Angewandte
Chemie
DOI: 10.1002/anie.201410814
Heterocycle Synthesis
Asymmetric Dearomatization of Indoles through Michael/Friedel–
Crafts-Type Cascade to Construct Polycyclic Spiroindolines**
Xiaohu Zhao, Xiaohua Liu,* Hongjiang Mei, Jing Guo, Lili Lin, and Xiaoming Feng*
Abstract: A highly efficient asymmetric dearomatization of
indoles was realized through a cascade reaction between 2-
isocyanoethylindole and alkylidene malonates catalyzed by
II
a chiral N,N’-dioxide/Mg catalyst. Fused polycyclic indolines
containing three stereocenters were afforded in good yields
with excellent diastereo- and enantioselectivities through
a Michael/Friedel–Crafts/Mannich cascade. When 2-substi-
tuted 2-isocyanoethylindoles were used, spiroindoline deriva-
tives were obtained through a Michael/Friedel–Crafts reaction.
T
he spiroindoline unit is a privileged heterocyclic substruc-
ture in a series of natural products and biologically active
[
1]
compounds. The desire to build such appealing polycyclic
skeletons with complete control over their stereochemistry
has inspired the development of numerous efficient synthetic
strategies. Cascade reactions are an attractive topic in
organic synthesis because of the rapid construction of
Scheme 1. Asymmetric dearomative cascade of 2-isocyanoethylindole.
Chemoselective synthesis of spiroindolines and pyrroles
have been achieved by using a 2-isocyanoethylindole-based
[
2]
[
12]
cascade reaction. Developing an enantioselective catalytic
version of this synthetic strategy towards these scaffolds is
lacking and interesting. In view of only a single diastereoiso-
mer of polycyclic spiroindoline formed in the cascade
[
3]
molecular complexity from simple starting materials. Par-
ticularly with the indole substrates, a dearomative cascade
annulation is efficient for novel polycyclic spiroindoline
compounds. A number of chemo-, regio-, and enantioselec-
tive methods have been used to modify and dearomatize the
[
12]
reaction, we surmise that the initial stereocenter generated
by an asymmetric Michael reaction would direct the enantio-
selective dearomative annulation, thus yielding the desired
spiroindoline with high stereoselectivity, even if the first
[
4–8]
indole unit.
You and co-workers have made significant
contributions to the catalytic enantioselective dearomatiza-
tion of indoles, thus affording a series of enantioenriched
[
12]
stereocenter disappeared in the end.
Additionally, the
[
9]
indoline derivatives. The group of MacMillan has discov-
ered the iminium catalysis for asymmetric construction of
rational choice of a Michael acceptor is critical because of
both background reactions and stereoselection. The reaction
performed well under catalyst-free conditions when the
[6]
various complex alkaloids through a dearomative process.
Isocyanides are versatile precursors which are used widely
malononitrile-derived acceptors were employed (EWG =
[
10]
[12a]
in cascade reactions to synthesize heterocyclic compounds.
2
CN; Scheme 1).
The reactivity decreased quite a bit after
[
11]
[12b]
-Isocyanoethylindole bearing a pendant nucleophilic iso-
one ester group was introduced.
As a key design element,
cyanide at the C3-position of the indole serves as a readily
available starting material and has potential as a precursor for
spiroindolines having multiple stereocenters (Scheme 1).
the alkylidene malonates incorporated a bidentate carbonyl
group (EWG = ester) to provide an opportunity to coordinate
chiral Lewis acid catalysts for both activation and stereo-
[
13c,f]
control.
Our group has successfully realized a number of
highly efficient asymmetric reactions by the privileged N,N’-
[
*] X. H. Zhao, Prof. X. H. Liu, H. J. Mei, J. Guo, Dr. L. L. Lin,
Prof. X. M. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
E-mail: liuxh@scu.edu.cn
[
13]
dioxide/metal complex catalysts. To construct enantiopure
polycyclic frameworks, we developed the catalytic asymmet-
ric dearomative cascade reactions of 2-isocyanoethylindole
and alkylidene malonates. A readily available chiral N,N’-
[13g,h]
dioxide/Mg(OTf)2
complex afforded the fused polycyclic
indolines and spiroindolines through Michael/Friedel–Crafts-
type cascades, and moderate to high yield, as well as excellent
diastereo- and enantioselectivity were achieved under mild
reaction conditions.
In the initial study, we chose diethyl 2-benzylidenemalo-
nate (2a) and 2-isocyanoethylindole (1a) as the model
substrates. The performance of metal salts combined with
Prof. X. M. Feng
Collaborative Innovation Center of Chemical Science and-
Engineering, Tianjin (China)
[
**] We appreciate the National Natural Science Foundation of China
Nos. 21290182, 21321061, 21222206, and 21432006), and the
National Basic Research Program of China (973 Program; No.
011CB808600) for financial support.
(
2
the chiral N,N’-dioxide ligand l-PrPr was evaluated (Table 1,
entries 1–3). To our delight, the alkaline-earth metal sources,
2
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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