Angewandte
Chemie
Organocatalysis
Squaramide-Catalyzed Synthesis of Enantioenriched Spirocyclic
Oxindoles via Ketimine Intermediates with Multiple Active Sites
Qiang-Sheng Sun, Hua Zhu, Yong-Jian Chen, Xiao-Di Yang, Xing-Wen Sun,* and Guo-
Qiang Lin
Abstract: A new method for the construction of five-mem-
bered spirocyclic oxindoles is based on a Michael–Mannich
cascade reaction of a ketimine intermediated catalyzed by
a bifunctional quinine-derived squaramide. The desired prod-
ucts were obtained in excellent yields (up to 94%) and
stereoselectivities (up to > 20:1 d.r., > 99% ee). A scaled-up
variant also proceeded smoothly showing that the one-pot
reaction might find application in the synthesis of bioactive-
compound libraries.
T
he spirocyclic oxindole architecture is prevalent in both
natural products and synthetic bioactive molecules
(Figure 1).[1] In particular, enantiopure five-membered spiro-
cyclic oxindoles have attracted tremendous attention owing to
their diverse bioactivities and structural complexity. The key
challenge for the construction of such structures lies in the
formation of multiple stereocenters, particularly for those
containing two adjacent quaternary centers. Therefore, new
strategies for the synthesis of such spirocyclic oxindoles[2] with
high levels of efficiency and selectivity from readily available
starting materials are always in great demand.
Figure 1. Bioactive five-membered spirocyclic oxindoles.
on nitrosoarenes,[15] we hypothesized that the addition of
b-dicarbonyl compounds to nitrosoarenes followed by
a Michael–Mannich sequence in the presence of a bifunctional
catalyst would be an appropriate strategy to prepare enan-
tioenriched spirocyclic oxindoles (Scheme 1d). As an inter-
esting electrophile, nitrosobenzene can react with ketones/
aldehydes to form either the a-aminooxylation[16] or the
a-oxyamination products[17] (Scheme 1a). However, very few
methods for the addition of b-dicarbonyl compounds[18] to
nitrosoarenes to generate a-imino-b-dicarbonyl compounds
have been reported thus far, and they all suffer from low
yields (Scheme 1b). These products are very useful synthons
that bear multiple nucleophilic and electrophilic sites. To the
best of our knowledge, the application of these novel
ketimines in asymmetric synthesis has not been reported
thus far.
At the outset of this study, a method for the preparation of
a-imino-b-dicarbonyl compounds was developed. We were
pleased to find that such a compound could be isolated in
nearly quantitative yield when acetylacetone (1a) and nitro-
sobenzene (2a) were coupled in the presence of 2 mol% of
quinine-derived squaramide A. In other words, the addition
promoted by the bifunctional catalyst was highly selective for
N-addition, and any O-addition products were not observed.
Meanwhile, the bifunctional catalyst exhibited good activity
in this Michael addition. Therefore, we attempted to prepare
various spirocyclic oxindoles through a one-pot process using
only one catalyst.
In the past few years, elegant advances have been made in
the development of enantioselective syntheses of five-mem-
bered spirocyclic oxindoles.[3] In 2007, Trost[4] and co-workers
disclosed a palladium-catalyzed [3+2] cycloaddition for the
assembly of such compounds. Aside from transition-metal
catalysis, organocatalytic cascade reactions provide an alter-
native powerful strategy for the preparation of spirocyclic
oxindoles. After [3+2] cycloadditions catalyzed by chiral
tertiary phosphines[5] or amines[6] had been reported, hydro-
gen bond donor catalyzed cascade reactions,[7] Michael–
Michael reactions promoted by primary[8] or secondary
amines,[9] NHC-catalyzed processes,[10] as well as alkylations
mediated by phase transfer catalysts (PTCs)[11] were devel-
oped. More recently, synergistic catalysis[12] and C H bond
À
oxygenation[13] were also applied to the asymmetric construc-
tion of five-membered spirocyclic oxindoles.
Inspired by our ongoing interest in the development of
reactions towards spirocyclic oxindoles[14] and previous work
[*] Q.-S. Sun, H. Zhu, Y.-J. Chen, Dr. X.-D. Yang, Prof. X.-W. Sun
Department of Chemistry, Fudan University
220 Handan Road, Shanghai 200433 (China)
E-mail: sunxingwen@fudan.edu.cn
Prof. G.-Q. Lin
Shanghai Institute of Organic Chemistry, CAS
354 Fenglin Road, Shanghai, 200032 (China)
Considering that both nitrosoarenes and methyleneindo-
linones are electrophilic, we initially investigated the one-pot
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 13253 –13257
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13253