Asymmetric conjugate addition of oxindoles to 2-chloroacrylonitrile: A highly effective organocatalytic strategy for simultaneous construction of 1,3-nonadjacent stereocenters leading to chiral pyrroloindolines

Article abstract of DOI:10.1002/chem.201002563

Chiral pyrroloindoles: A highly enantioselective catalytic conjugate addition of 3-substituted oxindoles with 2-chloroacrylonitrile has been developed with a readily accessible alkyl bifunctional tertiary amine thiourea catalyst. Excellent stereoselectivi

Full text of DOI:10.1002/chem.201002563

DOI: 10.1002/chem.201002563
Asymmetric Conjugate Addition of Oxindoles to 2-Chloroacrylonitrile:
A Highly Effective Organocatalytic Strategy for Simultaneous Construction
of 1,3-Nonadjacent Stereocenters Leading to Chiral Pyrroloindolines
Xin Li,[a] Sanzhong Luo,*[a] and Jin-Pei Cheng[b]
The chiral pyrroloindoline core I with 1,3-nonadjacent
carbon stereocenters (Scheme 1) is a key structural element
found in a wide range of indole alkaloids exhibiting diverse
bioactivity profiles.[1] For instance, biologically active natural
products, such as the Gliocladins A–C,[2] Mollenine A,[3] As-
perazine,[4] Brevianamide E,[5] and a great number of dimer-
ic diketopiperazine alkaloids,[6] are all based on structure I
(Scheme 1). Accordingly, these natural products have at-
tracted a great deal of attention in the pursuit of their total
synthesis and meanwhile still pose significant synthetic chal-
lenges due to their structural
complexity and unique bond
connections. One widely ex-
plored strategy for the synthesis
of these natural products is to
utilize the intramolecular ring-
closure reaction from trypto-
phan derivatives. Notable con-
tributions along this line in-
clude those from the groups of
Hino,[7] Crich,[8] Overman,[9]
Danishefsky,[10] and Movassa-
ghi.[11] Though quite straightfor-
ward, these methods lack the
flexibility to generate substitut-
ed pyrroloindolines, particularly
for those with 3-substituted
quaternary full-carbon stereo-
centers. To develop a new cata-
Scheme 1. Natural products with the pyrroloindole core containing 1,3-nonadjacent stereocenters and our syn-
thetic strategy.
lytic methodology for the effec-
tive construction of such asym-
metrical structural motifs is
thus highly important and re-
[a] Dr. X. Li, Prof. Dr. S. Luo
mains an elusive and fundamental goal in this area.
Beijing National Laboratory for Molecular Sciences (BNLMS)
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing, 100190 (P.R. China)
À
As one of the most versatile C C bond transformations,
asymmetric conjugate addition reactions with carbon nu-
ACHUTNGERNcNUG leoAHCTUNGTRNENpUGN hiles have been very successful in creating molecular
complexity with high stereocontrol.[12] In a particularly val-
uable context, such a process using 3-substituted oxindoles
as nucleophiles would serve as the key chiral transforma-
tions leading to complex structural motifs that are ubiqui-
tous in a number of biologically active indole alkaloids.[13]
For example, Barbas and co-workers reported a novel total
synthesis of (+)-physostigmine, in which they used an orga-
Fax : (+86)10-6255-4449
E-mail: luosz@iccas.ac.cn
[b] Prof. Dr. J.-P. Cheng
Department of Chemistry and State-key Laboratory
of Elementoorganic Chemistry, Nankai University
Tianjin, 300071 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002563.
14290
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Chem. Eur. J. 2010, 16, 14290 – 14294

COMMUNICATION
Table 1. Catalyst Screening.[a]
nocatalytic 1,4-addition of oxindoles to nitroolefins as the
key step.[13e] Analogous asymmetric catalysis, which generat-
ed one quaternary stereocenter or two 1, 2-adjacent stereo-
centers of chiral oxindole compounds have also been docu-
mented recently.[13,14] Despite these advances, highly diaster-
eo- and enantio- stereoselective synthesis of chiral oxindoles
containing 1,3-nonadjacent stereocenters, which serve as ver-
satile precursors for pyrroloindoles I, has not been achieved
so far. One conceivable strategy towards this end could be
to use conjugate addition reaction of 3-substituted oxindoles
with a-branched Michael acceptors, such as 2-chloroacrylo-
nitrile.[15] Catalytic process of this type would be a significant
challenge, however, particularly with regard to the stereo-
control of both the absolute and relative configurations, as
the whole catalysis is a tandem conjugate addition–protona-
tion with simultaneous control of two separated stereocen-
ters.
Herein, we present the first catalytic diastereo- and enan-
tioselective conjugate addition reaction of 3-substituted ox-
indoles to 2-chloroacrylonitrile, which generates chiral oxin-
doles as direct precursors for pyrroloindoles I with excellent
stereocontrol. This process was made possible by the use of
a chiral alkyl thiourea, which we previously developed by
electronic tuning and has since been successfully applied in
catalytic reactions featuring all-carbon quaternary stereo-
center formations.[16,17]
Entry
Cat.
Solvent
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
4a
4a
4a
4a
4a
4a
4a[e]
4a[f]
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
DCE
benzene
xylene
THF
DCE
DCE
12
12
12
12
12
12
12
12
12
12
12
12
36
36
98
97
99
96
51
80
80
70
96
97
99
40
92
95
4:1
3:1
3:1
2:1
1:2
3:1
4:1
4:1
4:1
4:1
3:1
2:1
11:1
12:1
77
76
75
64
À69
76
83
75
84
77
77
76
93
94
9
10
11
12
13
14
[a] The reaction was carried out on a 0.1 mmol scale in the solvent
(200 mL) at 48C, and the molar ratio of oxindole 1a/2 is 1:3. [b] Yield of
the isolated product. [c] Determined by H NMR spectroscopy. [d] Deter-
mined by chiral HPLC analysis. [e] The reaction was carried out on a
0.1 mmol scale in ClCH2CH2Cl (200 mL) at À208C. [f] The reaction was
carried out on a 0.1 mmol scale in ClCH2CH2Cl (200 mL) with 4 ꢁ molec-
ular sieves at À208C.
1
The Michael addition reaction of oxindole 1a to 2-chlo
ACHTUNGERTNrNUNG o-
A
As illustrated in Table 1, 1, 2-dichloroethane (DCE) gave
the best result among a range of screened solvents (Table 1,
entries 1 and 7–12). Further improvement could be achieved
by lowering the reaction tem-
used bifunctional tertiary amine thioureas or urea catalysts
4a–4 f[18] (Scheme 2) with different scaffolds were screened
perature (Table 1, entry 13).
Addition of 4 ꢁ molecular
sieves to the reaction mixture
slightly increased both the dia-
stereoselectivity and enantiose-
lectivity (Table 1, entry 14).
Collectively, the best results
with respect to yield and stereo-
selectivity were obtained by
performing the reaction at
À208C in DCE in the presence
of 4 ꢁ molecular sieves. Under
these conditions, the reaction
Scheme 2. Bifunctional tertiary amine thiourea (urea) catalysts tested in this study.
provided the desired product in
95% yield with 12:1 d.r. and
in the model reaction at 48C. To our delight, most of the
catalysts exhibited high catalytic activities and the Michael
products were isolated with good to excellent yields and
moderate stereoselectivities (2:1–4:1 d.r. and 64–77% ee)
except for 4e (Table 1, entry 5). Among the six bifunctional
hydrogen-bonding catalysts examined, our previously devel-
oped alkyl thiourea 4a was found to give the optimal stereo-
selectivity (Table 1, entry 1, 98% yield, 4:1 d.r. and
77% ee).
94% ee (Table 1, entry 14).
To investigate the scope of the reaction, we first examined
the reactions of a range of 3-aryl oxindoles 1a–1k with 2
under the optimized conditions. As shown in Table 2, oxin-
doles with 3-aryl groups containing either electron-with-
drawing or electron-donating moieties could be converted
into the desired products with excellent yields (81–95%),
good diastereoselectivity (up to 19:1) and enantioselectivity
(86–95% ee) (Table 2, entries 1–10). Slightly lower stereose-
lectivity was obtained with meta-substituted 3-aryl oxindoles
1c and 1 f (Table 2, entries 3 and 6). The reaction of a 5-me-
The reaction was then optimized by screening solvent,
temperature, and additive in the presence of 4a (10 mol%).
Chem. Eur. J. 2010, 16, 14290 – 14294
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14291

S. Luo et al.
Table 2. Substrate scope of 3-aryl oxindoles.[a]
presenting very good activity and stereoselectivity (Table 3,
entry 7, 97% yield, >30:1 d.r. and 98% ee).
The absolute configurations of both adducts 3 and 6 have
been determined by X-ray crystallographic analysis of com-
pound 3a and 6a (for details see the Supporting Informa-
tion).[19,20] The observed stereocontrol can be rationalized by
considering transition states I and II wherein effective
multi-hydrogen bonding plays a critical role in nucleophilic
addition (I) and subsequent protonation (II), which generate
the quaternary and tertiary stereocenters, respectively
(Scheme 3).
Entry
G1
G2
t
Product
(yield [%][b]
d.r.[c]
ee
[h]
G
)
[%][d]
1
2
3
4
5
6
7
8
1a: H
H
H
H
H
H
H
H
H
48
78
72
72
48
72
48
80
48
60
48
3a (95)
3b (81)
3c (86)
3d (85)
3e (93)
3 f (85)
3g (93)
3h (81)
3i (93)
3j (90)
3k (85)
12:1
10:1
7:1
11:1
8:1
6:1
9:1
19:1
9:1
12:1
14:1
94
92
86
93
92
86
92
95
93
95
93
1b: 4-CH3O
1c: 3-CH3O
1d: 4-EtO
1e: 4-CH3
1 f: 3,5-CH3
1g: 4-nBu
1h: 4-F
1i: 4-Cl
1j: 4-Ph
1k: H
9
10
11
H
H
5-CH3O
[a] The reaction was carried out on a 0.1 mmol scale in ClCH2CH2Cl
(200 mL) with 4 ꢁ molecular sieves at À208C, and the molar ratio of 3-
aryl-1-Boc-2-oxindoles/2-chloroacrylonitrile is 1:3. [b] Yield of the isolat-
ed product. [c] Determined by 1H NMR spectroscopy. [d] Determined by
chiral HPLC analysis.
Scheme 3. Proposed transition states.
To widen the applications of this Michael strategy, the re-
actions between 3-(3’-indolyl)oxindoles and 2-chloroacrylo-
nitrile have also been investigated (Scheme 4). The obtained
thoxyl substituted oxindole 1k also worked very well to give
the desired Michael product 3k with high yield (85%), good
diastereoselectivity (14:1 d.r.) and enantioselectivity
(93% ee) (Table 2, entry 11).
To further expand the substrate scope, 3-alkyl oxindoles
were also employed as nucleophiles. The corresponding re-
sults are present in Table 3. To our delight, all of the exam-
Table 3. Substrate scope of 3-alkyl oxindoles.[a]
Scheme 4. Catalytic result with 3-indolyl oxindoles as Michael donors.
chiral oxindoles 7 contain all the skeleton carbon atoms of
Gliocladin A, B, and C and can thus serve as a very promis-
ing and quick starting point for the total synthesis of Glio-
caldins.[2,21] An initial attempt with an unprotected 3-indolyl
group gave the corresponding conjugated product with mod-
erate yield (56%) and stereoselectivity (2:1 d.r., 74% ee).
Subsequent N-protection of the 3’-indolyl moiety led to con-
siderable improvement of both the reactivity and stereose-
lectivity, and the best results were obtained with the N-Boc
protected starting material. In this case, the desired product
7c was obtained in 70% yield, 7:1 d.r., and 91% ee in the
presence of 4a (10 mol%).
To demonstrate the potential of the current Michael strat-
egy in the context of chiral pyrroloindole synthesis, a large
scale synthesis of 3e was carried out. As shown in Scheme 5,
catalytic asymmetric Michael addition of 3-(4-methyl)-
phenyl-N-Boc oxindole 1e with 2-chloroacrylonitrile 2 was
accomplished with good results by using 4a (10 mol%).
Compound 3e can be easily converted to 8 by nucleophilic
Entry
R
G3
t
Product
(yield [%][b]
d.r.[c]
ee
[h]
G
)
[%][d]
1
2
3
4
5
6
7
5a: Me
5b: Me
5c: Et
5d: Et
5e: nPr
5 f: Bn
5g: allyl
H
48
60
36
48
48
48
36
6a (93)
6b (95)
6c (99)
6d (92)
6e (91)
6 f (94)
6g (97)
>30:1
>30:1
>30:1
19:1
>30:1
>30:1
>30:1
98
97
99
97
99
97
98
5-CH3O
H
5-CH3O
H
H
H
[a] The reaction was carried out on a 0.1 mmol scale in ClCH2CH2Cl
(400 mL) with 4 ꢁ molecular sieves at À25–À358C, and the molar ratio of
3-aryl-1-Boc-2-oxindoles/2-chloroacrylonitrile is 1:3. [b] Yield of the iso-
lated product. [c] Determined by 1H NMR spectroscopy. [d] Determined
by chiral HPLC analysis.
ined 3-alkyl oxindoles 5a–5 f smoothly reacted with 2 to
afford the corresponding Michael products 6a–6 f with very
good yields (91–99%), excellent diastereoselectivities (up to
>30:1 d.r.) and enantioselectivities (97–99% ee). 3-Allyl ox-
indole 5g can also be used in the current Michael strategy
14292
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Chem. Eur. J. 2010, 16, 14290 – 14294

Asymmetric Conjugate Addition of Oxindoles to 2-Chloroacrylonitrile
COMMUNICATION
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To summarize, in this work we have developed a highly
enantioselective conjugate addition reaction of 3-substituted
oxindole to 2-chloroacrylonitrile with a readily accessible
alkyl bifunctional tertiary amine thiourea as the catalyst.
The reactions demonstrated high efficiency and excellent
stereoselectivity (up to >30:1 d.r. and up to 99% ee) while
simultaneously generating two separated all-carbon stereo-
centers. We believe the current reaction provides a long
sought-after catalytic stereoselective approach for the syn-
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scope and synthetic utility of this chemistry is underway, and
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Acknowledgements
The project was supported by the Natural Science Foundation (NSFC
20632060 and 20902091), MOST (2009ZX09501-018) and the Chinese
Academy of Sciences. X.L. thanks China Postdoctoral Science Founda-
tion for support.
Keywords: Michael addition
·
natural products
·
organocatalysis · oxindoles · quaternary center
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Received: September 3, 2010
Published online: November 29, 2010
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