Facile synthesis of chiral spirooxindole-based isotetronic acids and 5-1H-pyrrol-2-ones through cascade reactions with bifunctional organocatalysts

Article abstract of DOI:10.1002/chem.201402945

Unprecedented organocatalyzed asymmetric cascade reactions have been developed for the facile synthesis of chiral spirooxindole-based isotetronic acids and 5-1H-pyrrol-2-ones.The asymmetric 1,2-addition reactions of α-ketoesters to isatins and imines by u

Full text of DOI:10.1002/chem.201402945

DOI: 10.1002/chem.201402945
Communication
&
Asymmetric Catalysis
Facile Synthesis of Chiral Spirooxindole-Based Isotetronic Acids
and 5-1H-Pyrrol-2-ones through Cascade Reactions with
Bifunctional Organocatalysts
Wengang Guo, Xu Wang, Boyu Zhang, Shuai Shen, Xin Zhou, Peng Wang, Yan Liu,* and
Can Li*[a]
ty through a three-component reaction involving chiral phos-
phoric acid as a catalyst (Scheme 1a, top reaction).[7] Owing to
Abstract: Unprecedented organocatalyzed asymmetric
the importance of discovering new bioactive compounds, the
development of efficient methods for the asymmetric synthesis
of spiroisotetronic acid derivatives and 5-1H-pyrrol-2-ones is in
high demand.
cascade reactions have been developed for the facile syn-
thesis of chiral spirooxindole-based isotetronic acids and
5-1H-pyrrol-2-ones.The asymmetric 1,2-addition reactions
of a-ketoesters to isatins and imines by using an acid–
base bifunctional 6’-OH cinchona alkaloid catalyst, fol-
lowed by cyclization and enolization of the resulting ad-
ducts, gave chiral spiroisotetronic acids and 5-1H-pyrrol-2-
ones, respectively, in excellent optical purities (up to 98%
ee). FT-IR analysis supported the existence of hydrogen-
bonding interaction between the 6’-OH group of the cin-
chona catalyst and an isatin carbonyl group, an interaction
that might be crucial for catalyst activity and stereo-
control.
Spiroisotetronic acids bearing an oxindole moiety represent
a new class of 3,3’-oxindole spiro-fused cyclic compounds,[8]
which are promising bioactive candidates for drug screening
according to the hybridization concept in medicinal chemis-
try.[9] As part of our continuing efforts to develop new methods
for the synthesis of chiral isotetronic acids and their deriva-
tives,[2d] we envisioned that spiroisotetronic acids and 5-1H-
pyrrol-2-ones could be accessed through a cascade reaction of
a-ketoacids (or esters) 2 with isatins 1 or imines 4 in the pres-
ence of an appropriate catalyst (Scheme 1b). The key step for
the synthesis of isotetronic acids or their nitrogen-based ana-
logues in such a cascade sequence would be the cross-aldol
reaction or Mannich reaction using a-ketoacids (or esters) 2 as
nucleophiles. Traditional organocatalysts for this type of 1,2-ad-
dition reaction are the proline-based secondary amine cata-
lysts, which activate a-ketoacids or esters through the forma-
tion of an enamine intermediate (Scheme 1a, lower reac-
tion).[10] However, in our preliminary investigations, enamine
catalysis by pyrrolidines was found to be ineffective for pro-
moting the cascade reactions, probably as a result of the
severe steric crowding in the coming together of the bulky
rigid enamine intermediates and isatins[11] or imines[12]
(Scheme 1b, top reaction; for more details, see the Supporting
Information). We thus shifted our attention to base-promoted
enolate formation,[13] with the expectation that such an eno-
late-mediated cascade reaction might be facilitated by a more
flexible noncovalent interaction between the protonated base
and the enolate (Scheme 1b, lower reaction). Furthermore,
even though there has been no report on the cross-aldol reac-
tion or Mannich reaction with a-ketoesters as donors through
enolate activation, the stronger acidity of a-ketoesters com-
pared to unfunctionalized enolizable ketones should also be
favorable for the reaction.[14]
Isotetronic acids are regarded as privileged structural units in
a large class of natural products and unnatural compounds.[1]In
the past few years, there has been significant progress in de-
veloping asymmetric methodology for the synthesis of simple
isotetronic acid derivatives.[2] In contrast, spiroisotetronic acids
and nitrogen-based analogues of isotetronic acids (5-1H-pyrrol-
2-ones) have captured much less attention, despite the promi-
nent biological activities of the molecules that contains these
motifs.[3,4] Optically pure isotetronic acids with a spiro back-
bone have primarily been confined to the arena of biosynthe-
sis for a long time.[3a–c] To date, only one non-biosynthetic
method has been reported, albeit one that yields the products
in racemic form.[5] Meanwhile, the general synthetic approach
for chiral pyrrol-2-ones relies on the 1,4-addition of amines
containing a chiral auxiliary to b,g-unsaturated a-oxoesters.[6]
So far, there has been only one asymmetric version in which
pyrrol-2-one was obtained with disappointing enantioselectivi-
[a] W. Guo,+ X. Wang,+ Dr. B. Zhang, S. Shen, Dr. X. Zhou, P. Wang, Prof. Y. Liu,
Prof. C. Li
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Road, Dalian, 116023 (China)
E-mail: yanliu503@dicp.ac.cn
Herein, we report an organocatalyzed cascade reaction of a-
ketoesters with isatins or imines for the synthesis of spiroisote-
tronic acids and nitrogen-based analogues of isotetronic acid,
respectively. The asymmetric versions of the reactions were ac-
complished by using a 6’-OH cinchona alkaloid catalyst, thus
affording a variety of oxindole-based spiroisotetronic acids and
canli@dicp.ac.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402945.
Chem. Eur. J. 2014, 20, 8545 – 8550
8545
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
ene (DBU; 10 mol%). We were
pleased to find that the reaction
proceeded smoothly within 12 h
in dichloromethane at room
temperature to give the corre-
sponding racemic spiroisotetron-
ic acid in 70% yield (Table 1,
entry 1). Encouraged by this
result, we proceeded to examine
the catalytic potential of chiral
guanidine A, which possesses
a tertiary amine group that is
similar to that in DBU.[15] Howev-
er, this catalyst fails to promote
the cascade reaction (Table 1,
entry 2). Bifunctional thiourea–
amine catalysts B and C, which
are efficient catalysts for prepar-
ing other types of 3,3’-oxindole
spiro-fused cyclic frameworks,[16]
were also found to be effective
in promoting the cascade reac-
tion between 2a and 1a
(Table 1, entry 3 and 4); however,
in both cases, spiroisotetronic
acid 3aa is obtained with poor
levels of enantioselectivity. Pleas-
ingly, screening various chiral or-
ganic base catalysts led to iden-
tification of Deng’s 6’-OH cincho-
na alkaloid catalyst, F,[17] the use
Scheme 1. Catalytic synthesis of chiral isotetronic acids and their nitrogen-based analogues: a) previous methods
using acid or enamine catalysis; b) present work using Brønsted base catalysis. PMP=para-methoxy phenyl.
5-1H-pyrrol-2-ones in high yields (up to 98%) with excellent ee
values (generally 91–98%). Notably, control experiments and
FT-IR analysis support a hydrogen-bonding interaction be-
tween the 6’-OH group on catalyst F (Figure 1) and a carbonyl
group in isatin 1. This interaction might work in synergy with
a-ketoester enolate formation by base catalysis, thus resulting
in a highly organized reaction assembly that may account for
the excellent catalytic performance.
of which gave 3aa in 64% ee and 89% yield (Table 1, entry 7).
The effect of the nature of the ester group (R) of the a-ketoest-
er on the reaction was then investigated. It was found that the
size of the ester group had a significant effect on reactivity
and enantioselectivity. For example, when ethyl and n-propyl
2-oxobutanoate were used as nucleophiles, the levels of reac-
tivity and enantioselectivity were similar (Table 1, entries 7 and
9). In contrast, the more bulky substrates, tert-butyl or benzyl
2-oxobutanoate, led to poor levels of reactivity and enantiose-
lectivity (see Table S1 in the Supporting Information). Thus, the
ethyl and n-propyl esters were adopted for further study. Di-
chloromethane was identified as the solvent of choice for opti-
mization of the reaction (see Table S1 in the Supporting Infor-
mation). To improve the enantioselectivity of this cascade reac-
tion, we investigated N-substituted isatins. Surprisingly, the
products were obtained in higher ee values when the size of
the N-substituent was increased. For example, with catalyst F,
N-methyl and N-trityl isatins led to the corresponding products
in 64% and 82% ee, respectively (Table 1, entries 9 and 10).
The enantioselectivity of the product was further increased to
90% ee by lowering the reaction temperature (Table 1, en-
tries 11 and 12). The yield could be improved in conjunction
with an increase in ee value to 93% when an n-propyl ester
was used as the nucleophile (Table 1, entries 12 and 13). Fur-
thermore, this reaction could be conducted on a gram scale
(Table 1, entries 14).
The study was started by using commercially available ethyl-
2-oxobutanoate 2a and N-Me isatin 1a as the substrates in the
presence of catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-
Figure 1. Chiral organic bases screened.
Chem. Eur. J. 2014, 20, 8545 – 8550
www.chemeurj.org
8546
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 1. Optimization of reaction conditions of cascade reactions of a-
keto esters and isatins.[a]
Table 2. Substrate scope for the cascade reaction of 2 with 1.[a]
Entry
Cat.
PG
R
t [h]
Conv.
[%][b]
ee
Entry
X
R1
Yield [%][b]
ee [%][c]
[%][c]
1
2
3
4
5
6
7
8
H
4-Cl
5-Cl
5-Br
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3a (97)
3b (85)
3c (88)
3d (90)
3e (99)
3 f (87)
3g (90)
3h (99)
3i (95)
3j (91)
3k (98)
3l (94)
3m (84)
3n (92)
3o (85)
93
95
91
92
93
92
93
94
93
93
86
96
94
95
77
1
2
3
4
5
6
7
8
DBU
A
B
C
D
E
F
G
F
F
F
F
F
Me
Me
Me
Me
Me
Me
Me
Me
Me
Tr
Et
Et
Et
Et
Et
Et
Et
Et
nPr
Et
Et
Et
nPr
nPr
12
24
36
12
12
12
12
24
24
10
36
36
48
60
99 (70)
N.R.
99
99
99
99
99
99
99
–
–
12
0
5-I
20
62
64
48
63
82
88
90
93
93
5-Me
5-MeO
5-CF3O
7-F
5-F
6-Br
5-CF3O
5-Me
5-MeO
5-MeO
9
9
10
11
12
13
14
15[d]
10
11[d]
12[e]
13[e]
14[e,f]
97
Tr
Tr
Tr
Tr
99 (90)
99 (92)
99 (97)
99 (95)
Et
Et
Bn
F
[a] Unless otherwise specified, all cascade reactions were conducted with
isatin (1, 0.30 mmol), a-ketoester (2, 2 equiv, 0.6 mmol), and catalyst
(0.03 mmol, 10 mol%) in CH2Cl2 (1.5 mL, 0.2m) at rt. [b] Determined by
1H NMR analysis of the crude mixture; the data in parentheses are the
yield of product after column chromatography. [c] Determined by HPLC
analysis using a Daicel AD-H column. [d] The tandem reaction was carried
out at 08C. [e] The cascade reaction was carried out at À58C. [f] 3.0 mmol
N-trityl isatin was used.
[a] Unless otherwise specified, all cascade reactions were conducted with
isatin (1, 0.30 mmol), a-ketoester (2, 2 equiv, 0.60 mmol), and catalyst (F,
0.03 mmol, 10 mol%) in CH2Cl2 (1.5 mL) at À58C, 48–72 h. [b] Yield of
product 3 after column chromatography. [c] Determined by HPLC analysis
using a Daicel AD-H column. [d] 0.75 mL CH2Cl2.
ucts, 5, with excellent levels of enantioselectivity (Table 3, en-
tries 1–13, 87–98% ee). A substrate bearing a 2-thienyl ring
was also tolerated (Table 3, entry 14). The absolute configura-
tion of 3k was unambiguously established to be S on the
Subsequently, the substrate scope for isatins and a-ketoest-
ers was investigated under the optimized reaction conditions.
A broad range of N-trityl isatins with diverse electronic and
steric properties are readily converted into the corresponding
products 3a–o in high yields with excellent levels of enantiose-
lectivity (Table 2). For example, N-trityl isatins with electron-do-
nating methyl and methoxy groups and electron-withdrawing
fluoro, chloro, bromo, trifluoromethoxy, and iodo groups at
the 4, 5, or 7 position are converted into the corresponding
products in up to 99% yield with 91–95% ee (Table 2, en-
tries 1–10). Nevertheless, the ee values were slightly lower with
substituents at the 6-position (Table 2, entry 11, 86% ee). With
an extra carbon atom on the ketoester (R1 =Et), the enantiose-
lectivity was slightly improved (Table 2, entries 12–14, 94–96%
ee) with equally excellent yield. Hindering the nucleophilic
carbon center of the a-ketoester by using a benzyl-substituted
a-ketoester slowed down the reaction and had a detrimental
effect on the enantioselectivity (Table 2, entry 15). Encouraged
by the successful development of the above cascade reactions,
we then attempted to extend the 1,2-addition reaction to
a Mannich reaction[18] for the synthesis of chiral 5-1H-pyrrol-2-
ones. After the investigation of a model reaction between 2a
and N-Ts protected imine 4a, we found that the same catalytic
systems were suitable for the new reaction with higher catalyst
loading under mild reaction conditions. Imines with both elec-
tron-donating and electron-withdrawing substituents at differ-
ent positions on the phenyl ring give the corresponding prod-
Table 3. The asymmetric cascade reaction of 2 with 4.[a]
Entry
R1
R2
Ar
Yield [%][b]
ee [%][c]
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Me
Et
Et
Et
Et
Et
Et
Et
C6H5
C6H5
5a (90)
5a (87)
5b (89)
5c (78)
5d (73)
5e (72)
5 f (77)
5g (80)
5h (79)
5i (83)
5j (90)
5k (78)
5l (74)
5m (76)
96
96
92
98
97
94
95
95
90
93
90
87
89
91
2[d]
3
4-ClC6H4
3-CF3C6H4
3-ClC6H4
2-ClC6H4
2-FC6H4
3-MeC6H4
4-MeOC6H4
4-BrC6H4
C6H5
4
5
6
7
8
9
10
11
12
13
14
Et
nPr
nPr
nPr
Et
Et
Et
Me
4-ClC6H4
4-BrC6H4
2-thienyl
[a] Unless otherwise specified, all cascade reactions were conducted with
imine (4, 0.30 mmol), a-ketoester (2, 2 equiv, 0.60 mmol), and catalyst (F,
0.045 mmol, 15 mol%) in CH2Cl2 (1.0 mL) at rt, 48..72 h. [b] Yield of prod-
uct 5 based on column chromatography. [c] Determined by HPLC analysis
using a chiral column. [d] See ref. [19].
Chem. Eur. J. 2014, 20, 8545 – 8550
www.chemeurj.org
8547
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
of the catalyst. The IR spectrum of isatin 1a in CH2Cl2 (0.02m)
is shown in Figure 3 (left, black line). When the same amount
of catalyst was added to the above solution, most of peaks do
not shift, except the peaks in the range from 1700 to
1760 cmÀ1 (Figure 3; left, red line) which are assigned to
stretching vibrations of carbonyl groups located on the isatin
1a. Enlarging this area (Figure 3, right), it is clear that the
peaks at 1726 cmÀ1 and 1746 cmÀ1 for the isatin 1a converge
into one nonsymmetric peak upon addition of the catalyst
(Figure 3; right, red line) which can be considered as the com-
bination of two peaks: 1726 cmÀ1 (Figure 3; right, blue line)
and 1741 cmÀ1 (Figure 2; right, green line) after calculation.
The red shift from 1746 cmÀ1 to 1741 cmÀ1 of the keto carbon-
yl group of 1a indicates the existence of hydrogen bonding
between the carbonyl group and catalyst F. To our best knowl-
edge, this study represents the first spectral evidence for a hy-
drogen-bonding interaction be-
Figure 2. X-ray crystal structure of TBS-protected 3k’.
basis of X-ray crystallographic analysis of its TBS ether, 3k’
(Figure 2), and those of others were assigned by analogy.
The N-trityl protecting group that is necessary for achieving
high enantioselectivity in this title cascade reaction could be
easily removed by using a reported procedure[20] to give TBS-
tween a substrate and a hydroxyl
group within
catalyst.[21]
a
bifunctional
On the basis of the observed
stereochemistry, the control ex-
periments, and the FT-IR study,
a possible transition state for the
aldol addition of a-ketoesters to
isatins is depicted in Scheme 3.
For this aldol reaction, bifunc-
tional catalysis involves electro-
philic activation of the isatin
through a hydrogen-bonding in-
teraction and concomitant de-
protonation of the a-ketoester
Scheme 2. Deprotection of the trityl group and gram-scale experiment. TBS=tert-butyldimethylsilyl, Tr=trityl,
Ts =para-toluenesulfonyl.
protected product 6 in good yield with almost no
loss of enantioselectivity (Scheme 2, top reaction). To
demonstrate the synthetic practicality of this meth-
odology, the cascade reaction of 2a and 4a was car-
ried out on a gram scale under optimized reaction
conditions with catalyst F. The corresponding prod-
uct, TBS protected 5-1H-pyrrol-2-ones 7a, could be
obtained with 85% yield and 96% ee (Scheme 2,
lower equation).
To gain further insight into the structural elements
of the catalyst that affect the key step, control experi-
ments were performed on the reaction of 1a with 2a
by using catalyst H wherein the 6’-OH is blocked
with a methyl group. In sharp contrast with the high
activity of 6’-OH catalyst F, no product was detected
in the presence of 6’-OMe protected catalyst H, even
after a prolonged reaction time (72 h). These results
suggested that there may exist a hydrogen-bonding
between the hydroxyl group of catalyst F and a car-
bonyl group of 1a, which plays an important role in
the reactivity and enantioselectivity of the reaction
between 1 and 2. This presence of this weak hydro-
gen-bonding interaction was also supported by FT-IR
spectral analysis of isatin in the presence or absence Figure 3. Control experiments and FT-IR analysis.
Chem. Eur. J. 2014, 20, 8545 – 8550
www.chemeurj.org
8548
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
43, 1098–1100; b) K. Justus, R. Herrmann, J. D. Klamann, G. Gruber, V.
Hellwig, A. Ingerl, K. Polborn, B. Steffan, W. Steglich, Eur. J. Org. Chem.
2007, 5560–5572; c) H. J. Krꢁmer, D. Kessler, U. C. Hipler, B. Irlinger, W.
Hort, R. H. Bodeker, W. Steglich, P. Mayser, ChemBioChem 2005, 6,
2290–2297; d) K. Zuther, P. Mayser, U. Hettwer, W. Y. Wu, P. Spiteller,
B. L. J. Kindler, P. Karlovsky, C. W. Basse, J. Schirawski, Mol. Microbiol.
2008, 68, 152–172; e) O. A. Mascaretti, C. J. Chang, D. Hook, H. Otsuka,
E. F. Kreutzer, H. G. Floss, Biochemistry 1981, 20, 919–924; for selected
bioactive spiroisotetronic acids, see the Scheme S1 in the Supporting.
[4] For selected examples of bioactive pyrrol-2-one compounds, see:
a) Z. Q. Feng, X. Z. Li, G. J. Zheng, L. Huang, Bioorg. Med. Chem. Lett.
2009, 19, 2112–2115; b) T. R. K. Reddy, C. Li, X. X. Guo, H. K. Myrvang,
P. M. Fischer, L. V. Dekker, J. Med. Chem. 2011, 54, 2080–2094; c) A.
Richter, R. Rose, C. Hedberg, H. Waldmann, C. Ottmann, Chem. Eur. J.
2012, 18, 6520–6527; d) Y. X. Zhao, Q. Wang, Q. Q. Meng, D. Z. Ding,
H. Y. Yang, G. W. Gao, D. W. Li, W. L. Zhu, H. C. Zhou, Bioorg. Med. Chem.
2012, 20, 1240–1250; e) C. L. Zhuang, Z. Y. Miao, L. J. Zhu, G. Q. Dong,
Z. Z. Guo, S. Z. Wang, Y. Q. Zhang, Y. L. Wu, J. Z. Yao, C. Q. Sheng, W. N.
Zhang, J. Med. Chem. 2012, 55, 9630–9642; f) V. L. Gein, A. V. Popov,
W. E. Kolla, N. A. Popova, Pharmazie 1993, 48, 107–109; for selected ex-
amples of bioactive 1,5-dihydro-2H-pyrrol-2-ones, see Scheme S1 in the
Supporting Information.
Scheme 3. Proposed transition states for the tandem reaction.
by the tertiary amine basic center (quinuclidine). The Re face of
the thermodynamically stable (Z)-enolate preferentially attacks
the Si face of the isatin (TS-1) compared to the sterically more
congested Re face (TS-2). Consequently, the reaction of 1 and
2 catalyzed by F provides the S isomers predominantly. TS-1 is
also in accordance with the substituent effects observed for
the isatin N position, as well as that for the R1 and ester group
of the a-ketoester.
[5] V. L. Gein, E. B. Levandovskaya, V. N. Vichegjanina, Chem. Heterocycl.
Compd. 2010, 46, 931–933.
[6] F. Palacios, J. Vicario, D. Aparicio, Eur. J. Org. Chem. 2006, 2843–2850.
[7] For pioneering work on the synthesis of 1,5-dihydro-2H-pyrrol-2-ones
by using a chiral phosphoric acid as catalyst, see: X. Li, H. Deng, S. Luo,
J. P. Cheng, Eur. J. Org. Chem. 2008, 4350–4356; for an achiral example
by using ytterbium as a catalyst, see: A. S. Nagarajan, B. S. R. Reddy,
Synth. Commun. 2013, 43, 1229–1236.
[8] For recent reviews about the asymmetric organocatalytic construction
of 3,3’-spirocyclic oxindoles, see: a) R. Dalpozzo, G. Bartoli, G. Benciven-
ni, Chem. Soc. Rev. 2012, 41, 7247–7290; b) L. Hong, R. Wang, Adv.
Synth. Catal. 2013, 355, 1023–1052; c) G. S. Singh, Z. Y. Desta, Chem.
Rev. 2012, 112, 6104–6155; d) D. Cheng, Y. Ishihara, B. Tan, C. F. Barbas,
ACS Catal. 2014, 4, 743–762.
[9] For an example of the hybridization concept in drug molecule design,
see: S. Gemma, G. Campiani, S. Butini, B. P. Joshi, G. Kukreja, S. S. Coc-
cone, M. Bernetti, M. Persico, V. Nacci, I. Fiorini, E. Novellino, D. Taramel-
li, N. Basilico, S. Parapini, V. Yardley, S. Croft, S. Keller-Maerki, M. Rott-
mann, R. Brun, M. Coletta, S. Marini, G. Guiso, S. Caccia, C. Fattorusso, J.
Med. Chem. 2009, 52, 502–513.
In conclusion, we have realized a highly enantioselective cas-
cade reaction of a-ketoesters with isatins and imines by using
a 6’-OH cinchona alkaloids catalyst, to give spiroisotetronic
acids bearing quaternary stereocenters and 5-1H-pyrrol-2-ones.
This method also represents the first example of an asymmet-
ric cross-aldol reaction and Mannich reaction involving enolate
intermediates from a-ketoester donors. Furthermore, a hydro-
gen-bonding interaction between the 6’-OH cinchona alkaloid
catalyst and the acceptor was observed through an FT-IR
study.
Acknowledgements
[10] a) B. List, Acc. Chem. Res. 2004, 37, 548–557; b) B. List, R. A. Lerner, C. F.
Barbas, J. Am. Chem. Soc. 2000, 122, 2395–2396.
This work was financially supported by the Natural Science
Foundation of China (21322202, 2100210) and National Basic
Research Program of China (2010CB833300).
[11] For selected examples of the use of isatins as activated ketones in or-
ganocatalytic aldol reactions, see: a) C. Cassani, P. Melchiorre, Org. Lett.
2012, 14, 5590–5593; b) J. R. Chen, X. P. Liu, X. Y. Zhu, L. Li, Y. F. Qiao,
J. M. Zhang, W. J. Xiao, Tetrahedron 2007, 63, 10437–10444; c) N. Hara,
S. Nakamura, N. Shibata, T. Toru, Chem-Eur. J. 2009, 15, 6790–6793; d) T.
Itoh, H. Ishikawa, Y. Hayashi, Org. Lett. 2009, 11, 3854–3857; e) X. X.
Jiang, Y. M. Cao, Y. Q. Wang, L. P. Liu, F. F. Shen, R. Wang, J. Am. Chem.
Soc. 2010, 132, 15328–15333; f) A. V. Malkov, M. A. Kabeshov, M. Bella,
O. Kysilka, D. A. Malyshev, K. Pluhackova, P. Kocovsky, Org. Lett. 2007, 9,
5473–5476; g) T. Min, J. C. Fettinger, A. K. Franz, ACS Catal. 2012, 2,
1661–1666; h) S. Nakamura, N. Hara, H. Nakashima, K. Kubo, N. Shibata,
T. Toru, Chem. Eur. J. 2008, 14, 8079–8081; i) A. J. Pearson, S. Panda, Org.
Lett. 2011, 13, 5548–5551; j) I. Saidalimu, X. Fang, X. P. He, J. Liang, X. Y.
Yang, F. H. Wu, Angew. Chem. 2013, 125, 5676–5680; Angew. Chem. Int.
Ed. 2013, 52, 5566–5570.
[12] For selected reviews on the organocatalytic asymmetric Mannich reac-
tion, see: a) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg,
F. P. J. T. Rutjes, Chem. Soc. Rev. 2008, 37, 29–41; b) X. H. Cai, B. Xie, Arki-
voc 2013, 264–293.
[13] For examples of organocatalyzed enantioselective direct aldol reactions
of ketones through the enolate mechanism, see: a) J. Guang, Q. S. Guo,
J. C. G. Zhao, Org. Lett. 2012, 14, 3174–3177; b) Q. S. Guo, M. Bhanusha-
li, C. G. Zhao, Angew. Chem. 2010, 122, 9650–9654; Angew. Chem. Int.
Ed. 2010, 49, 9460–9464; c) M. Markert, M. Mulzer, B. Schetter, R. Mahr-
wald, J. Am. Chem. Soc. 2007, 129, 7258–7259; d) T. K. M. Shing, H. M.
Cheng, Org. Lett. 2008, 10, 4137–4139.
Keywords: pyrrol-2-ones
· cascade reactions · isatins ·
isotetronic acids · organocatalysis
[1] a) I. Blank, J. M. Lin, R. Fumeaux, D. H. Welti, L. B. Fay, J. Agric. Food
Chem. 1996, 44, 1851–1856; b) A. J. Pallenberg, J. D. White, Tetrahedron
Lett. 1986, 27, 5591–5594; c) Y. S. Rao, Chem. Rev. 1964, 64, 353–388;
d) H. Sulser, J. Depizzol, W. Buchi, J. Food Sci. 1967, 32, 611–615.
[2] For an organocatalytic asymmetric synthesis of simple isotetronic acids,
see: a) P. Dambruoso, A. Massi, A. Dondoni, Org. Lett. 2005, 7, 4657–
4660; b) D. Lee, S. G. Newman, M. S. Taylor, Org. Lett. 2009, 11, 5486–
5489; c) J. M. Vincent, C. Margottin, M. Berlande, D. Cavagnat, T. Buffe-
teau, Y. Landais, Chem. Commun. 2007, 4782–4784; d) B. Zhang, Z.
Jiang, X. Zhou, S. Lu, J. Li, Y. Liu, C. Li, Angew. Chem. 2012, 124, 13336–
13339; Angew. Chem. Int. Ed. 2012, 51, 13159–13162; for simple isote-
tronic acids prepared by metal catalysis, see: e) N. Gathergood, K. Juhl,
T. B. Poulsen, K. Thordrup, K. A. Jørgensen, Org. Biomol. Chem. 2004, 2,
1077–1085; f) K. Juhl, N. Gathergood, K. A. Jørgensen, Chem. Commun.
2000, 2211–2212; g) V. Liautard, D. Jardel, C. Davies, M. Berlande, T. Buf-
feteau, D. Cavagnat, F. Robert, J. M. Vincent, Y. Landais, Chem. Eur. J.
2013, 19, 14532–14539.
[3] For selected examples, see: a) B. Irlinger, H. J. Kramer, P. Mayser, W. Steg-
lich, Angew. Chem. 2004, 116, 1119 – 1121; Angew. Chem. Int. Ed. 2004,
Chem. Eur. J. 2014, 20, 8545 – 8550
www.chemeurj.org
8549
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[14] Notably, isatins and Ts-protected imines have been established as
a class of excellent electrophiles, the use of which avoids the potential-
ly competing homoaldol reaction of a-ketoesters. For examples of
base-promoted homoaldol reactions of a-ketoesters, see: a) H. S. Chen,
X. P. Ma, Z. M. Li, Q. R. Wang, F. G. Tao, Arkivoc 2009, 87–105; b) D. Teje-
dor, A. Santos-Exposito, F. Garcia-Tellado, Chem. Commun. 2006, 2667–
2669; c) D. Tejedor, A. Santos-Exposito, F. Garcia-Tellado, Chem-Eur. J.
2007, 13, 1201–1209.
[15] For selected reviews on chiral guanidine catalyzed enantioselective re-
actions, see: D. Leow, C. H. Tan, Chem. Asian. J. 2009, 4, 488–507, and
references therein; for seminal work on chiral guanidine catalysis, see:
E. J. Corey, M. J. Grogan, Org. Lett. 1999, 1, 157–160.
[16] For selected examples, see: a) F. Pesciaioli, P. Righi, A. Mazzanti, G. Bar-
toli, G. Bencivenni, Chem. Eur. J. 2011, 17, 2842–2845; b) W. S. Sun,
G. M. Zhu, C. Y. Wu, G. F. Li, L. Hong, R. Wang, Angew. Chem. 2013, 125,
8795–8799; Angew. Chem. Int. Ed. 2013, 52, 8633–8637; c) B. Tan, X. F.
Zeng, W. W. Y. Leong, Z. G. Shi, C. F. Barbas, G. F. Zhong, Chem. Eur. J.
2012, 18, 63–67.
[18] For examples of Mannich reactions involving pyruvates or a-keto-
amides as nucleophiles, as catalyzed by Lewis acids and that cannot be
used to prepare 5-1H-pyrrol-2-ones, see: a) K. Juhl, N. Gathergood, K. A.
Jørgensen, Angew. Chem. 2001, 113, 3083–3085; Angew. Chem. Int. Ed.
2001, 40, 2995–2997; b) G. Lu, H. Morimoto, S. Matsunaga, M. Shibasa-
ki, Angew. Chem. 2008, 120, 6953–6956; Angew. Chem. Int. Ed. 2008, 47,
6847–6850; c) Y. J. Xu, G. Lu, S. Matsunaga, M. Shibasaki, Angew. Chem.
2009, 121, 3403–3406; Angew. Chem. Int. Ed. 2009, 48, 3353–3356.
[19] The fact that all products 5 obtained in this study are liquids or amor-
phous solids hampers the direct determination of the absolute configu-
ration of the stereogenic centers by X-ray crystal structure analysis.
Thus, a comparison of the experimental ECD spectra of compound 5a’
(in CHCl3, blue line) with the calculated spectra for (R)-5a’ (red line 1)
and (S)-5a’ (black line 2) allows us to speculate that the absolute con-
figuration of compound 5 is R. For details, see Scheme S2 in the Sup-
porting Information.
[20] E. Vedejs, A. Klapars, D. L. Warner, A. H. Weiss, J. Org. Chem. 2001, 66,
7542–7546.
[17] a) H. M. Li, J. Song, X. F. Liu, L. Deng, J. Am. Chem. Soc. 2005, 127, 8948–
8949; b) H. M. Li, Y. Wang, L. Tang, L. Deng, J. Am. Chem. Soc. 2004, 126,
9906–9907; c) H. M. Li, Y. Wang, L. Tang, F. H. Wu, X. F. Liu, C. Y. Guo,
B. M. Foxman, L. Deng, Angew. Chem. 2005, 117, 107–110; Angew.
Chem. Int. Ed. 2005, 44, 105–108; d) X. F. Liu, H. M. Li, L. Deng, Org. Lett.
2005, 7, 167–169. e) Y. Wang, L. Deng, Asymmetric Acid–Base Bifunc-
tional Catalysis with Organic Molecules in Catalytic Asymmetric Synthesis
(Ed.: I. Ojima), Wiley, Hoboken, New Jersey, 2010, Chap. 2.2B. 59.
[21] For an example of spectral evidence for a hydrogen-bonding interac-
tion between a substrate and a thiourea-containing bifunctional cata-
lyst, see: T. Inokuma, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2006,
128, 9413–9419.
Received: February 28, 2014
Published online on June 4, 2014
Chem. Eur. J. 2014, 20, 8545 – 8550
www.chemeurj.org
8550
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim