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The solution-state fluxional behavior of bullvalene has fascinated physical organic and supramolecular chemists alike. Little effort, however, has been put into investigating bullvalene applications in bulk, partially due to difficulties in characterizing such dynamic systems. To address this knowledge gap, we herein probe whether bullvalene Hardy-Cope rearrangements can be mechanically perturbed in bulk polymer networks. We use dynamic mechanical analysis to demonstrate that the activation barrier to the glass transition process is significantly elevated for bullvalene-containing materials relative to "static" control networks. Furthermore, bullvalene rearrangements can be mechanically perturbed at low temperatures in the glassy region; such behavior facilitates energy dissipation (i.e., increased hysteresis energy) and polymer chain alignment to stiffen the material (i.e., increased Young's modulus) under load. Computational simulations corroborate our work that showcases bullvalene as a reversible "low-force" covalent mechanophore in the modulation of viscoelastic behavior.
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Selectivity in organic chemistry is generally presumed to arise from energy differences between competing selectivity-determining transition states. However, in cases where static density functional theory (DFT) fails to reproduce experimental product distributions, dynamic effects can be examined to understand the behavior of more complex reaction systems. Previously, we reported a method for nitrogen deletion of secondary amines which relies on the formation of isodiazene intermediates that subsequently extrude dinitrogen with concomitant C-C bond formation via a caged diradical. Herein, a detailed mechanistic analysis of the nitrogen deletion of 1-aryl-tetrahydroisoquinolines is presented, suggesting that in this system the previously determined diradical mechanism undergoes dynamically controlled partitioning to both the normal 1,5-coupling product and an unexpected spirocyclic dearomatized intermediate, which converges to the expected indane by an unusually facile 1,3-sigmatropic rearrangement. This mechanism is not reproduced by static DFT but is supported by quasi-classical molecular dynamics calculations and unifies several unusual observations in this system, including partial chirality transfer, nonstatistical isotopic scrambling at the ethylene bridge, the isolation of spirocyclic dearomatized species in a related heterocyclic series, and the observation that introduction of an 8-substituent dramatically improves enantiospecificity.
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Organophosphorus (OP) nerve agents inhibit acetylcholinesterase (AChE), creating a cholinergic crisis in which death can occur. The phosphylated serine residue spontaneously dealkylates to the OP-aged form, which current therapeutics cannot reverse. Soman's aging half-life is 4.2 min, so immediate recovery (resurrection) of OP-aged AChE is needed. In 2018, we showed pyridin-3-ol-based quinone methide precursors (QMPs) can resurrect OP-aged electric eel AChE in vitro, achieving 2% resurrection after 24 h of incubation (pH 7, 4 mM). We prepared 50 unique 6-alkoxypyridin-3-ol QMPs with 10 alkoxy groups and five amine leaving groups to improve AChE resurrection. These compounds are predicted in silico to cross the blood-brain barrier and treat AChE in the central nervous system. This library resurrected 7.9% activity of OP-aged recombinant human AChE after 24 h at 250 µM, a 4-fold increase from our 2018 report. The best QMP (1b), with a 6-methoxypyridin-3-ol core and a diethylamine leaving group, recovered 20.8% (1 mM), 34% (4 mM), and 42.5% (predicted maximum) of methylphosphonate-aged AChE activity over 24 h. Seven QMPs recovered activity from AChE aged with Soman and a VX degradation product (EA-2192). We hypothesize that QMPs form the quinone methide (QM) to realkylate the phosphylated serine residue as the first step of resurrection. We calculated thermodynamic energetics for QM formation, but there was no trend with the experimental biochemical data. Molecular docking studies revealed that QMP binding to OP-aged AChE is not the determining factor for the observed biochemical trends; thus, QM formation may be enzyme-mediated.
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Reativadores da Colinesterase , Indolquinonas , Intoxicação por Organofosfatos , Soman , Humanos , Idoso , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Simulação de Acoplamento Molecular , Compostos Organofosforados/farmacologia , Compostos Organofosforados/metabolismo , Serina , Oximas , Reativadores da Colinesterase/químicaRESUMO
The advent of covalent adaptable networks (CANs) through the incorporation of dynamic covalent bonds has led to unprecedented properties of macromolecular systems, which can be engineered at the molecular level. Among the various types of stimuli that can be used to trigger chemical changes within polymer networks, light stands out for its remote and spatiotemporal control under ambient conditions. However, most examples of photoactive CANs need to be transparent and they exhibit slow response, side reactions, and limited light penetration. In this vein, it is interesting to understand how molecular engineering of optically active dynamic linkages that offer fast response to visible light can impart "living" characteristics to CANs, especially in opaque systems. Here, the use of carbazole-based thiuram disulfides (CTDs) that offer dual reactivity as photoactivated reshuffling linkages and iniferters under visible light irradiation is reported. The fast response to visible light activation of the CTDs leads to temporal control of shape manipulation, healing, and chain extension in the polymer networks, despite the lack of optical transparency. This strategy charts a promising avenue for manipulating multifunctional photoactivated CANs in a controlled manner.
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Poly(p-phenylenevinylene) (PPV) is a staple of the family of conjugated polymers with desirable optoelectronic properties for applications including light-emitting diodes (LEDs) and photovoltaic devices. Although the significant impact of olefin geometry on the steady-state optical properties of PPVs has been extensively studied, PPVs with precise stereochemistry have yet to be investigated using nonlinear optical spectroscopy for quantum sensing, as well as light harvesting for biological applications. Herein, we report our investigation of the influence of olefin stereochemistry on both linear and nonlinear optical properties through the synthesis of all-cis and all-trans PPV copolymers. We performed two-photon absorption (TPA) using a classical and entangled light source and compared both classical TPA and entangled two-photon absorption (ETPA) cross sections of these stereodefined PPVs. Whereas the TPA cross section of the all-trans PPV was expectedly higher than that of all-cis PPV, presumably because of the larger transition dipole moment, the opposite trend was measured via ETPA, with the all-cis PPV exhibiting the highest ETPA cross section. DFT calculations suggest that this difference might stem from the interaction of entangled photons with lower-lying electronic states in the all-cis PPV variant. Additionally, we explored the photoinduced processes for both cis and trans PPVs through time-resolved fluorescence upconversion and femtosecond transient absorption techniques. This study revealed that the sensitivity of PPVs in two-photon absorption varies with classical versus quantum light and can be modulated through the control of the geometry of the repeating alkenes, which is a key stepping stone toward their use in quantum sensing, bioimaging, and the design of polymer-based light-harvesting systems.
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COVID-19, the disease responsible for the recent pandemic, is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (Mpro) of SARS-CoV-2 is an essential proteolytic enzyme that plays a number of important roles in the replication of the virus in human host cells. Blocking the function of SARS-CoV-2 Mpro offers a promising and targeted, therapeutic option for the treatment of the COVID-19 infection. Such an inhibitory strategy is currently successful in treating COVID-19 under FDA's emergency use authorization, although with limited benefit to the immunocompromised along with an unfortunate number of side effects and drug-drug interactions. Current COVID vaccines protect against severe disease and death but are mostly ineffective toward long COVID which has been seen in 5-36% of patients. SARS-CoV-2 is a rapidly mutating virus and is here to stay endemically. Hence, alternate therapeutics to treat SARS-CoV-2 infections are still needed. Moreover, because of the high degree of conservation of Mpro among different coronaviruses, any newly developed antiviral agents should better prepare us for potential future epidemics or pandemics. In this paper, we first describe the design and computational docking of a library of novel 188 first-generation peptidomimetic protease inhibitors using various electrophilic warheads with aza-peptide epoxides, α-ketoesters, and ß-diketones identified as the most effective. Second-generation designs, 192 compounds in total, focused on aza-peptide epoxides with drug-like properties, incorporating dipeptidyl backbones and heterocyclic ring motifs such as proline, indole, and pyrrole groups, yielding 8 hit candidates. These novel and specific inhibitors for SARS-CoV-2 Mpro can ultimately serve as valuable alternate and broad-spectrum antivirals against COVID-19.Communicated by Ramaswamy H. Sarma.
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COVID-19 , Proteases 3C de Coronavírus , Humanos , SARS-CoV-2 , Simulação de Dinâmica Molecular , Síndrome de COVID-19 Pós-Aguda , Antivirais/farmacologia , Antivirais/química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Peptídeos , Compostos de Epóxi , Simulação de Acoplamento MolecularRESUMO
The alkynylation of 4-siloxyquinolinium triflates has been achieved under the influence of copper bis(oxazoline) catalysis. The identification of the optimal bis(oxazoline) ligand was informed through a computational approach that enabled the dihydroquinoline products to be produced with up to 96% enantiomeric excess. The conversions of the dihydroquinoline products to biologically relevant and diverse targets are reported.
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The effects of Lewis basic phosphoramides on the aggregate structure of t-BuLi have been investigated in detail by NMR and DFT methods. It was determined that hexamethylphosphoramide (HMPA) can shift the equilibrium of t-BuLi to include the triple ion pair (t-Bu-Li-t-Bu)-/HMPA4Li+ which serves as a reservoir for the highly reactive separated ion pair t-Bu-/HMPA4Li+. Because the Li-atom's valences are saturated in this ion pair, the Lewis acidity is significantly decreased; in turn, the basicity is maximized which allowed for the typical directing effects within oxygen heterocycles to be overridden and for remote sp3 C-H bonds to be deprotonated. Furthermore, these newly accessed lithium aggregation states were leveraged to develop a simple γ-lithiation and capture protocol of chromane heterocycles with a variety of alkyl halide electrophiles in good yields.
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Enantiopure homoallylic boronate esters are versatile intermediates because the C-B bond in these compounds can be stereospecifically transformed into C-C, C-O, and C-N bonds. Regio- and enantioselective synthesis of these precursors from 1,3-dienes has few precedents in the literature. We have identified reaction conditions and ligands for the synthesis of nearly enantiopure (er >97:3 to >99:1) homoallylic boronate esters via a rarely seen cobalt-catalyzed [4,3]-hydroboration of 1,3-dienes. Monosubstituted or 2,4-disubstituted linear dienes undergo highly efficient regio- and enantioselective hydroboration with HBPin catalyzed by [(L*)Co]+[BARF]-, where L* is typically a chiral bis-phosphine ligand with a narrow bite angle. Several such ligands (e.g., i-PrDuPhos, QuinoxP*, Duanphos, and BenzP*) that give high enantioselectivities for the [4,3]-hydroboration product have been identified. In addition, the equally challenging problem of regioselectivity is uniquely solved with a dibenzooxaphosphole ligand, (R,R)-MeO-BIBOP. A cationic cobalt(I) complex of this ligand is a very efficient (TON >960) catalyst while also providing excellent regioselectivities (rr >98:2) and enantioselectivities (er >98:2) for a broad range of substrates. A detailed computational investigation of the reactions using Co complexes from two widely different ligands (BenzP* and MeO-BIBOP) employing the B3LYP-D3 density functional theory provides key insights into the mechanism and the origins of selectivities. The computational results are in full agreement with the experiments. For the complexes we have examined thus far, the relative stabilities of the diastereomeric diene-bound complexes [(L*)Co(η4-diene)]+ lead to the initial diastereofacial selectivity, which in turn is retained in the subsequent steps, providing exceptional enantioselectivity for the reactions.
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Two-dimensional infrared (2D IR) spectroscopy, infrared pump-infrared probe spectroscopy, and density functional theory calculations were used to study vibrational relaxation by ring and carbonyl stretching modes in a series of methylated xanthine derivatives in acetonitrile and deuterium oxide (heavy water). Isotropic signals from the excited symmetric and asymmetric carbonyl stretch modes decay biexponentially in both solvents. Coherent energy transfer between the symmetric and asymmetric carbonyl stretching modes gives rise to a quantum beat in the time-dependent anisotropy signals. The damping time of the coherent oscillation agrees with the fast decay component of the carbonyl bleach recovery signals, indicating that this time constant reflects intramolecular vibrational redistribution (IVR) to other solute modes. Despite their similar frequencies, the excited ring modes decay monoexponentially with a time constant that matches the slow decay component of the carbonyl modes. The slow decay times, which are faster in heavy water than in acetonitrile, approximately match the ones observed in previous UV pump-IR probe measurements on the same compounds. The slow component is assigned to intermolecular energy transfer to solvent bath modes from low-frequency solute modes, which are populated by IVR and are anharmonically coupled to the carbonyl and ring stretch modes. 2D IR measurements indicate that the carbonyl stretching modes are weakly coupled to the delocalized ring modes, resulting in slow exchange that cannot explain the common solvent-dependence. IVR is suggested to occur at different rates for the carbonyl vs ring modes due to differences in mode-specific couplings and not to differences in the density of accessible states.
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Removal of a ß,ß'-bond from meso-tetraarylporphyrin using [3 + 2]-cycloadditions generates meso-tetraarylhydroporphyrins. Literature evidence indicates that meso-tetraphenylporphyrins react more sluggishly with 1,3-dipoles such as ylides and OsO4 (in the presence of pyridine) than meso-tetrakis(pentafluorophenyl)porphyrin. The trend is counterintuitive for the reaction with OsO4, as this formal oxidation reaction is expected to proceed more readily with more electron-rich substrates. This work presents a density functional theory-based computational study of the frontier molecular orbital (FMO) interactions and reaction profile thermodynamics involved in the reaction of archetypical cycloaddition reactions (a simple ylide, OsO4, OsO4·py, OsO4·(py)2, and ozone) with the ß,ß'-double bonds of variously fluorinated meso-arylporphyrins. The trend observed for the Type I cycloaddition of an ylide is straightforward, as lowering the LUMO of the porphyrin with increasing meso-phenyl-fluorination also lowers the reaction barrier. The corresponding simple FMO analyses of Type III cycloadditions do not correctly model the reaction energetics. This is because increasing fluorination leads to lowering of the porphyrin HOMO-2, thus increasing the reaction barrier. However, coordination of pyridine to OsO4 preorganizes the transition state complex; lowering of the energy barrier by the preorganization exceeds the increase in repulsive orbital interactions, overall accelerating the cycloaddition and rationalizing the counterintuitive experimental findings.
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Porfirinas , Reação de Cicloadição , Porfirinas/química , Termodinâmica , Oxirredução , PiridinasRESUMO
Radical addition reactions of olefins have emerged as an attractive tool for the rapid assembly of complex structures, and have plentiful applications in organic synthesis, however, such reactions are often limited to polymerization or 1,2-difunctionalization. Herein, we disclose an unprecedented radical relay 1,4-oxyimination of two electronically differentiated olefins with a class of bifunctional oxime carbonate reagents via an energy transfer strategy. The protocol is highly chemo- and regioselective, and three different chemical bonds (C-O, C-C, and C-N bonds) were formed in a single operation in an orchestrated manner. Notably, this reaction provides rapid access to a large variety of structurally diverse 1,4-oxyimination products, and the obtained products could be easily converted into valuable biologically relevant δ-hydroxyl-α-amino acids. With a combination of experimental and theoretical methods, the mechanism for this 1,4-oxyimination reaction has been investigated. Theoretical calculations reveal that a radical chain mechanism might operate in the reaction.
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Alcenos , Radical Hidroxila , Alcenos/química , Técnicas de Química Sintética , Oximas , PolimerizaçãoRESUMO
A catalytic and highly enantioselective dearomative alkynylation of chromanones has been discovered that enables the construction of biologically relevant tertiary ether stereogenic centers. This methodology is robust, accommodating a variety of alkynes and chromanones. More than 40 substrates tested gave rise to >90% ee. Computational studies have indicated that the optimal indanyl ligand identified for most cases likely affords a network of supportive, non-covalent interactions that drive the enantioselective nature of the reaction.
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Host-guest complexations can be described by two competing mechanisms, conformational selection (CS) and induced fit (IF). In this work, we used a combination of nudged elastic band (NEB), adaptive steered molecular dynamics (ASMD), and density functional theory (DFT, with a correction for dispersion) to study the dynamics of the pathways (IF/CS) by which two conformers of basket B(+) and B(-) interconvert and trap CX4 guests (X = Cl and Br). While the results from NEB/DFT studies disclosed host-guest noncovalent contacts reducing the basket's conformational dynamics, ASMD methodology suggested an associative mechanism for the guest complexation. With theory in excellent agreement with experiments, NEB and ASMD emerge as the methods of choice for studying dynamics of supramolecular systems.
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Two intermolecular hydroalkenylation reactions of 1,6-enynes are presented which yield substituted 5-membered carbo- and -heterocycles. This reactivity is enabled by a cationic bis-diphenylphosphinopropane (DPPP)CoI species which forms a cobaltacyclopentene intermediate by oxidative cyclization of the enyne. This key species interacts with alkenes in distinct fashion, depending on the identity of the coupling partner to give regiodivergent products. Simple alkenes undergo insertion reactions to furnish 1,3-dienes whereby one of the alkenes is tetrasubstituted. When acrylates are employed as coupling partners, the site of intermolecular C-C formation shifts from the alkyne to the alkene motif of the enyne, yielding Z-substituted-acrylate derivatives. Computational studies provide support for our experimental observations and show that the turnover-limiting steps in both reactions are the interactions of the alkenes with the cobaltacyclopentene intermediate via either a 1,2-insertion in the case of ethylene, or an unexpected ß-C-H activation in the case of most acrylates. Thus, the H syn to the ester is activated through the coordination of the acrylate carbonyl to the cobaltacycle intermediate, which explains the uncommon Z-selectivity and regiodivergence. Variable time normalization analysis (VTNA) of the kinetic data reveals a dependance upon the concentration of cobalt, acrylate, and activator. A KIE of 2.1 was observed with methyl methacrylate in separate flask experiments, indicating that C-H cleavage is the turnover-limiting step in the catalytic cycle. Lastly, a Hammett study of aryl-substituted enynes yields a ρ value of -0.4, indicating that more electron-rich substituents accelerate the rate of the reaction.
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Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate "instructs" the host to change its shape after complexation, while CS asserts that a guest "selects" the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsule M-1, encompassing two conformers M-1(+) and M-1(-), trap CX4 (X=Cl, Br) to give CX4 âM-1(+) and CX4 âM-1(-), with all four states being in thermal equilibrium. With the assistance of 2D EXSY, we found that CBr4 would, at its lower concentrations, bind M-1 via a M-1(+)âM-1(-)âCBr4 âM-1(-) pathway corresponding to conformational selection. For M-1 complexing CCl4 though, data from 2D EXSY measurements and 1D NMR line-shape analysis suggested that lower CCl4 concentrations would favor CS while the IF pathway prevailed at higher proportions of the guest. Since CS and IF are not mutually exclusive, we reason that our work sets the stage for characterizing the dynamics of a wide range of already existing hosts to broaden our fundamental understanding of their action. The objective is to master the way in which encapsulation takes place for designing novel and allosteric sequestering agents, catalysts and chemosensors akin to those found in nature.
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Tetracloreto de Carbono/química , Hidrocarbonetos Bromados/química , Piridinas/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação MolecularRESUMO
A robust, catalytic enantioselective method to construct challenging, biologically relevant, tertiary ether stereocenters has been developed. The process capitalizes on readily accessible bis(oxazoline) ligands to control the facial selectivity of the addition of copper acetylides to benzopyrylium triflates, reactive species generated in situ. Up to 99% enantiomeric excesses are achieved with a broad substrate scope. Using density functional theory (DFT) calculations, the origin of the experimentally observed enantiocontrol was attributed to additional non-covalent interactions observed in the transition state leading to the major enantiomer, such as π-stacking. The resultant substrates have direct applications in the synthesis of naturally occurring bioactive chromanones and tetrahydroxanthones.
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Chemical warfare nerve agents (CWNAs) present a global threat to both military and civilian populations. The acute toxicity of CWNAs stems from their ability to effectively inhibit acetylcholinesterase (AChE). This inhibition can lead to uncontrolled cholinergic cellular signaling, resulting in cholinergic crisis and, ultimately, death. Although the current FDA-approved standard of care is moderately effective when administered early, development of novel treatment strategies is necessary. Butyrylcholinesterase (BChE) is an enzyme which displays a high degree of structural homology to AChE. Unlike AChE, the roles of BChE are uncertain and possibilities are still being explored. However, BChE appears to primarily serve as a bioscavenger of toxic esters due to its ability to accommodate a wide variety of substrates within its active site. Like AChE, BChE is also readily inhibited by CWNAs. Due to its high affinity for binding CWNAs, and that null-BChE yields no apparent health effects, exogenous BChE has been explored as a candidate therapeutic for CWNA intoxication. Despite years of research, minimal strides have been made to develop a catalytic bioscavenger. Furthermore, BChE is only in early clinical trials as a stoichiometric bioscavenger of CWNAs, and large quantities must be administered to treat CWNA toxicity. Here, we describe previously unidentified mutations to residues within and adjacent to the acyl binding pocket (positions 282-285 were mutagenized from YGTP to NHML) of BChE that confer catalytic degradation of the CWNA, sarin. These mutations, along with corresponding future efforts, may finally lead to a novel therapeutic to combat CWNA intoxication.
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Butirilcolinesterase/metabolismo , Substâncias para a Guerra Química/metabolismo , Inibidores da Colinesterase/metabolismo , Sarina/metabolismo , Sítios de Ligação , Butirilcolinesterase/genética , Catálise , Células HEK293 , Humanos , Mutação , Ligação Proteica , Especificidade por SubstratoRESUMO
A coumarin-tetrapeptide conjugate, EFEK(DAC)-NH2 (1), is reported to undergo a pH-dependent interconversion between nanotubes and nanoribbons. An examination of zeta potential measurements, circular dichroism (CD) spectra, and microscopy imaging (transmission electron microscopy and atomic force microscopy) identified three different self-assembly regimes based on pH: (1) pH 2-5, positively charged, left-handed helical nanotubes; (2) pH 6-8, negatively charged, right-handed helical nanoribbons; and (3) pH ≥ 9.0, a monomeric/disassembled peptide. The nanotubes exhibited uniform diameters of 41 ± 5 nm and wall thicknesses of 4.8 ± 0.8 nm, whereas the nanoribbons existed as either flat or twisted sheets ranging in width from 11 to 60 nm with heights of 8 ± 1 nm. The UV-vis and CD spectra of the most common antiparallel, ß-sheet conformation of 1-dimer were simulated at the B3LYP/def2svpd level of theory in implicit water. These studies indicated that the transition from nanotubes to nanoribbons was coupled to an M â P helical inversion of the coumarin packing orientation, respectively, within the nanostructures. The assembly process was driven by ß-sheet aggregation and π-π interactions, leading to the formation of nanoribbons, which progressively wound into helical ribbons and laterally grew into smooth nanotubes as the pH decreased.