Higher-order
cycloadditions
are
a
simple
and
effective
strategy
for
constructing
significant
medium-sized
architectures.
Azaheptafulvenes
reacting
with
readily
accessible
bicyclo[1.1.0]butanes
(BCBs)
through
FeCl3-promoted
intermolecular
formal
[8π+2σ]
cycloaddition
reactions
to
access
cycloheptatriene-fused
2-azabicyclo[3.1.1]heptanes
have
been
developed.
This
new
reaction
tolerated
wide
range
of
azaheptafulvenes
BCBs.
Furthermore,
the
amplification
experiment
synthetic
transformations
adducts,
including
modifications
marketed
drugs,
further
highlighted
their
practicalities.
Control
experiments
DFT
calculations
suggest
that
diastereoselective
product
formation
may
involve
stepwise
pathway.
Angewandte Chemie International Edition,
Год журнала:
2024,
Номер
63(48)
Опубликована: Сен. 2, 2024
Abstract
The
cycloaddition
reaction
involving
bicyclo[1.1.0]butanes
(BCBs)
offers
a
versatile
and
efficient
synthetic
platform
for
producing
C(sp
3
)‐rich
rigid
bridged
ring
scaffolds,
which
act
as
phenyl
bioisosteres.
However,
there
is
scarcity
of
catalytic
asymmetric
cycloadditions
BCBs
to
fulfill
the
need
enantioenriched
saturated
bicycles
in
drug
design
development.
In
this
study,
an
synthesis
valuable
azabicyclo[2.1.1]hexanes
(aza‐BCHs)
by
enantioselective
zinc‐catalyzed
(3+2)
with
imines
reported.
proceeds
effectively
novel
type
BCB
that
incorporates
2‐acyl
imidazole
group
diverse
array
alkynyl‐
aryl‐substituted
imines.
target
aza‐BCHs,
consist
α‐chiral
amine
fragments
two
quaternary
carbon
centers,
are
efficiently
synthesized
up
94
%
96.5:3.5
er
under
mild
conditions.
Experimental
computational
studies
reveal
follows
concerted
nucleophilic
ring‐opening
mechanism
This
distinct
from
previous
on
Lewis
acid‐catalyzed
BCBs.
Journal of the American Chemical Society,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 19, 2024
Saturated
nitrogen
heterocycles
are
among
the
most
significant
structural
components
in
small-molecule
pharmaceuticals.
Herein,
a
protocol
for
construction
of
enantiopure
2-azabicyclo[3.1.1]heptane
derivatives
by
stereospecific
intermolecular
formal
cycloaddition
aziridines
with
bicyclo[1.1.0]butanes
is
described.
The
reaction
run
using
B(C
Journal of the American Chemical Society,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 25, 2024
The
selective
construction
of
bridged
bicyclic
scaffolds
has
garnered
increasing
attention
because
their
extensive
use
as
saturated
bioisosteres
arene
in
pharmaceutical
industry.
However,
sharp
contrast
to
racemic
counterparts,
assembling
chiral
structures
an
enantioselective
and
regioselective
manner
remains
challenging.
Herein,
we
describe
our
protocol
for
constructing
2-oxa-3-azabicyclo[3.1.1]heptanes
(BCHeps)
by
[4π
+
2σ]
cycloadditions
bicyclo[1.1.0]butanes
(BCBs)
nitrones
taking
advantage
a
copper(II)
complex
Lewis
acid
catalyst.
This
method
features
mild
conditions,
good
functional
group
tolerance,
high
yield
(up
99%),
excellent
enantioselectivity
99%
ee).
Density
theory
(DFT)
calculation
elucidates
the
origin
reaction's
mechanism
BCB
activation
Cu(II)
complex.
Journal of the American Chemical Society,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 28, 2025
Asymmetric
synthesis
presents
many
challenges,
with
the
selective
formation
of
chiral
bridged
polyheterocycles
being
a
notable
example.
Cycloadditions
using
bicyclo[1.1.0]butanes
(BCB)
offer
promising
solution
along
those
lines,
yet,
despite
significant
advances
in
that
emerging
area,
asymmetric
control
has
remained
limited
thus
far.
Here,
we
describe
an
organocatalytic,
enantioselective
formal
(3
+
3)-cycloaddition
BCBs
1H-indol-3-yl((hetero)aryl)methanol
derivatives.
This
approach
enables
rapid
and
efficient
tetrahydro-1H-1,3-methanocarbazole
derivatives
(34
examples)
from
readily
available
starting
materials,
very
good
stereochemical
(up
to
98:2
er).
Successful
scale-up
experiments
product
modification
demonstrated
potential
this
methodology.
Control
DFT
calculations
provide
insights
into
mechanistic
pathway.
Journal of the American Chemical Society,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 30, 2024
Achieving
structural
and
stereogenic
diversity
from
the
same
starting
materials
remains
a
fundamental
challenge
in
organic
synthesis,
requiring
precise
control
over
selectivity.
Here,
we
report
divergent
catalytic
methods
that
selectively
yield
either
cycloaddition
or
addition/elimination
products
bicyclo[1.1.0]butanes
α,β-unsaturated
ketones.
By
employing
chiral
Lewis
acid
Brønsted
catalysts,
achieved
excellent
regio-,
diastereo-,
enantioselectivity
across
all
three
distinct
transformations,
affording
diverse
array
of
synthetically
valuable
bicyclo[2.1.1]hexanes
cyclobutenes.
The
outcomes
are
controlled
by
differential
activation
substrates
specific
catalyst
with
reaction
conditions
dictating
pathway
This
strategy
demonstrates
power
catalysis
creating
molecular
complexity
diversity,
offering
tool
for
synthesis
enantioenriched
building
blocks.
Angewandte Chemie International Edition,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 13, 2024
Abstract
The
synthesis
of
bicyclic
scaffolds
has
garnered
considerable
interest
in
drug
discovery
because
their
ability
to
mimic
benzene
bioisosteres.
Herein,
we
introduce
a
new
approach
that
utilizes
Lewis
acid
(Sc(OTf)
3
)‐catalyzed
σ‐bond
cross‐exchange
reaction
between
the
C−C
bond
bicyclobutanes
and
C−N
diaziridines
produce
multifunctionalized
medicinally
interesting
azabicyclo[3.1.1]heptane
derivatives.
proceeds
well
with
different
broad
range
aryl‐
as
alkenyl‐,
but
also
alkyl‐substituted
(up
98
%
yield).
Conducting
scale‐up
experiment
exploring
synthetic
transformations
cycloadducts
emphasized
practical
application
synthesis.
Furthermore,
zinc‐based
chiral
catalytic
system
was
developed
for
enantioselective
version
this
96
ee
).
