Angewandte Chemie,
Journal Year:
2023,
Volume and Issue:
135(47)
Published: Oct. 10, 2023
Abstract
Fluorinated
amino
acids
and
related
peptides/proteins
have
been
found
widespread
applications
in
pharmaceutical
agricultural
compounds.
However,
strategies
for
introducing
a
C−F
bond
into
an
enantioselective
manner
are
still
limited
no
such
asymmetric
catalysis
strategy
has
reported.
Herein,
we
successfully
developed
Pd/Cu/Li
ternary
system
stereodivergent
synthesis
of
chiral
fluorinated
acids.
This
method
involves
sequential
desymmetrization
geminal
difluoromethylenes
allylic
substitution
with
acid
Schiff
bases
via
Pd/Li
Pd/Cu
dual
activation,
respectively.
A
series
non‐natural
bearing
allylic/benzylic
fluorine
motif
easily
synthesized
high
yields
excellent
regio‐,
diastereo‐,
enantioselectivities
(up
to
>20
:
1
dr
>99
%
ee).
density
functional
theory
(DFT)
study
revealed
the
F−Cu
interaction
substrate
Cu
catalyst
significantly
influence
stereoselectivity.
ACS Catalysis,
Journal Year:
2024,
Volume and Issue:
14(8), P. 6358 - 6368
Published: April 11, 2024
Enzyme-catalyzed
stereodivergent
synthesis
to
access
all
possible
stereoisomers
of
organofluorine
compounds
bearing
multiple
stereogenic
centers
remains
an
important
and
challenging
subject.
By
integrative
data-driven
mining
mechanism-guided
engineering
ketoreductases,
we
identified
a
biocatalytic
platform
produce
four
stereoisomeric
fluoroalkyl
amino
acid
esters
two
vicinal
stereocenters.
Fast
triple-parameter
coevolution
via
semirational
CAST/ISM
strategy
provided
the
quadruple
mutant
M5
(A140K/L203T/G92A/V84I)
ketoreductase
BgADH
not
only
displayed
high
stereoselectivity
toward
target
(99:1
dr,
99%
ee)
but
also
observed
with
enhanced
activity
(kcat/Km,
6.3
folds)
improved
thermostability
(T5015,
4
°C).
Crystal
structural
analysis
molecular
dynamics
(MD)
simulation
studies
unveil
residues
(A140
F148)
be
key
sites
that
are
responsible
for
control
stereoselectivity.
The
L203T/G92A
mutation
by
affecting
conformational
distribution
α-helix
within
active-site
region,
V84I
thermal
stability
strengthening
hydrogen
bonding
network
neighboring
residues.
synthetic
utility
was
further
demonstrated
substrate
scope
expansion,
gram-scale
reactions
(648
g
L–1
day–1),
transformations
chiral
fluorinated
β-lactams
antibiotic
carbapenem
cores.
Journal of the American Chemical Society,
Journal Year:
2021,
Volume and Issue:
143(17), P. 6376 - 6381
Published: April 26, 2021
Difluoromethyl
amino
acids
(DFAA)
exhibit
intriguing
biological
properties,
making
them
highly
desirable
motifs
in
agrochemical
and
pharmaceutical
science.
However,
stereochemical
control
of
direct
difluoromethyl
transformation
via
the
difluorocarbene
species
has
not
been
demonstrated.
Here
we
describe
an
efficient
copper-catalyzed
asymmetric
difluoromethylation
reaction
that
systematically
delivers
chiral
DFAA
as
rationally
designed
mechanism-based
inhibitors
PLP-dependent
acid
decarboxylases.
The
employs
difluoromonochloromethane,
abundant
raw
material,
precursor
species,
enabling
unprecedentedly
conversion
esters
into
corresponding
valuable
products
good
yields
with
excellent
enantioselectivities.
This
de
novo
synthesis
creates
opportunities
to
integrate
catalytic
platform
for
preparation
diverse
libraries
biologically
important
derivatives
will
support
efforts
both
drug
discovery
development.
Angewandte Chemie International Edition,
Journal Year:
2023,
Volume and Issue:
62(47)
Published: Oct. 10, 2023
Fluorinated
amino
acids
and
related
peptides/proteins
have
been
found
widespread
applications
in
pharmaceutical
agricultural
compounds.
However,
strategies
for
introducing
a
C-F
bond
into
an
enantioselective
manner
are
still
limited
no
such
asymmetric
catalysis
strategy
has
reported.
Herein,
we
successfully
developed
Pd/Cu/Li
ternary
system
stereodivergent
synthesis
of
chiral
fluorinated
acids.
This
method
involves
sequential
desymmetrization
geminal
difluoromethylenes
allylic
substitution
with
acid
Schiff
bases
via
Pd/Li
Pd/Cu
dual
activation,
respectively.
A
series
non-natural
bearing
allylic/benzylic
fluorine
motif
easily
synthesized
high
yields
excellent
regio-,
diastereo-,
enantioselectivities
(up
to
>20
:
1
dr
>99
%
ee).
density
functional
theory
(DFT)
study
revealed
the
F-Cu
interaction
substrate
Cu
catalyst
significantly
influence
stereoselectivity.
Chirality,
Journal Year:
2021,
Volume and Issue:
34(1), P. 86 - 103
Published: Oct. 29, 2021
Abstract
Amino
acids
(AAs)
play
an
important
role
in
the
modern
health
industry
as
key
synthetic
precursors
for
pharmaceuticals,
biomaterials,
biosensors,
and
drug
delivery
systems.
Currently,
over
30%
of
small‐molecule
drugs
contain
residues
tailor‐made
AAs
or
derived
from
them
amino‐alcohols
di‐amines.
In
this
review
article,
we
profile
12
AA‐derived
new
pharmaceuticals
approved
by
FDA
2020.
These
newly
introduced
include
Tazverik
(epithelioid
sarcoma),
Gemtesa
(overactive
bladder),
Zeposia
(multiple
sclerosis),
Byfavo
(induction
maintenance
procedural
sedation),
Cu
64
dotatate,
Gallium
68
PSMA‐11
(both
PET
imaging),
Rimegepant
(acute
migraine),
Zepzelca
(lung
cancer),
Remdesivir
(COVID‐19),
Amisulpride
(nausea
vomiting),
Setmelanotide
(obesity),
Lonafarnib
(progeria
syndrome).
For
each
compound,
describe
spectrum
biological
activity,
medicinal
chemistry
discovery,
preparation.
The Journal of Organic Chemistry,
Journal Year:
2023,
Volume and Issue:
88(18), P. 13169 - 13177
Published: Sept. 6, 2023
The
incorporation
of
fluorinated
groups
into
peptides
significantly
affects
their
biophysical
properties.
We
report
herein
the
synthesis
Fmoc-protected
trifluoromethylthiolated
tyrosine
(CF3S-Tyr)
and
tryptophan
(CF3S-Trp)
analogues
on
a
gram
scale
(77–93%
yield)
demonstrate
use
as
highly
hydrophobic
building
blocks
for
peptide
chemistry.
developed
methodology
was
successfully
applied
to
late-stage
regioselective
trifluoromethylthiolation
Trp
residues
in
short
(66–80%
various
CF3S-analogues
biologically
active
monoamines.
To
prove
concept,
Fmoc-(CF3S)Tyr
-Trp
were
incorporated
endomorphin-1
chain
(EM-1)
model
tripeptides
by
solid-phase
synthesis.
A
remarkable
enhancement
local
hydrophobicity
quantified
chromatographic
index
determination
method,
demonstrating
high
potential
CF3S-containing
amino
acids
rational
design
bioactive
peptides.
Journal of the American Chemical Society,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 17, 2025
1,2-Amino-difunctionalization
reactions
of
alkenes
allow
the
efficient
introduction
different
functional
groups
and
rapid
construction
valuable
functionalized
amines.
In
this
respect,
we
report
a
copper-catalyzed
1,2-amino-alkoxycarbonylation
unactivated
with
CO
alkylamine
precursors
in
presence
Lewis
acid
additive.
The
novel
protocol
allows
direct
access
to
β-amino
derivatives
from
easily
available
starting
materials.
presented
methods
feature
high
chemo-
regioselectivities,
good
group
tolerance,
substrate
scope
including
diverse
bioactive
compounds
drug-like
molecules.
Mechanistic
studies
indicate
that
additive
is
key
realizing
umpolung
addition
nucleophilic
aminyl
radicals
electron-rich
alkenes,
which
represents
an
elegant
activation
strategy
for
radicals.
Molecules,
Journal Year:
2023,
Volume and Issue:
28(17), P. 6192 - 6192
Published: Aug. 22, 2023
Side
chain-fluorinated
amino
acids
are
useful
tools
in
medicinal
chemistry
and
protein
science.
In
this
review,
we
outline
some
general
strategies
for
incorporating
fluorine
atom(s)
into
acid
side
chains
elaborating
such
building
blocks
more
complex
fluorinated
peptides
proteins.
We
then
describe
the
diverse
benefits
that
can
offer
when
located
within
chains,
including
enabling
19F
NMR
18F
PET
imaging
applications,
enhancing
pharmacokinetic
properties,
controlling
molecular
conformation,
optimizing
target-binding.
