Novel tartrate-derived guanidine-catalyzed highly enantio- and diastereoselective Michael addition of 3-substituted oxindoles to nitroolefins

Article abstract of DOI:10.1039/c4cc01817f

The Michael addition of 3-substituted oxindoles to nitroolefins was catalyzed by a novel tartrate-derived guanidine in high yield with excellent diastereo- and enantioselectivity. This method showed an extraordinarily broad substrate scope in terms of both reaction partners. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01817f

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Novel tartrate-derived guanidine-catalyzed highly
enantio- and diastereoselective Michael addition
of 3-substituted oxindoles to nitroolefins†
Cite this: Chem. Commun., 2014,
50, 5760
Received 11th March 2014,
Accepted 4th April 2014
Liwei Zou, Xiaoze Bao, Yuanyuan Ma, Yuming Song, Jingping Qu and
Baomin Wang*
DOI: 10.1039/c4cc01817f
www.rsc.org/chemcomm
The Michael addition of 3-substituted oxindoles to nitroolefins was the introduction of more efficient catalysts demonstrating broad
catalyzed by a novel tartrate-derived guanidine in high yield with substrate generality with excellent stereoselectivity is still highly
excellent diastereo- and enantioselectivity. This method showed an desirable.
extraordinarily broad substrate scope in terms of both reaction
partners.
Chiral guanidines represent a prominent catalyst class in the
field of organocatalysis, which have enabled a broad array of
asymmetric transformations.10 Despite various chiral guanidine
catalysts introduced thus far, the development in this area is still
hampered by the lack of a skeleton that is both synthetically easily
accessible and readily tunable in terms of steric and electronic
properties. Given the abundant availability and ready diversifica-
tion of tartaric acid and derivatives thereof, very recently we
developed a novel library of chiral guanidines featuring a tartaric
acid skeleton, which showed remarkable catalytic activity toward
the enantioselective a-hydroxylation of b-dicarbonyl compounds.11
To further expand the utility of this library of guanidines, herein
we report the conjugate addition of 3-substituted oxindoles to
nitroolefins by the tartrate-based guanidine with a broad substrate
scope and excellent stereocontrol (Fig. 1).
The frequent occurrence of the 3,3-disubstituted oxindole scaf-
fold in alkaloid natural products and pharmaceutically relevant
compounds has stimulated significant synthetic effort toward
the construction of this privileged structural motif.1 In this regard,
a variety of strategies have been developed depending on the
varying starting materials used, which generally include anilides,2
isatins,3 3-alkylidene oxindoles4 and 3-substituted oxindoles.5–8
Among these methods, those with 3-substituted oxindoles have
garnered intense recent interest since they have proven to be
extremely straightforward and versatile, particularly in terms of
the catalytic asymmetric assembly of C3 quaternary oxindoles.
Since the initial report by Barbas III and co-workers on the
catalytic asymmetric Michael addition of 3-sustituted oxindoles
to nitroolefins by a chiral thiourea organocatalyst,7a a handful of
catalyst systems have been evaluated with this reaction.7,8 The
challenge and advantage of this process involves the simulta-
neous creation of vicinal tertiary and all-carbon quaternary
stereocenters, and the incorporation of a nitro group in the
product as a versatile synthetic handle for further elaboration.9
Aside from thiourea-based chiral organocatalysts as the majority of
the promoters,7a,c,d,g,h,l,m other catalysts reported include cinchona
alkaloids,7e, j a phase-transfer catalyst,7b an indane-based amino-
alcohol,7f and a proline-derived secondary amine.7i In addition,
two reports concerning chiral Lewis acid catalysis were also
documented.8 Despite these achievements, few catalyst systems can
afford both a broad substrate scope and an excellent stereocontrol.
Therefore, given the significant value of this conjugate addition,
Initial experiments were focused on the identification of optimal
reaction conditions (Table 1). Thus, guanidine catalysts were
evaluated with the Michael addition of N-Boc 3-benzyloxindole
9a to b-nitrostyrene 10a as the model reaction. The tartrate-based
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and
Technology, Dalian University of Technology, Dalian 116024, P. R. China.
E-mail: bmwang@dlut.edu.cn
† Electronic supplementary information (ESI) available. CCDC 990860. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc01817f
Fig. 1 The guanidine catalysts used in this work.
5760 | Chem. Commun., 2014, 50, 5760--5762
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate generality for nitroolefinsa
t (h) Yieldb (%) drc
eec (%)
Entry
Cat.
Solvent
t (h)
Yieldb (%)
drc
eed (%)
Entry
R
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
1
1
17
16
3
72
77
70
72
73
87
81
79
92
95
74
89
93
97
99
99
89/11
88/12
95/5
95/5
66/34
94/6
41/59
44/56
77/23
91/9
89/11
92/8
37
33
16
77
À61
48
1
22
47
51
16
79
81
87
91
94
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10g
10h
10i
Ph
p-FC6H4
41
47
47
50
24
47
24
49
48
71
40
36
216
240
99
93
89
98
91
94
93
96
99
92
92
97
91
82
99/1
98/2
98/2
98/2
97/3
92/8
99/1
499/1
97/3
99/1
99/1
94
93
93
92
93
91
97
95
94
94
90
p-ClC6H4
p-BrC6H4
p-CF3C6H4
o-ClC6H4
3,4-Cl2C6H3
p-MeC6H4
p-iPrC6H4
p-MeOC6H4
2-Furanyl
2-Thiophenyl
2
5 min
5 min
23
7
7
5
4
6
12
41
9
CH2Cl2
EA
9
10
11
12
13
14d
15e
16 f
10
11
12
13
14
10j
10k
10l
THF
MTBE
Et2O
Et2O
Et2O
Et2O
99/1 499
499/1
499/1
94/6
96/4
98/2
99/1
10m C6H5CH2
10n n-Pr
97
98
a
Unless otherwise noted, reactions were conducted with 3-substitued
oxindole 9a (0.2 mmol), catalyst 4 (10 mol%) and nitroalkene 10
(1.2 equiv.) in diethyl ether (2 mL). Isolated yield. Determined by
chiral HPLC analysis.
a
b
c
Unless otherwise noted, reactions were conducted with 3-substitued
oxindole 9a (0.1 mmol), catalyst (10 mol%) and nitroalkene 10a
(1.2 equiv.) in solvent (1 mL) at 25 1C. Isolated yield. Determined
by chiral HPLC analysis (Chiralcel AD-H). 0 1C. À20 1C. À40 1C.
b
c
d
e
f
subjected to the reaction conditions. Gratifyingly, all these
guanidine 1 displaying a benzyl group afforded the product in Michael acceptors afforded uniformly high product yields with
good yield with good diastereoselectivity and modest enantio- excellent diastereo- and enantioselectivities. Moreover, heteroaryl
selectivity for the major diastereomer (entry 1). Comparable nitroolefins also performed well, with 2-thiophenyl nitroolefin
results were observed with guanidine 2 bearing a 4-tert-butyl delivering virtually pure stereoisomers (entry 12). Notably, alkyl
benzyl group (entry 2). While 2,6-diisopropyl aniline-derived nitroolefins also participated in this reaction with excellent stereo-
guanidine 3 exhibited respectable dr but poor enantioselectivity, control although much longer reaction times were needed to
its 3,5-di-tert-butyl congener 4 afforded a very promising ee of maintain high yields (entries 13 and 14). The absolute configu-
77% with the same diastereoselectivity (entries 3 and 4). ration of product 11ad was determined to be R at the quaternary
Although a modest dr of 66: 34 was observed with guanidine 5 carbon and S at the other one by X-ray crystallographic analysis
derived from a chiral aminoalcohol, it is interesting to note that (entry 4, for details see the ESI†), and those of others were
a reversal in the sense of the enantioselectivity for the major assigned by analogy.
diastereomer occurred (entry 5). The ketal moiety of the guanidine
Following the establishment of the broad generality of nitro-
catalyst was also found to markedly influence the stereoselectivity, olefins, the substrate scope with respect to 3-substituted oxindoles
as can be seen from the fact that guanidine 6 displaying a was next investigated (Table 3). Similarly, a wide array of oxindoles
cyclohexanone ketal afforded a drastically decreased ee of 48% were proved to be suitable substrates. Various 3-benzyl and hetero-
compared to 4 (entry 6). Furthermore, two known guanidines, the benzyl oxindoles reacted smoothly with a selection of aryl
widely used bicyclic guanidine 7 introduced by Tan12 and the nitroolefins, affording the adducts in high yields with excellent
easily accessible proline-based guanidine 8 developed by Feng,13 diastereo- and enantioselectivities. 3-Phenyl oxindole was also
were also investigated, but both afforded poor diastereo- and accommodated albeit with a marginally decreased enantio-
enantioselectivities (entries 7 and 8). With guanidine 4 as the selectivity. Furthermore, 3-alkyl oxindoles underwent the Michael
catalyst of choice, the reaction media were screened (entries 9–13), addition with the same levels of efficiency and stereoselectivity.
which led to the identification of diethyl ether as the optimum Hence, the tartrate-based guanidine catalyst exhibits extraordinarily
solvent, affording 93% yield, 96 : 4 dr and 81% ee in 4 hours at broad substrate generality with respect to both 3-substituted
room temperature. The stereoselectivity was found to be sensitive oxindoles and nitroolefins, which stands in sharp contrast to
to the reaction temperature (entries 14–16), thus by lowering the the catalyst systems reported so far.
temperature to À40 1C an excellent stereocontrol of 99 : 1 dr and
In summary, a novel tartrate-derived guanidine was demon-
strated to be a highly competent organocatalyst for the asymmetric
94% ee was achieved.
With the optimal reaction conditions established, the sub- conjugate addition of 3-substituted oxindoles to nitroolefins. The
strate generality with respect to nitroolefins was then explored Michael adduct was obtained in high yield with excellent diastereo-
(Table 2). Initially, nitrostyrene derivatives displaying electronically and enantioselectivities. This catalyst system revealed very
diverse phenyl rings with varying substitution patterns were broad generality in terms of both 3-substituted oxindole and
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Table 3 Substrate generality for 3-substitued oxindolesa
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Unless otherwise noted, reactions were conducted with 3-substitued
oxindole 9 (0.2 mmol), catalyst 4 (10 mol%) and nitroalkene 10
(1.2 equiv.) in diethyl ether (2 mL). Isolated yield. Determined by chiral
HPLC analysis. The absolute configuration of 11ia was determined by
comparison of the optical rotation and retention time with literature data
b
c
d
(ref. 7b).
nitroolefin substrates, as a broad array of aryl, alkyl, and benzyl
substituents on both components were well accommodated.
Studies toward further expanding the catalytic applications of
the tartrate-derived guanidines for other asymmetric trans-
formations are currently underway in our laboratory.
We thank the National Natural Science Foundation of China
(No. 21076035, 20972022), the Program for New Century Excellent
Talents in University (NCET-11-0053), the Fundamental Research
Funds for the Central Universities (DUT13ZD202), and the Science
and Technology Department of Liaoning Province (No. 20102032)
for support of this work.
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5762 | Chem. Commun., 2014, 50, 5760--5762
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