6 research outputs found
Mechanistic Insights and the Origin of Regioselective Borylation in an Iridium-Catalyzed Alkyl C(sp<sup>3</sup>)–H Bond Functionalization
Iridium-catalyzed <i>ortho</i> benzylic C(sp<sup>3</sup>)–H borylation of
(2-propylphenyl)dimethylsilane, using
bis(ethylene glycolato)diborane as borylating agent, is investigated
using B3LYP-D3 density functional theory. The reaction is found to
proceed, first, through a very facile oxidative addition of a Si–H
bond at the Ir center. This is followed by reductive elimination of
ethylene-glycolborane. The subsequent C–H activation step,
accompanied by elimination of another molecule of ethylene-glycolborane,
leads to formation of a racemic mixture of four diastereomeric chiral
iradacycle intermediates. The ensuing chirality at the metal center
is accompanied by stereodifferentiation of the two enantiotopic hydrogen
atoms due to steric interaction between the alkyl group and the boryl
ligands. Our calculations also correctly predict the experimentally
observed regioselectivity. The propensity for C–H bond activation
was found to be in the order benzylic C(sp<sup>3</sup>)–H >
terminal alkyl C(sp<sup>3</sup>)–H > <i>ortho</i> C(sp<sup>2</sup>)–H of the aryl > secondary internal C(sp<sup>3</sup>)–H bonds. This is succeeded by oxidative addition
of bis(ethylene glycolato)diborane at the Ir center. The resulting
Ir(III) (bpy)trisboryl species then undergoes borylation at the benzyllic
carbon. The relative free energies of the transition states for C–H
activation and C–B bond formation are found to be comparable
Mechanistic Insights and the Origin of Regioselective Borylation in an Iridium-Catalyzed Alkyl C(sp<sup>3</sup>)–H Bond Functionalization
Iridium-catalyzed <i>ortho</i> benzylic C(sp<sup>3</sup>)–H borylation of
(2-propylphenyl)dimethylsilane, using
bis(ethylene glycolato)diborane as borylating agent, is investigated
using B3LYP-D3 density functional theory. The reaction is found to
proceed, first, through a very facile oxidative addition of a Si–H
bond at the Ir center. This is followed by reductive elimination of
ethylene-glycolborane. The subsequent C–H activation step,
accompanied by elimination of another molecule of ethylene-glycolborane,
leads to formation of a racemic mixture of four diastereomeric chiral
iradacycle intermediates. The ensuing chirality at the metal center
is accompanied by stereodifferentiation of the two enantiotopic hydrogen
atoms due to steric interaction between the alkyl group and the boryl
ligands. Our calculations also correctly predict the experimentally
observed regioselectivity. The propensity for C–H bond activation
was found to be in the order benzylic C(sp<sup>3</sup>)–H >
terminal alkyl C(sp<sup>3</sup>)–H > <i>ortho</i> C(sp<sup>2</sup>)–H of the aryl > secondary internal C(sp<sup>3</sup>)–H bonds. This is succeeded by oxidative addition
of bis(ethylene glycolato)diborane at the Ir center. The resulting
Ir(III) (bpy)trisboryl species then undergoes borylation at the benzyllic
carbon. The relative free energies of the transition states for C–H
activation and C–B bond formation are found to be comparable
Insights into Intrastrand Cross-Link Lesions of DNA from QM/MM Molecular Dynamics Simulations
DNA damages induced by oxidative intrastrand cross-links
have been
the subject of intense research during the past decade. Yet, the currently
available experimental protocols used to isolate such lesions only
allow to get structural information about linked dinucleotides. The
detailed structure of the damaged DNA macromolecule has remained elusive.
In this study we generated in silico the most frequent oxidative intrastrand
cross-link adduct, G[8,5-Me]T, embedded in a solvated DNA dodecamer
by means of quantum mechanics/molecular mechanics (QM/MM) Car–Parrinello
simulations. The free energy of activation required to bring the reactant
close together and to form the C–C covalent-bond is estimated
to be ∼10 kcal/mol. We observe that the G[8,5-Me]T tandem lesion
is accommodated with almost no perturbation of the Watson–Crick
hydrogen-bond network and induces bend and unwinding angles of ∼20°
and 8°, respectively. This rather small structural distortion
of the DNA macromolecule compared to other well characterized intrastrand
cross-links, such as cyclobutane pyrimidines dimers or cisplatin-DNA
complex adduct, is a probable rationale for the known lack of efficient
repair of oxidative damages
Structure, Dynamics, and Interactions of a C4′-Oxidized Abasic Site in DNA: A Concomitant Strand Scission Reverses Affinities
Apurinic/apyrimidinic
(AP) sites constitute the most frequent form
of DNA damage. They have proven to produce oxidative interstrand cross-links,
but the structural mechanism of cross-link formation within a DNA
duplex is poorly understood. In this work, we study three AP-containing
d[GCGCGCXCGCGCG]·d[CGCGCGKGCGCGC]
duplexes, where X = C, A, or
G and K denotes an α,β-unsaturated ketoaldehyde derived
from elimination of a C4′-oxidized AP site featuring a 3′
single-strand break. We use explicit solvent molecular dynamics simulations,
complemented by quantum chemical density functional theory calculations
on isolated X:K pairs. When X = C, the K moiety in the duplex flips
around its glycosidic bond to form a stable C:K pair in a near-optimal
geometry with two hydrogen bonds. The X = A duplex shows no stable
interaction between K and A, which contrasts with AP sites lacking
a strand scission that present a preferential affinity for adenine.
Only one, transient G:K hydrogen bond is formed in the X = G duplex,
although the isolated G:K pair is the
most stable one. In the duplex, the stable C:K pair induces unwinding
and sharp bending into the major groove at the lesion site, while
the internal structure of the flanking DNA remains unperturbed. Our
simulations also unravel transient hydrogen bonding between K and
the cytosine 5′ to the orphan base X = A. Taken
together, our results provide a mechanistic explanation for the experimentally
proven high affinity of C:K sites in forming cross-links in DNA duplexes
and support experimental hints that interstrand cross-links can be
formed with a strand offset
What Singles Out the G[8–5]C Intrastrand DNA Cross-Link? Mechanistic and Structural Insights from Quantum Mechanics/Molecular Mechanics Simulations
Naturally occurring intrastrand oxidative cross-link
lesions have
proven to be a potent source of endogenous DNA damage. Among the variety
of lesions that can be formed and have been identified, G[8–5]C
damage (in which the C8 atom of a guanine is covalently bonded to
the C5 atom of a nearby cytosine belonging to the same strand) occurs
with a low incidence yet takes on special importance because of its
high mutagenicity. Hybrid Car–Parrinello molecular dynamics
simulations, rooted in density functional theory and coupled to molecular
mechanics, have been performed to shed light on the cyclization process.
The activation free energy of the reacting subsystem embedded in a
solvated dodecamer is estimated to be ∼12.4 kcal/mol, which
is ∼3 kcal/mol higher than the value for the prototypical G[8–5m]T
lesion inferred employing the same theoretical framework [Garrec,
J., Patel, C., Rothlisberger, U., and Dumont, E. (2012) <i>J.
Am. Chem. Soc.</i> <i>134</i>, 2111–2119]. This
study also situates the G[8–5m]mC lesion at an intermediate
activation free energy (∼10.5 kcal/mol). The order of reactivity
in DNA (T<sup>•</sup> > mC<sup>•</sup> > C<sup>•</sup>) is reversed compared to that in the reacting subsystems
in the
gas phase (C<sup>•</sup> > mC<sup>•</sup> > T<sup>•</sup>), stressing the crucial role of the solvated B-helix
environment.
The results of our simulations also characterize a more severe distortion
for G[8–5]C than for methylene-bridged intrastrand cross-links
Hypercoordinate Iodine Catalysts in Enantioselective Transformation: The Role of Catalyst Folding in Stereoselectivity
The
need for metal-free environmentally benign catalysts has provided
a strong impetus toward the emergence of hypercoordinate iodine reagents.
At this stage of development, molecular insights on the mechanism
and origin of stereoselectivity are quite timely. In this study, the
origin of stereoinduction in a class of iodoresorcinol-based chiral
hypercoordinate iodine-catalyzed synthesis of biologically important
spirocyclic bisoxindoles from aryl dianilides has been established
by using density functional computations. Formation of an interesting
helical fold by the 2,6-chiral amide arms on the resorcinol framework
is found to be facilitated by a network of noncovalent interactions.
In the chiral environment provided by the helical fold, enantioselectivity
is surprisingly controlled in a mechanistic event prior to the ring
closure to the final spirocyclic product, unlike that commonly found
in spirocyclic ring formation. A vital 1,3-migration of the chiral
aryl iodonium (Ar*-I(CF<sub>3</sub>COO)) in an O-iodonium enolate
to the corresponding C-iodonium enolate, which retains the chiral
memory, holds the key to the enantiocontrol in this reaction and thus
renders ring closure to be stereospecific