Mechanistic Insights and the Origin of Regioselective Borylation in an Iridium-Catalyzed Alkyl C(sp³)–H Bond Functionalization

Iridium-catalyzed <i>ortho</i> benzylic C­(sp³)–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(sp³)–H > terminal alkyl C­(sp³)–H > <i>ortho</i> C­(sp²)–H of the aryl > secondary internal C­(sp³)–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(sp³)–H Bond Functionalization

Iridium-catalyzed <i>ortho</i> benzylic C­(sp³)–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(sp³)–H > terminal alkyl C­(sp³)–H > <i>ortho</i> C­(sp²)–H of the aryl > secondary internal C­(sp³)–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^• > mC^• > C^•) is reversed compared to that in the reacting subsystems in the gas phase (C^• > mC^• > T^•), 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(CF₃COO)) 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