Harnessing Multistep Chalcogen Bonding Activation in the α-Stereoselective Synthesis of Iminoglycosides.

The use of noncovalent interactions (NCIs) has received significant attention as a pivotal synthetic handle. Recently, the exploitation of unconventional NCIs has gained considerable traction in challenging reaction manifolds such as glycosylation due to their capacity to facilitate entry into difficult-to-access sugars and glycomimetics. While investigations involving oxacyclic pyrano- or furanoside scaffolds are relatively common, methods that allow the selective synthesis of biologically important iminosugars are comparatively rare. Here, we report the capacity of a phosphonochalcogenide (PCH) to catalyze the stereoselective α-iminoglycosylation of iminoglycals with a wide array of glycosyl acceptors with remarkable protecting group tolerance. Mechanistic studies have illuminated the counterintuitive role of the catalyst in serially activating both the glycosyl donor and acceptor in the up/downstream stages of the reaction through chalcogen bonding (ChB). The dynamic interaction of chalcogens with substrates opens up new mechanistic opportunities based on iterative ChB catalyst engagement and disengagement in multiple elementary steps.

Exploiting π and Chalcogen Interactions for the ß-Selective Glycosylation of Indoles through Glycal Conformational Distortion.

Harnessing unconventional noncovalent interactions (NCIs) is emerging as a formidable synthetic approach in difficult-to-access glycosidic chemical space. C-Glycosylation, in particular, has gained a flurry of recent attention. However, most reported methods are restricted to the relatively facile access to α-C-glycosides. Herein, we disclose a ß-stereoselective glycosylation of indoles by employing a phosphonoselenide catalyst. The robustness of this protocol is exemplified by its amenability for reaction at both the indolyl C- and N- reactivity sites. In contrast to previous reports, in which the chalcogens were solely involved in Lewis acidic activation, our mechanistic investigation unraveled that the often neglected flanking aromatic substituents of phosphonoselenides can substantially contribute to catalysis by engaging in π-interactions. Computations and NMR spectroscopy indicated that the chalcogenic and aromatic components of the catalyst can be collectively exploited to foster conformational distortion of the glycal away from the usual half-chair to the boat conformation, which liberates the convex ß-face for nucleophilic attack.

Asymmetric Pd/Organoboron-Catalyzed Site-Selective Carbohydrate Functionalization with Alkoxyallenes Involving Noncovalent Stereocontrol.

Herein, we demonstrate the robustness of a synergistic chiral Pd/organoboron system in tackling a challenging suite of site-, regio-, enantio- and diastereoselectivity issues across a considerable palette of biologically relevant carbohydrate polyols, when prochiral alkoxyallenes were employed as electrophiles. In view of the burgeoning role of noncovalent interactions (NCIs) in stereoselective carbohydrate synthesis, our mechanistic experiments and DFT modeling of the reaction path unexpectedly revealed that NCIs such as hydrogen bonding and CH-π interactions between the resting states of the Pd-π-allyl complex and the borinate saccharide are critically involved in the stereoselectivity control. Our strategy thus illuminates the untapped potential of harnessing NCIs in the context of transition metal catalysis to tackle stereoselectivity challenges in carbohydrate functionalization.

Enantioconvergent and Site-Selective Etherification of Carbohydrate Polyols through Chiral Copper Radical Catalysis.

Going beyond currently reported two electron transformations that formed the core backdrop of asymmetric catalytic site-selective carbohydrate polyol functionalizations, we herein report a seminal demonstration of an enantioconvergent copper catalyzed site-selective etherification of minimally protected saccharides through a single-electron radical pathway. Further, this strategy paves a rare strategy, through which a carboxamide scaffold that is present in some glycomimetics of pharmacological relevance, can be selectively introduced. In light of the burgeoning interest in chiral radical catalysis, and the virtual absence of such stereocontrol broadly in carbohydrate synthesis, our strategy showcased the unknown capability of chiral radical copper catalysis as a contemporary tool to address the formidable site-selectivity challenge on a remarkable palette of naturally occurring saccharides. When reducing sugars were employed, a further dynamic kinetic resolution type glycosylation can be activated by the catalytic system to selectively generate the challenging ß-O-glycosides.

Stereoselective Entry into α,α'-C-Oxepane Scaffolds through a Chalcogen Bonding Catalyzed Strain-Release C-Septanosylation Strategy.

The utility of unconventional noncovalent interactions (NCIs) such as chalcogen bonding has lately emerged as a robust platform to access synthetically difficult glycosides stereoselectively. Herein, we disclose the versatility of a phosphonochalcogenide (PCH) catalyst to facilitate access into the challenging, but biologically interesting 7-membered ring α,α'-C-disubstituted oxepane core through an α-selective strain-release C-glycosylation. Methodically, this strategy represents a switch from more common but entropically less desired macrocyclizations to a thermodynamically favored ring-expansion approach. In light of the general lack of stereoselective methods to access C-septanosides, a remarkable palette of silyl-based nucleophiles can be reliably employed in our method. This include a broad variety of useful synthons, such as easily available silyl-allyl, silyl-enol ether, silyl-ketene acetal, vinylogous silyl-ketene acetal, silyl-alkyne and silylazide reagents. Mechanistic investigations suggest that a mechanistic shift towards an intramolecular aglycone transposition involving a pentacoordinate silicon intermediate is likely responsible in steering the stereoselectivity.

Cooperative Bifurcated Chalcogen Bonding and Hydrogen Bonding as Stereocontrolling Elements for Selective Strain-Release Septanosylation.

The exploitation of noncovalent interactions (NCIs) is emerging as a vital handle in tackling broad stereoselectivity challenges in synthesis. In particular, there has been significant recent interest in the harnessing of unconventional NCIs to surmount difficult selectivity challenges in glycosylations. Herein, we disclose the exploitation of an unconventional bifurcated chalcogen bonding and hydrogen bonding (HB) network, which paves the way for a robust catalytic strategy into biologically useful seven-membered ring sugars. Through 13C nuclear magnetic resonance (NMR) in situ monitoring, NMR titration experiments, and density functional theory (DFT) modeling, we propose a remarkable contemporaneous activation of multiple functional groups consisting of a bifurcated chalcogen bonding mechanism working hand-in-hand with HB activation. Significantly, the ester moiety installed on the glycosyl donor is critical in the establishment of the postulated ternary complex for stereocontrol. Through the 13C kinetic isotopic effect and kinetic studies, our data corroborated that a dissociative SNi-type mechanism forms the stereocontrolling basis for the excellent α-selectivity.

The Location of the Parasympathetic Fibres within the Vagus Nerve Rootlets: A Case Report and a Review of the Literature.

The vagus nerve has motor, sensory, and parasympathetic components. Understanding the nerve's internal anatomy, its variations, and relationship to the glossopharyngeal nerve are crucial for neurosurgeons decompressing the lower cranial nerves. We present a case report demonstrating the location of the parasympathetic fibres within the vagus nerve rootlets. A 47-year-old woman presented with a 1-year history of medically refractory left-sided glossopharyngeal neuralgia and a more recent history of left-sided hemi-laryngopharyngeal spasm. magnetic resonance imaging showed her left posterior inferior cerebellar artery distorting the lower cranial nerves on the affected left side. The patient consented to microvascular decompression of the lower cranial nerves with possible sectioning of the glossopharyngeal and upper sensory rootlets of the vagus nerve. During surgery, electrical stimulation of the most caudal rootlet of the vagus nerve triggered profound bradycardia. None of the more rostral rootlets had a similar parasympathetic response. This case is the first demonstration, to our knowledge, of the location of the cardiac parasympathetic fibres within the human vagus nerve rootlets. This new understanding of the vagus nerve rootlets' distribution of pure sensory (most rostral), motor/sensory (more caudal), and parasympathetic (most caudal) fibres may lead to a better understanding and diagnosis of the vagal rhizopathies. Approximately 20% of patients with glossopharyngeal neuralgia also have paroxysmal cough. This could be due to the anatomical juxtaposition of the IXth cranial nerve with the rostral vagal rootlets with pure sensory fibres (which mediate a tickling sensation in the lungs). A subgroup of patients with glossopharyngeal neuralgia have neuralgia-induced syncope. The cause of this rare condition, "vago-glossopharyngeal neuralgia," has been debated since it was first described by Riley in 1942. Our case supports the theory that this neuralgia-induced bradycardia is reflexively mediated through the brainstem with afferent impulses in the IXth and efferent impulses in the Xth cranial nerve. The rarer co-occurrence of glossopharyngeal neuralgia with hemi-laryngopharyngeal spasm (as seen in this case) may be explained by the proximity of the IXth nerve with the more caudal vagus rootlets which have motor (and probably sensory) supply to the throat. Finally, if there is a vagal rhizopathy related to compression of its parasympathetic fibres, one would expect it to be at the most caudal rootlet of the vagus nerve.

A Multistage Halogen Bond Catalyzed Strain-Release Glycosylation Unravels New Hedgehog Signaling Inhibitors.

Halogen bonding (XB) has recently emerged as a promising noncovalent activation mode that can be employed in catalysis. However, methodologies utilizing XB remain rare, and the hydrogen-bonding (HB) catalysis congeners are more widespread in comparison. Herein, we demonstrate a remarkable case whereby employment of XB catalysis in strain-release glycosylation generates O, N-glycosides in excellent anomeric selectivity exceeding HB activation. Deeper investigation unraveled XB catalyst dependencies on multiple stages of the mechanism and a hitherto unknown XB-glycosyl acceptor activation. We present a proof of concept to interrogate sp3-rich glycosidic chemical space for novel biological activity, by integrating XB-catalyzed construction of a glycosidic compound collection, and evaluating these analogues via cell-based phenotypic screens. We show that XB-catalyzed strain-release glycosylation defines a new class of glycosides that inhibit the hedgehog signaling pathway through a nonsmoothened mode of action, opening new opportunities to combat acquired cancer resistance.

The effect of nicotine and nicotine+monoamine oxidase inhibitor on the value of alcohol.

Alcohol is the most commonly abused drug in the USA and many people suffer from alcohol use disorder. Many factors are associated with alcohol use disorder, but the causal role of comorbid nicotine use has not been extensively considered. Nicotine has reward-enhancing properties and may increase the value of alcohol. Monoamine oxidase inhibition increases nicotine self-administration and may increase the reward-enhancing effects of nicotine. We assessed the effect of nicotine and nicotine in combination with a commonly used monoamine oxidase inhibitor (tranylcypromine) on the value of alcohol using a progressive ratio schedule of reinforcement in rats. Nicotine administration increased the breakpoint for alcohol, but nicotine in combination with tranylcypromine decreased the breakpoint for alcohol. The current study adds to previous research showing that nicotine increases the value of alcohol. This finding has important implications for the etiology of addiction because of the comorbidity of smoking with many drugs of abuse. The finding that nicotine in combination with tranylcypromine reduces the value of alcohol warrants further investigation.

Defining the Anatomy of the Vagus Nerve and Its Clinical Relevance for the Neurosurgical Treatment of Glossopharyngeal Neuralgia.

The neurosurgical treatment of glossopharyngeal neuralgia includes microvascular decompression or rhizotomy of the nerve. When considering open section of the glossopharyngeal nerve, numerous authors have recommended additional sectioning of the 'upper rootlets' of the vagus nerve because these fibers can occasionally carry the pain fibers causing the patient's symptoms. Sacrifice of vagus nerve rootlets, however, carries the potential risk of dysphagia and dysphonia. In this study, the anatomy and physiology of the vagus nerve rootlets are characterized to provide guidance for surgical decision-making. Twelve patients who underwent posterior fossa craniotomy with intraoperative electrophysiological monitoring of the vagus nerve rootlets were included in this study. In the 7 patients with glossopharyngeal neuralgia, the clinical outcomes and complications were further analyzed. In half of the patients, electrophysiological data demonstrated pure sensory function in the rostral rootlet(s) of the vagus nerve and motor responses in its caudal rootlets. This orientation of the vagus nerve, with some pure sensory function in its most rostral rootlet(s), was defined as Type A. In the other half of patients, all vagus nerve rootlets (including the most rostral) had motor responses. This was defined as Type B. The surgical strategy was guided by whether the patient had a Type A or Type B vagus nerve. For those with Type B, no vagus nerve rootlets were sacrificed. None of the patients with glossopharyngeal neuralgia developed any permanent neurological deficits. We recommend intraoperative electrophysiological testing of the vagus nerve rootlets. If the testing reveals motor innervation in the rostral vagal rootlet (Type B), that rootlet may be decompressed but should not be sectioned to avoid a motor complication. Patients with pure sensory innervation of the rostral rootlet(s) (Type A) can have decompression or section of those rootlets without complication.

Floc Formation Reduces the pH Stress Experienced by Microorganisms Living in Alkaline Environments.

The survival of microorganisms within a cementitious geological disposal facility for radioactive wastes heavily depends on their ability to survive the calcium-dominated, hyperalkaline conditions resulting from the dissolution of the cementitious materials. The results from this study show that the formation of flocs, composed of a complex mixture of extracellular polymeric substances (EPS), provides protection against alkaline pH values up to 13.0. The flocs were dominated by Alishewanella and Dietzia spp., producing a mannose-rich carbohydrate fraction incorporating extracellular DNA, resulting in Ca2+ sequestration. EPS provided a ∼10-µm thick layer around the cells within the center of the flocs, which were capable of growth at pH values of 11.0 and 11.5, maintaining internal pH values of 10.4 and 10.7, respectively. Microorganisms survived at a pH of 12.0, where an internal floc pH of 11.6 was observed, as was a reduced associated biomass. We observed limited floc survival (<2 weeks) at a pH of 13.0. This study demonstrates that flocs maintain lower internal pHs in response to the hyperalkaline conditions expected to occur within a cementitious geological disposal facility for radioactive wastes and indicates that floc communities within such a facility can survive at pHs up to 12.0.IMPORTANCE The role of extracellular polymeric substances (EPS) in the survival of microorganisms in hyperalkaline conditions is poorly understood. Here, we present the taxonomy, morphology, and chemical characteristics of an EPS-based microbial floc, formed by a consortium isolated from an anthropogenic hyperalkaline site. Short-term (<2 weeks) survival of the flocs at a pH of 13 was observed, with indefinite survival observed at a pH of 12.0. Measurements from micro-pH electrodes (10-µm-diameter tip) demonstrated that flocs maintain lower internal pHs in response to hyperalkaline conditions (pH 11.0, 11.5, and 12.0), demonstrating that floc formation and EPS production are survival strategies under hyperalkaline conditions. The results indicate how microbial communities may survive and propagate within the hyperalkaline environment that is expected to prevail in a cementitious geological disposal facility for radioactive wastes; the results are also relevant to the wider extremophile community.

Rhodium-Catalyzed Enantioselective Isomerization of meso-Oxabenzonorbornadienes to 1,2-Naphthalene Oxides.

Herein we describe a rhodium-catalyzed enantioselective isomerization of meso-oxabicyclic alkenes to 1,2-naphthalene oxides. These potentially useful building blocks can be accessed in moderate to excellent yields with impressive enantioselectivities. Additionally, experimental findings supported by preliminary computations suggest that ring-opening reactions of bridgehead disubstituted oxabicyclic alkenes proceed through the intermediacy of these epoxides and may point to a kinetically and thermodynamically favored reductive elimination as the origin for the observed enantioselectivities.

Differences in defence responses of Pinus contorta and Pinus banksiana to the mountain pine beetle fungal associate Grosmannia clavigera are affected by water deficit.

We tested the hypotheses that responses to the mountain pine beetle fungal associate Grosmannia clavigera will differ between the evolutionarily co-evolved host lodgepole pine (Pinus contorta var. latifolia) and the naïve host jack pine (Pinus banksiana) and that these responses will be influenced by water availability. G. clavigera inoculation resulted in more rapid stem lesion development in lodgepole than in jack pine; water deficit delayed lesion development in both species. Decreased hydraulic conductivity was observed in inoculated lodgepole pine seedlings, likely because of tracheid occlusion by fungal hyphae and/or metabolite accumulation. Drought but not inoculation significantly impacted bark abscisic acid levels. Jasmonic and salicylic acid were implicated in local and systemic responses of both species to G. clavigera, with salicylic acid appearing to play a greater role in jack pine response to G. clavigera than lodgepole pine. Water deficit increased constitutive levels and/or attenuated induced responses to G. clavigera for several monoterpenes in lodgepole but not jack pine. Instead, inoculation of well-watered but not water deficit jack pine resulted in a greater number of xylem resin ducts. These findings reveal mechanisms underlying differences in G. clavigera-induced responses between lodgepole and jack pine hosts, and how water availability modulates these responses.

Exploiting Distal Reactivity of Coumarins: A Rhodium-Catalyzed Vinylogous Asymmetric Ring-Opening Reaction.

While the utility of vinylogous enolates is well established in the setting of vinylogous aldol, Mannich, and Michael chemistries, literature reports concerning γ-reactivity are scarce for other reaction classes. Presented herein is an unprecedented example of vinylogous reactivity exemplified by the rhodium-catalyzed asymmetric ring-opening reaction of oxabicycles. This strategy also provides a powerful route to incorporate the biologically useful coumarin motif into the hydronapthalene scaffold.

Rhodium-Catalyzed Asymmetric Cycloisomerization and Parallel Kinetic Resolution of Racemic Oxabicycles.

While desymmetrizations by intermolecular asymmetric ring-opening reactions of oxabicyclic alkenes with various nucleophiles have been reported over the past two decades, the demonstration of an intramolecular variant is unknown. Reported herein is the first rhodium-catalyzed asymmetric cycloisomerization of meso-oxabicyclic alkenes tethered to bridgehead nucleophiles, thus providing access to tricyclic scaffolds through a myriad of enantioselective C-O, C-N, and C-C bond formations. Moreover, we also demonstrate a unique parallel kinetic resolution, whereby racemic oxabicycles bearing two different bridgehead nucleophiles can be resolved enantioselectively.

Benzylic Functionalization of Anthrones via the Asymmetric Ring Opening of Oxabicycles Utilizing a Fourth-Generation Rhodium Catalytic System.

While anthrones exist as privileged scaffolds in bioactive molecules, the enantioselective functionalization of anthrones is surprisingly scarce in the literature, with no asymmetric transition metal catalyzed example to date. Herein, we report the first asymmetric transition metal catalyzed benzylic functionalization of anthrones through the rhodium(I) catalyzed desymmetrization of oxabicycles. As previously developed rhodium(I) systems were found to be unsuitable for this substrate, a new robust fourth-generation [Rh(cod)OH]2 based catalytic system was developed to address synthetic challenges in this protocol.

Merging gold and organocatalysis: a facile asymmetric synthesis of annulated pyrroles.

The combination of cinchona-alkaloid-derived primary amine and Au(I) -phosphine catalysts allowed the selective C-H functionalization of two adjacent carbon atoms of pyrroles under mild reaction conditions. This sequential dual activation provides seven-membered-ring-annulated pyrrole derivatives in excellent yields and enantioselectivities.

Recent Experience Affects Delay Discounting: Evidence across Temporal Framing, Signs, and Magnitudes.

Delay discounting, the decrease in outcome value as a function of delay to receipt, is an extensive area of research. How delays are framed (i.e., temporal framing), as well as the sign and magnitude of an outcome, produce important effects on the degree to which outcomes are discounted. Here, we examined how recent experience (i.e., order of presentation) modifies these well-known findings. Experiment 1 examined the effects of temporal framing across gains and losses. Regardless of outcome sign, the order of task presentation affected the effect of temporal framing. In particular, when typical delay frames (e.g., 1 week) preceded delays framed as actual dates (e.g., February 15), discounting was less in the date-framed task. However, when dates were followed by the delay frame, there was no difference in the degree of discounting. The experience of date-framed delays persisted or carried over to the delay-framed task. Experiment 2 examined recent experience and the magnitude effect. In particular, $10 and $100 were discounted similarly between-subjects when it was the first task completed. However, once participants completed the second magnitude task, the magnitude effect was present both within-subjects and across subjects. Furthermore, $10 was discounted more steeply when it followed $100, and $100 was discounted less steeply when it followed $10. The impact of recent experience on delay discounting has important implications for understanding mechanisms that may contribute to delay discounting. Recent experience should be considered when designing delay discounting experiments as well as when implementing interventions to reduce steep delay discounting.

Integrated microscopy techniques for comprehensive pathology evaluation of an implantable left atrial pressure sensor.

The safety and efficacy of an implantable left atrial pressure (LAP) monitoring system is being evaluated in a clinical trial setting. Because the number of available specimens from the clinical trial for histopathology analysis is limited, it is beneficial to maximize the usage of each available specimen by relying on integrated microscopy techniques. The aim of this study is to demonstrate how a comprehensive pathology analysis of a single specimen may be reliably achieved using integrated microscopy techniques. Integrated microscopy techniques consisting of high-resolution gross digital photography followed by micro-computed tomography (micro-CT) scanning, low-vacuum scanning electron microscopy (LVSEM), and microground histology with special stains were applied to the same specimen. Integrated microscopy techniques were applied to eight human specimens. Micro-CT evaluation was beneficial for pinpointing the location and position of the device within the tissue, and for identifying any areas of interest or structural flaws that required additional examination. Usage of LVSEM was reliable in analyzing surface topography and cell type without destroying the integrity of the specimen. Following LVSEM, the specimen remained suitable for embedding in plastic and sectioning for light microscopy, using the positional data gathered from the micro-CT to intersect areas of interest in the slide. Finally, hematoxylin and eosin (H&E) and methylene blue staining was deployed on the slides with high-resolution results. The integration of multiple techniques on a single specimen maximized the usage of the limited number of available specimens from the clinical trial setting. Additionally, this integrated microscopic evaluation approach was found to have the added benefit of providing greater assurance of the derived conclusions because it was possible to cross-validate the results from multiple tests on the same specimen.

Asymmetric synthesis of pyrroloindolones by N-heterocyclic carbene catalyzed [2+3] annulation of α-chloroaldehydes with nitrovinylindoles.

NHC-enolate plus 3: N-heterocyclic carbenes (NHCs) serve as organocatalysts for the [2+3] annulation of nitrovinylindoles with α-chloroaldehydes via an intermediate azolium enolate. The method provides trans-disubstituted pyrroloindolones with good yields and excellent diastereo- and enantioselectivities. Further transformations lead to tetracyclic pyrrolo[1,2-a]indoles with potential psychotropic and other bioactivities.