Chemical Science,
Год журнала:
2024,
Номер
unknown
Опубликована: Янв. 1, 2024
The
previously
unreported
combination
of
nucleophilic
phosphine
catalysis
and
energy
transfer
allows
for
the
rapid
construction
structurally
distinct
2-oxabicyclo[2.1.1]hexanes
(2-oxa-BCH)
from
readily
available
building
blocks
with
high
atom
economy.
Previous
multistep
routes
to
these
important
phenyl
ring
bioisosteres
have
largely
depended
on
use
bespoke
strain-release
agents
or
multiple
post-functionalisation
reactions
access
structural
diversity
scaffold.
In
contrast,
this
cascade
reaction
medicinal
chemist
exploit
breadth
commercial
allyl
alcohols
synthesise
systematically
diverse
2-oxa-BCH
architectures.
Using
a
polar
radical
disconnections
in
same
flask,
every
position
scaffold
can
be
substituted
useful
functional
handles
such
as
protected
amines,
esters
alcohols,
well
arenes
alkyl
groups.
Cyclic
even
employed
yield
single
diastereomers
sp
Replacement
of
the
aromatic
rings
in
drug
candidates
with
isosteric
rigid
sp3-rich
scaffolds
can
improve
physicochemical
properties,
increase
chance
progressing
molecule
development,
and
open
new
chemical
space.
Isosteres
meta-substituted
benzenes
remain
challenging
due
to
difficulty
mimicking
exit
vector
angles
bond
distances.
Herein,
we
report
synthesis
1,5-disubstituted
3-oxabicyclo[3.1.1]heptanes
(oxa-BCHeps),
which
serve
as
saturated
isosteres
phenyl
a
similar
geometric
arrangement.
This
structural
motif
be
obtained
under
mild
reaction
conditions
via
acid-mediated
isomerization
(2-oxaspiro[3.3]heptan-6-yl)methanols
using
catalytic
quantities
pyridinium
chloride
(PyrHCl).
We
demonstrate
utility
this
methodology
by
preparing
various
building
blocks
for
use
medicinal
chemistry
incorporating
3-oxa-BCHep
into
anticancer
sonidegib,
improving
its
such
permeability,
metabolic
stability,
solubility.
Abstract
The
synthesis
of
bicyclo[3.1.1]heptane
(BCHeps)
derivatives,
which
serve
as
three-dimensional
(3D)
bioisosteres
benzenes
and
are
the
core
skeleton
several
terpene
natural
products,
is
garnering
growing
interest.
(3+3)
cycloadditions
bicyclobutanes
(BCBs)
represent
an
attractive
method
for
efficiently
accessing
(hetero)BCHep
skeletons
with
100%
atom
economy.
Herein,
we
give
a
brief
summary
recent
achievements
in
this
approach
diverse
BCHep
emphasizing
our
progress
initial
palladium-catalyzed
vinyl
oxiranes.
1
Introduction
2
Radical
Cycloaddition
Reaction
3
Polar
4
Palladium-Catalyzed
Enantioselective
5
Conclusion
Abstract
Recently,
many
saturated
bioisosteres
of
the
benzene
ring
have
been
developed,
and
their
applications
in
drug
development
evaluated.
Most
these
are
caged
hydrocarbons,
which
rigid
skeletons
three-dimensional
spaces.
Recent
efforts
to
synthesize
hydrocarbons
enabled
access
multi-functionalized
congeners
that
expected
be
(bio)isosteres
benzenes.
This
short
review
summarizes
recently
reported
methods
for
obtaining
(typically
more
than
disubstituted)
hydrocarbons.
1
Introduction
2
Proposed
Structures
Caged
Hydrocarbons
as
Saturated
(Bio)isosteres
Benzene
Ring:
A
Brief
Summary
3
Access
Multi-functionalized
Hydrocarbons:
De
Novo
Synthetic
Approaches
3.1
Bicyclo[1.1.1]pentanes
(BCPs)
3.2
Bicyclo[2.1.1]hexanes
(BCHs)
3.3
Bicyclo[3.1.1]heptanes
(BCHeps)
3.4
Others
4
C–H
Functionalization
5
Conclusion
Chemical Science,
Год журнала:
2024,
Номер
15(46), С. 19488 - 19495
Опубликована: Янв. 1, 2024
We
present
the
first
enantioselective
dearomative
(3+3)
cycloadditions
of
bicyclobutanes
(BCBs)
utilizing
a
chiral
Lewis
acid
catalyst
and
bidentate
chelating
BCB
substrates.
A
palladium-catalyzed
[2π
+
2σ]
cycloaddition
of
vinyl
bicyclo[1.1.0]butanes
with
methyleneindolinones
has
been
developed.
The
reaction
enables
the
construction
spirobicyclo[2.1.1]hexanes
bearing
an
all-carbon
quaternary
center
in
moderate
to
good
yields
excellent
diastereoselectivities.
This
method
features
a
broad
substrate
scope
functional
group
compatibility.
practical
utility
this
protocol
was
further
demonstrated
by
gram-scale
synthesis
and
postsynthetic
transformations
desired
product.
