Potent Henipavirus Neutralization by Antibodies Recognizing Diverse Sites on Hendra and Nipah Virus Receptor Binding Protein.

Hendra (HeV) and Nipah (NiV) viruses are emerging zoonotic pathogens in the Henipavirus genus causing outbreaks of disease with very high case fatality rates. Here, we report the first naturally occurring human monoclonal antibodies (mAbs) against HeV receptor binding protein (RBP). All isolated mAbs neutralized HeV, and some also neutralized NiV. Epitope binning experiments identified five major antigenic sites on HeV-RBP. Animal studies demonstrated that the most potent cross-reactive neutralizing mAbs, HENV-26 and HENV-32, protected ferrets in lethal models of infection with NiV Bangladesh 3 days after exposure. We solved the crystal structures of mAb HENV-26 in complex with both HeV-RBP and NiV-RBP and of mAb HENV-32 in complex with HeV-RBP. The studies reveal diverse sites of vulnerability on RBP recognized by potent human mAbs that inhibit virus by multiple mechanisms. These studies identify promising prophylactic antibodies and define protective epitopes that can be used in rational vaccine design.

Site Reversal in Nucleophilic Addition to 1,2,3-Triazine 1-Oxides.

One of the most important reactions of 1,2,3-triazines with a dienophile is inverse electron demand Diels-Alder (IEDDA) cycloaddition, which occurs through nucleophilic addition to the triazine followed by N2 loss and cyclization to generate a heterocycle. The site of addition is either at the 4- or 6-position of the symmetrically substituted triazine core. Although specific examples of the addition of nucleophiles to triazines are known, a comprehensive understanding has not been reported, and the preferred site for nucleophilic addition is unknown and unexplored. With access to unsymmetrical 1,2,3-triazine-1-oxides and their deoxygenated 1,2,3-triazine compounds, we report C-, N-, H-, O-, and S-nucleophilic additions on 1,2,3-triazine and 1,2,3-triazine-1-oxide frameworks where the 4- and 6-positions could be differentiated. In the IEDDA cycloadditions using C- and N-nucleophiles, the site of addition is at C-6 for both heterocyclic systems, but product formation with 1,2,3-triazine-1-oxides is faster. Other N-nucleophile reactions with triazine 1-oxides show addition at either the 4- or 6-position of the triazine 1-oxide ring, but nucleophilic attack only occurs at the 6-position on the triazine. Hydride from NaBH4 undergoes addition at the 6-position on the triazine and the triazine 1-oxide core. Alkoxides show a high nucleophilic selectivity for the 4-position of the triazine 1-oxide. Thiophenoxide, cysteine, and glutathione undergo nucleophilic addition on the triazine core at the 6-position, while addition occurs at the 4-position of the triazine 1-oxide. These nucleophilic additions proceed under mild reaction conditions and show high functional group tolerance. Computational studies clarified the roles of the nucleophilic addition and nitrogen extrusion steps and the influence of steric and electronic factors in determining the outcomes of the reactions with different nucleophiles.

Divergent Construction of N-Doped Polycyclic Aromatic Hydrocarbons with Indole as the Nitrogen Source Building Block.

An Ag/Au-catalyzed divergent cascade reaction of alkyne embedded diazoketones with indoles has been described. Preliminary mechanistic studies indicate that the reaction goes through a [4+2]-cycloaddition of an in situ formed isobenzopyrylium intermediate with indole, followed by a sequential retro-Michael addition/carbene N-H insertion process to give the benzo[i]phenanthridines products with gold catalysis; whereas a dearomatization/rearomatization sequence occurs favourably when the reaction is catalyzed by a silver catalyst, delivering benzo[b]carbazoles in generally high to excellent yields. Notably, this is a rare example of using indole as the dienophile for cycloaddition with the isobenzopyrylium species, providing a concise and practical approach for the selective construction of N-doped polycyclic aromatic hydrocarbons (PAHs) with structural diversity and broad functional-group compatibility.

Brønsted Acid Catalyzed Oxocarbenium-Olefin Metathesis/Rearrangements of 1H-Isochromene Acetals with Vinyl Diazo Compounds.

An oxocarbenium-olefin cross metathesis occurs during Brønsted acid catalyzed reactions of 1H-isochromene acetals with vinyl diazo compounds. Formally a carbonyl-alkene [2 + 2]-cyclization between isobenzopyrylium ions and the vinyl group of vinyl diazoesters, the retro-[2 + 2] cycloaddition produces a tethered alkene and a vinyl diazonium ion that, upon loss of dinitrogen, undergoes a highly selective carbocationic cascade rearrangements to diverse products whose formation is controlled by reactant substituents. Polysubstituted benzobicyclo[3.3.1]oxocines, benzobicyclo[3.2.2]oxepines, benzobicyclopropane, and naphthalenes are obtained in good to excellent yields and selectivities. Furthermore, isotopic tracer and control experiments shed light on the oxocarbenium-olefin metathesis/rearrangement process as well as on the origin of the interesting substituent-dependent selectivity.

Precise Introduction of the -CHnX3-n (X = F, Cl, Br, I) Moiety to Target Molecules by a Radical Strategy: A Theoretical and Experimental Study.

Addition of halomethyl radicals to form bioactive molecules has recently become an efficient strategy. The reaction has a bottleneck, however, which is the effective and selective generation of the proper halomethyl •CHnX3-n radical by combining CHnX4-n with a carbon radical. Understanding the reactivity and selectivity of carbon radicals in the hydrogen atom transfer (HAT) and halogen atom transfer (XAT) reactions of CHnX4-n is key to the development of such an attractive method. With the help of the emerging data-driven strategy, DFT calculations were used to explore various correlations. For selectivity, the relative energy barriers between HAT and XAT reactions (ΔG⧧H - ΔG⧧X) correlate reasonably well with the three parameters ΔGH, ΔGX, and IP, and the correlation studies reveal that the calculated IPinver and the experimental ΔBDE can be used to conveniently predict the selectivity. Predicted selectivities are consistent with experimental determinations. This work not only provides a possibility for selecting carbon radicals with the known or easily obtained physicochemical data but also demonstrates that the informatic workflow such as generating data and identifying correlations has potential applications in mining reaction rules.

Strain-Induced Nucleophilic Ring Opening of Donor-Acceptor Cyclopropenes for Synthesis of Monosubstituted Succinic Acid Derivatives.

1,2,3-Trisubstituted donor-acceptor cyclopropenes (DACPs) generated in situ from enoldiazo compounds react with nucleophiles to form α-substituted succinic acid derivatives in high yields. Initial dirhodium(II) carboxylate catalysis rapidly converts enoldiazo-acetates or -acetamides to DACPs that undergo catalyst-free Favorskii ring opening with amines, and also with anilines, alcohols, and thiols, when facilitated by catalytic amounts of 4-dimethylaminopyridine (DMAP). This methodology provides easy access to mixed esters and amides of monosubstituted succinic acids, including derivatives of naturally occurring compounds. It also affords dihydrazide, dihydroxamic acid, and diamide derivatives, as well as α-substituted tetrahydropyridazine-3,6-diones in high yields. Attempts to generate optically enriched DACPs were not successful because their populations having the R and S configurations formed with a chiral dirhodium catalyst are quite similar, and the loss of enantiocontrol likely originates from the DACP ring forming step which is reversible with its intermediate metal carbene.

Challenges in the Highly Selective [3 + 1]-Cycloaddition of an Enoldiazoacetamide to Form a Donor-Acceptor Cis-Cyclobutenecarboxamide.

A substituted donor-acceptor cyclobutenecarboxamide is synthesized with modest enantiocontrol through a chiral copper(I) complex catalyzed [3 + 1]-cycloaddition reaction of α-acyl diphenylsulfur ylides with 3-siloxy-2-diazo-3-butenamides. With a methyl substituent on the 4-position of the 3-butenamide, the cis-vicinal-3,4-disubstituted cyclobutenecarboxamide is formed with >20:1 diastereocontrol. Donor-acceptor 3-methyl-2-siloxycyclopropenecarboxamide is rapidly formed from the reactant enoldiazoamide and undergoes catalytic ring opening to give only the Z-γ-substituted metallo-enolcarbene. Elimination from 3-siloxy-2-diazo-3-pentenamide to form the conjugated 3-siloxy-2,4-pentadienamide is competitive but minimized at low temperature.

Generation of Diazomethyl Radicals by Hydrogen Atom Abstraction and Their Cycloaddition with Alkenes.

A general catalytic methodology for the synthesis of pyrazolines from α-diazo compounds and conjugated alkenes is reported. The direct hydrogen atom transfer (HAT) process of α-diazo compounds promoted by the tert-butylperoxy radical generates electrophilic diazomethyl radicals, thereby reversing the reactivity of the carbon atom attached with the diazo group. The regiocontrolled addition of diazomethyl radicals to carbon-carbon double bonds followed by intramolecular ring closure on the terminal diazo nitrogen and tautomerization affords a diverse set of pyrazolines in good yields with excellent regioselectivity. This strategy overcomes the limitations of electron-deficient alkenes in traditional dipolar [3+2]-cycloaddition of α-diazo compounds with alkenes. Furthermore, the straightforward formation of the diazomethyl radicals provides umpolung reactivity, thus opening new opportunities for the versatile transformations of diazo compounds.

AgI -Catalyzed Reaction of Enol Diazoacetates and Imino Ethers: Synthesis of Highly Functionalized Pyrroles.

An unprecedented AgI -catalyzed efficient method for the coupling of imino ethers and enol diazoacetates through a [3+2]-cycloaddition/C-O bond cleavage/[1,5]-proton transfer cascade process is reported. The general class of imino ethers that includes oxazolines, benzoxazoles and benzimidates are applicable substrates for these reactions that provide direct access to fully substituted pyrroles with uniformly high chemo- and regioselectivity. High variability in substitution at the pyrrole 2-, 5- and N-positions characterizes this methodology that also presents an entry point for further pyrrole diversification via facile modification of resulting N-functional pyrroles.

Radical-Mediated Strategies for the Functionalization of Alkenes with Diazo Compounds.

One of the most common reactions of diazo compounds with alkenes is cyclopropanation, which occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and a methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2═CR2) across a carbon-carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes, delivering new carbon radical species, and then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.

Combination of levulinic acid and sodium dodecyl sulfate on inactivation of foodborne microorganisms: A review.

The combination of levulinic acid and sodium dodecyl sulfate (SDS) in recent years has shown considerable promise as an antimicrobial intervention. Both ingredients have been designated by the U.S. Food and Drug Administration (FDA) as Generally Recognized as Safe (GRAS) for being used as a flavoring agent and multipurpose food additive, respectively. The use of levulinic acid and SDS alone has limited antimicrobial efficacy on tested microorganisms, and synergism between levulinic acid and SDS has been observed. The postulated mechanism of action of the synergistic effect is presented. The antimicrobial efficacy of levulinic acid plus SDS remains high even when organic materials are present. The other features, including penetration, foamability, and being readily soluble, extend its potential applications to disinfection of difficult-to-access areas and control of foodborne pathogens both in a planktonic state and in a biofilm. These features indicate that the levulinic acid plus SDS combination may have the potential to be applied within the food processing environment on a large scale.

Chiral 3-Acylglutaric Acid Derivatives from Strain-Induced Nucleophilic Retro-Claisen Ring-Opening Reactions.

A nucleophilic retro-Claisen ring-opening of donor-acceptor cyclobutenes, formed with high stereocontrol by [3 + 1]-cycloaddition of TIPS-protected enoldiazoacetates with α-acyl sulfur ylides, has been developed. Removal of the TIPS group to form the isolable ß-keto ester precedes the strain-induced ring-opening. Various amines, alcohols, thiols, and amino acid derivatives are effective nucleophiles, and their products are formed in very high yields via stoichiometric reactions. The chirality of the reactant donor-acceptor cyclobutenes is fully retained in the ring-opening reactions. The 3-acylglutaric acid products are converted to various valuable structures, including amido-diols, γ-aminobutyric acid (GABA) derivatives, and heterocycles.

Catalytic Oxidative Cleavage Reactions of Arylalkenes by tert-Butyl Hydroperoxide - A Mechanistic Assessment.

Oxidative cleavage reactions of arylalkenes by tert-butyl hydroperoxide that occur by free radical processes provide access to carboxylic acid or ketone products. However, the pathway to these cleavage products is complex, initiated by regioselective oxygen radical addition to the carbon-carbon double bond. Subsequent reactions of the initially formed benzyl radical lead eventually to carbon-carbon cleavage. Thorough investigations of these reactions have identified numerous reaction intermediates that are on the pathways to final product formation, and they have identified a new synthetic methodology for the synthesis of peroxy radical addition-induced hydroperoxide formation.

Case Study of Phrenic Nerve Paralysis: "I Can't Breathe!"

BACKGROUND: The anatomic course of the phrenic nerve runs in the fascia covering the anterior scalene muscle. Interscalene blocks are commonly performed by an anesthesiologist for shoulder surgery, such as a rotator cuff repair, total shoulder replacement, humeral fracture, or other arm surgery. Phrenic nerve palsy or paralysis is a known complication from interscalene block and is covered in multiple case reports and series in both Anesthesia and Neurosurgical literature, but only one case report in the Emergency Medicine literature. CASE REPORT: This case involves a 57-year-old man who had an uncomplicated arthroscopic rotator cuff repair with placement of interscalene block under care of anesthesia. He was discharged with a pain pump in place and then subsequently presented to the Emergency Department (ED) later that same day for evaluation of dyspnea. Using point-of-care ultrasound, his right diaphragm did not appear to be moving. Chest x-ray study revealed an elevated right hemidiaphragm. He was diagnosed with iatrogenic right phrenic nerve paralysis from interscalene block. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergent diagnosis of phrenic nerve paralysis in the ED is complicated by a distressed patient and need for quick intervention. Most formal tests for this diagnosis are not immediately available to emergency physicians. Ultrasound is a rapid and reproducible, noninvasive resource with high sensitivity and specificity, making it an ideal imaging modality for the emergent evaluation of possible phrenic nerve palsy or paralysis.

Brønsted Acid Catalyzed Friedel-Crafts-Type Coupling and Dedinitrogenation Reactions of Vinyldiazo Compounds.

The direct Friedel-Crafts-type coupling and dedinitrogenation reactions of vinyldiazo compounds with aromatic compounds using a metal-free strategy are described. This Brønsted acid catalyzed method is efficient for the formation of α-diazo ß-carbocations (vinyldiazonium ions), vinyl carbocations, and allylic or homoallylic carbocation species via vinyldiazo compounds. By choosing suitable nucleophilic reagents to selectively capture these intermediates, both trisubstituted α,ß-unsaturated esters, ß-indole-substituted diazo esters, and dienes are obtained with good to high yields and selectivity. Experimental insights implicate a reaction mechanism involving the selective protonation of vinyldiazo compounds and the subsequent release of dinitrogen to form vinyl cations that undergo intramolecular 1,3- and 1,4- hydride transfer processes as well as fragmentation.

Generation of Halomethyl Radicals by Halogen Atom Abstraction and Their Addition Reactions with Alkenes.

α-Aminoradicals undergo halogen atom abstraction to form halomethyl radicals in reactions initiated by the combination of tert-butyl hydroperoxide, aliphatic trialkylamine, halocarbon, and copper(I) iodide. The formation of the α-aminoradical circumvents preferential hydrogen atom transfer in favor of halogen atom transfer, thereby releasing the halomethyl radical for addition to alkenes. The resulting radical addition products add the tert-butylperoxy group to form α-peroxy-ß,ß-dichloropropylbenzene products that are convertible to their corresponding ß,ß-dichloro-alcohols and to novel pyridine derivatives. Computational analysis clearly explains the deviation from traditional HAT of chloroform and also establishes formal oxidative addition/reductive elimination as the lowest energy pathway.

Catalytic asymmetric cycloaddition reactions of enoldiazo compounds.

This review describes catalytic asymmetric cycloaddition reactions of silyl-protected enoldiazo compounds for the construction of highly functionalized carbo- and heterocycles which possess one or more chiral center(s). The enoldiazo compound or its derivative, donor-acceptor cyclopropene, form electrophilic vinylogous metal carbene intermediates that combine stepwise with nucleophilic dipolar reactants to form products from [3 + 1]-, [3 + 2]-, [3 + 3]-, [3 + 4]-, and [3 + 5]-cycloaddition, generally in high yield and with exceptional stereocontrol and regioselectivity.

Catalytic Desymmetric Cycloaddition of Diaziridines with Metalloenolcarbenes: The Role of Donor-Acceptor Cyclopropenes.

A chiral copper(I) complex catalyzes reactions of symmetric diaziridines with enol diazo compounds, which react through N-N bond ring opening in a formal [3+3] cycloaddition to form four chiral centers with high stereocontrol. A broad spectrum of bridged dinitrogen heterocycles were obtained in high yields and excellent diastereo- and enantioselectivities from γ-substituted enol diazoacetates, while their geometrical isomers gave different enantioselectivities. Donor-acceptor cyclopropenes formed from the geometrical isomers of the γ-substituted enol diazoacetates underwent catalytic ring opening to give only the Z isomer of the metalloenolcarbene intermediate, provided excellent yields and selectivities for the 1,5-diazabicyclo[n.3.1]non-2-ene derivatives.

Synthesis of Chiral Tetrasubstituted Azetidines from Donor-Acceptor Azetines via Asymmetric Copper(I)-Catalyzed Imido-Ylide [3+1]-Cycloaddition with Metallo-Enolcarbenes.

The all-cis stereoisomers of tetrasubstituted azetidine-2-carboxylic acids and derivatives that possess three chiral centers have been prepared in high yield and stereocontrol from silyl-protected Z-γ-substituted enoldiazoacetates and imido-sulfur ylides by asymmetric [3+1]-cycloaddition using chiral sabox copper(I) catalysis followed by Pd/C catalytic hydrogenation. Hydrogenation of the chiral p-methoxybenzyl azetine-2-carboxylates occurs with both hydrogen addition to the C=C bond and hydrogenolysis of the ester.

Synthesis of 1 H-Pyrrol-3(2 H)-ones via Three-Component Reactions of 2,3-Diketo Esters, Amines, and Ketones.

An efficient one-pot, three-component reaction of 2,3-diketo esters with amines and ketones has been developed for the synthesis of 1 H-pyrrol-3(2 H)-ones. By using trifluoroacetic acid (TFA) as the additive and acetonitrile (MeCN) as the solvent, this convenient method provides a library of 1 H-pyrrol-3(2 H)-ones in moderate to good yields. The simple protocol features readily available starting materials, a straightforward process, good functional group tolerance, and broad substrate scope.