywords:
Aldol
Quinine amine
Isatin
Ó 2012 Elsevier Ltd. All rights reserved.
Acetaldehyde
Enantioselective
The 3-alkyl-3-hydroxyindolin-2-one moiety may be found in
many natural products that have important biological activities,
such as TMC-95 A–D,1 donaxaridine,2 convolutamydines,2 dioxi-
brassinine,3 and 30-hydroxyglucoisatisin.4 Moreover, organic mole-
cules containing this moiety frequently exhibit different biological
activities and, therefore, are important medicinal compounds.5 Due
to its importance as a pharmacophore, many catalytic asymmetric
methods,6–8 especially asymmetric organocatalysis,7,8 have been
developed for the enantioselective synthesis of 3-alkyl-3-hydrox-
yindolin-2-ones in recent years. Among these reported methods,
organocatalyzed cross aldol reaction of isatin and enolizable
ketones or aldehydes provides an easy access to these derivatives.7,8
While many organocatalysts have been developed for the cross al-
dol reaction of isatin with ketones,7 only a handful of reports are
available on the cross aldol reaction of isatin with acetaldehyde.8
Nakamura and co-workers reported the first enantioselective aldol
reaction of acetaldehyde with an isatin derivative using N-(2-thi-
ophenesulfonyl)-prolinamide as the catalyst in 2009.8a The reaction
was used for the enantioselective synthesis of convolutamydine E.8a
A recyclable version of this catalyst was also reported recently.7i
Almost simultaneously, Wang and Hayashi also reported the asym-
metric aldol reaction of isatins and acetaldehyde.8b,c Wang’s group
used (S)-pyrrolidine tetrazole as the catalyst8b; and in this study,
products containing two highly hindered contiguous quaternary
centers may also be obtained since enolizable aldehydes other than
acetaldehyde may also be applied.8b Hayashi’s group used
4-hydroxydiarylprolinol as the organocatalyst.8c A similar catalytic
system was also reported later by Yuan’s group.8d It should be
pointed that these reported catalysts are all proline derivatives.
Moreover, sometimes the reported reactions were very slow (up
to 5 days),8 which might be due to the low activity of these second-
ary amine catalysts.
As part of our on-going research7i,9 on using activated carbonyl
compounds in organocatalyzed asymmetric aldol reactions as en-
amine or enolate acceptors10 for the synthesis of enantioenriched
biologically active molecules, we recently developed a highly enan-
tioselective synthesis of 3-alkyl-3-hydroxyindolin-2-ones using
quinidine thiourea as the catalyst, which involves an enolate
mechanism.7i While this reaction may also be applied to acetalde-
hyde, the ee value obtained for the product is only mediocre.7i On
the other hand, we recently found primary amine catalysts derived
from cinchona alkaloids catalyze the cross aldol reaction of a-keto-
phosphonates and acetaldehyde in a highly enantioselective man-
ner.9g We reasoned that these primary amines should also be good
catalysts for the asymmetric aldol reaction of acetaldehyde with
isatins. It should be pointed out that, although primary amines
are also frequently used as catalysts in reactions that involve the
enamine intermediates,11 to our knowledge, only recently Cheng
and co-workers have reported a primary-tertiary diamine catalyst
for the enantioselective reaction of isatins with acetaldehyde to
obtain the corresponding aldol products in good ee values.12
Herein we wish to report our study on the use of primary amines
derived from cinchona alkaloids as the catalysts in the asymmetric
aldol reaction of isatins with acetaldehyde and related compounds.
Using isatin (1a) and acetaldehyde as the model substrates, we
first screened a series of chiral primary amine catalysts (3–9, Fig. 1)
for their ability to catalyze the desired aldol reactions. THF was
used as the standard solvent, and the reactions were carried out
at 5 °C. The results of this screening are summarized in
Table 1. As shown by the results in Table 1, when quinine-derived
⇑
Corresponding author. Tel.: +1 210 458 4464; fax: +1 210 458 7428.
E-mail address: cong.zhao@utsa.edu (J.C.-G. Zhao).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.108

Q. Guo, J.C.-G. Zhao / Tetrahedron Letters 53 (2012) 1768–1771
1769
product is not very stable, it was directly reduced by NaBH4 to
the diol 2a. In this way, 2a was obtained in a 90% yield and 87%
ee for the major S-enantiomer (entry 1). Similarly, cinchonidine-
derived amine catalyst 4 yielded 2a in a 92% yield and 60% ee (en-
try 2). In contrast, although the quindine- and cinchonine-derived
amine catalysts 5 and 6 are the pseudo-enantiomers of 3 and 4,
respectively, when 5 and 6 were used as the catalysts, the ee values
obtained for the opposite R-enantiomer were much lower (entries
NH2
NH2
H2N
N
N
N
H
N
H
N
N
H
MeO
OMe
3
4
5
3 and 4). L-Phenylglycine (7) was also found to catalyze the desired
aldol reaction; nonetheless, the reactivity is poor (23% yield) and a
racemic product was obtained (entry 5). Poor results were also
obtained with the primary amine catalysts derived from (S,S)-
1,2-diphenylethane-1,2-diamine (8) and (S,S)-1,2-cyclohexanedi-
amine (9) (entries 6 and 7). Thus, this screening identified the
quinine-derived amine 3 as the best catalyst for this reaction.
The reaction conditions were then further optimized for catalyst
3. We were intrigued by reports that water may be used as an addi-
tive to improve the reactivities and/or enantioselectivities in cross
aldol reactions.13 Thus, water was intentionally added to the reac-
tions catalyzed by 3. Indeed, big improvements in the reactivity
were observed: When 1–3 equiv of water was used, the reaction
time was gradually shortened from 48 to 15 h, and the ee value
of the product was also slightly improved to 92% (entries 8–10).
However, no further improvement in the reactivity was observed
when more water was added. Instead, slightly negative effects on
the enantioselectivity of the reaction were observed (entries 11
and 12). When a large excess of water (40 equiv) was added, the
reaction again became sluggish and a poor ee value of the product
H2N
NH2
N
1
NHTs
NH2
COOH
N
H
7
6
8
CF3
NH2
S
N
H
N
CF3
H
9
Figure 1. Catalysts screened for the aldol reaction of acetaldehyde and isatin.
amine 3 (10 mol %) was used as the catalyst and benzoic acid as the
cocatalyst (30 mol %), the reaction of 1a and acetaldehyde led to
the desired cross aldol product in 48 h. Since the obtained aldol
Table 1
Screening of the catalysts and optimization of the reaction conditionsa
O
HO
OH
O
NaBH4 (5 eq)
catalyst, acid
solvent, 5 °C
+
O
O
MeOH, 0 °C
H
N
N
H
H
1a
2a
Entry
Catalyst
Acid cocatalyst
H2O (equiv)
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
PhCO2H
PhCO2H
PhCO2H
PhCO2H
None
None
None
None
None
None
None
None
1
2
3
4
5
40
3
3
3
3
3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
48
48
48
48
48
48
48
40
30
15
15
15
24
15
15
15
15
15
15
15
15
15
15
15
90
92
93
89
87
60
46d
17d
0
23
None
None
Not determined
-
89
83
88
90
88
88
88
81
82
86
86
67
60
52
87
88
29
90
6d
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
4-MeOC6H4CO2H
4-(i-Pr)C6H4CO2H
2,4-(NO2)2C6H3CO2H
MeCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
90
91
92
91
89
61
89
89
69
78
49
64
55
88
79
26
92
THF
CH2Cl2
Toluene
3
3
3
3
3
3
Et2O
DMEe
EtOAc
CH3CN
1,4-Dioxane/THF (5:1)
a
Unless otherwise noted, all reactions were conducted with 1a (0.1 mmol) and acetaldehyde (0.5 mmol) in the presence of the catalyst (0.01 mmol, 10 mol %) and the acid
cocatalyst (0.03 mmol, 30 mol %) in the specified solvent (1.0 mL) at 5 °C.
b
Yield of the isolated product after column chromatography.
Unless otherwise noted, ee values were determined by HPLC analysis on a ChiralCel AD-H column. The major enantiomer obtained was determined to be S-configured by
c
comparing the measured optical rotation with the reported data.
d
The R-enantiomer was obtained as the major product.
Dimethoxyethane.
e

1770
Q. Guo, J.C.-G. Zhao / Tetrahedron Letters 53 (2012) 1768–1771
Table 2
O
Cross-aldol reaction of isatins and acetaldehydea
HO
3 (10 mol %), H2O
O
CHO
O
PhCO2H (30 mol %)
O
+
+
HO
O
OH
3, CH3CHO
PhCO2H, H2O
THF, 5 °C
THF, 15 h, 5 °C, 93%
H
N
H
NaBH4 (5 eq)
MeOH, 0 °C
N
H
O
O
2l
N
N
1a
R2
R2
R1
dr:61:39, 48% ee
HO
R1
1
2
O
3 (10 mol %), H2O
PhCO2H (30 mol %)
THF, 15 h, 5 °C, 96%
O
O
R1
R2
Time (h)
2/Yieldb (%)
eec (%)
1a
1a
Entry
O
N
H
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
Bn
H
15
12
10
12
6
7
5
16
12
16
10
2a/90
2b/90
2c/95
2d/87
2e/95
2f/96
2g/95
2h/91
2i/93
2j/97
2k/96
92
93
92
90
87
88
89
82
30
75
92
5-Me
5-MeO
5,7-Me2
4-Cl
4-Br
4,7-Cl2
5-F
5-Br
6-Br
H
2m
61% ee
O
3
(10 mol %), H2O
PhCO H (30 mol %)
THF, 72 h, 5 °C, 98%
HO
2
+
O
N
H
10
11
2n
dr: 97:3, 25% ee
a
All reactions were conducted with 1 (0.1 mmol) and acetaldehyde (0.5 mmol) in
the presence of catalyst 3 (0.01 mmol, 10 mol %) and benzoic acid (0.03 mmol,
Scheme 1. Cross-aldol reaction of isatins with propanal, acetone, and
cyclohexanone.
30 mol %) in THF (1.0 mL) at 5 °C.
b
Yield of the isolated product after column chromatography.
Unless otherwise noted, ee values were determined by HPLC analysis on a
c
ChiralPak AD-H or a ChiralCel OJ-H column.
H
PhCO2
O
HO
N
H
N
CHO
O
was obtained (61% ee, entry 13). Thus, the best results were
obtained when the reaction was conducted in the presence of three
equivalents of added water (entry 10). The acid cocatalyst was then
optimized under these reaction conditions. As the data showed,
benzoic acid is the best cocatalyst (entry 10) since all the other
acids screened led to worse results in enantioselectivity (Table 1,
entries 14–17). The solvents were also examined. Most of the com-
mon organic solvents, such as, CH2Cl2, toluene, ether, DME, EtOAc,
and CH3CN all yielded poorer results (entries 18–23). Nonetheless,
a 1,4-dioxane-THF (5:1, v/v) mixture was found to be as good as
THF in terms of the reactivity and the enantioselectivity obtained
(entry 24). Thus, THF was adopted as the solvent in our further
studies due to its superior behaviors and simplicity.
favored
NH
MeO
H
O
N
H
NH
PhCO2
N
H
N
HO
CHO
O
NH
disfavored
O
O
N
H
HN
MeO
The scope of this catalytic system was then evaluated under the
optimized reaction conditions with different isatin derivatives as
well as other enolizable aldehydes and ketones. The results of this
investigation are summarized below in Table 2 and Scheme 1. As
shown in Table 2, when acetaldehyde was used, besides the parent
isatin (entry 1), isatins with electron-donating substituents at dif-
ferent positions on the phenyl all gave the desired cross aldol prod-
ucts in excellent ee values (90–93% ee, entries 2–4). In contrast,
isatins substituted with electron-withdrawing groups lead to
slightly lower ee values (entries 5–8). 5-Bromo- and 6-bromoisa-
tins yielded much lower ee values of the corresponding aldol prod-
ucts (entries 9 and 10) as compared to that of 4-bromoisatin (entry
6). This is most likely due to a combination of electronic and steric
effects. On the other hand, N-benzyl protected isatin yields the
corresponding aldol product in a high ee value of 92% (entry 11).
Besides acetaldehyde, propanal, acetone, and cyclohexanone
may also be used as substrates in this reaction (Scheme 1). When
propanal was reacted under the optimized conditions, the desired
aldol product was obtained in a 93% yield. The two diastereomers
were obtained in a ratio of 61:39 and the major (S,S)-diastereomer
(2l) was obtained in 48% ee.14 When acetone was applied in this
reaction, the corresponding aldol product (2m) was obtained in a
96% yield with moderate enantioselectivity (61% ee). In contrast,
cyclohexanone yields the expected aldol product in excellent
diastereoselectivity (dr 97:3); nevertheless, the ee value of the
major syn diastereomer is low (25%).15
Scheme 2. Proposed transition states for the quinine amine catalyzed aldol
reaction.
Based on the absolute configuration of compounds 2, a plausible
catalytic model for the reaction of acetaldehyde and isatin was pro-
posed (Scheme 2). The primary amine moiety of quinine-derived
amine 3 reacts with acetaldehyde to form an enamine intermedi-
ate. The acid cocatalyst has multiple roles in this catalysis. It can
accelerate the formation of the enamine intermediate through acid
catalysis. Simultaneously, it also protonates the nitrogen atom in
the quinuclidine backbone of the amine catalyst 3 to form an
ammonium salt. The proton in this ammonium salt then forms
hydrogen bonds with the isatin carbonyl groups (Scheme 2). Such
hydrogen bonds not only activate isatin for the cross aldol reaction,
but also direct the approach of isatin. Among the two possible
orientations of isatin, the re face orientation (Scheme 2, top left)
is favored since the unfavorable interaction between the isatin
benzene ring and the catalyst is avoided. Attacking of the enamine
to the re face of the isatin ketone group leads to the observed major
S-enantiomer.
In summary, we have developed an asymmetric aldol reaction
of isatins and acetaldehyde using a quinine-derived primary amine
as organocatalysts. The corresponding aldol products were
obtained in high enantioselectivities (up to 93% ee). When other
aldehydes and ketones were applied in this reaction, the expected

Q. Guo, J.C.-G. Zhao / Tetrahedron Letters 53 (2012) 1768–1771
1771
J. 2009, 15, 6790–6793; (b) Xue, F.; Zhang, S.-L.; Liu, L.; Duan, W.-H.; Wang, W.
Chem. Asian J. 2009, 4, 1664–1667; (c) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org.
Lett. 2009, 11, 3854–3857; (d) Chen, W.-B.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Tetrahedron 2010, 66, 1441–1446.
aldol products were obtained in excellent yields, but with only
mediocre enantioselectivities.
9. (a) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006, 128, 7442–7443; (b) Dodda,
R.; Zhao, C.-G. Org. Lett. 2006, 8, 4911–4914; (c) Samanta, S.; Perera, S.; Zhao, C.-
G. J. Org. Chem. 2010, 75, 1101–1106; (d) Dodda, R.; Zhao, C.-G. Synlett 2007,
1605–1609; (e) Mandal, T.; Samanta, S.; Zhao, C.-G. Org. Lett. 2007, 9, 943–945;
(f) Ding, D.; Zhao, C.-G.; Guo, Q.-S.; Arman, H. Tetrahedron 2010, 66, 4423–
4427; (g) Perera, S.; Naganaboina, V. K.; Wang, L.; Zhang, B.; Guo, Q.-S.; Rout, L.;
Zhao, C.-G. Adv. Synth. Catal. 2011, 353, 1729–1734; (h) Guang, J.; Zhao, C.-G.
Tetrahedron: Asymmetry 2011, 22, 1205–1211; For a review, see: (i) Bhanushali,
M.; Zhao, C.-G. Synthesis 2011, 1815–1830.
Acknowledgments
The authors thank the generous financial support of this
research from the Welch Foundation (Grant No. AX-1593) and
the NSF (Grant No. CHE-0909954).
Supplementary data
10. For examples of using activated carbonyl compounds in organocatalyzed
aldol reactions, see: (a) Shen, Z.; Li, B.; Wang, L.; Zhang, Y. Tetrahedron Lett.
2005, 46, 8785–8788; (b) Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto, T.;
Maruoka, K. Org. Lett. 2005, 7, 5103–5105; (c) Samanta, S.; Zhao, C.-G.
Tetrahedron Lett. 2006, 47, 3383–3386; (d) Pousse, G.; Le Cavelier, F.;
Humphreys, L.; Rouden, J.; Blanchet, J. Org. Lett. 2010, 12, 3582–3585; (e)
Qiu, L.-H.; Shen, Z.-X.; Shi, C.-Q.; Liu, Y.-H.; Zhang, Y.-W. Chinese J. Chem.
2005, 23, 584–588; (f) Liu, J.; Yang, Z.; Wang, Z.; Wang, F.; Chen, X.; Liu, X.;
Feng, X.; Su, Z.; Hu, C. J. Am. Chem. Soc. 2008, 130, 5654–5655; (g) Jiang, J.;
Chen, X.; Wang, J.; Hui, Y.; Liu, X.; Lin, L.; Feng, X. Org. Biomol. Chem. 2009,
7, 4355–4357; (h) Urushima, T.; Yasui, Y.; Ishikawa, H.; Hayashi, Y. Org. Lett.
2010, 12, 2966–2969; (i) Tang, Z.; Cun, L.-F.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. Org. Lett. 2006, 8, 1263–1266; (j) Hara, N.; Tamura, R.; Funahashi,
Y.; Nakamura, S. Org. Lett. 2011, 13, 1662–1665.
11. For selected examples of primary amine catalyzed enantioselective reactions,
see: (a) Reisinger, C. M.; Wang, X.; List, B. Angew. Chem., Int. Ed. 2008, 47, 8112–
8115; (b) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368–13369; (c)
Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008, 130, 8134–
8135; (d) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008, 130, 6070–
6071; (e) McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599–602; (f) Liu, T.-Y.;
Cui, H.-L.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.-Q.; Chen, Y.-C. Org. Lett. 2007, 9,
3671–3674; (g) Zheng, B.-L.; Liu, Q.-Z.; Guo, C.-S.; Wang, X.-L.; He, L. Org.
Biomol. Chem. 2007, 5, 2913–2915; (h) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B.
Angew. Chem., Int. Ed. 2008, 47, 7656–7658; (i) Bartoli, G.; Melchiorre, P. Synlett
2008, 1759–1772; (j) Chen, Y.-C. Synlett 2008, 1919–1930; (k) Gogoi, S.; Zhao,
C.-G.; Ding, D. Org. Lett. 2009, 11, 2249–2252; (l) Mandal, T.; Zhao, C.-G. Angew.
Chem., Int. Ed. 2008, 47, 7714–7717; (m) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.;
Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed.
2007, 46, 389–392; (n) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128,
7170–7171; (o) Ding, D.-R.; Zhao, C.-G. Eur. J. Org. Chem. 2010, 3802–3805; for
a review on primary amine catalysis, see: (p) Peng, F.; Shao, Z. J. Mol. Catal. A
2008, 285, 1–13.
Supplementary data (detailed experimental procedures, com-
pound characterization data and HPLC conditions, copy of HPLC
chromatograms) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2012.01.108.
References and notes
1. (a) Koguchi, Y.; Kohno, J.; Nishio, M.; Takahashi, K.; Okuda, T.; Ohnuki, T.;
Komatsubara, S. J. Antibiot. 2000, 53, 105–109; (b) Khono, J.; Koguchi, Y.; Nishio,
M.; Nakao, K.; Juroda, M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem.
2000, 65, 990–995; (c) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41,
512–515; (d) Albrecht, B. K.; Williams, R. M. Org. Lett. 2003, 5, 197–200.
2. (a) Kim, S. C.; Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2006, 47, 3463–3466;
(b) Takayama, H.; Matsuda, Y.; Masubuchi, K.; Ishida, A.; Kitajima, M.; Aimi, N.
Tetrahedron 2004, 60, 893–900; (c) Khuzhaev, V. U. Chem. Nat. Compd. 2004, 40,
516–517; (d) Ubaidullaev, K. A.; Shakirov, R.; Yunosov, S. Y. Khim. Prir. Soedin.
1976, 12, 553–554; (e) Rasmussen, H. B.; MacLeod, J. K. J. Nat. Prod. 1997, 60,
1152–1154; (f) Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon, R.;
Ogawa, A. Tetrahedron 2004, 60, 3493–3503.
3. (a) Monde, K.; Sasaki, K.; Shirata, A.; Takasugi, M. Phytochemistry 1991, 30,
2915–2917; (b) Suchy, M.; Kutschy, P.; Monde, K.; Goto, H.; Harada, N.;
Takasugi, M.; Dzurilla, M.; Balentova, E. J. Org. Chem. 2001, 66, 3940–3947.
4. Fréchard, A.; Fabre, N.; Péan, C.; Montaut, S.; Fauvel, M.-T.; Rollin, P.; Fourasté,
I. Tetrahedron Lett. 2001, 42, 9015–9017.
5. For examples, see: (a) Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi, M.
C.; Wolfe, J. F. J. Am. Chem. Soc. 1985, 107, 435–443; (b) Labroo, R. B.; Cohen, L.
A. J. Org. Chem. 1990, 55, 4901–4904; (c) Tokunaga, T.; Hume, W. E.; Umezome,
T.; Okazaki, K.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.;
Noguchi, H.; Nagata, R. J. Med. Chem. 2001, 44, 4641–4649; (d) Tokunaga, T.;
Hume, W. E.; Nagamine, J.; Kawamura, T.; Taiji, M.; Nagata, R. Bioorg. Med.
Chem. Lett. 2005, 15, 1789–1792.
6. For examples, see: (a) Zheng, K.; Yin, C.-K.; Liu, X.-H.; Lin, L.-L.; Feng, X.-M.
Angew. Chem., Int. Ed. 2011, 50, 2573–2577; (b) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv.
Synth. Catal. 2010, 352, 1381–1407; (c) Shintani, R.; Inoue, M.; Hayashi, T.
Angew. Chem., Int. Ed. 2006, 45, 3353–3356; (d) Toullec, P. Y.; Jagt, R. B. C.; Vries,
J. G.; Feringa, B. L.; Minnaard, A. J. Org. Lett. 2006, 8, 2715–2718; (e) Liu, Y.-L.;
Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang, C.; Zhou, J. J. Am. Chem. Soc.
2010, 132, 15176–15178; (f) Nakamura, T.; Shirokawa, S.; Hosokawa, S.;
Nakazaki, A.; Kobayashi, S. Org. Lett. 2006, 8, 677–679; (g) Wang, C.-C.; Wu, X.-
Y. Tetrahedron 2011, 67, 2974–2978; (h) Guan, X.-Y.; Wei, Y.; Shi, M. Chem. Eur.
J. 2010, 16, 13617–13621; (i) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.;
Fettinger, J. C.; Franz, A. K. Angew. Chem., Int. Ed. 2010, 49, 744–747.
12. During the progress of our research, Cheng and coworkers published a chiral
primary–tertiary diamine catalyzed aldol reaction of acetaldehyde and isatins,
see: Hu, S.-S.; Zhang, L.; Li, J.-Y.; Luo, S.-Z.; Cheng, J.-P. Eur. J. Org Chem. 2011,
3347–3352.
13. For selected examples, see: (a) Hernandez, J. G.; Juaristi, E. Tetrahedron 2011,
67, 6953–6959; (b) Bhanushali, M.; Zhao, C.-G. Tetrahedron Lett. 2012, 53,
359–362; (c) Miura, T.; Ina, M.; Imai, K.; Nakashima, K.; Yasaku, Y.; Koyata, N.;
Murakami, Y.; Imai, N.; Tada, N.; Itoh, A. Tetrahedron: Asymmetry 2011, 22,
1028–1034; (d) Kumar, A.; Singh, S.; Kumar, V.; Chimni, S. S. Org. Biomol. Chem.
2011, 9, 2731–2742; (e) Hayashi, Y.; Yasui, Y.; Kawamura, T.; Kojima, M.;
Ishikawa, H. Angew. Chem., Int. Ed. 2011, 50, 2804–2807; (f) Hayashi, Y.;
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int.
Ed. 2006, 45, 958–961; (g) Fu, Y.-Q.; An, Y.-J.; Liu, W.-M.; Li, Z.-C.; Zhang, G.;
Tao, J. C. Catal. Lett. 2008, 124, 397–404; (h) Giacalone, F.; Gruttadauria, M.;
Meo, P. L.; Riela, S.; Noto, R. Adv. Synth. Catal. 2008, 350, 2747–2760; (i) Font,
D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2008, 10, 337–
340; (j) Liu, Y.-X.; Sun, Y.-N.; Tan, H.-H.; Liu, W.; Tao, J.-C. Tetrahedron:
Asymmetry 2007, 18, 2649–2656; (k) Raj, M.; Maya, V.; Ginotra, S. K.; Singh, V.
K. Org. Lett. 2006, 8, 4097–4099; (l) Peng, F.-Z.; Shao, Z.-H.; Pu, X.-W.; Zhang,
H.-B. Adv. Synth. Catal. 2008, 350, 2199–2204; (m) Fu, Y.-Q.; Li, Z.-C.; Ding, L.-
N.; Tao, J.-C.; Zhang, S.-H.; Tang, M.-S. Tetrahedron: Asymmetry 2006, 17, 3351–
3357; (n) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas,
C. F., III J. Am. Chem. Soc. 2006, 128, 734–735; (o) Zu, L.; Xie, H.; Li, H.; Wang, J.;
Wang, W. Org. Lett. 2008, 10, 1211–1214; For a review, see: (p) Gruttadauria,
M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33–57.
7. For reports of the enantioselective aldol reaction of ketones to isatin by using
organocatalysts, see: (a) Luppi, G.; Monari, M.; CorrTa, R. J.; Violante, F. A.;
Pinto, A. C.; Kaptein, B.; Broxterman, A. B.; Garden, S. J.; Tomasini, C.
Tetrahedron 2006, 62, 12017–12024; (b) Chen, J.-R.; Liu, X.-P.; Zhu, X.-Y.; Li,
L.; Qiao, Y.-F.; Zhang, J.-M.; Xiao, W.-J. Tetrahedron 2007, 63, 10437–10444; (c)
Malkov, A. V.; Kabeshov, M. A.; Bella, M.; Kysilka, O.; Malyshev, D. A.;
ˇ
ˇ
Pluhácková, K.; Kocovsky, P. Org. Lett. 2007, 9, 5473–5476; (d) Luppi, G.; Cozzi,
P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J. Org. Chem. 2005,
70, 7418–7421; (e) Chen, G.; Wang, Y.; He, H.; Gao, S.; Yang, X.; Hao, X.
Heterocycles 2006, 68, 2327–2333; (f) Nakamura, S.; Hara, N.; Nakashima, H.;
Kubo, K.; Shibata, N.; Toru, T. Chem. Eur. J. 2008, 14, 8079–8081; (g) Angelici, G.;
Corrêa, R. J.; Garden, S. J.; Tomasini, C. Tetrahedron Lett. 2009, 50, 814–817; (h)
Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Adv. Synth. Catal. 2010, 352, 1621–
1624; (i) Guo, Q.-S.; Bhanushali, M.; Zhao, C.-G. Angew. Chem., Int. Ed. 2010, 49,
9460–9464; (j) Raj, M.; Veerasamy, N.; Singh, V. K. Tetrahedron Lett. 2010, 51,
2157–2159; (k) Allu, S.; Molleti, N.; Panem, R.; Singh, V. K. Tetrahedron Lett.
2011, 52, 4080–4083; (l) Kinsella, M.; Duggan, P. G.; Lennon, C. M. Tetrahedron:
Asymmetry 2011, 22, 1423–1433.
14. The relative stereochemistry of the two stereogenic centers in this compound
was determined by reducing product 21 to the corresponding diol, for which
the stereochemistry is known. For details, please see the Supplementary data
and: Higuchi, K.; Saito, K.; Hirayama, T.; Watanabe, Y.; Kobayashi, E.; Kawasaki,
T. Synthesis 2010, 3609–3614.
15. The relative stereochemistry of the two stereogenic centers in this compound
was determined by comparing the spectroscopic data of this product with
those of an authentic sample prepared according to Ref. 7j
8. For reports of the enantioselective addition of acetaldehyde to isatin by using
organocatalysts, see: (a) Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Chem. Eur.