bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 6, 2024
Abstract
Macrocyclic
peptides,
an
intriguing
class
of
molecules,
embody
promising
frameworks
for
the
development
chemical
probes
and
prospective
therapeutic
agents.
However,
lack
established
wide-substrate
scope
synthesis
methodology
has
made
it
challenging
to
achieve
both
efficiency
selectivity
simultaneously.
P450-catalyzed
ribosomal
synthesized
post-translational
modification
peptides
(RiPPs)
are
a
new
family
macrocyclic
with
typical
biaryl
crosslinks.
In
this
study,
we
report
discovery
RiPP-modified
P450
macrocyclase,
GpeC,
which
natively
catalyzes
C(sp
2
)-C(sp
)
crosslink
tryptophan-tyrosine
in
tetrapeptide
module.
Unlike
most
previously
documented
P450-RiPPs
that
possess
substantial
leader
peptide
region,
hindering
biocatalytic
applications,
our
GpeC
exhibits
catalytic
potential
leaderless
precursor
wide
substrate
tolerance,
highlighting
its
adaptability
creating
diverse
structures.
The
crystal
structure
combined
silico
calculations
site-directed
mutagenesis,
provides
strong
evidence
extreme
flexibility
intra-cyclic
amino
acids
within
biaryl-cyclized
tetrapeptide.
This
enables
substitution
any
other
19
acids,
indicating
is
robust
adaptable
catalyst
cyclization,
providing
valuable
resource
complex
compounds.
Journal of the American Chemical Society,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 23, 2025
Visible
light-driven
pyridoxal
radical
biocatalysis
has
emerged
as
a
new
strategy
for
the
stereoselective
synthesis
of
valuable
noncanonical
amino
acids
in
protecting-group-free
fashion.
In
our
previously
developed
dehydroxylative
C–C
coupling
using
engineered
PLP-dependent
tryptophan
synthases,
an
enzyme-controlled
unusual
α-stereochemistry
reversal
and
pH-controlled
enantiopreference
were
observed.
Herein,
through
high-throughput
photobiocatalysis,
we
evolved
set
stereochemically
complementary
PLP
enzymes,
allowing
both
l-
d-amino
with
enhanced
enantiocontrol
across
broad
pH
window.
These
newly
acid
synthases
permitted
use
range
organoboron
substrates,
including
boronates,
trifluoroborates,
boronic
acids,
excellent
efficiency.
Mechanistic
studies
unveiled
unexpected
racemase
activity
earlier
enzyme
variants.
This
promiscuous
was
abolished
shedding
light
on
origin
enantiocontrol.
Further
mechanistic
investigations
suggest
switch
proton
donor
to
account
stereoinvertive
formation
highlighting
stereoinversion
mechanism
that
is
rare
conventional
two-electron
enzymology.
Journal of the American Chemical Society,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 16, 2025
Heteroaromatic
alkylations
are
indispensable
reactions
for
synthesizing
biologically
active
molecules.
The
anti-Markovnikov
hydroarylation
of
olefins
using
heteroaryl
halides
furnishes
the
product
as
a
single
regioisomer;
however,
catalytic
variants
ineffective
at
controlling
stereochemical
outcome
these
reactions.
Here,
we
report
synergistic
photoenzymatic
flavin-dependent
"ene"-reductases
with
ruthenium
photoredox
catalysts.
Enzyme
homologues
were
identified,
which
provide
access
to
both
enantiomers
in
greater
than
80%
yield
up
99:1
er.
This
method
is
effective
styrenyl-
and
unactivated
alkenes,
highlighting
generality
this
approach.
highest
yielding
system
involves
carboxylated
photocatalyst
increased
affinity
enzyme.
work
expands
types
radical
intermediates
that
enzymes
can
use
stereoselective
intermolecular
coupling
Chinese Journal of Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 24, 2025
Comprehensive
Summary
The
[2+1]
cycloaddition
of
alkynes
with
fluoroalkyl
carbenes
represents
the
most
straightforward
approach
for
constructing
fluoroalkylated
cyclopropenes.
However,
until
now,
this
strategy
has
not
been
applicable
to
difluoromethyl
carbene,
as
its
precursor,
diazomethane,
tends
undergo
[3+2]
form
pyrazoles.
This
study
presents
first
example
copper‐catalyzed
cyclopropenation
employing
difluoroacetaldehyde
triftosylhydrazone
carbene
precursor.
A
wide
range
internal
and
terminal
alkynes,
featuring
diverse
functional
groups,
were
efficiently
converted
into
corresponding
cyclopropenes
in
good
high
yields.
Mechanistic
investigations,
supported
by
DFT
calculations,
revealed
that
bulky
Tp
Br3
Cu(NCMe)
catalyst
plays
a
pivotal
role
facilitating
via
concerted
pathway.
