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A convenient, efficient, and inexpensive method has been developed for the synthesis of 1,2,3-triazine derivatives via deoxygenation of 1,2,3-triazine 1-oxide using trialkyl phosphites. Triethyl phosphite is more reactive than trimethyl phosphite, and both phosphites form their corresponding phosphates in these reactions. This procedure provides a range of aromatic and aliphatic substituted 1,2,3-triazine-4-carboxylate derivatives cleanly in high yields. Unexpected 1,2,4-triazine derivatives were also obtained as minor products during deoxygenation of 1,2,3-triazine-4-carboxylate 1-oxides having an aliphatic substituent at the 5-position.

α-Aminoalkyl radicals are easily accessible through multiple pathways from various precursors. Apart from their utilization as nitrogen-containing building blocks, they have recently been used as halogen atom abstraction reagents or single-electron reductants to transform organic halides or sulfonium salts into their corresponding highly reactive radical species. Benefiting from the richness of various halides and the diverse reactivity of radical intermediates, new transformations of halides and sulfonium salts have been developed. This short review summarizes this emerging chemistry that uses α-aminoalkyl radicals as the reaction activators.1 Introduction2 Activation of Halides as Halogen-Atom Transfer Agents2.1 Addition to Unsaturated Bonds2.1.1 Addition to C=C Bonds2.1.2 Addition to C=O Bonds2.2 Substitution Reactions2.2.1 Deuteration2.2.2 Olefination2.2.3 Allylation2.2.4 Aromatic Substitution2.2.5 Amination3 Activation of Sulfonium Salts as Single-Electron Reductants4 Conclusion and Outlook

An oxocarbenium-olefin cross metathesis occurs during Bronsted 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.

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.

1,2,3-Triazine 1-oxides are formed by nitrosyl addition from tert-butyl nitrite to the vinylogous position of vinyl diazo compounds. This transformation, which is a formal intermolecular [5 + 1] cycloaddition, occurs under mild conditions, with high functional group tolerance and regioselectivity, and can be employed for late-stage functionalization. Upon heating at refluxing chlorobenzene temperature, these triazine-N-oxides undergo dinitrogen extrusion to form isoxazoles in very high yields.

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.

A highly enantioselective synthesis of chiral heterobicyclic spiroketals is reported via a "one-pot" cyclopropanation-rearrangement (CP-RA) cascade reaction that is sequentially catalyzed by a chiral Rh(II) catalyst and tetrabutylammonium fluoride (TBAF). Exocyclic vinyl substrates form spirocyclopropanes with tert-butyldimethylsilyl-protected enoldiazoacetates in excellent yields and with excellent enantioselectivities when catalyzed by chiral dirhodium(II) carboxylates, and following desilylation with simultaneous rearrangement in the presence of TBAF, they give (S)-spiroketals in high yields with excellent chirality retention (>95% ee).

An unprecedented Ag(I)-catalyzed efficient method for the coupling of β-oxoimides 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.

Catalyst-directed access to divergent products involving three different metals that exclusively form three different products from the same reactants is reported. Each catalyst directs an individu...

Brønsted acid catalyzed formal [4 + 4]-, [4 + 3]-, and [4 + 2]-cycloadditions of donor–acceptor cyclobutenes, cyclopropenes, and siloxyalkynes with benzopyrylium ions are reported. [4 + 2]-cyclization/deMayo-type ring-extension cascade processes produce highly functionalized benzocyclooctatrienes, benzocycloheptatrienes, and 2-naphthols in good to excellent yields and selectivities. Moreover, the optical purity of reactant donor–acceptor cyclobutenes is fully retained during the cascade. The 1,3-dicarbonyl product framework of the reaction products provides opportunities for salen-type ligand syntheses and the construction of fused pyrazoles and isoxazoles that reveal a novel rotamer-diastereoisomerism., Brønsted acid catalysis realizes formal [4 + 4]-, [4 + 3]-, and [4 + 2]-cycloadditions of donor–acceptor cyclobutenes, cyclopropanes, and siloxyalkynes with benzopyrylium ions.

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.

A general catalytic methodology for 1,2-RF/Y-difunctionalization of conjugated alkenes is reported. Diverse functionalized carbon radicals (RF•), which are generated through copper(I)-initiated sel...

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.

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.

Chiral copper(I) catalysts are preferred over chiral dirhodium(II) catalysts for [3 + 3]-cycloaddition reactions of γ-alkyl-substituted enoldiazoacetates compounds with nitrones. Using the In-SaBox ligand these reactions effectively produce cis-3,6-dihydro-1,2-oxazine derivatives under mild conditions in high yield and with exceptional stereocontrol, and enantioselectivity increases with the size of the γ-substituent. Mechanistic studies show that cycloaddition occurs solely through the formation of (Z)-γ-substituted metallo-enolcarbene intermediates that are catalytically gennerated from both (Z)- and (E)-γ-substituted enoldiazoactates via donor–acceptor cyclopropene intermediates.

Envelope protein-targeted vaccines for flaviviruses are limited by concerns of antibody-dependent enhancement (ADE) of infections. Nonstructural protein 1 (NS1) provides an alternative vaccine target that avoids this risk since this protein is absent from the virion. Beyond its intracellular role in virus replication, extracellular forms of NS1 function in immune modulation and are recognized by host-derived antibodies. The rational design of NS1-based vaccines requires an extensive understanding of the antigenic sites on NS1, especially those targeted by protective antibodies. Here, we isolated human monoclonal antibodies (MAbs) from individuals previously naturally infected with WNV, mapped their epitopes using structure-guided mutagenesis, and evaluated their efficacy in vivo against lethal WNV challenge. The most protective epitopes clustered at three antigenic sites that are exposed on cell surface forms of NS1: (i) the wing flexible loop, (ii) the outer, electrostatic surface of the wing, and (iii) the spaghetti loop face of the β-ladder. One additional MAb mapped to the distal tip of the β-ladder and conferred a lower level of protection against WNV despite not binding to NS1 on the surface of infected cells. Our study defines the epitopes and modes of binding of protective anti-NS1 MAb antibodies following WNV infection, which may inform the development of NS1-based countermeasures against flaviviruses. IMPORTANCE Therapeutic antibodies against flaviviruses often promote neutralization by targeting the envelope protein of the virion. However, this approach is hindered by a possible concern for antibody-dependent enhancement of infection and paradoxical worsening of disease. As an alternative strategy, antibodies targeting flavivirus nonstructural protein 1 (NS1), which is absent from the virion, can protect against disease and do not cause enhanced infection. Here, we evaluate the structure-function relationships and protective activity of West Nile virus (WNV) NS1-specific monoclonal antibodies (MAbs) isolated from the memory B cells of a naturally infected human donor. We identify several anti-NS1 MAbs that protect mice against lethal WNV challenge and map their epitopes using charge reversal mutagenesis. Antibodies targeting specific regions in the NS1 structure could serve as the basis for countermeasures that control WNV infection in humans.

An oxocarbenium-olefin cross metathesis occurs during Brønsted acid catalyzed reactions of 1

1,2,3-Triazine 1-oxides are formed by nitrosyl addition from

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-β,β-dichloropropylbenzene products that are convertible to their corresponding β,β-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.

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.

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.

The influence of geometrical isomers of silyl-protected γ-substituted enoldiazoacetates has been examined in transition-metal-catalyzed vinylcarbene cycloaddition reactions. These reactions often o...

A robust and efficient synthesis of triisopropylsilyl (TIPS)-protected γ-substituted enoldiazoacetates with excellent Z stereocontrol by using lithium bis(trimethylsilyl)azanide (LiHMDS) as a base and TIPSOTf as a silyl transfer reagent is reported. Despite their increased size compared to previously tert-butyldimethylsilyl (TBS)-protected γ-unsubstituted enoldiazoacetates, a high product yield with exceptional stereocontrol has been achieved in copper-catalyzed [3+3] cycloaddition reaction with nitrones by using a chiral indeno bisoxazoline ligand.

Introduction: We previously reported our amyotrophic lateral sclerosis (ALS) video televisit experience. Here we report on video televisit versus in‐clinic costs, adjusting for perceived medical usefulness (MU). Methods: We take the patient‐perspective and a focused institutional‐perspective. Costs are adjusted for patient/caregiver and physician perceptions of visit MU. The base‐case reflects our outpatient ALS practice. Results: In the base‐case, from the patient perspective, in‐clinic visits cost $1,116 and video televisits cost $89 ($119 after MU‐adjustment). From the institutional perspective, clinic visits cost $799, and video televisits cost $354 ($472 after MU‐adjustment). Adjusted cost‐savings per televisit are $997 (patient) and $327 (institution). Sensitivity analyses on 5 variables accounted for uncertainty in base‐case assumptions. Conclusions: Video televisits provide marked adjusted cost‐savings for patients and institutions. Adjusted costs are sensitive to perceived MU of video televisits. Future research should explore the ability of video televisits to reduce healthcare resource usage. Muscle Nerve 60: 147–154, 2019

Enoldiazosulfones undergo [3 + 3]-cycloaddition with nitrones when catalyzed by copper(I) catalysts, but not with dirhodium(II) catalysts. Under mild reaction conditions with chiral bisoxazoline ligands, copper(I) catalysts produce 1,2-oxazine-sulfone derivatives in high yields and enantioselectivities. Dirhodium(II) catalysts form stable donor-acceptor cyclopropenes that undergo uncatalyzed [3 + 2]-cycloaddition reactions with nitrones.

West Nile virus (WNV), a member of the Flavivirus genus, is a leading cause of viral encephalitis in the United States1. The development of neutralizing antibodies against the flavivirus envelope (E) protein is critical for immunity and vaccine protection2. Previously identified candidate therapeutic mouse and human neutralizing monoclonal antibodies (mAbs) target epitopes within the E domain III lateral ridge and the domain I-II hinge region, respectively3. To explore the neutralizing antibody repertoire elicited by WNV infection for potential therapeutic application, we isolated ten mAbs from WNV-infected individuals. mAb WNV-86 neutralized WNV with a 50% inhibitory concentration of 2 ng ml-1, one of the most potently neutralizing flavivirus-specific antibodies ever isolated. WNV-86 targets an epitope in E domain II, and preferentially recognizes mature virions lacking an uncleaved form of the chaperone protein prM, unlike most flavivirus-specific antibodies4. In vitro selection experiments revealed a neutralization escape mechanism involving a glycan addition to E domain II. Finally, a single dose of WNV-86 administered two days post-infection protected mice from lethal WNV challenge. This study identifies a highly potent human neutralizing mAb with therapeutic potential that targets an epitope preferentially displayed on mature virions. One of the most potently neutralizing flavivirus-specific monoclonal antibodies ever isolated, WNV-86, targets an epitope in E domain II of the West Nile virus (WNV), preferentially recognizes mature virions lacking an uncleaved form of the prM chaperone protein and protects mice from lethal WNV challenge when administered two days after infection.

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