Brønsted Acids Promote Olefin Oxidations by Bioinspired Nonheme CoIII(PhIO)(OH) Complexes: A Role for Low-Barrier Hydrogen Bonds.

Introduction of Brønsted acids into biomimetic nonheme reactions promotes the oxidative ability of metal-oxygen complexes significantly. However, the molecular machinery of the promoted effects is missing. Herein, a comprehensive investigation of styrene oxidation by a cobalt(III)-iodosylbenzene complex, [(TQA)CoIII(OIPh)(OH)]2+ (1, TQA = tris(2-quinolylmethyl)amine), in the presence and absence of triflic acid (HOTf) was performed using density functional theory calculations. Results revealed for the first time that there is a low-barrier hydrogen bond (LBHB) between HOTf and the hydroxyl ligand of 1, which forms two valence-resonance structures [(TQA)CoIII(OIPh)(HO---HOTf)]2+ (1LBHB) and [(TQA)CoIII(OIPh)(H2O--OTf-)]2+ (1'LBHB). Due to the oxo-wall, these complexes (1LBHB and 1'LBHB) cannot convert to high-valent cobalt-oxyl species. Instead, styrene oxidation by these oxidants (1LBHB and 1'LBHB) shows novel spin-state selectivity, i.e., on the ground closed-shell singlet state, styrene is oxidized to an epoxide, whereas on the excited triplet and quintet states, an aldehyde product, phenylacetaldehyde, is formed. The preferred pathway is styrene oxidation by 1'LBHB, which is initiated by a rate-limiting bond-formation-coupled electron transfer process with an energy barrier of 12.2 kcal mol-1. The nascent PhIO-styrene-radical-cation intermediate undergoes an intramolecular rearrangement to produce an aldehyde. The halogen bond between the OH-/H2O ligand and the iodine of PhIO modulates the activity of the cobalt-iodosylarene complexes 1LBHB and 1'LBHB. These new mechanistic findings enrich our knowledge of nonheme chemistry and hypervalent iodine chemistry and will play a positive role in the rational design of new catalysts.

Elusive Active Intermediates and Reaction Mechanisms of ortho-/ipso-Hydroxylation of Benzoic Acid by Hydrogen Peroxide Mediated by Bioinspired Iron(II) Catalysts.

Aromatic hydroxylation of benzoic acids (BzOH) to salicylates and phenolates is fundamentally interesting in industrial chemistry. However, key mechanistic uncertainties and dichotomies remain after decades of effort. Herein, the elusive mechanism of the competitive ortho-/ipso-hydroxylation of BzOH by H2O2 mediated by a nonheme iron(II) catalyst was comprehensively investigated using density functional theory calculations. Results revealed that the long-postulated FeV(O)(anti-BzO) oxidant is an FeIV(O)(anti-BzO•) species 2 (anti- and syn- are defined by the orientation of the carboxyl oxygen of BzO to the oxo), which rules out the noted two-oxidant mechanism proposed previously. We propose a new mechanism in which, following the formation of an FeV(O)(syn-BzO) species (3) and its electromer FeIV(O)(syn-BzO•) (3'), 3/3' either converts to salicylate and phenolate via intramolecular self-hydroxylation (route A) or acts as an oxidant to oxygenate another BzOH to generate the same products (route B). In route A, the rotation of the BzO group along the C-O bond forms 2, in which the BzO group is orientated by π-π stacking interactions. An electrophilic ipso-addition forms a phenolate by concomitant decarboxylation or an ortho-attack forms a cationic complex, which readily undergoes an NIH shift and a BzOH-assisted proton shift to form a salicylate. In route B, 3 oxidizes an additional BzOH molecule directed by hydrogen bonding and π-π stacking interactions. In both routes, selectivity is determined by the chemical property of the BzO ring. These mechanistic findings provide a clear mechanistic scenario and enrich the knowledge of hydroxylation of aromatic acids.

The Regioselective Functionalization Reaction of Unprotected Carbazoles with Donor-Acceptor Cyclopropanes.

The regioselective functionalization reaction of unprotected carbazoles with donor-acceptor (D-A) cyclopropanes has been demonstrated for the first time. With Sc(OTf)3 as Lewis acid catalyst, the N-H functionalization of carbazoles takes place through a highly selective nitrogen-initiated nucleophilic ring opening reaction. Significantly, by engaging TfOH as Brønsted acid catalyst, a straightforward C-H functionalization at the 3-position of the unprotected carbazole proceeds via Friedel-Crafts-type addition. This strategy facilitates the diversity-oriented synthesis of carbazole-containing heterocycles and expands the novel application of D-A cyclopropanes.

Molecular dynamics investigation of stereoselective inhibition mechanism of HIF-2α/ARNT heterodimer.

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors related with the onset and progression of solid tumors. Studies demonstrated a class of tetrazole containing chiral inhibitors could stereoselectively disrupt the HIF-2 dimerization and reduce the target gene expression. However, the dynamical features and structural motifs of the HIF-2 heterodimer caused by the binding of enantiomers have not been rationalized at the atomistic level. In this work, molecular dynamics (MD) simulations combined with adaptive steered MD (ASMD) simulations were used to investigate stereoselective interrupting mechanism of HIF-2. Our results decipher that the binding of ligand A (S, R)-24 begets the significant conformation changes of ß-sheets and interrupts the HIF-2α/ARNT heterodimerization, which may be attributed to the disruption of the hydrogen bond and salt bridge interactions formed by the 4 foremost residues (Asp240, Arg247, Glu362, and Arg366) and the destruction of hydrophobic interactions on the binding interface. By contrast, the binding of ligand B (R, S)-24 does not disrupt protein dimerization and causes the motion of Fα helix in HIF-2α PAS-B domain to further change the major tunnel for ligand ingress and engress. The present work provides important molecular-level insight into the effect of the binding enantiomers on HIF-2 heterodimerization and bridges the gap between theory and the experimental results, which may conduce to develop highly potent antagonists for intervening the HIF-2-driven tumors.

Exploring the inhibition mechanism on HIF-2 by inhibitor PT2399 and 0X3 using molecular dynamics simulations.

Targeting transcription factors HIF-2 is currently considered to be the most direct way for the therapy of clear cell renal cell carcinoma. The preclinical inhibitor PT2399 and artificial inhibitor 0X3 have been identified as promising on-target inhibitors to inhibit the heterodimerization of HIF-2. However, the inhibition mechanism of PT2399 and 0X3 on HIF-2 remains unclear. To this end, molecular dynamics (MD) simulations and molecular docking were applied to investigate the effects of 2 inhibitors on structural motifs and heterodimerization of HIF-2. Our simulation results reveal that the binding of inhibitors disrupts the crucial hydrogen bond and hydrophobic interactions of interdomain of HIF-2 heterodimer due to the local conformational changes of binding interface, confirming the hypothesis that the perturbation of few residues is sufficient to disrupt the heterodimerization of HIF-2. In addition, it can be found that PT2399 with dominant substituents (cyano, fluorine, sulfuryl, and hydroxyl) is more preferred than 0X3 as HIF-2 inhibitor and these substituents play a crucial role in involving more hydrogen bond interactions with residues of interface and then cause the larger structural change of protein. This study may provide a deeper atomic-level insight into the effect of on-target inhibitors on HIF-2 heterodimer, which is expected to contribute to further rational design of effective clear cell renal cell carcinoma drugs.

The elusive reaction mechanism of Mn(II)-mediated benzylic oxidation of alkylarene by H2O2: a gem-diol mechanism or a dual hydrogen abstraction mechanism?

The direct oxygenation of alkylarenes at the benzylic position employing bioinspired nonheme catalysts has emerged as a promising strategy for the production of bioactive arene ketone scaffolds in drugs. However, the structure-activity relationship of the active species and the mechanism of these reactions remain elusive. Herein, the reaction mechanism of the Mn(II)-mediated benzylic oxygenation of phenylbutanoic acid (PBA) to 4-oxo-4-phenylbutyric acid (4-oxo-PBA) by H2O2 was investigated using density functional theory calculations. The calculated results demonstrated that the MnIII-OOH species (1) is a sluggish oxidant and needs to be converted to a high-valent manganese-oxo species (2). The conversion of PBA to 4-oxo-PBA by 2 occurs via the consecutive hydroxylation of PBA to 4-hydroxyl-4-phenylbutyric acid (4-OH-PBA) and the alcohol oxidation of 4-OH-PBA to 4-oxo-PBA. The hydroxylation of PBA proceeds via a novel hydride transfer/hydroxyl-rebound mechanism and the alcohol oxidation of 4-OH-PBA occurs via three pathways (gem-diol, dual hydrogen abstraction (DHA), and reversed-DHA pathways). The regio-selectivity of benzylic oxidations was caused by a strong π-π stacking interaction between the pyridine ring of the nonheme ligand and the phenyl ring of the substrate. These mechanistic findings enrich the knowledge of biomimetic alcohol oxidations and play a positive role in the rational design of new non-heme catalysts.

The elusive active species in nickel(II)-mediated oxidations of hydrocarbons by peracids: a NiII-oxyl species, an aroyloxy radical, or a NiII-peracid complex?

Nonheme nickel(II)-mediated oxidations of hydrocarbons by meta-chloroperbenzoic acid (mCPBA) show promising activity and selectivity; however, the active species and the reaction mechanism of these reactions are still elusive after decades of efforts. Herein, a novel free radical chain mechanism of the Ni(II)-mediated oxidation of cyclohexane by mCPBA is investigated using density functional theory calculations. In this study, we rule out the involvement of a long speculated NiII-oxyl species. Instead, an aroyloxy radical (mCBA˙) and a NiIII-hydroxyl species formed by a rate-limiting O-O homolysis of a NiII-mCPBA complex are active species in the C-H bond activation to form a carbon-centered radical R˙, where mCBA˙ is more robust than the NiIII-hydroxyl species. The nascent R˙ radical either reacts with mCPBA to form a hydroxylated product and a mCBA˙ radical to propagate the radical chain or reacts with the solvent dichloromethane to form a chlorinated product. In addition, the NiII-mCPBA complex is found for the first time to be a robust oxidant in hydroxylation of cyclohexane, with an activation energy of 13.4 kcal mol-1. These mechanistic findings support the free radical chain mechanism and enrich the mechanistic knowledge of metal-peracid oxidation systems containing transition metals after group 8 in periodic table of elements.

Unique recognition of the microalgal plastidial glycerol-3-phosphate acyltransferase for acyl-ACP.

Plastidial glycerol-3-phosphate acyltransferases (GPATs) catalyze acyl-ACP and glycerol-3-phosphate to synthesize lysophosphatidic acid in vivo, which initiates the formation of various glycerolipids. Although the physiological substrates of plastidial GPATs are acyl-ACPs, acyl-CoAs have been commonly studied on the GPATs in vitro. However, little is known whether there are any distinct features of GPATs towards acyl-ACP and acyl-CoA. In this study, the results showed that the microalgal plastidial GPATs preferred acyl-ACP to acyl-CoA, while surprisingly, the plant-derived plastidial GPATs showed no obvious preferences towards these two acyl carriers. The key residues responsible for the distinct feature of microalgal plastidial GPATs were compared with plant-derived plastidial GPATs in their efficiency to catalyze acyl-ACP and acyl-CoA. Microalgal plastidial GPATs uniquely recognized acyl-ACP as compared to with other acyltransferases. The structure of the acyltransferases-ACP complex highlights only the involvement of the large structural domain in ACP in microalgal plastidial GPAT while in the other acyltransferases, both large and small structural domains were involved in the recognition process. The interaction sites on the plastidial GPAT from the green alga Myrmecia incisa (MiGPAT1) with ACP turned out to be K204, R212 and R266. A unique recognition between the microalgal plastidial GPAT and ACP was elucidated.

Theoretical investigation on the elusive structure-activity relationship of bioinspired high-valence nickel-halogen complexes in oxidative fluorination reactions.

Very recently, bioinspired high-valence metal-halogen complexes have been proven to be competent oxidants in the C-H bond activation and heteroatom dihalogenation reactions. However, the structure-activity relationship of such active species and the reaction mechanisms of oxidations mediated by these oxidants are still elusive. In this study, density functional theory (DFT) calculations were performed to systematically study the oxidizing ability of the high-valence NiIII-X (X = F and Cl) complexes Et4N[NiIII(Cl/F)(L)], (1Cl/F, Et = ethyl, L = N,N'-(2,6-dimethylphenyl)-2,6-pyridinedicarboxamide), such as the reaction mechanism of fluorination of 1,4-cyclohexadiene (CHD) by 1F in the presence of AgF and the reaction mechanism of difluorination of triphenyl phosphine (PPh3) by 1F. All calculated results fit well with the experiments and present new mechanistic findings. The C-H bond activation by the high-valence nickel(III)-halogen complexes was found to proceed via a hydrogen-atom transfer (HAT) mechanism by analysis of the molecular orbitals of the transition states. C-H bond activation by 1F takes a Ni-F-H angle of ca. 180°, whereas that by 1Cl takes an angle of ca. 120° on the transition states. These results indicate that the exchange-enhanced reactivity is responsible for the dramatic oxidative difference between these two oxidants. The role of AgF in C-H fluorination of CHD by 1F is proposed to act as a Lewis acid adduct, AgF-binding Ni(III)-fluorine complex 1F-Ag-F, which acts both as an oxidant in C-H bond activation and as a fluorine donor in the fluorination step. A cooperative oxidation mechanism involving two 1F oxidants was proposed for the difluorination of PPh3 by 1F. These theoretical findings will enrich the knowledge of high-valence metal-halogen chemistry and play a positive role in the rational design of new catalysts.

The chameleon-like nature of elusive cobalt-oxygen intermediates in C-H bond activation reactions.

High-valence metal-oxo (M-O, M = Fe, Mn, etc.) species are well-known reaction intermediates that are responsible for a wide range of pivotal oxygenation reactions and water oxidation reactions in metalloenzymes. Although extensive efforts have been devoted to synthesizing and identifying such complexes in biomimetic studies, the structure-function relationship and related reaction mechanisms of these reaction intermediates remain elusive, especially for the cobalt-oxygen species. In the present manuscript, the calculated results demonstrate that the tetraamido macrocycle ligated cobalt complex, Co(O)(TAML) (1), behaves like a chameleon: the electronic structure varies from a cobalt(III)-oxyl species to a cobalt(IV)-oxo species when a Lewis acid Sc3+ salt coordinates or an acidic hydrocarbon attacks 1. The dichotomous correlation between the reaction rates of C-H bond activation by 1 and the bond dissociation energy (BDE) vs. the acidity (pKa) was rationalized for the first time by different reaction mechanisms: for normal C-H bond activation, the Co(III)-oxyl species directly activates the C-H bond via a hydrogen atom transfer (HAT) mechanism, whereas for acidic C-H bond activation, the Co(III)-oxyl species evolves to a Co(IV)-oxo species to increase the basicity of the oxygen to activate the acidic C-H bond, via a novel PCET(PT) mechanism (proton-coupled electron transfer with a PT(proton-transfer)-like transition state). These theoretical findings will enrich the knowledge of biomimetic metal-oxygen chemistry.

Transition-Metal-Free [3+2] Dehydration Cycloaddition of Donor-Acceptor Cyclopropanes With 2-Naphthols.

A Brønsted acid-catalyzed domino ring-opening cyclization transformation of donor-acceptor (D-A) cyclopropanes and 2-naphthols has been developed. This formal [3+2] cyclization reaction provided novel and efficient access to the naphthalene-fused cyclopentanes in the absence of any transition-metal catalysts or additives. This robust procedure was completed smoothly on a gram-scale to afford the corresponding product with comparable efficiency. Furthermore, the synthetic application of the prepared product has been demonstrated by its transformation into a variety of synthetically useful molecules.

Theoretical Investigation on the Elusive Reaction Mechanism of Spirooxindole Formation Mediated by Cytochrome P450s: A Nascent Feasible Charge-Shift C-O Bond Makes a Difference.

Spirooxindoles are pivotal biofunctional groups widely distributed in natural products and clinic drugs. However, construction of such subtle chiral skeletons is a long-standing challenge to both organic and bioengineering scientists. The knowledge of enzymatic spirooxindole formation in nature may inspire rational design of new catalysts. To this end, we presented a theoretical investigation on the elusive mechanism of the spiro-ring formation at the 3-position of oxindole mediated by cytochrome P450 enzymes (P450). Our calculated results demonstrated that the electrophilic attack of CpdI, the active species of P450, to the substrate, shows regioselectivity, i.e., the attack at the C9 position forms a tetrahedral intermediate involving an unusual feasible charge-shift C9δ+-Oδ- bond, while the attack at the C1 position forms an epoxide intermediate. The predominant route is the first route with the charge-shift bonding intermediate due to holding a relatively lower barrier by >5 kcal mol-1 than the epoxide route, which fits the experimental observations. Such a delocalized charge-shift bond facilitates the formation of a spiro-ring mainly through elongation of the C1-C9 bond to eliminate the aromatization of the tricyclic beta-carboline. Our theoretical results shed profound mechanistic insights for the first time into the elusive spirooxindole formation mediated by P450s.

Theoretical studies unveil the unusual bonding in oxygenation reactions involving cobalt(ii)-iodylarene complexes.

DFT calculations reveal that the iodine of cobalt(ii)-iodylarene complexes acts as a directing group via halogen bonding interaction to substrates. A transient 3c-4e bond is formed during oxidation reactions to decrease the activation energy by electron delocalization. Dehydrogenation of dihydroantharacene proceeds via a novel concerted hydride transfer/proton transfer mechanism.

Cyclic Dipeptides Formation From Linear Dipeptides Under Potentially Prebiotic Earth Conditions.

Cyclic dipeptides (DKPs) are peptide precursors and chiral catalysts in the prebiotic process. This study reports proline-containing DKPs that were spontaneously obtained from linear dipeptides under an aqueous solution. Significantly, the yields of DKPs were affected by the sequence of linear dipeptides and whether the reaction contains trimetaphosphate. These findings provide the possibility that DKPs might play a key role in the origin of life.

Theoretical Study on the Structural-Function Relationship of Manganese(III)-Iodosylarene Adducts.

Metal-iodosylarene complexes have been recently viewed as a second oxidant alongside of the well-known high-valent metal-oxo species. Extensive efforts have been exerted to unveil the structure-function relationship of various metal-iodosylarene complexes. In the present manuscript, density functional theoretical calculations were employed to investigate such relationship of a specific manganese-iodosylbenzene complex [MnIII(TBDAP)(PhIO)(OH)]2+ (1). Our results fit the experimental observations and revealed new mechanistic findings. 1 acts as a stepwise 1e+1e oxidant in sulfoxidation reactions. Surprisingly, C-H bond activation of 9,10-dihydroanthracene (DHA) by 1 proceeds via a novel ionic hydride transfer/proton transfer (HT/PT) mechanism. As a comparison to 1, the electrophilicity of an iodosylbenzene monomer PhIO was investigated. PhIO performs concerted 2e-oxidations both in sulfoxidation and C-H activation. Hydroxylation of DHA by PhIO was found to proceed via a novel ionic and concerted proton-transfer/hydroxyl-rebound mechanism involving 2e-oxidation to form a transient carbonium species.

Coupled electron and proton transfer in the piperidine drug metabolism pathway by the active species of cytochromes P450.

Ring contraction of piperidine drugs by cytochrome P450 enzymes (P450s) is among the most important drug metabolisms for human beings. However, the underlying mechanism remains elusive and controversial even after decades of experimental study. Kohn-Sham density functional theory (KS-DFT) combined with multistate density functional theory (MSDFT) was used to explore the chemical nature of ring contraction of 2,2',6,6'-tetramethylpiperidine (2,2',6,6'-TMPi) mediated by the active species, Compound I of P450s. Our calculated results demonstrate that ring contraction is initiated by N-H bond activation. MSDFT combined with KS-DFT methods revealed that the N-H bond activation involves an initial tightly coupled electron-proton pair, essentially of hydrogen atom transfer (HAT) character prior to the diabatic crossing point, after which the mechanism is dominated by the concerted electron proton transfer (CEPT) product formation. The nascent N-centered radical intermediate undergoes electron tautomerism via rate-limiting homolytic C-C bond cleavage (ca. 21 kcal mol-1) to form a ring-opened, carbon-centered radical imine intermediate. The following barrierless C-N bond formation concomitant with hydroxyl rebound from the Fe-OH moiety forms the ring-contracted pyrrolidine product. To the best of our knowledge, this is the first application of MSDFT in P450 chemistry, and also the first comprehensive theoretical report on the ring contraction mediated by P450, in which the revealed new mechanism will undoubtedly promote relative rational drug design.

2D-QSAR study, molecular docking, and molecular dynamics simulation studies of interaction mechanism between inhibitors and transforming growth factor-beta receptor I (ALK5).

Transforming growth factor type 1 receptor (ALK5) is kinase associated with a wide variety of pathological processes, and inhibition of ALK5 is a good strategy to treat many kinds of cancer and fibrotic diseases. Recently, a series of compounds have been synthesized as ALK5 inhibitors. However, the study of their selectivity against other potential targets remains elusive. In this research, a data-set of ALK5 inhibitors were collected and studied based on the combination of 2D-QSAR, molecular docking and molecular dynamics simulation. The quality of QSAR models were assessed statistically by F, R2, and R2ADJ, proved to be credible. The cross-validations for the models (q2LOO = 0.571 and 0.629, respectively) showed their robustness, while the external validations (r2test = 0.703 and 0.764, respectively) showed their predictive power. Besides, the predicted binding free energy results calculated by MM/GBSA method were in accordance with the experimental data, and the van der Waals energy term was the factor that had the most significant impact on ligand binding. What is more, several important residues were found to significantly affect the binding affinity. Finally, based on our analyses above, a proposed series of molecules were designed.

Probing the interaction mechanism of small molecule inhibitors with matriptase based on molecular dynamics simulation and free energy calculations.

Matriptase is a serine protease associated with a wide variety of human tumors and carcinoma progression. Up to now, many promising anti-cancer drugs have been developed. However, the detailed structure-function relationship between inhibitors and matriptase remains elusive. In this work, molecular dynamics simulation and binding free energy studies were performed to investigate the biochemistry behaviors of two class inhibitors binding to matriptase. The binding free energies predicted by MM/GBSA methods are in good agreement with the experimental bioactivities, and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. The key residues responsible for achieving strong binding have been identified by the MM/GBSA free energy decomposition analysis. Especially, Trp215 and Phe99 had an important impact on active site architecture and ligand binding. The results clearly identify the two class inhibitors exist different binding modes. Through summarizing the two different modes, we have mastered some important and favorable interaction patterns between matriptase and inhibitors. Our findings would be helpful for understanding the interaction mechanism between the inhibitor and matriptase and afford important guidance for the rational design of potent matriptase inhibitors.