Article
Palladium-Catalyzed Highly
Stereoselective Dearomative [3 + 2]
Cycloaddition of Nitrobenzofurans
Qiang Cheng,1 Hui-Jun Zhang,1 Wen-Jun Yue,1 and Shu-Li You1,2,3,
*
SUMMARY
The Bigger Picture
There has been an increasing
demand for chiral compounds,
which find wide applications in
areas of biological science and
pharmaceuticals because of the
different performance of the two
enantiomers in living organisms.
Asymmetric catalysis appears to
be the most productive method
among chiral technologies for
access to enantiopure
Stereoselective construction of highly functionalized heterocyclic molecules is
an ongoing concern for the chemical community. Among the various strategies
developed with this goal, catalytic asymmetric dearomatization, an attractive
method for constucting cyclic molecules with multiple stereocenters from
readily available aromatic compounds, has received extensive attention in
recent years. Here, we report a highly stereoselective construction of tetrahy-
drofurobenzofurans and tetrahydrofurobenzothiophenes via palladium-cata-
lyzed dearomative [3 + 2] cycloaddition of nitrobenzofurans and nitrobenzothio-
phenes, respectively. Good to excellent yields (63%–92%), diastereoselectivity
(13/1 / >20/1 dr), and enantioselectivity (75%–95% ee) were obtained, leading
to products with vicinal stereogenic carbon centers. The reaction features wide
substrate scope and diverse transformations of the products.
compounds. In this regard,
catalytic asymmetric
dearomatization has emerged as a
highly efficient strategy for the
construction of complex chiral
molecules from planar aromatic
compounds.
INTRODUCTION
Tetrahydrofurobenzofuran occurs as a well-known structural core for many natural
products isolated from herbal plants (Figure 1).1–5 In recent years, modification of
this unique structure has been implemented to obtain more pharmaceutically rele-
vant compounds.6–9 However, to date, most synthetic strategies for the construction
of tetrahydrofurobenzofuran, especially those bearing continuous chiral carbon ster-
eogenic centers, have been based on stepwise ring-closing processes.6–8 Therefore,
a convenient one-step construction of this tricyclic ring system appears to be more
attractive.
Tetrahydrofurobenzofurans are
the core structures of many
biologically active natural
products and pharmaceuticals.
Thus, developing a new method
for the rapid construction of these
structures is particularly attractive.
Here, we report a highly
Palladium-catalyzed formal [3 + 2] cycloaddition reaction10–12 between electron-
deficient alkenes and epoxybutenes13 is a powerful and atom-economic tool for
the synthesis of substituted tetrahydrofurans.14–21 Unfortunately, control of the
enantioselectivity and diastereoselectivity of this kind of reaction remains chal-
lenging because of the long distance between the reactive site and the chiral catalyst
in the stereoselectivity-determining transition state.22 Limited successful examples
using specific substrates have been reported.20,23–27 To figure out a more general
methodology for highly stereoselective [3 + 2] ring formation reactions is still urgent.
stereoselective construction of
tetrahydrofurobenzofurans via
palladium-catalyzed dearomative
[3 + 2] cycloaddition of
nitrobenzofurans.
The catalytic asymmetric dearomatization (CADA) reaction plays a significant role in
the synthesis of complex organic compounds by disruption of structurally simple
arenes.28–31 Dearomatization of electron-rich arenes such as indole, pyrrole, phenol,
or naphthol usually relies on their inherent nucleophilicity.32–55 By turning these
electron-rich arenes into electrophiles, which can be done by decorating an elec-
tron-withdrawing group on the arene, novel types of reactions are expected.
428 Chem 3, 428–436, September 14, 2017 ª 2017 Elsevier Inc.