Synthesis of spiro[chroman/tetrahydrothiophene-3,3'-oxindole] scaffolds via heteroatom-michael-michael reactions: Easily controlled enantioselectivity via bifunctional catalysts

Article abstract of DOI:10.1002/adsc.201300833

An efficient method for the construction of chiral spirooxindole-chroman and spirooxindoletetrahydrothiophene scaffolds with three consecutive chiral centers including an all-carbon quaternary spirocenter has been developed. This method features an asymmetric thia/oxa-Michael-Michael cascade sequence in a single operation in the presence of chiral tertiary amine-thioureas as the catalysts, providing the desired products in good chemical yields and optical purities.

Full text of DOI:10.1002/adsc.201300833

UPDATES
DOI: 10.1002/adsc.201300833
Synthesis of Spiro[chroman/tetrahydrothiophene-3,3’-oxindole]
Scaffolds via Heteroatom-Michael–Michael Reactions: Easily
Controlled Enantioselectivity via Bifunctional Catalysts
Youming Huang,a Changwu Zheng,a Zhuo Chai,a and Gang Zhaoa,*
a
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 lingling Road, Shanghai 200032, Peopleꢀs Republic of China
E-mail: zhaog@mail.sioc.ac.cn
Received: September 12, 2013; Published online: January 20, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300833.
Abstract: An efficient method for the construction
of chiral spirooxindole-chroman and spirooxindole-
tetrahydrothiophene scaffolds with three consecu-
tive chiral centers including an all-carbon quaterna-
ry spirocenter has been developed. This method
features an asymmetric thia/oxa-Michael–Michael
cascade sequence in a single operation in the pres-
ence of chiral tertiary amine-thioureas as the cata-
lysts, providing the desired products in good chemi-
cal yields and optical purities.
been reported.[6] Among these sequences, the domino
Michael–Michael reaction can be considered as one
of the most powerful and reliable tools for the stereo-
controlled assembly of molecular architectures, as
demonstrated by numerous examples in which it has
also been used as a key transformation in total syn-
thesis.[7]
Very recently, we have developed an organocata-
lyzed aza-Michael–Michael cascade reaction to con-
struct spirooxindole-tetrahydroquinolines with high
yields and stereoselectivities.[8] As an extension of this
work, we reported herein asymmetric organocatalytic
oxa/thia-Michael–Michael cascade reactions to syn-
thesize highly useful spirooxindole-chroman and spi-
rooxindole-tetrahydrothiophene scaffolds[9] which
have been found as core structural motifs in numer-
ous natural products with intriguing biological and
pharmaceutical activities (<Figure 1).[10,11]
Keywords: asymmetric catalysis; cascade reactions;
heteroatom-Michael–Michael reaction; organocatal-
ysis; spirooxindoles
Spirocyclic oxindoles have recently emerged as attrac-
The asymmetric oxa-Michael-Michael cascade reac-
tive synthetic targets because of their prevalence in tion was first evaluated and the reaction between
an array of fascinating natural products and pharma- methyleneindolinone 1a and ortho-hydroxychalcone
ceutical candidates.[1] For this reason, the develop- 2a was selected as the model. As we expected, Cin-
ment of general and efficient methodologies to access chona alkaloid-derived thiourea catalyst 4a provided
this family of alkaloids is of great interest in organic the desired product with 67% ee and 85% yield
synthesis.[2,3] Moreover, it has been reported that the (Table 1, entry 1). A further screening of the solvents
presence of the spirocyclic center is highly beneficial indicated that toluene was the best one with regard to
to the biological activity of relevant compounds.[4] enantioselectivity (Table 1, entries 1–5). On lowering
Thus, the building of these fused spiroheterocycles the reaction temperature to 08C, the reaction was
has been intensively studied by organic chemists, and completely inhibited (Table 1, entry 6). Based on ex-
some impressive progress in the construction of citing reports about amine-acid derived thioureas
densely functionalized spiroheterocycle compounds from our group and others,[12] we then turned our at-
has been achieved.[3]
tention to the various amino acid-based bifunctional
The asymmetric organocatalytic cascade reaction catalysts (Table 1, entries 7–18). The examination of
has emerged as a powerful tool in constructing chiral a variety of catalysts with different chiral backbones
molecule scaffolds bearing multiple stereocenters showed that the selectivity of the reaction was depen-
from simple and readily available starting materials in dent on the steric hindrance of the R group. The cata-
a single operation.[5] In recent years, very many inno- lyst 4f with a bulky tert-butyl group provided the
vative and impressive cascade sequences to afford highest distereoselectivity and enantioselectivity
compounds with highly molecular complexity have (Table 1, entries 9–11). As for the tertiary amine
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Youming Huang et al.
Figure 1. Structures of chiral catalysts used in the cascade reactions.
Table 1. Optimization of the reaction conditions of the oxa-
Michael-Michael reaction.[a]
moiety, the catalyst 4g endowed with diethylamine
gave a slightly higher ee value (Table 1, entry 12). No-
tably, replacement of the 3,5-bis(trifluoromethyl)
phenyl group in the thiourea part with other aryl
groups had a deleterious effect on yield and selectivi-
ty (Table 1, entries 14–17). In order to further im-
prove the above results, we presumed that an increase
in the size of the R group would probably enhance
the stereoselectivity based on the experience from
catalysts 4d–4f. Recently Ye and co-workers reported
the Michael addition of substituted rhodanines to a,b-
unsaturated ketones by bulky amino-acid derived pri-
mary-tertiary amine catalysts with good results.[13] In-
spired by their work, we synthesized a novel bulky
tertiary amine-thiourea catalyst 4m. Pleasingly, reac-
tion using this catalyst provided the corresponding
product with a dr of >20:1 and an enantiomeric
excess of 88% (Table 1, entry 18). As we observed,
the best catalysts 4g and 4m gave the two enantio-
mers, respectively, with high yields and selectivities.
Considering the potential utilization of both isomers
in the synthesis, we decide to evaluate the generality
of this reaction with catalysts 4g and 4m.
The experiment to construct different spirooxindole
chromans is shown in Scheme 1. Several methylenein-
dolinones 1 were reacted with ortho-hydroxychalcone
2a under the two optimized conditions, respectively
(Scheme 1). As for the catalyst 4m (Conditions A),
the presence of electron-withdrawing or electron-do-
nating substituents on the aromatic ring of the oxin-
doles had little effect on the stereoselectivity (3a–3g).
Ester and ketone groups at the carbon-carbon double
bond were well tolerated under these conditions (3h–
3j). Notably, when the N-protecting groups of the
methyleneindolinone was replaced by Ac or Bn, the
reaction could not proceed.[14] ortho-Hydroxychal-
cones with various substituents on the benzene ring
also gave the corresponding products with excellent
Entry Catalyst Solvent Yield [%][b] dr[c]
ee [%][d]
1
2
3
4
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
PhCH3 85
PhCF3 95
CH2Cl2 70
1.2/1
3/1
4/1
67
48
18
30
50
–
60
47
À70
À67
À82
À84
À80
À59
À63
À54
À80
DCE
Et2O
95
95
6/1
5
2/1
6[f]
7
PhCH3 trace
PhCH3 63
PhCH3 26
PhCH3 88
PhCH3 95
PhCH3 94
PhCH3 92
PhCH3 87
PhCH3 60
PhCH3 54
PhCH3 38
PhCH3 85
PhCH3 85
–
[e]
[e]
3/1
3/2
3/1
3/2
4/1
5/1
4/1
2/1
3/1
3/2
4/1
8
9
10
11
12
13
14
15
16
17
18
4j
4k
4l
4m
>20/1 88
[a]
Reaction conditions: 1a (1.2 equiv.), 2a (1.0 equiv.), 4
(20 mol%), toluene (1.0 mL).
[b]
Yield of the isolated product after column chromatogra-
phy.
[c]
[d]
[e]
[f]
1
Determined by H NMR of crude product.
Determined by chiral HPLC.
Not determined.
The reaction was carried out at 08C.
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Synthesis of Spiro[chroman/tetrahydrothiophene-3,3’-oxindole] Scaffolds
Scheme 1. Substrate scope of the oxa-Michael–Michael reaction. Reaction conditions: 1 (0.05 mmol), 2 (0.06 mmol), 4g or
4m (0.01 mmol), toluene (1.0 mL). Conditions A: with catalyst 4m; conditions B: with catalyst 4g. Yield reporteds after isola-
1
tion. Diastereomeric ratios (dr) were determined by H NMR of the crude product. Enantiomeric excesses (ee) were deter-
mined by chiral HPLC.
ee and moderate to excellent dr (3k–3o), regardless of matic ring gave invariably excellent yields ranging
their electronic nature or positions. When the catalyst from 92% to 98% and enantioselectivities ranging
4g was used (Conditions B), we found that the reac- from 85% to 93% (Scheme 2, products 6a–6i), irre-
tions provided the corresponding enantiomers in rela- spective of their electronic nature. A little more influ-
tively higher yields than that under conditions A ence was observed on the diastereoselectivities which
albeit with slightly decreased stereoselectivities indi- altered from 88:12 dr to 97:3 dr. A variety of ester
cated by the substrates examined. The absolute con- substituents attached to the carbon-carbon double
figuration of 3b was unambiguously determined by bond centers was also tolerated, providing the corre-
single-crystal X-ray analysis and others can therefore sponding compounds in excellent yields, moderate to
be assigned by analogy.
good diastereoselectivities, and good to excellent
After we had established the methodologies for the enantioselectivities (Scheme 2, products 6j–6l). It
oxa-Michael–Michael reaction, the related thia-Mi- should be noted that when we prepared the 4-substi-
chael–Michael reaction with methyleneindolinone tuted methyleneindolinones as the substrates (see 6d
came to mind and trans-ethyl 4-mercapto-2-butenoate and 6h), we observed cis-alkenes in the compounds,
5 was chosen as the reaction partner. Based on the re- which are different from other substituted methyle-
sults we had obtained above, various reaction condi- neindolinones we synthesized (trans-alkenes were ob-
tions including the catalysts, solvents were also exam- served), probably due to the steric hindrance between
ined in the same manner and finally the optimal con- the ester and the 4-substituents. In view of the transi-
ditions were obtained when methyleneindolinone 1a tion state the absolute configuration of 6d and 6h
(1.0 equiv.) was treated with trans-ethyl 4-mercapto-2- should also be altered compared with the others (see
butenoate 5 (1.5 equiv.) in trifluorotoluene at À208C the Supporting Information for details). Unfortunate-
in the presence of catalyst 4a (20 mol%) and 3ꢂ MS, ly, efforts to get a crystal of 6g failed although we can
providing the desired spriooxindole-tetrahydrothio- determine the configurations of the products 6h and
phene in high yield and stereoselectivity (see the Sup- 6d by X-ray analysis. In an alternative pathway, we
port Information for details).
presumed that the stereochemistry of the spiro
Having established the optimized reaction condi- carbon center is the same in all the products 6a–6l.
tions, the generality of the reaction with different Thus we can determine the absolute configuration of
methyleneindolinones was explored. Changing the the products 6a–6c, 6e–6g and 6i–6l with an additional
substituents at the C-4 to C-6 positions on the aro-
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Youming Huang et al.
Scheme 2. Substrate scope of the thia-Michael–Michael reaction. Reaction conditions: 1 (1.0 equiv.), 5 (1.5 equiv.), 4a
1
(20 mol%), PhCF3 (1.0 mL). Yields reported after isolation. Diastereomeric ratios (dr) were determined by H NMR of
crude product. Enantiomeric excesses (ee) were determined by chiral HPLC.
NOE experiment (see the Supporting Information for (0.5 mL). Then the ortho-hydroxychalcone 2 (0.05 mmol,
1.0 equiv.) was added and the resulting mixture was stirred
for 4 days at room temperature. The crude mixture was di-
rectly subjected to column chromatography to provide the
corresponding product 3 (with hexanes/ethyl acetate=4/1).
details).
In summary, we have successfully developed
a highly enantioselective oxa/thia-Michael–Michael
cascade reaction for the construction of spirooxin-
dole-chroman and spirooxindole-tetrahydrothiophene
scaffolds. The novel amino acid-derived steric thio-
General Procedure for the Thia-Michael–Michael
Reaction
ACHTUNGTRENNUNGurea 4m was identified as a highly efficient catalyst in
the oxa-Michael–Michael cascade reaction. With the
best catalysts 4g and 4m used, two enantiomers with
high yields and selectivities were obtained, respective-
ly. The reactions between trans-ethyl 4-mercapto-2-
butenoate and methyleneindolinones were also devel-
oped, providing the spirooxindole-tetrahydrothio-
phenes with high yields and excellent enantioselectivi-
ties. Studies on the development of novel and concise
methods to construct divergent heterocyclic oxindoles
are still ongoing in our laboratory.
Methyleneindolinone 1 (0.05 mmol, 1.0 equiv.) was added to
a solution of thiourea 4 (0.01 mmol, 0.2 equiv) in PhCF3
(1 mL). The resulting solution was cooled down to À208C,
then
the
trans-methyl
4-mercapto-2-butenoate
5
(0.075 mmol, 1.5 equiv.) and 10 mg of 3ꢂ MS were added.
The progress of the reaction was monitored by TLC analy-
sis. At the end of the reaction, the mixture was purified by
flash column chromatography to afford the corresponding
product 6 (with hexanes/ethyl acetate=5/1).
Acknowledgements
Experimental Section
Financial support for this research from National Basic Re-
search Program of China (973 Program, 2010CB833200), the
National Natural Science Foundation of China (Nos.
21032006, 203900502, 20532040, 21290180), and Science and
Technology Commission of Shanghai Municipality
(11XD1406400) is gratefully acknowledged.
General Procedure for the Oxa-Michael–Michael
Reaction
Methyleneindolinone 1 (0.06 mmol, 1.2 equiv.) was added to
a solution of thiourea 4 (0.01 mmol, 20 mol%) in toluene
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Synthesis of Spiro[chroman/tetrahydrothiophene-3,3’-oxindole] Scaffolds
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