Developing synthetically useful enzymatic reactions that are not known in biochemistry and organic chemistry is an important challenge in biocatalysis. Through the synergistic merger of photoredox ...catalysis and pyridoxal 5'-phosphate (PLP) biocatalysis, we developed a pyridoxal radical biocatalysis approach to prepare valuable noncanonical amino acids, including those bearing a stereochemical dyad or triad, without the need for protecting groups. Using engineered PLP enzymes, either enantiomeric product could be produced in a biocatalyst-controlled fashion. Synergistic photoredox
pyridoxal radical biocatalysis represents a powerful platform with which to discover previously unknown catalytic reactions and to tame radical intermediates for asymmetric catalysis.
We report a QM/MM computational study of the cycloaddition between carbon dioxide (CO2) and styrene oxide in two different metal–organic frameworks (MOFs), Co-MOF-74 and Mg-MOF-74, to obtain ...atomic-level insights into the catalytic mechanism. The results suggest that both reactions begin by forming Lewis acid–base pairs between the epoxide and an open metal site and between CO2 and a phenolate moiety in the linker. Consequently, higher electrophilic and nucleophilic reactivities are conferred on the epoxide and CO2 (CO2(A)), respectively, thereby facilitating the initial ring-opening of the epoxide moiety. The ring-opening process is followed by the adsorption of a second CO2 molecule (CO2(B)), which is necessary for the subsequent ring closure to occur. In the case of Co-MOF-74, the binding of CO2(B) to the alkoxide oxygen increases the flexibility of the substrate moiety, enabling the cyclization pathway in which CO2(A) is incorporated into the final product. In contrast, the carbonate intermediate in the Mg-MOF-74-catalyzed reaction undergoes an intramolecular nucleophilic attack to form a 5-membered cyclic product. During this step, CO2(A) behaves essentially as a cocatalyst and is released back into the framework upon product formation. Our QM/MM results also suggest that the Lewis acid site has somewhat different coordination geometries in Co-MOF-74 and Mg-MOF-74 during the final ring-closure step.
1,1-Diboryl alkenes are versatile building blocks in organic synthesis and medicinal chemistry. However, there have been only a small number of established methods to prepare this class of compounds, ...and most of them used transition-metal catalysts, which are undesirable in the preparation of biologically relevant compounds. Herein, we report an unprecedented application of P1– t Bu phosphazene as a superbasic organocatalyst to promote 1,1-diboration reactions of unactivated aromatic and electron-deficient terminal alkynes. The dual Brønsted and Lewis basicity of this phosphazene enables the activation of reaction substrates and allows for high regio- and stereoselectivity to be obtained. A combination of thorough experimental and computational studies suggests interesting mechanistic insights for these phosphazene-catalyzed diboration reactions, which are also discussed in detail.
A catalyst system of mononuclear manganese precursor 3 combined with potassium alkoxide served as a superior catalyst compared with our previously reported manganese homodinuclear catalyst 2 a for ...esterification of not only tertiary aryl amides, but also tertiary aliphatic amides. On the basis of stoichiometric reactions of 3 and potassium alkoxide salt, kinetic studies, and density functional theory (DFT) calculations, we clarified a plausible reaction mechanism in which in situ generated manganese–potassium heterodinuclear species cooperatively activates the carbonyl moiety of the amide and the OH moiety of the alcohols. We also revealed details of the reaction mechanism of our previous manganese homodinuclear system 2 a, and we found that the activation free energy (ΔG≠) for the manganese–potassium heterodinuclear complex catalyzed esterification of amides is lower than that for the manganese homodinuclear system, which was consistent with the experimental results. We further applied our catalyst system to deprotect the acetyl moiety of primary and secondary amines.
Cooperative cleavage: A catalyst system involving a mononuclear manganese precursor combined with potassium alkoxide serves as a catalyst for the esterification of both tertiary aryl amides and tertiary aliphatic amides. The catalyst system can be applied for the deprotection of an acetyl moiety of primary and secondary amines.
Hydroboration reaction of alkynes is one of the most synthetically powerful tools to access organoboron compounds, versatile precursors for cross-coupling chemistry. This type of reaction has ...traditionally been mediated by transition-metal or main group catalysts. Herein, we report a novel method using tropylium salts, typically known as organic oxidants and Lewis acids, to promote the hydroboration reaction of alkynes. A broad range of vinylboranes can be easily accessed via this metal-free protocol. Similar hydroboration reactions of alkenes and epoxides can also be efficiently catalyzed by the same tropylium catalysts. Experimental studies and DFT calculations suggested that the reaction follows an uncommon mechanistic pathway, which is triggered by the hydride abstraction of pinacolborane with tropylium ion. This is followed by a series of in situ counterion-activated substituent exchanges to generate boron intermediates that promote the hydroboration reaction.
► We study binding affinity of R-125489 and its prodrug CS-8958 to neuraminidase of pathogenic influenza viruses by molecular dynamics simulations. ► It is shown that, in agreement with experiments, ...R-125489 binds to neuraminidase more tightly than CS-8958. ► We predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus. ► The high correlation between theoretical and experimental data implies that SMD is a very promising tool for drug design.
Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson–Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design.
Two‐state reactivity (TSR) is often used to explain the reaction of transition‐metal–oxo reagents in the bare form or in the complex form. The evidence of the TSR model typically comes from ...quantum‐mechanical calculations for energy profiles with a spin crossover in the rate‐limiting step. To prove the TSR concept, kinetic profiles for CH activation by the FeO+ cation were explored. A direct dynamics approach was used to generate potential energy surfaces of the sextet and quartet H‐transfers and rate constants and kinetic isotope effects (KIEs) were calculated using variational transition‐state theory including multidimensional tunneling. The minimum energy crossing point with very large spin–orbit coupling matrix element was very close to the intrinsic reaction paths of both sextet and quartet H‐transfers. Excellent agreement with experiments were obtained when the sextet reactant and quartet transition state were used with a spin crossover, which strongly support the TSR model.
A direct dynamics approach was used to generate potential energy surfaces of the sextet and quartet H‐transfers for transition‐metal–oxo reagents. Variational transition‐state‐theory rate constants and kinetic isotope effects including multidimensional tunneling revealed that the reaction proceeds from the sextet reactant to quartet transition state with a spin crossover along the intrinsic reaction paths.
Herein we disclosed an unprecedented photochemically driven nickel‐catalyzed carboxylative Buchwald–Hartwig amination to access a wide range of aryl carbamate derivatives. This reaction is performed ...under mild condition of temperature and atmospheric pressure of CO2 starting from commercially available (hetero)aryl iodides/bromides derivatives and alkyl amines preventing the formation of hazardous and/or toxic waste. Moreover, preliminary mechanistic investigations including stochiometric experiments as well as DFT calculations allow us to shed light on the reaction mechanism.
The carboxylative Buchwald–Hartwig amination is disclosed herein under mild conditions of temperature and under atmospheric pressure of CO2. The key to success is the use of a dual strategy organophotocatalysis/nickel catalysis under visible light irradiation. The developed conditions demonstrated high functional group tolerance toward (hetero)aryl iodide and bromide. Furthermore, preliminary mechanistic investigations including stoichiometric reactions and DFT calculations shed light on the reaction mechanism.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the COVID-19 pandemic, resulting in several million deaths being reported. Numerous investigations have been carried ...out to discover a compound that can inhibit the biological activity of the SARS-CoV-2 main protease, which is an enzyme related to the viral replication. Among these, PF-07321332 (Nirmatrelvir) is currently under clinical trials for COVID-19 therapy. Therefore, in this work, atomistic and electronic simulations were performed to unravel the binding and covalent inhibition mechanism of the compound to M
. Initially, 5 μs of steered-molecular dynamics simulations were carried out to evaluate the ligand-binding process to SARS-CoV-2 M
. The successfully generated
state between the two molecules showed the important role of the PF-07321332 pyrrolidinyl group and the residues Glu166 and Gln189 in the ligand-binding process. Moreover, from the MD-refined structure, quantum mechanics/molecular mechanics (QM/MM) calculations were carried out to unravel the reaction mechanism for the formation of the thioimidate product from SARS-CoV-2 M
and the PF-07321332 inhibitor. We found that the catalytic triad Cys145-His41-Asp187 of SARS-CoV-2 M
plays an important role in the activation of the PF-07321332 covalent inhibitor, which renders the deprotonation of Cys145 and, thus, facilitates further reaction. Our results are definitely beneficial for a better understanding of the inhibition mechanism and designing new effective inhibitors for SARS-CoV-2 M
.
Protonolysis by platinum or palladium complexes has been extensively studied because it is the microscopic reverse of the C–H bond activation reaction. The protonolysis of (COD)PtIIMe2, which ...exhibits abnormally large kinetic isotope effects (KIEs), is proposed to occur via a concerted pathway (SE2 mechanism) with large tunneling. However, further investigation of KIEs for the protonolysis of ZnMe2 and others led to a conclusion that there is no noticeable correlation between the mechanism and magnitude of KIE. In this study, we demonstrated that variational transition state theory including multidimensional tunneling (VTST/MT) could accurately predict KIEs and Arrhenius parameters of the protonolysis of alkylmetal complexes based on the potential energy surfaces generated by density functional theory. The predicted KIEs, E a D – E a H values, and A H/A D ratios for the protonolysis of (COD)PtIIMe2 and ZnIIMe2 by TFA agreed very well with experimental values. The protonolysis of ZnMe2 with the concerted pathway has a very flat potential energy surface, which produces a very small tunneling effect and therefore a small KIE. The predicted KIE for the stepwise protonolysis (SE(ox) mechanism) of (COD)PtIIMe2 was much smaller than that of the concerted pathway, but greater than the KIE of the concerted protonolysis of ZnMe2. A large KIE, which entails a significant tunneling effect, could be used as an experimental probe of the concerted pathway. However, a normal or small KIE should not be used as an indicator of the stepwise mechanism, and the interplay between experiments and reliable theory including tunneling would be essential to uncover the mechanism correctly.
PDF
