Diastereoselective (3 + 3)-Annulations of Trisubstituted Michael Acceptors for Access to Polyfunctional Cyclohexanones.

Michael-aldol domino reactions are powerful tools for rapidly assembling carbocyclic scaffolds. We herein disclose a base-catalyzed Michael-aldol domino reaction of trisubstituted Michael acceptors with ß-keto ester nucleophiles. The cyclohexanone products are obtained in excellent diastereoselectivity (up to >20:1 dr) and good yields (up to 84%). An attractive practical consideration is that pure products are isolated directly via filtration of the unpurified reaction mixtures. Further functionalization of the cyclohexanones is achieved without perturbation of stereocenters installed through the preceding annulation.

Neurocognitive reward processes measured via event-related potentials are associated with binge-eating disorder diagnosis and ecologically-assessed behavior.

Altered reward processing has been implicated in the onset and maintenance of binge-eating disorder (BED). However, it is unclear which precise neurocognitive reward processes may contribute to BED. In the present study, 40 individuals with BED and 40 age-, sex-, and BMI-matched controls completed a reward (incentive delay) task while their neural activity was recorded using electroencephalography (EEG). Individuals with BED also completed a 10-day ecological momentary assessment (EMA) protocol assessing binge-eating behavior in the natural environment. Event-related potential (ERP) analysis of the EEG indicated that individuals with BED had stronger anticipatory (CNV) and outcome-related (RewP) neural reward activity to food and monetary rewards, compared to controls. However, within the BED group, greater frequency of binge eating during the EMA protocol was associated with stronger anticipatory (CNV) but weaker outcome-related (RewP) neural reward activity. These associations within the BED group were unique to food, and not monetary, rewards. Although preliminary, these results suggest that both anticipatory ("wanting") and outcome ("liking") reward processes may be generally amplified in BED. However, they also suggest that among individuals with BED, disorder severity may be associated with increased anticipatory reward processes ("wanting"), but relatively decreased reward-outcome processing ("liking"), of food rewards specifically.

Catalytic, Asymmetric Michael-Aldol Annulations via a Stereodivergent/Stereoconvergent Path Operating under Curtin-Hammett Control.

A bifunctional iminophosphorane (BIMP)-catalyzed method for the synthesis of densely functionalized cyclohexanols establishes five contiguous stereocenters (diastereoselection up to >20:1, enantioselectivity up to >99:1) in a Michael/aldol domino reaction between trisubstituted electrophilic alkenes and γ-nitroketones. Mechanistic studies suggest a scenario in which stereoconvergency is achieved by kinetically controlled cyclization after the initial diastereodivergent Michael addition. Diastereoconvergency during cyclization is shown to result from Curtin-Hammett kinetics, a finding that contrasts the crystallization-driven stereoconvergency previously reported in similar systems. Despite the change in the stereocontrol mechanism, the operational attributes remain attractive, with the crystalline products typically isolated in analytically pure form upon filtration of the reaction mixture.

Back to the future: Progressing memory research in eating disorders.

OBJECTIVE: Human behaviors, thoughts, and emotions are guided by memories of the past. Thus, there can be little doubt that memory plays a fundamental role in the behaviors (e.g., binging), thoughts (e.g., body-image concerns), and emotions (e.g., guilt) that characterize eating disorders (EDs). Although a growing body of research has begun to investigate the role of memory in EDs, this literature is limited in numerous ways and has yet to be integrated into an overarching framework. METHODS: In the present article, we provide an operational framework for characterizing different domains of memory, briefly review existing ED memory research within this framework, and highlight crucial gaps in the literature. RESULTS: We distinguish between three domains of memory-episodic, procedural, and working-which differ based on functional attributes and underlying neural systems. Most recent ED memory research has focused on procedural memory broadly defined (e.g., reinforcement learning), and findings within all three memory domains are highly mixed. Further, few studies have attempted to assess these different domains simultaneously, though most behavior is achieved through coordination and competition between memory systems. We, therefore, offer recommendations for how to move ED research forward within each domain of memory and how to study the interactions between memory systems, using illustrative examples from other areas of basic and clinical research. DISCUSSION: A stronger and more integrated understanding of the mechanisms that connect memory of past experiences to present ED behavior may yield more comprehensive theoretical models of EDs that guide novel treatment approaches. PUBLIC SIGNIFICANCE: Memories of previous eating-related experiences may contribute to the onset and maintenance of eating disorders (EDs). However, research on the role of memory in EDs is limited, and distinct domains of ED memory research are rarely connected. We, therefore, offer a framework for organizing, progressing, and integrating ED memory research, to provide a better foundation for improving ED treatment and intervention going forward.

Rhodium-Catalyzed Asymmetric Arylation-Induced Glycolate Aldol Additions of Silyl Glyoxylates.

(Diene)Rh(I) complexes catalyze the stereoselective three-component coupling of silyl glyoxylates, arylboronic acids, and aldehydes to give glycolate aldol products. The participation of Rh-alkoxides in the requisite Brook rearrangement was established through two component Rh-catalyzed couplings of silyl glyoxylates with ArB(OH)2 to give silyl-protected mandelate derivatives. The intermediacy of a chiral Rh-enolate was inferred through enantioselective protonation using a chiral Rh-catalyst. Diastereoselective three-component couplings with aldehydes as terminating electrophiles to give racemic products were best achieved with a bulky aryl ester on the silyl glyoxylate reagent. Optimal enantioselective couplings were carried out with the tert-butyl ester variant using an anisole-derived enantiopure tricyclo[3.2.2.02,4 ]nonadiene ligand.

Crystallization-Enabled Henry Reactions: Stereoconvergent Construction of Fully Substituted [N]-Asymmetric Centers.

Tetrasubstituted stereogenic carbon centers bearing a nitrogen substituent represent important motifs in medicinal chemistry and natural products; therefore, the development of efficient methods for the stereoselective synthesis of this class of compounds continues to be an important problem. This article describes stereoconvergent Henry reactions of γ,γ-disubstituted nitroalkanes to deliver highly functionalized building blocks containing up to five contiguous stereogenic centers including a fully substituted [N]-asymmetric center. Henry reactions of higher order nitroalkanes are often characterized by their reversibility and minimal accompanying thermodynamic stereocontrol. In contrast, mechanistic studies for the present case suggest a scenario in which reversibility is productively leveraged through crystallization-based stereocontrol, thereby enabling the efficient sequential π-additions of readily accessible starting materials to assemble complex acyclic stereoarrays.

The potential application of event-related potentials to enhance research on reward processes in eating disorders.

OBJECTIVE: Reward-related processes have been posited as key mechanisms underlying the onset and persistence of eating disorders, prompting a growing body of research in this area. Existing studies have primarily utilized self-report, behavioral, and functional magnetic resonance imaging measures to interrogate reward among individuals with eating disorders. However, limitations inherent in each of these methods (e.g., poor temporal resolution) may obscure distinct neurocognitive reward processes, potentially contributing to underdeveloped models of reward dysfunction within eating disorders. The temporal precision of event-related potentials (ERPs), derived from electroencephalography, may thus offer a powerful complementary tool for elucidating the neurocognitive underpinnings of reward. Indeed, a considerable amount of research in other domains of psychopathology (e.g., depression, substance use disorders), as well as studies investigating food reward among non-clinical samples, highlights the utility of ERPs for probing reward processes. However, no study to date has utilized ERPs to directly examine reward functioning in eating disorders. METHODS: In this paper, we review evidence underscoring the clinical utility of ERP measures of reward, as well as a variety of reward-related tasks that can be used to elicit specific ERP components with demonstrated relevance to reward processing. We then consider the ways in which these tasks/components may be used to help answer a variety of open questions within the eating disorders literature on reward. RESULTS/DISCUSSION: Given the promise of ERP measures of reward to the field of eating disorders, we ultimately hope to spur and guide research in this currently neglected area. PUBLIC SIGNIFICANCE: Abnormalities in reward functioning appear to contribute to eating disorders. Event-related potentials (ERPs) offer temporally precise measures of neurocognitive reward processing and thus may be important tools for understanding the relationship between reward and disordered eating. However, research in this area is currently lacking. This paper attempts to facilitate the use of ERPs to study reward among individuals with eating disorders by reviewing the relevant theories and methods.

Stereodivergent Nucleophilic Additions to Racemic ß-Oxo Acid Derivatives: Fast Addition Outcompetes Stereoconvergence in the Archetypal Configurationally Unstable Electrophile.

Additions of carbon nucleophiles to racemic α-stereogenic ß-oxo acid derivatives that deliver enantiomerically enriched tertiary alcohols are valuable, but uncommon. This article describes stereodivergent Cu-catalyzed borylative cyclizations of racemic ß-oxo acid derivatives bearing tethered pro-nucleophilic olefins to deliver highly functionalized cyclopentanols containing four contiguous stereogenic centers. The reported protocol is applicable to a range of ß-oxo acid derivatives, and the diastereomeric products are readily isolable by typical chromatographic techniques. α-Stereogenic-ß-keto esters are typically thought to have extreme or spontaneous configurational fragility, but mechanistic studies for this system reveal an unusual scenario wherein productive catalysis occurs on the same time scale as background substrate racemization and completely outcompetes on-cycle epimerization, even under the basic conditions of the reaction.

Choice-related activity and neural encoding in primary auditory cortex and lateral belt during feature-selective attention.

Selective attention is necessary to sift through, form a coherent percept of, and make behavioral decisions on the vast amount of information present in most sensory environments. How and where selective attention is employed in cortex and how this perceptual information then informs the relevant behavioral decisions is still not well understood. Studies probing selective attention and decision-making in visual cortex have been enlightening as to how sensory attention might work in that modality; whether or not similar mechanisms are employed in auditory attention is not yet clear. Therefore, we trained rhesus macaques on a feature-selective attention task, where they switched between reporting changes in temporal (amplitude modulation, AM) and spectral (carrier bandwidth) features of a broadband noise stimulus. We investigated how the encoding of these features by single neurons in primary (A1) and secondary (middle lateral belt, ML) auditory cortex was affected by the different attention conditions. We found that neurons in A1 and ML showed mixed selectivity to the sound and task features. We found no difference in AM encoding between the attention conditions. We found that choice-related activity in both A1 and ML neurons shifts between attentional conditions. This finding suggests that choice-related activity in auditory cortex does not simply reflect motor preparation or action and supports the relationship between reported choice-related activity and the decision and perceptual process.NEW & NOTEWORTHY We recorded from primary and secondary auditory cortex while monkeys performed a nonspatial feature attention task. Both areas exhibited rate-based choice-related activity. The manifestation of choice-related activity was attention dependent, suggesting that choice-related activity in auditory cortex does not simply reflect arousal or motor influences but relates to the specific perceptual choice.

Catalytic, Asymmetric Dearomative Synthesis of Complex Cyclohexanes via a Highly Regio- and Stereoselective Arene Cyclopropanation Using α-Cyanodiazoacetates.

Arene cyclopropanation offers a direct route to higher-order, non-aromatic carbocycles; however, the inherent issue of dictating site selectivity has cumbered the development of novel intermolecular reactions that directly engage the arene pool. This paper describes a highly regio- and stereoselective, Rh2[(S)-PTTL]4-catalyzed arene cyclopropanation using α-cyanodiazoacetates to afford stable norcaradienes bearing three stereogenic centers, one of which is an all-carbon quaternary center. The enantioenriched norcaradienes served as tunable templates for further transformation into stereochemically dense, fused and bicyclic carbocycles containing transmutable functionality.

Amplitude modulation encoding in the auditory cortex: comparisons between the primary and middle lateral belt regions.

In macaques, the middle lateral auditory cortex (ML) is a belt region adjacent to the primary auditory cortex (A1) and believed to be at a hierarchically higher level. Although ML single-unit responses have been studied for several auditory stimuli, the ability of ML cells to encode amplitude modulation (AM)-an ability that has been widely studied in A1-has not yet been characterized. Here, we compared the responses of A1 and ML neurons to amplitude-modulated (AM) noise in awake macaques. Although several of the basic properties of A1 and ML responses to AM noise were similar, we found several key differences. ML neurons were less likely to phase lock, did not phase lock as strongly, and were more likely to respond in a nonsynchronized fashion than A1 cells, consistent with a temporal-to-rate transformation as information ascends the auditory hierarchy. ML neurons tended to have lower temporally (phase-locking) based best modulation frequencies than A1 neurons. Neurons that decreased their firing rate in response to AM noise relative to their firing rate in response to unmodulated noise became more common at the level of ML than they were in A1. In both A1 and ML, we found a prevalent class of neurons that usually have enhanced rate responses relative to responses to the unmodulated noise at lower modulation frequencies and suppressed rate responses relative to responses to the unmodulated noise at middle modulation frequencies.NEW & NOTEWORTHY ML neurons synchronized less than A1 neurons, consistent with a hierarchical temporal-to-rate transformation. Both A1 and ML had a class of modulation transfer functions previously unreported in the cortex with a low-modulation-frequency (MF) peak, a middle-MF trough, and responses similar to unmodulated noise responses at high MFs. The results support a hierarchical shift toward a two-pool opponent code, where subtraction of neural activity between two populations of oppositely tuned neurons encodes AM.

De Novo Synthesis of the DEF-Ring Stereotriad Core of the Veratrum Alkaloids.

The synthesis of the stereotriad core in the eastern portion of the Veratrum alkaloids jervine (1), cyclopamine (2), and veratramine (3) is reported. Starting from a known ß-methyltyrosine derivative (8), the route utilizes a diastereoselective substrate-controlled 1,2-reduction to establish the stereochemistry of the vicinal amino alcohol motif embedded within the targets. Oxidative dearomatization is demonstrated to be a viable approach for the synthesis of the spirocyclic DE ring junction found in jervine and cyclopamine.

Autophosphorylated CaMKII Facilitates Spike Propagation in Rat Optic Nerve.

Repeated spike firing can transmit information at synapses and modulate spike timing, shape, and conduction velocity. These latter effects have been found to result from voltage-induced changes in ion currents and could alter the signals carried by axons. Here, we test whether Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates spike propagation in adult rat optic nerve. We find that small-, medium-, and large-diameter axons bind anti-Thr286-phosphorylated CaMKII (pT286) antibodies and that, in isolated optic nerves, electrical stimulation reduces pT286 levels, spike propagation is hastened by CaMKII autophosphorylation and slowed by CaMKII dephosphorylation, single and multiple spikes slow propagation of subsequently activated spikes, and more frequent stimulation produces greater slowing. Likewise, exposing freely moving animals to flickering illumination reduces pT286 levels in optic nerves and electrically eliciting spikes in vivo in either the optic nerve or optic chiasm slows subsequent spike propagation in the optic nerve. By increasing the time that elapses between successive spikes as they propagate, pT286 dephosphorylation and activity-induced spike slowing reduce the frequency of propagated spikes below the frequency at which they were elicited and would thus limit the frequency at which axons synaptically drive target neurons. Consistent with this, the ability of retinal ganglion cells to drive at least some lateral geniculate neurons has been found to increase when presented with light flashes at low and moderate temporal frequencies but less so at high frequencies. Activity-induced decreases in spike frequency may also reduce the energy required to maintain normal intracellular Na+ and Ca2+ levels.SIGNIFICANCE STATEMENT By propagating along axons at constant velocities, spikes could drive synapses as frequently as they are initiated. However, the onset of spiking has been found to alter the conduction velocity of subsequent ("follower") spikes in various preparations. Here, we find that spikes reduce spike frequency in rat optic nerve by slowing follower spike propagation and that electrically stimulated spiking ex vivo and spike-generating flickering illumination in vivo produce net decreases in axonal Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation. Consistent with these effects, propagation speed increases and decreases, respectively, with CaMKII autophosphorylation and dephosphorylation. Lowering spike frequency by CaMKII dephosphorylation is a novel consequence of axonal spiking and light adaptation that could decrease synaptic gain as stimulus frequency increases and may also reduce energy use.

Enantioselective Phenolic α-Oxidation Using H2O2 via an Unusual Double Dearomatization Mechanism.

Feedstock aromatic compounds are compelling low-cost starting points from which molecular complexity can be generated rapidly via oxidative dearomatization. Oxidative dearomatizations commonly rely heavily on hypervalent iodine or heavy metals to provide the requisite thermodynamic driving force for overcoming aromatic stabilization energy. This article describes oxidative dearomatizations of 2-(hydroxymethyl)phenols via their derived bis(dichloroacetates) using hydrogen peroxide as a mild oxidant that intercepts a transient quinone methide. A stereochemical study revealed that the reaction proceeds by a new mechanism relative to other phenol dearomatizations and is complementary to extant methods that rely on hypervalent iodine. Using a new chiral phase-transfer catalyst, the first asymmetric syntheses of 1-oxaspiro[2.5]octa-5,7-dien-4-ones were reported. The synthetic utility of the derived 1-oxaspiro[2.5]octadienones products is demonstrated in a downstream complexity-generating transformation.

Synthesis of Complex Glycolates by Enantioconvergent Addition Reactions.

The unique role that stereochemistry plays in molecular recognition events continues to provide a driving force for synthesizing organic compounds in enantioenriched form. The tendency of enantioenriched organic compounds to revert to an entropically favored racemic state in the presence of viable racemization pathways (e.g., the enolization of stereogenic carbonyl derivatives) can sometimes interfere with this objective; however, beginning with Noyori's foundational disclosure of a dynamic kinetic transfer hydrogenation, the ability to channel racemic, configurationally labile starting materials through stereoconvergent reaction pathways has been recognized as a powerful strategy in asymmetric synthesis. Proton transfer, retro-aldol, retro-Michael, reversible redox events, and other processes that can be deleterious to asymmetric synthesis are exploitable in enantioconvergent reactions using chiral small molecules and enzymes as asymmetric catalysts. Enantioselective reduction of configurationally labile carbonyl derivatives bearing a C-H acidic chiral center are particularly common. Because facile racemization is vital to stereocontrol in these transformations, hydrogenations of ß-dicarbonyls are commonplace, while less activated substrates have been used less commonly. Our entry into enantioconvergent catalysis evolved from a long-standing interest in the synthesis of complex glycolates and began with the development of a general Noyori-type transfer hydrogenation of α-keto esters. Key innovations in this work include the identification of a new terphenylsulfonamide-Ru(II) complex, which displays unusual preference toward reduction of α-keto esters, and the observation that α-keto esters racemize under mildly basic conditions. This work was extended to the dynamic kinetic hydrogenation of racemic acyl phosphonates. Moreover, the recent recognition that the mechanistic paradigm underlying enantioconvergent hydrogenation chemistry can be extended to diverse carbon-centered nucleophiles has led to advances in the art. Our lab has developed a number of enantioconvergent tertiary alcohol syntheses. In the context of carbon-centered nucleophiles, we have focused on the use of α-keto esters; however, in the latter part of this Account, we will briefly describe our nascent efforts to develop dynamic kinetic additions of carbon-centered nucleophiles to ß-oxo acid derivatives. While the enantioconvergent hydrogenation of ß-keto acid derivatives is carried out on 100-ton scale annually, non-hydrogenative transformations of these compounds constitute an underexplored subclass of enantioconvergent reactions. With regard to future prospects, a trend toward transformations that afford increasing levels of molecular complexity is apparent. It can be expected that the burgeoning field of asymmetric 1,2-addition chemistry will further drive this chemistry to encompass a wider array of enantioconvergent additions. Additionally, the continued exploration of these chemistries in the context of less conventional electrophiles, as well as identifying novel or overlooked modes of racemization, holds considerable potential.

Synthesis and Desymmetrization of meso Tricyclic Systems Derived from Benzene Oxide.

Ozonolysis of the Diels-Alder adducts derived from benzene oxides and N-alkylmaleimides resulted in fully substituted, meso bicyclic systems bearing six contiguous stereocenters, isolated as diols upon reductive workup with NaBH4. Variation in the workup allowed for isolation of two different diastereoisomers, through double epimerization of the imide stereocenters. Desymmetrization of the resulting meso diols via asymmetric nucleophilic epoxide opening and acylation reactions provided access to highly substituted, enantioenriched fused rings.

Asymmetric Organocatalytic Sulfa-Michael Addition to Enone Diesters.

An asymmetric sulfa-Michael addition of alkyl thiols to enone diesters is reported. The reaction is catalyzed by a bifunctional triaryliminophosphorane-thiourea organocatalyst and provides a range of α-sulfaketones in high yields and enantioselectivities. Leveraging the gem-diester functional handle via a subsequent diastereotopic group discrimination generates functionalized lactones with three contiguous stereocenters.

A systematic review of reviews of neurocognitive functioning in eating disorders: The state-of-the-literature and future directions.

OBJECTIVE: In recent years there has been increasing clinical and empirical interest in neurocognitive functioning in eating disorders (EDs), which has resulted in numerous quantitative and qualitative reviews. However, there has yet to be a comprehensive synthesis or critical review of this literature to identify future directions to advance the field in this area. Therefore the aim of this systematic review of systematic reviews was to (a) characterize the existing literature on neurocognitive functioning in EDs based on recent reviews (i.e., published since 2010), (b) describe related limitations, and (c) suggest avenues for future research to address gaps in the current literature. METHOD: Electronic databases were queried for reviews of neurocognitive domains (i.e., inhibitory control, decision-making, central coherence, set-shifting, working memory, and attention bias) in EDs, which identified 28 systematic and meta-analytic reviews. RESULTS: Broadly, the literature indicates deficits across these neurocognitive domains in EDs, though heterogeneity was noted in the magnitude of these effects, which varied to some extent across ED subtypes, sample characteristics, and methodological approaches. DISCUSSION: While these reviews have generally suggested varying patterns of neurocognitive deficits across EDs, there remain critical limitations regarding the methodological quality of these studies (e.g., the lack of prospective designs, consideration of confounding influences, or examination of interrelationships between neurocognitive domains and relationships between neurocognition and other relevant behavioral constructs). Specifically, we outline 10 key areas that are imperative to address in future research in this area in order to move our field forward.

Assessing the Effect of Early Visual Cortex Transcranial Magnetic Stimulation on Working Memory Consolidation.

Maintaining visual working memory (VWM) representations recruits a network of brain regions, including the frontal, posterior parietal, and occipital cortices; however, it is unclear to what extent the occipital cortex is engaged in VWM after sensory encoding is completed. Noninvasive brain stimulation data show that stimulation of this region can affect working memory (WM) during the early consolidation time period, but it remains unclear whether it does so by influencing the number of items that are stored or their precision. In this study, we investigated whether single-pulse transcranial magnetic stimulation (spTMS) to the occipital cortex during VWM consolidation affects the quantity or quality of VWM representations. In three experiments, we disrupted VWM consolidation with either a visual mask or spTMS to retinotopic early visual cortex. We found robust masking effects on the quantity of VWM representations up to 200 msec poststimulus offset and smaller, more variable effects on WM quality. Similarly, spTMS decreased the quantity of VWM representations, but only when it was applied immediately following stimulus offset. Like visual masks, spTMS also produced small and variable effects on WM precision. The disruptive effects of both masks and TMS were greatly reduced or entirely absent within 200 msec of stimulus offset. However, there was a reduction in swap rate across all time intervals, which may indicate a sustained role of the early visual cortex in maintaining spatial information.