Highly enantioselective organocatalytic michael addition/cyclization cascade reaction of ylideneoxindoles with isothiocyanato oxindoles: A formal [3+2] cycloaddition approach to optically active bispirooxindole derivatives

Article abstract of DOI:10.1002/ejoc.201300081

A formal [3+2] cycloaddition involving the organocatalytic asymmetric Michael addition/cyclization cascade reaction of ylideneoxindoles with isothiocyanato oxindoles was developed. This method allows efficient and rapid synthesis of highly functionalized bispirooxindole products bearing three contiguous stereogenic centers with two quaternary stereocenters in almost quantitative yields with extremely high enantio- and diastereoselectivities. A formal [3+2] cycloaddition involving the organocatalytic Michael addition/cyclization of ylideneoxindoles with isothiocyanato oxindoles was developed. This method allows efficient and rapid synthesis of highly functionalized bispirooxindoles bearing three contiguous stereogenic centers with two quaternary stereocenters in almost quantitative yields with extremely high enantio- and diastereoselectivities. Copyright

Full text of DOI:10.1002/ejoc.201300081

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300081
Highly Enantioselective Organocatalytic Michael Addition/Cyclization Cascade
Reaction of Ylideneoxindoles with Isothiocyanato Oxindoles: A Formal [3+2]
Cycloaddition Approach to Optically Active Bispirooxindole Derivatives
Fen Tan,[a] Hong-Gang Cheng,[a] Bin Feng,[a] You-Quan Zou,[a] Shu-Wen Duan,[a]
Jia-Rong Chen,*[a] and Wen-Jing Xiao*[a]
Keywords: Asymmetric synthesis / Organocatalysis / Michael addition / Domino reactions / Cascade reaction / Cyclization /
Spiro compounds
A formal [3+2] cycloaddition involving the organocatalytic
asymmetric Michael addition/cyclization cascade reaction of
ylideneoxindoles with isothiocyanato oxindoles was devel-
oped. This method allows efficient and rapid synthesis of
highly functionalized bispirooxindole products bearing three
contiguous stereogenic centers with two quaternary stereo-
centers in almost quantitative yields with extremely high en-
antio- and diastereoselectivities.
ones.[6q] These reactions afforded the corresponding spiro-
cyclopentane bioxindoles in good yields with moderate to
excellent stereoselectivity. Despite advances, to the best of
our knowledge, the catalytic enantioselective synthesis of
bispirooxindoles connected by pyrrolidinyl motif has rarely
been documented.
Recently, 3-isothiocyanato oxindole has become a robust
and versatile synthon in the construction of complex tar-
gets,[6h,7] and it has also been used in a diastereoselective
synthesis of structurally diverse bispirooxindole derivatives
Introduction
Spirooxindole frameworks are commonly found in natu-
ral products and bioactive and pharmaceutically relevant
compounds.[1] As a result, structure variation of this “privi-
leged” pharmacophore has received much attention over
the last decade. A variety of three-,[2] four-,[3] five-,[4] and
six-membered[5] carbo- and heterocyclic ring systems were
successfully incorporated at the C3 position of the oxindolic
architecture as a result of the possible application of these
scaffolds in medicinal chemistry or in the synthesis of com-
plex heterocycles. In particular, extensive research effort has
been devoted to the asymmetric construction of spiroox-
indoles.[6] In this context, the bispirooxindole scaffold has
recently attracted considerable interest because of its unique
structure and stereochemical diversity.[6k,6q,6r] However,
only limited examples have been reported to date, probably
because of the challenges associated with the assembly of
the highly sterically congested spirocyclic moiety and mul-
tiple stereogenic centers. For example, the Barbas group has
pioneered an organocatalytic Michael addition/aldol cas-
cade reaction between 3-substituted oxindoles and methyl-
eneindolinones,[6k] whereas Wang and co-workers have
documented an alternative chiral squaramide-catalyzed
Michael addition/alkylation cascade reaction of finely de-
signed 3-substituted oxindoles and methyleneindolin-
[a] Key Laboratory of Pesticide & Chemical Biology Ministry
of Education, College of Chemistry, Central China Normal
University,
152 Luoyu Road, Wuhan, Hubei 430079, China
Fax: +86-27-6786-2041
E-mail: wxiao@mail.ccnu.edu.cn
jiarongchen2003@yahoo.com.cn
Scheme 1. Reaction design: organocatalytic asymmetric Michael
addition/cyclization cascade reaction of ylideneoxindoles with iso-
thiocyanato oxindoles.
Homepage: http://chem-xiao.ccnu.edu.cn/default.aspx
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300081.
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J.-R. Chen, W.-J. Xiao et al.
SHORT COMMUNICATION
through Michael addition/aldol and Michael addition/ Table 1. Optimization of the asymmetric synthesis of bispiroox-
indole product 3aa.[a]
Mannich reactions with isatins/isatinimines.[8] As part of
our ongoing research efforts toward the synthesis of biolo-
gically important heterocycles,[9] we developed two types of
cyclization reactions of 3-ylideneoxindoles 1 to establish the
spirooxindole motif: 1) organocatalytic Michael addition/
aldol cascade[9d] and 2) visible-light-induced [2+2] cycload-
dition (Scheme 1).[10] The corresponding spirooxindole
tetrahydrothiophene and bispirooxindole cyclobutane de-
rivatives were obtained with excellent stereoselectivities. In
this communication, we disclose highly efficient squar-
amide-catalyzed Michael addition/cyclization cascade reac-
tions of 3-ylideneoxindoles 1 with 3-isothiocyanato oxind-
oles 2. This formal [3+2] cycloaddition reaction provides
highly functionalized bispirooxindole derivatives in ex-
tremely high chemical yield, diastereoselectivity, and
enantioselectivity with very low catalyst loading
(Scheme 1).[11]
Results and Discussion
We selected (E)-ethyl 2-(1-methyl-2-oxoindolin-3-yl-
idene)acetate (1a) and 3-isothiocyanato oxindole (2a) as the
model substrates to examine the possibility of the designed
asymmetric Michael addition/cyclization sequence. A series
of common bifunctional squaramide and thiourea organo-
catalysts were screened at 10 mol-% loading at room tem-
perature. Representative results are summarized in Table 1.
To our delight, the reaction worked very well and afforded
desired bispirooxindole product 3aa in 95% isolated yield
with extremely high stereoselectivity (Ͼ99%ee and
Ͼ95:5dr[12]) in the presence of quinine-derived catalyst I
within only 2 min (Table 1, entry 1). Chiral squaramide or-
ganocatalysts II and III[13] can also catalyze this transfor-
mation efficiently, albeit with slightly longer reaction time
(Table 1, entries 2 and 3 vs. entry 1; 20 vs. 2 min). The use
of amine–thiourea catalysts IV–VI[14] also gave the desired
products in high yields with high diastereoselectivities, but
with decreased enantioselectivities (Table 1, entries 4–6).
With optimal catalyst I identified, we continued to screen
solvents and other reaction parameters. It was found that
the reaction media had little influence on the reaction effi-
ciency, except toluene (Table 1, entries 7–10); CH2Cl2
proved to be the best choice. Further investigation of the
reaction conditions including concentration of the substrate
and catalyst loading resulted in optimal reaction condi-
Entry Cat. Solvent t [min] Yield [%][b] ee [%][c]
dr[d]
1
2
3
4
5
6
7
8
I
CH2Cl2
CH2Cl2
2
20
20
60
60
60
10
2
2
5
10
10
55
120
95
96
98
98
84
93
94
99
99
99
94
95
99
97
Ͼ99
–95
–93
87
–85
–81
94
79
94
94
Ͼ99
99
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
II
III CH2Cl2
IV CH2Cl2
V
CH2Cl2
VI CH2Cl2
I
I
I
I
I
I
I
I
CHCl3
PhMe
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11[e]
12[f]
13[g]
14[h]
Ͼ99
Ͼ99
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.21 mmol), cat.
(10 mol-%) in solvent (4 mL) at room temperature. [b] Yield of iso-
lated product after chromatography. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] Determined by analysis of
the crude reaction mixture by 1H NMR spectroscopy. [e] CH2Cl2
(8 mL) was used. [f] Performed with a catalyst loading of 5 mol-%.
[g] Performed with a catalyst loading of 1 mol-%. [h] Performed
with a catalyst loading of 0.5 mol-%.
tions: 1a (1 equiv.), 2a (1.05 equiv.) I (1 mol-%), CH2Cl2 yields (up to 99% yield) with excellent enantio- and dia-
(4.0 mL per 0.2 mmol of 1a), room temperature (99% yield, stereoselectivities (up to Ͼ99%ee, Ͼ95:5dr). For example,
Ͼ99%ee, Ͼ95:5dr; Table 1, entry 13). Importantly, the en- incorporation of one or more substituents on the aromatic
antiomer of 3aa could also be readily accessed by simply ring of 3-ylideneoxindole moiety 1 had little effect on the
changing quinine-derived squaramide I to its quinidine ana- efficiency and stereochemical outcome of this cyclization
logue under identical conditions (91% yield, –95%ee, reaction. Moreover, both electron-withdrawing and elec-
Ͼ95:5dr).[15]
tron-donating substituents at different positions in 1 were
We evaluated the generality of this methodology under tolerated, providing the corresponding cycloadducts in high
the optimized conditions. As illustrated in Table 2, the reac- yields with great stereoselectivities. Notably, the reaction
tion showed excellent functional group tolerance, and a with sterically hindered 4-bromo-substituted 3-ylideneox-
variety of bispirooxindole products were obtained in high indole 1j gave rise to corresponding product 3ja in 98%
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Organocatalytic Michael addition/Cyclization Cascade Reactions
Table 2. Substrate scope of the asymmetric Michael addition/cycli- yield with 90%ee and Ͼ95:5dr. In addition, excellent re-
zation sequence for the synthesis of bispirooxindole derivatives.[a]
sults were achieved by changing the ester moiety or the pro-
tecting group on the N atom. The cascade process with N-
free substrate 1p was performed, and the reaction afforded
3pa in 99% yield with 88%ee and Ͼ95:5dr. To further vali-
date the compatibility of this strategy, we then investigated
the scope of 3-isothiocyanato oxindoles 2. It was found that
incorporation of various functional groups to the aromatic
ring of 2 could be realized, affording products 3ab–ad in a
highly stereoselective fashion. In addition, benzyl-protected
substrate 2e also participated in this reaction to give corre-
sponding product 3ae in good yield (83% yield) with excel-
lent enantio- and diastereoselectivity (99%ee; Ͼ95:5dr).
The absolute configuration of 3aa was determined to be
(8S,11R,12S) by X-ray crystallographic analysis (Fig-
ure 1).[16] To demonstrate the synthetic utility of this
Michael addition/cyclization cascade reaction, a gram-scale
reaction was carried out with a catalyst loading of 0.5 mol-
%. To our delight, bispirooxindole compound 3aa was ob-
tained in 98% yield with 98%ee and Ͼ95:5dr within 3 h,
highlighting the potential of the current reaction in the syn-
thesis of bispirooxindole-containing natural products and
medicinal reagents (Scheme 2).
Figure 1. X-ray crystal structure of compound 3aa.
Scheme 2. Gram-scale synthesis of 3aa.
More importantly, these bispirooxindolic compounds
can be easily converted into other important building
blocks and valuable complex targets. As shown in
Scheme 3, treatment of 3aa with CH3I under basic condi-
tions gave product 4[6f,8] in 91% yield with Ͼ99%ee and
Ͼ95:5dr. Furthermore, the oxidation of bispirooxindole
3aa with 30% aqueous H2O2 and 98% formic acid ef-
[a] Unless otherwise noted, the reaction was carried out with 3-ylidene-
ficiently generated corresponding lactam 5 (99% yield,
oxindole 1 (0.2 mmol), 3-isothiocyanato oxindole 2 (0.21 mmol), and
Ͼ99%ee, Ͼ95:5dr).[6g,6h,8] Note that no loss of the dia-
cat. I(1 mol-%) in CH2Cl2 (4 mL) at room temperature. [b] The reaction
was conducted at –60 °C. [c] The reaction was conducted at –25 °C.
stereo- or enantioselectivity was observed.
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J.-R. Chen, W.-J. Xiao et al.
SHORT COMMUNICATION
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Scheme 3. Synthetic transformations of product 3aa.
Conclusions
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In conclusion, we have developed a practical and highly
efficient Michael addition/cyclization cascade reaction, a
formal [3+2] cycloaddition, for the rapid construction of
bispirooxindole skeletons in very high chemical yields with
excellent enantio- and diastereoselectivities. The mild reac-
tion conditions, low catalyst loading, short reaction time,
and high tolerance of functional groups make this strategy
an attractive method for the construction of bispirooxind-
ole-containing natural products and pharmaceutically im-
portant drug leads. Further applications of this transforma-
tion to synthesize other important complex heterocycles are
currently in progress.
[5]
For selected examples of the asymmetric synthesis of spiroox-
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Experimental Section
Typical Procedure: 3-Ylideneoxindole 1a (46 mg, 0.20 mmol), 3-iso-
thiocyanato 2a (43 mg, 0.21 mmol), and cat. I (1.26 mg, 1 mol-%)
were dissolved in CH2Cl2 (4 mL). The resulting solution was stirred
at room temperature until the reaction was complete, as monitored
by TLC (Note: The reaction was usually complete when the color
of the mixture changed from red to colorless around 55 min). The
crude reaction mixture was directly purified by flash column
chromatography (petroleum ether/ethyl acetate = 3:1 to 1:1) to af-
ford 3aa as a white solid in 99% yield with Ͼ99%ee and Ͼ95:5dr.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental methods and characterization data.
Acknowledgments
[6]
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We are grateful to the National Natural Science Foundation of
China (NSFC) (grant numbers 21072069, 21002036, 21232003, and
21202053) for support of this research.
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