Organic Letters,
Journal Year:
2021,
Volume and Issue:
23(12), P. 4828 - 4833
Published: June 8, 2021
The
use
of
bicyclo[1.1.1]pentanes
(BCPs)
as
para-disubstituted
aryl
bioisosteres
has
gained
considerable
momentum
in
drug
development
programs.
Carbon–carbon
bond
formation
via
transition-metal-mediated
cross-coupling
represents
an
attractive
strategy
to
generate
BCP–aryl
compounds
for
late-stage
functionalization,
but
these
typically
require
reactive
organometallics
prepare
BCP
nucleophiles
on
demand
from
[1.1.1]propellane.
In
this
study,
the
synthesis
and
Ni-catalyzed
functionalization
redox-active
esters
with
(hetero)aryl
bromides
action
a
photoactive
electron
donor–acceptor
complex
are
reported.
Journal of Medicinal Chemistry,
Journal Year:
2021,
Volume and Issue:
64(19), P. 14046 - 14128
Published: Sept. 30, 2021
The
benzene
moiety
is
the
most
prevalent
ring
system
in
marketed
drugs,
underscoring
its
historic
popularity
drug
design
either
as
a
pharmacophore
or
scaffold
that
projects
pharmacophoric
elements.
However,
introspective
analyses
of
medicinal
chemistry
practices
at
beginning
21st
century
highlighted
indiscriminate
deployment
phenyl
rings
an
important
contributor
to
poor
physicochemical
properties
advanced
molecules,
which
limited
their
prospects
being
developed
into
effective
drugs.
This
Perspective
deliberates
on
and
applications
bioisosteric
replacements
for
have
provided
practical
solutions
range
developability
problems
frequently
encountered
lead
optimization
campaigns.
While
effect
compound
contextual
nature,
substitution
can
enhanced
potency,
solubility,
metabolic
stability
while
reducing
lipophilicity,
plasma
protein
binding,
phospholipidosis
potential,
inhibition
cytochrome
P450
enzymes
hERG
channel.
Chemical Reviews,
Journal Year:
2023,
Volume and Issue:
123(12), P. 7692 - 7760
Published: May 10, 2023
Site-predictable
and
chemoselective
C–H
bond
functionalization
reactions
offer
synthetically
powerful
strategies
for
the
step-economic
diversification
of
both
feedstock
fine
chemicals.
Many
transition-metal-catalyzed
methods
have
emerged
selective
activation
bonds.
However,
challenges
regio-
chemoselectivity
with
application
to
highly
complex
molecules
bearing
significant
functional
group
density
diversity.
As
molecular
complexity
increases
within
structures
risks
catalyst
intolerance
limited
applicability
grow
number
groups
potentially
Lewis
basic
heteroatoms.
Given
abundance
bonds
already
diversified
such
as
pharmaceuticals,
natural
products,
materials,
design
selection
reaction
conditions
tolerant
catalysts
has
proved
critical
successful
direct
functionalization.
such,
innovations
formation
carbon–carbon
been
discovered
developed
overcome
these
limitations.
This
review
highlights
progress
made
metal-catalyzed
C–C
forming
including
alkylation,
methylation,
arylation,
olefination
targets.
Chemical Science,
Journal Year:
2022,
Volume and Issue:
13(40), P. 11721 - 11737
Published: Jan. 1, 2022
A
flurry
of
reports
for
preparing,
functionalizing,
and
using
bicyclo[1.1.0]butanes
(BCBs)
have
positioned
them
to
be
powerful
synthons
with
numerous
applications.
This
review
discusses
the
recent
developments
regarding
this
strained
carbocycle.
Journal of the American Chemical Society,
Journal Year:
2022,
Volume and Issue:
144(51), P. 23685 - 23690
Published: Dec. 16, 2022
The
development
of
synthetic
strategies
for
the
preparation
bioisosteric
compounds
is
a
demanding
undertaking
in
medicinal
chemistry.
Numerous
have
been
developed
synthesis
bicyclo[1.1.1]pentanes
(BCPs),
bridge-substituted
BCPs,
and
bicyclo[2.1.1]hexanes.
However,
progress
on
bicyclo[3.1.1]heptanes,
which
serve
as
meta-substituted
arene
bioisosteres,
has
not
previously
explored.
Herein,
we
disclose
first
photoinduced
[3σ
+
2σ]
cycloaddition
trisubstituted
bicyclo[3.1.1]heptanes
using
bicyclo[1.1.0]butanes
cyclopropylamines.
This
transformation
only
uses
mild
operationally
simple
conditions
but
also
provides
unique
bioisosteres.
applicability
this
method
showcased
by
derivatization
reactions.
ACS Catalysis,
Journal Year:
2023,
Volume and Issue:
13(7), P. 5096 - 5103
Published: March 30, 2023
Bicyclo[2.1.1]hexanes
(BCHs)
represent
an
intriguing
class
of
structurally
rigid
hydrocarbons
that
can
serve
as
the
bioisosteres
benzenoids
in
medicinal
chemistry.
Methods
for
synthesis
BCHs
are,
however,
limiting.
Reported
herein
is
a
facile
via
strain-release-driven
[2π
+
2σ]
cycloaddition
bicyclo[1.1.0]butanes
(BCBs)
with
alkenes
facilitated
by
pyridine-boryl
radical
catalyst.
The
mild
reaction
conditions,
broad
substrate
scope,
and
decent
functional
group
tolerance
this
protocol
render
it
appealing
relevant
fields
drug
design
synthesis.
Theoretical
mechanistic
studies
reveal
relay
mechanism
involved.
Synthetic
applications
products
are
performed.
Journal of the American Chemical Society,
Journal Year:
2023,
Volume and Issue:
145(46), P. 25411 - 25421
Published: Nov. 7, 2023
We
report
the
use
of
photocatalysis
for
homolytic
ring-opening
carbonyl
cyclopropanes.
In
contrast
to
previous
studies,
our
approach
does
not
require
a
metal
cocatalyst
or
strong
reductant.
The
cyclopropanes
can
be
employed
both
[2σ
+
2σ]
and
2π]
annulation
with
either
alkenes/alkynes
bicyclo[1.1.0]butanes,
yielding
cyclopent-anes/-enes
bicyclo[3.1.1]heptanes
(BCHs),
respectively.
BCHs
are
promising
bioisosteres
1,2,4,5
tetra-substituted
aromatic
rings.
Mechanistic
including
density
functional
theory
computation
trapping
experiment
DMPO,
support
1,3-biradical
generated
from
cyclopropane
as
key
intermediate
these
transformations.
Journal of the American Chemical Society,
Journal Year:
2022,
Volume and Issue:
144(34), P. 15871 - 15878
Published: Aug. 19, 2022
The
concurrent
installation
of
C-C
and
C-N
bonds
across
alkene
frameworks
represents
a
powerful
tool
to
prepare
motifs
that
are
ubiquitous
in
pharmaceuticals
bioactive
compounds.
To
construct
such
prevalent
bonds,
most
difunctionalization
methods
demand
the
use
precious
metals
or
activated
alkenes.
We
report
metal-free,
photochemically
mediated
imino-alkylation
electronically
diverse
alkenes
install
both
alkyl
iminyl
groups
highly
efficient
manner.
exceptionally
mild
reaction
conditions,
broad
substrate
scope,
excellent
functional
group
tolerance,
facile
one-pot
protocol
highlight
utility
this
method
privileged
from
readily
available
acid
feedstocks.
One
key
striking
feature
transformation
is
an
electrophilic
trifluoromethyl
radical
equally
with
electron-deficient
electron-rich
Additionally,
dispersion-corrected
density
theory
(DFT)
empirical
investigations
provide
detailed
mechanistic
insight
into
reaction.
Journal of Agricultural and Food Chemistry,
Journal Year:
2023,
Volume and Issue:
71(47), P. 18087 - 18122
Published: March 24, 2023
The
design
of
bioisosteres
represents
a
creative
and
productive
approach
to
improve
molecule,
including
by
enhancing
potency,
addressing
pharmacokinetic
challenges,
reducing
off-target
liabilities,
productively
modulating
physicochemical
properties.
Bioisosterism
is
principle
exploited
in
the
bioactive
compounds
interest
both
medicinal
agricultural
chemists,
this
review,
we
provide
synopsis
applications
where
kind
molecular
editing
has
proved
be
advantageous
molecule
optimization.
examples
selected
for
discussion
focus
on
carboxylic
acids,
fluorine
fluorinated
motifs
compound
design,
some
sulfoximine
functionality,
drug-H2O
complexes,
phenyl
ring.
