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Abstract Background Surfactant protein C (SP-C) is important for the function of pulmonary surfactant. Heterozygous mutations in SFTPC, the gene encoding SP-C, cause sporadic and familial interstitial lung disease (ILD) in children and adults. Mutations mapping to the BRICHOS domain located within the SP-C proprotein result in perinuclear aggregation of the proprotein. In this study, we investigated the effects of the mutation A116D in the BRICHOS domain of SP-C on cellular homeostasis. We also evaluated the ability of drugs currently used in ILD therapy to counteract these effects. Methods SP-CA116D was expressed in MLE-12 alveolar epithelial cells. We assessed in vitro the consequences for cellular homeostasis, immune response and effects of azathioprine, hydroxychloroquine, methylprednisolone and cyclophosphamide. Results Stable expression of SP-CA116D in MLE-12 alveolar epithelial cells resulted in increased intracellular accumulation of proSP-C processing intermediates. SP-CA116D expression further led to reduced cell viability and increased levels of the chaperones Hsp90, Hsp70, calreticulin and calnexin. Lipid analysis revealed decreased intracellular levels of phosphatidylcholine (PC) and increased lyso-PC levels. Treatment with methylprednisolone or hydroxychloroquine partially restored these lipid alterations. Furthermore, SP-CA116D cells secreted soluble factors into the medium that modulated surface expression of CCR2 or CXCR1 receptors on CD4+ lymphocytes and neutrophils, suggesting a direct paracrine effect of SP-CA116D on neighboring cells in the alveolar space. Conclusions We show that the A116D mutation leads to impaired processing of proSP-C in alveolar epithelial cells, alters cell viability and lipid composition, and also activates cells of the immune system. In addition, we show that some of the effects of the mutation on cellular homeostasis can be antagonized by application of pharmaceuticals commonly applied in ILD therapy. Our findings shed new light on the pathomechanisms underlying SP-C deficiency associated ILD and provide insight into the mechanisms by which drugs currently used in ILD therapy act.

Abstract Background Heterozygous mutations of SFTPC, the gene encoding surfactant protein C (SP-C), cause sporadic and familial interstitial lung disease (ILD) in children and adults. The most frequent SFTPC mutation in ILD patients leads to a threonine for isoleucine substitution at position 73 (I73T) of the SP-C preprotein (proSP-C), however little is known about the cellular consequences of SP-CI73T expression. Results To address this, we stably expressed SP-CI73T in cultured MLE-12 alveolar epithelial cells. This resulted in increased intracellular accumulation of proSP-C processing intermediates, which matched proSP-C species recovered in bronchial lavage fluid from patients with this mutation. Exposure of SP-CI73T cells to drugs currently used empirically in ILD therapy, cyclophosphamide, azathioprine, hydroxychloroquine or methylprednisolone, enhanced expression of the chaperones HSP90, HSP70, calreticulin and calnexin. SP-CI73T mutants had decreased intracellular phosphatidylcholine level (PC) and increased lyso-PC level without appreciable changes of other phospholipids. Treatment with methylprednisolone or hydroxychloroquine partially restored these lipid alterations. Furthermore, SP-CI73T cells secreted into the medium soluble factors that modulated surface expression of CCR2 or CXCR1 receptors on CD4+ lymphocytes and neutrophils, suggesting a direct paracrine influence of SP-CI73T on neighboring cells in the alveolar space. Conclusion We show that I73T mutation leads to impaired processing of proSP-C in alveolar type II cells, alters their stress tolerance and surfactant lipid composition, and activates cells of the immune system. In addition, we show that some of the mentioned cellular aspects behind the disease can be modulated by application of pharmaceutical drugs commonly applied in the ILD therapy.

The Wittig reaction is renowned as exceptionally versatile method for converting a diversity of aldehydes and ketones into alkenes. Recently, strategies for chiral phosphine catalysis under P III /P V =O redox cycling emerged to render this venerable transformation stereoselective. Herein, we describe that phosphine redox catalysis enables the enantioselective synthesis of pertinent biaryl atropisomers by means of a stereocontrolled arene-forming Wittig reaction. Key to the process is the release of an endogenous base from readily accessible tert-butyloxycarbonylated Morita-Baylis-Hillman adducts triggered by catalyst intramolecularization, permitting mild phosphine redox catalysis for atroposelective Wittig reactions. By this strategy, a broad diversity of biaryl atropisomers is obtained with up to 94 : 6 enantioselectivity., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Atropisomeric compounds-stereoisomers that arise from the restricted rotation about a single bond-have attracted widespread attention in recent years due to their immense potential for applications in a variety of fields, including medicinal chemistry, catalysis and molecular nanoscience. This increased interest led to the invention of new molecular motors, the incorporation of atropisomers into drug discovery programmes and a wide range of novel atroposelective reactions, including those that simultaneously control multiple stereogenic axes. A diverse set of synthetic methodologies, which can be grouped into desymmetrizations, (dynamic) kinetic resolutions, cross-coupling reactions and de novo ring formations, is available for the catalyst-controlled stereoselective synthesis of various atropisomer classes. In this Review, we generalize the concepts for the catalyst-controlled stereoselective synthesis of atropisomers within these categories with an emphasis on recent advancements and underdeveloped atropisomeric scaffolds beyond stereogenic C(sp 2 )-C(sp 2 ) axes. We also discuss more complex systems with multiple stereogenic axes or higher-order stereogenicity., (© 2024. Springer Nature Limited.)

An efficient methodology for the photoredox- and nickel-catalyzed aminocarbonylation of (hetero)aryl bromides was developed. The utilization of readily available oxamic acids, the application of a broadly used organic photoredox catalyst (4CzIPN), and mild reaction conditions make this transformation an appealing alternative to classical amidation procedures. The generation of carbamoyl radicals was supported by trapping reactions with a hydrogen atom transfer catalyst in the presence of D 2 O, yielding the deuterated formamide. The generality of this deuteration protocol was confirmed for various oxamic acids.

Objectives: The transforming growth factor-Beta (TGF-ß) pathway may be involved in the radioresistance of head and neck squamous cell carcinoma (HNSCC). This study analyzed TGF-ß receptor 1 (TGFBR1) expression in HNSCC patients and evaluated the antineoplastic and radiosensitizing effects of vactosertib, a novel TGFBR1 inhibitor, in vitro., Materials and Methods: TGFBR1 expression was examined in HNSCC patients at the mRNA level in silico and the protein level by immunohistochemistry, including surgical specimens of primary tumors, matched lymph node metastasis, and recurrent disease. Furthermore, a novel small molecule TGFBR1 inhibitor was evaluated in HNSCC cell lines. Finally, an indirect coculture model using patient-derived cancer-associated fibroblasts was applied to mimic the tumor microenvironment., Results: Patients with high TGFBR1 mRNA levels showed significantly worse overall survival in silico (OS, p = 0.024). At the protein level, an association between TGFBR1 + tumor and OS was observed for the subgroup with TGFBR1-stroma (p = 0.001). Those results prevailed in multivariable analysis. Inhibition of TGFBR1 showed antineoplastic effects in vitro. In combination with radiation, vactosertib showed synergistic effects., Conclusion: Our results indicate a high risk of death in tumor TGFBR1+ |stroma TGFBR1- expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib., (© 2023 The Authors. Oral Diseases published by Wiley Periodicals LLC.)

A monumental diversity of catalytic methods imparts the ability to select one of two configurations of tetravalent stereocentres. Conversely, catalyst control over pentavalent stereocentres, where a fifth moiety bound to the central atom encodes an expanded stereochemical space, remained a challenge to be accomplished. Herein, we report the feasibility of the catalytic tractability of pentavalent stereocentres. A bifunctional iminophosphorane thiourea catalyst enables enantio- and diastereocontrol over pentavalent phosphoranes to differentiate configurationally stable enantiomers and ensembles of diastereomers which emerge together from a single stereocentre. The desired dioxophosphorane stereoisomers are obtained with excellent yield and selectivity (up to 99% yield, 96:4 e.r. and 99:1 d.r.), while stereodivergent catalysis reroutes the reaction for selective access to each of the viable stereoisomeric states of pentavalent phosphoranes. Considering the diversity of high-valent main group species, it is expected that catalyst control over pentavalent stereocentres significantly increases the synthetically addressable stereochemical space., (© 2023. The Author(s).)

Alterations in the DNA damage response play a crucial role in radio- and chemoresistance of neoplastic cells. Activation of the Ataxia telangiectasia and Rad3-related (ATR) pathway is an important DNA damage response mechanism in head and neck squamous cell carcinoma (HNSCC). Berzosertib, a selective ATR inhibitor, shows promising radio- and chemosensitizing effects in preclinical studies and is well tolerated in clinical studies. The aim of this study was to elucidate the effect of berzosertib treatment in combination with radiation and cisplatin in HNSCC. The HNSCC cell lines Cal-27 and FaDu were treated with berzosertib alone and in combination with radiation or cisplatin. Cell viability and clonogenic survival were evaluated. The effect of combination treatment was evaluated with the SynergyFinder or combination index. Apoptosis was assessed via measurement of caspase 3/7 activation and migration was evaluated using a wound healing assay. Berzosertib treatment decreased cell viability in a dose-dependent manner and increased apoptosis. The IC 50 of berzosertib treatment after 72 h was 0.25-0.29 µM. Combination with irradiation treatment led to a synergistic increase in radiosensitivity and a synergistic or additive decrease in colony formation. The combination of berzosertib and cisplatin decreased cell viability in a synergistic manner. Additionally, berzosertib inhibited migration at high doses. Berzosertib displays a cytotoxic effect in HNSCC at clinically relevant doses. Further evaluation of combination treatment with irradiation and cisplatin is strongly recommended in HNSCC patients as it may hold the potential to overcome treatment resistance, reduce treatment doses and thus mitigate adverse events., (© 2023. The Author(s).)

Metal-based photosensitizers commonly undergo quantitative intersystem crossing into photoactive triplet excited states. In contrast, organic photosensitizers often feature weak spin-orbit coupling and low intersystem crossing efficiencies, leading to photoactive singlet excited states. By modifying the well-known acridinium dyes, we obtained a new family of organic photocatalysts, the isoacridones, in which both singlet- and triplet-excited states are simultaneously photoactive. These new isoacridone dyes are synthetically readily accessible and show intersystem crossing efficiencies of up to 52%, forming microsecond-lived triplet excited states (T 1 ), storing approximately 1.9 eV of energy. Their photoactive singlet excited states (S 1 ) populated in parallel have only nanosecond lifetimes, but store ∼0.4 eV more energy and act as strong oxidants. Consequently, the new isoacridone dyes are well suited for applications requiring parallel triplet-triplet energy transfer and photoinduced electron transfer elementary steps, which have become increasingly important in modern photocatalysis. In proof-of-principle experiments, the isoacridone dyes were employed for Birch-type arene reductions and C-C couplings via sensitization-initiated electron transfer, substituting the commonly used iridium or ruthenium based photocatalysts. Further, in combination with a pyrene-based annihilator, sensitized triplet-triplet annihilation upconversion was achieved in an all-organic system, where the upconversion quantum yield correlated with the intersystem crossing quantum yield of the photosensitizer. This work seems relevant in the greater contexts of developing new applications that utilize biphotonic photophysical and photochemical behavior within metal-free systems., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Alongside enantioselective catalysis, synthetic chemists are often confronted by the challenge of achieving catalyst control over the relative configuration to stereodivergently access desired diastereomers. Typically, these approaches iteratively or simultaneously control multiple stereogenic units for which dual catalytic methods comprising sequential, relay, and synergistic catalysis emerged as particularly efficient strategies. In this Perspective, the benefits and challenges of catalyst-controlled diastereodivergence in the construction of carbon stereocenters are discussed on the basis of illustrative examples. The concepts are then transferred to diastereodivergent catalysis for atropisomeric systems with twofold and higher-order stereogenicity as well as diastereodivergent catalyst control over E - and Z -configured alkenes., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Herein, we describe the feasibility of atroposelective P III /P V =O redox organocatalysis by the Staudinger-aza-Wittig reaction. The formation of isoquinoline heterocycles thereby enables the synthesis of a broad range of valuable atropisomers under mild conditions with enantioselectivities of up to 98 : 2 e.r. Readily prepared azido cinnamate substrates convert in high yield with stereocontrol by a chiral phosphine catalyst, which is regenerated using a silane reductant under Brønsted acid co-catalysis. The reaction provides access to diversified aryl isoquinolines, as well as benzoisoquinoline and naphthyridine atropisomers. The products are expeditiously transformed into N-oxides, naphthol and triaryl phosphine variants of prevalent catalysts and ligands. With dinitrogen release and aromatization as ideal driving forces, it is anticipated that atroposelective redox organocatalysis provides access to a multitude of aromatic heterocycles with precise control over their configuration., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Catalyst control over higher-order stereogenicity addresses significantly extended stereochemical space, but selective methods to govern threefold stereogenic units remained elusive. Herein, we report the stereoselective synthesis of threefold stereogenic triptycyl sulfones with atropisomerism arising from a C(sp 3 )-S bond. An oxidation of a stereodynamic thioether controlled by a chiral phosphoric acid catalyst allowed selective access to enantioenriched triptycyl sulfoxides. The ensuing enantiospecific and diastereoselective catalytic oxidation to a threefold stereogenic sulfone provided overall control over the stereogenic C-S axis. All three stereoisomers were addressable with enantio- and diastereodivergence and a stereoselectivity of up to (-sc): (+sc) : (ap)=94 : 6 :<1., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Alkene metathesis catalyzed by enantiopure metal alkylidene complexes enables exceptionally versatile strategies to products with configurationally-defined stereocenters. Desymmetrization processes thereby provide reliable stereoselective routes to aliphatic structures, while the differentiation of aromatic stereogenic units remained an outstanding challenge. Herein, we describe the feasibility of alkene metathesis to catalytically control stereogenic axes by traceless arene formation. Stereodynamic trienes are selectively converted into corresponding binaphthalene atropisomers upon exposure to a chiral molybdenum catalyst. Remarkably, stereoselective arene-forming metathesis allows enantioselectivities of up to 98 : 2 e.r. and excellent yields. As the disconnection of each bond of an aromatic target is retrosynthetically conceivable, it is anticipated that forging arenes by means of stereoselective metathesis will enable versatile approaches for the synthesis of a broad range of molecular topologies with precisely defined configuration., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

o-Quinodimethanes have remarkable utility as reactive intermediates in Diels-Alder reactions, enabling significantly accelerated routes to complex polycyclic compounds. The discovery of different discrete precursors to thermally generate o-quinodimethanes thereby greatly augmented their availability and versatility. However, due to the required high temperatures and the immense reactivity of o-quinodimethanes, stereoselectivity to afford isomerically defined products still constitutes a critical challenge. Herein, we describe the accessibility of atropisomeric o-quinodimethanes, the enantioselective synthesis of their precursors, their remarkable configurational stability and the stereospecific transformation by the benzannulation of dienophiles. A catalyst-stereocontrolled [2+2+2] cycloaddition, the generation of o-quinodimethane atropisomers and ensuing stereospecific Diels-Alder reactions enabled enantioselectivities through these transient intermediates with of up to 96 : 4 e.r., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The deracemisation of fourfold stereogenic cobalt(III) diketonates with a chiral photocatalyst is described. With only 0.5 mol% menthyl Ru(bpy) 3 2+ photocatalyst, an enantiomeric enrichment of up to 88 : 12 e.r. was obtained for the major meridional diastereomers. Moreover, a distribution of configurationally stable diastereomers distinct from the thermodynamic ratio was observed upon reaching the photostationary state.

Simultaneous control over the configuration of multiple stereocenters is accomplished by numerous catalytic methods, providing a reliable basis for the synthesis of stereochemically complex targets in isomerically defined form. In contrast, addressing the configurations of multiple stereogenic axes with diastereodivergent catalyst control is thus far only possible by stepwise approaches. Herein we now describe that all four stereoisomers of atropisomeric two-axis systems are directly tractable by assembling a central aromatic unit of teraryls through an arene-forming aldol condensation. By using cinchona alkaloid-based ion-pairing catalysts, the four feasible reaction pathways are differentiated from identical substrates under defined basic conditions without preactivation, thus enabling complete stereodivergence with enantioselectivities of up to 99 : 1 e.r., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Quinone methides are fundamental intermediates for a wide range of reactions in which catalyst stereocontrol is often achieved by hydrogen bonding. Herein, we describe the feasibility of an intramolecular Friedel-Crafts 6π electrocyclization through ortho-quinone methide iminiums stereocontrolled by a contact ion pair. A disulfonimide catalyst activates racemic trichloroacetimidate substrates and imparts stereocontrol in the cyclization step, providing a new avenue for selective ortho-quinone methide iminium functionalization. A highly stereospecific oxidation readily transforms the enantioenriched acridanes into rotationally restricted acridiniums. Upon ion exchange, the method selectively affords atropisomeric acridinium tetrafluoroborate salts in high yields and an enantioenrichment of up to 93 : 7 e.r. We envision that ion-pairing catalysis over ortho-quinone methide iminiums enables the selective synthesis of a diversity of heterocycles and aniline derivatives with distinct stereogenic units., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Overcrowded alkenes are expeditiously prepared by the versatile Barton-Kellogg olefination and have remarkable applications as functional molecules owing to their unique stereochemical features. The induced stereodynamics thereby enable the controlled motion of molecular switches and motors, while the high configurational stability prevents undesired isomeric scrambling. Bistricyclic aromatic enes are prototypical overcrowded alkenes with outstanding stereochemical properties, but their stereocontrolled preparation was thus far only feasible in stereospecific reactions and with chiral auxiliaries. Herein we report that direct catalyst control is achieved by a stereoselective Barton-Kellogg olefination with enantio- and diastereocontrol for various bistricyclic aromatic enes. Using Rh 2 (S-PTAD) 4 as catalyst, several diazo compounds were selectively coupled with a thioketone to give one of the four anti-folded overcrowded alkene stereoisomers upon reduction. Complete stereodivergence was reached by catalyst control in combination with distinct thiirane reductions to provide all four stereoisomers with e.r. values of up to 99:1. We envision that this strategy will enable the synthesis of topologically unique overcrowded alkenes for functional materials, catalysis, energy- and electron transfer, and bioactive compounds., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Nanopatterned surfaces enhance incident electromagnetic radiation and thereby enable the detection and characterization of self-assembled monolayers (SAMs), for instance in surface-enhanced Raman spectroscopy (SERS). Herein, Au nanohole arrays, developed and characterized as SERS substrates, are exemplarily used for monitoring a solid-phase deprotection and a subsequent copper(I)-catalyzed azide-alkyne cycloaddition "click" reaction, performed directly on the corresponding SAMs. The SERS substrate was found to be highly reliable in terms of signal reproducibility and chemical stability. Furthermore, the intermediates and the product of the solid-phase synthesis were identified by SERS. The spectra of the immobilized compounds showed minor differences compared to spectra of the microcrystalline solids. With its uniform SERS signals and the high chemical stability, the platform paves the way for monitoring molecular manipulations in surface functionalization applications., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

A mild photocatalytic phenol oxygenation enabled by a continuous-flow photoreactor using visible light and pressurized air is described herein. Products for wide-ranging applications, including the synthesis of vitamins, were obtained in high yields by precisely controlling principal process parameters. The reactor design permits low organophotocatalyst loadings to generate singlet oxygen. It is anticipated that the efficient aerobic phenol oxygenation to benzoquinones and p-quinols contributes to sustainable synthesis., (© 2021 Wiley-VCH GmbH.)

The steadily growing interest in substituting precious-metal photoredox catalysts with organic surrogates is vibrantly sustained by emerging methodologies to vary their photochemical behavior. Herein, we report an ad hoc approach for the preparation of acridinium salts with a particularly broad range of photoredox properties. The method involves an aryne-imine-aryne coupling to a linchpin tetrafluoro acridinium salt for a late-stage diversification by nucleophilic aromatic substitution reactions to form diaminoacridinium and undescribed aza-rhodol photocatalysts. The different functionalities and redox properties of the organic acridinium photocatalysts render them suitable for bifunctional photoredox catalysis and organocatalytic photochemical C-N cross-couplings.

The organocatalytic epoxidation of unactivated alkenes using aqueous hydrogen peroxide provides various indispensable products and intermediates in a sustainable manner. While formyl functionalities typically undergo irreversible oxidations when activating an oxidant, an atropisomeric two-axis aldehyde capable of catalytic turnover was identified for high-yielding epoxidations of cyclic and acyclic alkenes. The relative configuration of the stereogenic axes of the catalyst and the resulting proximity of the aldehyde and backbone residues resulted in high catalytic efficiencies. Mechanistic studies support a non-radical alkene oxidation by an aldehyde-derived dioxirane intermediate generated from hydrogen peroxide through the Payne and Criegee intermediates., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Contradictory to the first intuitive impression that forging putatively flat aromatic rings evades stereoisomerism, a striking variety of atropisomeric compounds are conceivable by the formation of arenes, offering captivating avenues for catalyst-controlled stereoselective strategies. Since the assembled atropisomeric products that contain one or several rotationally restricted single bonds are characterized by especially well defined molecular architectures, they are distinctly suitable for numerous pertinent applications. In view of the fascinating arene-forming aldol condensation pathways taking place in polyketide biosynthesis (cyclases/aromatases (CYC/ARO)), the versatile small-molecule-catalyzed aldol reaction appeared as an exceptionally appealing synthetic means to prepare various unexplored atropisomeric compounds in our efforts presented herein. In our initial studies, the use of secondary amine organocatalysts provided excellent selectivities in stereoselective arene-forming aldol condensations for a broad range of atropisomeric products, such as biaryls and rotationally restricted aromatic amides. In further analogy to polyketide biosynthesis, it was also conceivable that several aromatic rings are formed in catalytic cascade reactions. The use of small-molecule catalysts thereby enabled us to transfer this concept to the conversion of unnatural and noncanonical polyketide substrates, thus giving access to atropisomers with particular value for synthetic applications. The versatility of the stereoselective aldol reactions with numerous catalytic activation modes further provided a strategy to individually control several stereogenic axes, similar to the various methodologies developed for controlling stereocenter configurations. By the use of iterative building block additions combined with catalyst-controlled aldol reactions to form the aromatic rings, stereodivergent pathways for catalyst-substrate-matched and -mismatched products were obtained. Besides secondary amines, cinchona-alkaloid-based quaternary ammonium salts also proved to be highly efficient in overcoming severe substrate bias. The obtained atropisomeric multiaxis systems, with all of the biaryl bonds suitably restricted in rotation even at high temperatures, are spatially distinctly defined. The helical secondary structure is therefore excellently suited for several captivating applications.While previous catalyst-controlled stereoselective methods distinguish two stereoisomers for each stereogenic unit, catalyst control beyond the realms of this dualistic stereoisomerism remained unexplored. By the selective preparation of O̅ki atropisomers characterized by their sixfold stereogenicity in Rh-catalyzed [2 + 2 + 2] cyclotrimerizations, one out of the six possible stereoisomers resulting from the restricted rotation of a single bond was shown to be catalytically addressable. Catalyst control over higher-order stereogenicity therefore further interconnects conformational analysis and stereoselective catalysis and offers captivating avenues to explore uncharted stereochemical space for creating a broad range of unprecedented molecular motifs.

Background Creating useful recommendations for changes in surgical protocols during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been difficult due to a lack of studies based on representative samples. This study evaluates the clinical outcomes and characteristics of patients undergoing urgent or emergent surgeries. Methods This is a multi-center (eight-hospital), retrospective, observational study of urgent and emergent surgical patients from Colorado and Kansas, the United States, in the early stages of the SARS-CoV-2 pandemic. Patient groups were divided based on their coronavirus disease 2019 (COVID-19) status: positive, negative and untested. COVID-19 testing was performed after the surgery if patients were symptomatic. Results The analysis includes 5,547 patients who underwent surgery from March 1, 2020 to May 17, 2020. Seventy-four percent (4,096) were not tested for COVID-19 due to lack of symptoms. Out of the 1,451 tested patients, 1,412 tested negative, and 39 tested positive. Out of all the patients who tested positive, 69.23% were admitted to the intensive care unit (ICU), whereas 16.72% of untested and 21.25% of the negative patients. The invasive ventilation rate for the patients that tested positive was 46.15%, 4.22% for untested, and 8.85% for patients who tested negative. The mortality rate in the positive group was 7.69%, 1.10% in the untested group, and 1.56% in the positive group.    Conclusion Patients who tested positive for COVID-19 had worse clinical outcomes than patients who tested negative and untested. We recommend creating criteria for testing based on patient characteristics and surgical procedure rather than testing all patients awaiting surgery; this would allow us to conserve resources moving forward., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Colosimo et al.)

Background: Inpatient data for COVID-19 (SARS-CoV-2) afflicted inpatients remain sparse. Data are needed to create accurate projections for resource consumption as the pandemic continues. Published reports of inpatient data have come from China, Italy, Singapore, and both the East and West coasts of the United States., Objective: The objective is to present our inpatient experience with COVID-19. Design, Setting, and Participants . This is a retrospective study of 681 patients with laboratory-confirmed COVID-19 from six hospitals in the Denver metropolitan area admitted between February 18 and April 30, 2020. Clinical outcomes of patients discharged or expired by April 30, 2020, were analyzed. Main Outcomes . We compiled patient demographics, length of stay, number of patients transferred to or admitted to the ICU, ICU length of stay, mechanical ventilation requirements, and mortality rates., Results: Of the 890 patients with laboratory-confirmed COVID-19, 681 had discharged and were included in this analysis. We observed 100% survival of the 0-18 age group ( n  = 2), 97% survival of the 19-30 age group, 95% survival of the 31-64 age group, 79% survival of the 65-84 age group, and 75% survival of the 85 and older age group. Our total inpatient mortality was 13% (91 patients), rising to 29% (59 patients) for those requiring ICU care., Conclusions: Compared to similar reports from other metropolitan areas, our analysis of discharged or expired COVID-19 patients from six major hospitals in the Denver metropolitan area revealed a lower mortality. This includes the subset of patients admitted to the ICU regardless of the need for intubation. A lower ICU length of stay was also observed., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Paula J. Watts et al.)

The biomimetic synthesis of aromatic polyketides from macrocyclic substrates by means of catalyst-controlled transannular cyclization cascades is described. The macrocyclic substrates, which feature increased stability and fewer conformational states, were thereby transformed into several distinct polyketide scaffolds. The catalyst-controlled transannular cyclizations selectively led to aromatic polyketides with a defined folding and oxygenation pattern, thus emulating β-keto-processing steps of polyketide biosynthesis., (© 2020 Wiley-VCH GmbH.)

Aldol reactions belong to the most important methods for carbon-carbon bond formation and are also involved in one of the most astonishing biosynthetic processes: the biosynthesis of polyketides governed by an extraordinarily sophisticated enzymatic machinery. In contrast to the typical linear or convergent strategies followed in chemical synthesis, this late-stage catalysis concept allows Nature to assemble intermediates that are diversified into a broad range of scaffolds, which assume various crucial biological functions. To transfer this concept to small-molecule catalysis to access products beyond the natural systems, a stepwise approach to differentiate increasingly complex substrates was followed by investigating arene-forming polyketide cyclizations. An outline of our efforts to develop and apply these concepts are presented herein.

A topologically well-defined atropisomeric teraryl monophosphine ligand system, prepared by a highly stereoselective arene-forming aldol condensation combined with a direct ester-to-anthracene transformation, is described herein. The ligands were evaluated for gold(I)-catalyzed [2+2] cycloaddition and cycloisomerization reactions as well as a unique intramolecular Pd-catalyzed C-N cross-coupling for the atroposelective synthesis of a N-aryl-indoline bearing a C-N stereogenic axis. The ligand structure induced up to 95:5 stereoselectivity in the asymmetric allylic alkylation reaction and features an interesting dynamic behavior as observed by X-ray crystallographic studies., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The folding and cyclization of poly-β-carbonyl chains controlled by the intricate enzymatic polyketide synthase machinery results in a remarkable diversity of aromatic natural products. Synthetic methods that allow for the preparation of highly reactive polyketide chains while governing their folding in ensuing cyclizations likewise lead to versatile divergent preparations of aromatic scaffolds valuable for numerous applications. Although biomimetic polyketide cyclizations have repeatedly been applied in the total synthesis of polyphenol natural products, their utility for the preparation of the broad range of polyaromatic architectures has yet to reach its full potential. This Minireview highlights some of the virtues of applying polyketide logic to the retrosynthetic analysis of polycyclic aromatic scaffolds, the increasing accessibility of precursors, and the potential of small-molecule catalysts for controlling polyketide cyclizations to provide polyaromatic scaffolds., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Recent developments in preparative photocatalysis have reshaped synthetic strategies and now represent an integral part of current organic chemistry. Due to their favourable electrochemical and photophysical properties, the nowadays most frequently used photocatalysts are based on precious Ru- and Ir-polypyridyl complexes. Apart from that, organic catalysts such as the acridinium salts are now commonly employed to complement transition metals to provide potentially sustainable strategies amenable to large-scale synthesis. In this feature article, the design, synthesis and application of aminoacridinium photoredox catalysts as well as their exceptionally broad range of redox properties are highlighted. Due to their modularity, this burgeoning class of organophotocatalysts is anticipated to contribute significantly to synthetic methodology development and the translation to a wide range of innovative implementations.

A catalyst repurposing strategy based on a sequential aldol addition and transfer hydrogenation giving access to enantiomerically enriched α-hydroxy-γ-butyrolactones is described. The combination of a stereoselective, organocatalytic step, followed by an efficient catalytic aldehyde reduction induces an ensuing lactonization to provide enantioenriched butyrolactones from readily available starting materials. By capitalizing from the capacity of prolineamides to act as both an organocatalyst and a transfer hydrogenation ligand, catalyst repurposing allowed the development of an operationally simple, economic, and efficient sequential catalysis approach.

Atropisomeric 1,2-naphthylene scaffolds provide access to donor-acceptor compounds with helical oligomer-based bridges, and transient absorption studies revealed a highly unusual dependence of the electron-transfer rate on oligomer length, which is due to their well-defined secondary structure. Close noncovalent intramolecular contacts enable shortcuts for electron transfer that would otherwise have to occur over longer distances along covalent pathways, reminiscent of the behavior seen for certain proteins. The simplistic picture of tube-like electron transfer can describe this superposition of different pathways including both the covalent helical backbone, as well as noncovalent contacts, contrasting the wire-like behavior reported many times before for more conventional molecular bridges. The exquisite control over the molecular architecture, achievable with the configurationally stable and topologically defined 1,2-naphthylene-based scaffolds, is of key importance for the tube-like electron transfer behavior. Our insights are relevant for the emerging field of multidimensional electron transfer and for possible future applications in molecular electronics., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mimicking an enzyme's exquisite activity and selectivity is a long-standing goal for sustainable chemical method development in aqueous media. The use of interface-rich aqueous systems, such as single-chain polymers, micelles and vesicle membranes recently emerged as strategy to emulate the compartmentalization of natural systems. In aqueous solution, aggregates such as micelles or microemulsion droplets are formed, providing reaction environments different from bulk solutions that frequently improve selectivity and accelerate reaction rates for a wide array of chemical transformations. We present here selected examples of interface-rich aqueous systems and discuss the advantages they offer for chemical synthesis. In particular metal-catalyzed cross-coupling reactions are highlighted and future challenges to perform reactions in interface-rich aqueous media are discussed.

Oligo-arginines are thoroughly studied cell-penetrating peptides (CPPs, Figures 1 and 2). Previous in-vitro investigations with the octaarginine salt of the phosphonate fosmidomycin (herbicide and anti-malaria drug) have shown a 40-fold parasitaemia inhibition with P. falciparum , compared to fosmidomycin alone (Figure 3). We have now tested this salt, as well as the corresponding phosphinate salt of the herbicide glufosinate, for herbicidal activity with whole plants by spray application, hoping for increased activities, i.e. decreased doses. However, both salts showed low herbicidal activity, indicating poor foliar uptake (Table 1). Another pronounced difference between in-vitro and in-vivo activity was demonstrated with various cell-penetrating octaarginine salts of fosmidomycin: intravenous injection to mice caused exitus of the animals within minutes, even at doses as low as 1.4 μmol/kg (Table 2). The results show that use of CPPs for drug delivery, for instance to cancer cells and tissues, must be considered with due care. The biopolymer cyanophycin is a poly-aspartic acid containing argininylated side chains (Figure 4); its building block is the dipeptide H- β Asp- α Arg-OH (H-Adp-OH). To test and compare the biological properties with those of octaarginines we synthesized Adp 8 -derivatives (Figure 5). Intravenouse injection of H-Adp 8 -NH 2 into the tail vein of mice with doses as high as 45 μmol/kg causes no symptoms whatsoever (Table 3), but H-Adp 8 -NH 2 is not cell penetrating (HEK293 and MCF-7 cells, Figure 6). On the other hand, the fluorescently labeled octamers FAM-(Adp(OMe)) 8 -NH 2 and FAM-(Adp(NMe 2 )) 8 -NH 2 with ester and amide groups in the side chains exhibit mediocre to high cell-wall permeability (Figure 6), and are toxic (Table 3). Possible reasons for this behavior are discussed (Figure 7) and corresponding NMR spectra are presented (Figure 8).

A strategy for the remote central-to-axial chirality conversion by simultaneous planarization of an encoding and a transient stereocenter is presented. Based on a diastereoselective double addition of a chiral 1,5-bifunctional organomagnesium alkoxide reagent to a broad range of aryl ester substrates, axially chiral biaryls are directly obtained upon in situ reduction. Various structurally distinct atropisomeric biaryl silanes that serve as valuable chiral biaryl anion surrogates are accessible in one step with e.r. values of up to 98:2., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

While aromatic hydrocarbons are ubiquitous in organic chemistry, they are typically not associated with chirality and stereoisomerism. Due to the planarity and symmetry of simple arenes, methods to assemble aromatic rings are not routinely considered for the stereoselective synthesis of chiral compounds. The aim of this tutorial review is to contrast this common perception with the counterintuitive circumstance that stereoselective arene formation offers a means to stereoselectively prepare an exceptional range of chiral aromatic structures. The versatility of these methods across various types of molecular scaffolds allows to control stereocentre configuration, helical chiral compounds, the configuration of rotationally restricted stereogenic axes, planar chiral molecules or curved polyaromatic systems. Furthermore, stereoselective arene formation holds great promise for the selective construction of extended but structurally well-defined chiral structures.

Molecular scaffolds with multiple rotationally restricted bonds allow a precise spatial positioning of functional groups. However, their synthesis requires methods addressing the configuration of each stereogenic axis. We report here a catalyst-stereocontrolled synthesis of atropisomeric multiaxis systems enabling divergence from the prevailing stereochemical reaction path. By using ion-pairing catalysts in arene-forming aldol condensations, a strong substrate-induced stereopreference can be overcome to provide structurally well-defined helical oligo-1,2-naphthylenes. The configuration of up to four stereogenic axes was individually catalyst-controlled, affording quinquenaphthalenes with a unique topology., Competing Interests: The authors declare no competing financial interest.

Despite the manifold use of heterocyclic fluorophores, only a fraction of the desired dye diversity can be accessed by contemporary synthetic approaches. Herein, we describe a modular method that converts various carboxylic acid esters directly into a broad spectrum of heteroanthrylium fluorophores. The double addition of heteroatom-bridged 1,5-bifunctional organomagnesium reagents to esters leads to the formation of acridinium, xanthylium, and SiR fluorophores after dehydrative acidic work-up. This one-step synthetic method provides access to organophotoredox catalysts for dual catalysis with nickel and dyes amenable to fluorescence enhancement., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: To characterize Internet and social media use among adults with moderate to severe traumatic brain injury (TBI) and to compare demographic and socioeconomic factors associated with Internet use between those with and without TBI., Setting: Ten Traumatic Brain Injury Model Systems centers., Participants: Persons with moderate to severe TBI (N = 337) enrolled in the TBI Model Systems National Database and eligible for follow-up from April 1, 2014, to March 31, 2015., Design: Prospective cross-sectional observational cohort study., Main Measures: Internet usage survey., Results: The proportion of Internet users with TBI was high (74%) but significantly lower than those in the general population (84%). Smartphones were the most prevalent means of Internet access for persons with TBI. The majority of Internet users with TBI had a profile account on a social networking site (79%), with more than half of the sample reporting multiplatform use of 2 or more social networking sites., Conclusion: Despite the prevalence of Internet use among persons with TBI, technological disparities remain in comparison with the general population. The extent of social media use among persons with TBI demonstrates the potential of these platforms for social engagement and other purposes. However, further research examining the quality of online activities and identifying potential risk factors of problematic use is recommended.

By taking inspiration from the fascinating biosynthetic machinery that creates aromatic polyketides, our group investigates analogous reactions catalyzed by small molecules. We are particularly captivated by the prospects of intramolecular aldol condensation reactions to generate different rotationally restricted aromatic compounds. In a first project of our independent research group, a highly stereoselective amine catalyzed synthesis of axially chiral biaryls, tertiary aromatic amides and oligo-1,2-naphthylenes has been developed. In this article, we outline the twists and turns for our escape from the aromatic flatland to structurally intriguing chiral arene scaffolds relevant for various fields of application.

The fundamental role that aldol chemistry adopts in various disciplines, such as stereoselective catalysis or the biosynthesis of aromatic polyketides, illustrates its exceptional versatility. On the one hand, numerous aldol addition reactions reliably transfer the stereochemical information from catalysts into various valuable products. On the other hand, countless aromatic polyketide natural products are produced by an ingenious biosynthetic machinery based on arene-forming aldol condensations. With the aim of complementing aldol methodology that controls stereocenter configuration, we recently combined these two tenets by investigating small-molecule-catalyzed aldol condensation reactions that stereoselectively form diverse axially chiral compounds through the construction of a new aromatic ring., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The increasing awareness of the importance of amide atropisomers prompts the development of novel strategies for their selective preparation. Described herein is a method for the enantioselective synthesis of atropisomeric aromatic amides by an amine-catalyzed arene-forming aldol condensation. The high reactivity of the glyoxylic amide substrates enables a remarkably efficient construction of a new aromatic ring, which proceeds within minutes at ambient temperature to afford products with excellent stereoselectivity. The high rotational barriers of the reduced products highlight the utility of this stable, spatially organized chiral scaffold., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Structurally well-defined oligomers are fundamental for the functionality of natural molecular systems and key for the design of synthetic counterparts. Herein, we describe a strategy for the efficient synthesis of individual stereoisomers of 1,2-naphthylene oligomers by iterative building block additions and consecutive stereoselective arene-forming aldol condensation reactions. The catalyst-controlled atropoenantioselective and the substrate-controlled atropodiastereoselective aldol condensation reaction provide structurally distinct ter- and quaternaphthalene stereoisomers, which represent configurationally stable analogues of otherwise stereodynamic, helically shaped ortho-phenylenes., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)