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.

Enantio- and Diastereoselective Mannich Reactions of ß-Dicarbonyls by Second Stage Diastereoconvergent Crystallization.

The synthesis of chiral α-monosubstituted-ß-dicarbonyls is a challenging task in asymmetric catalysis due to the rapid, typically uncontrolled, product racemization or epimerization under most reaction conditions. For this reason, diastereoselective additions of unsubstituted ß-dicarbonyls to π-electrophiles are unusual. Herein, we disclose a simple catalytic crystallization-driven enantio- and diastereoselective Mannich reaction for the synthesis of stereodefined α-monosubstituted-ß-keto esters, dissymmetric ß-diesters, dissymmetric ß-diketones, and ß-keto amides that productively leverages product epimerization in solution. Mechanistic studies suggest a scenario where the initial enantioselective, diastereodivergent skeletal assembly is catalyzed by a chiral tertiary amine organocatalyst, which then facilitates second stage crystallization-induced diastereoconvergence to provide the challenging α-stereocenter in excellent stereoselectivity.

A Site-Specific Synthetic Route to Substituted Inda(box) Ligands.

Aminoindanol-derived bis(oxazoline) ligands are widely used in metal-catalyzed transformations, but the synthesis of structural derivatives is challenging. We report the gram-scale, seven-step synthesis of five bromine-functionalized inda(box) ligands that have varied bridge substituents. The bromoinda(box) ligands undergo late-stage modification via Pd-catalyzed cross-couplings, which allows for the synthesis of twelve unique inda(box) ligands. This complementary synthetic route could enable the discovery of new asymmetric metal-catalyzed transformations through the modification of the inda(box) ligand architecture.

Oxidative Spirocyclization of ß-Furyl Amides for the Assembly of Spiro-γ-butenolide-γ-butyrolactones.

The synthesis of heretofore unknown γ-spirobutenolides has been achieved via an m-CPBA-mediated oxidation of ß-furyl amides. The reaction employs a tethered amide, ostensibly a poorly reactive carbonyl, as a nontraditional nucleophile resulting in spirolactone formation and concurrent amide cleavage. The transformation exhibits functional group tolerance and compatibility with complex compounds. In situ 1H NMR spectroscopic studies reveal the identities of key intermediates in the oxidation-spirolactonization-oxidation cascade, suggesting a plausible mechanistic pathway. The distinct diastereofaces of the electrophilic butenolide product may be used for diastereoselective cycloaddition and conjugate addition reactions.

Development of New Reactions Driven by N-O Bond Cleavage: from O-Acyl Hydroxylamines to Tetrodotoxin.

This Account describes new reactions that have been developed in the Johnson laboratories at UNC Chapel Hill enabled by considerations of N-O bond cleavage. Three main case studies are highlighted: the metal-catalyzed electrophilic amination of O-acyl hydroxyl amines, multihetero-Cope rearrangements driven by O-N bond breakage, and merged dearomatization/N=O cycloadditions for the synthesis of complex 4-aminocyclohexanols such as those found in the natural product tetrodotoxin.

Crystallization-Enabled Stereoconvergent Michael Additions of ß-Keto Esters to Nitroolefins.

Asymmetric Michael additions are powerful tools to meet the growing need for stereochemically complex products. While 1,3-dicarbonyls are common nucleophiles, the successful use of configurationally unstable ß-keto esters in diastereoselective variants remains understudied. In this Letter, crystalline ß-keto esters were leveraged in a two-phase, one-pot merger of an asymmetric Michael addition with a crystallization-induced diastereomer transformation. Tuning the crystallinity of ß-keto ester adducts enabled stereoconvergence of the products, which were isolated by filtration.

Simplified Synthesis of an Air-Stable Copper-Complexed Josiphos Ligand via Ugi's Amine: Complete Preparation and Analysis from Ferrocene.

Ligands containing ferrocene backbones often feature both planar chirality and asymmetric centers, making them attractive options for asymmetric catalysis. Ugi's amine is a ubiquitous ferrocene-based chiral building block that can be functionalized to form a variety of tunable Josiphos ligands; however, few sources lay out the route from start to finish. Starting from ferrocene, we compile a synthetic route to an air- and moisture-stable copper(I)-Josiphos complex via enantiopure Ugi's amine, providing a potential one-stop shop for the synthesis of a wide range of Josiphos ligands.

Counting steps.

The use of step count as a metric of synthetic efficiency carries opportunities and challenges. Here, proposals are made to standardize what constitutes a synthetic step and how steps are counted. These proposals may be beneficial in the holistic evaluation of published synthetic routes.

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.

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.

Development of organic reactions that productively leverage physical properties.

Crystallization-induced stereoconvergent Michael additions demonstrate the potential of using physical properties to reveal unique reactivity.

Enantioconvergent iso-Pictet-Spengler Reactions: Organocatalytic Synthesis of Chiral Tetrahydro-γ-carbolines.

Enantioconvergent iso-Pictet-Spengler reactions of chiral racemic ß-formyl esters and a ß-keto ester are reported, providing complex tetrahydro-γ-carbolines containing two contiguous stereocenters. The reactions are catalyzed by a chiral thiourea and benzoic acid cocatalytic system and constitute rare cases of nonhydrogenative stereoconvergent additions to racemic α-stereogenic-ß-dicarbonyls. Elaboration of the products to chiral aminoalcohols and carbamates is demonstrated.

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.

Dearomatization of Cyclic Diphenylhydrazines: Harnessing the o-Semidine Rearrangement for the Synthesis of Spirocyclic Tetrahydroquinolines.

The synthesis of novel tetrahydroquinoline-containing spirocycles has been achieved through an acid-promoted dearomatization of cyclic diarylhydrazines. The reaction, proceeding through a dearomative o-semidine rearrangement, furnishes a stable, yet reactive spirocyclohexadieniminium ion, which can further be used as an electrophile or a diene in a one-pot sequence. These transformations efficiently produce novel diazaspirocycles and allow for further synthetic elaboration of the cyclohexadienamine products.

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.

Neural interactions in working memory explain decreased recall precision and similarity-based feature repulsion.

Over the last several years, the study of working memory (WM) for simple visual features (e.g., colors, orientations) has been dominated by perspectives that assume items in WM are stored independently of one another. Evidence has revealed, however, systematic biases in WM recall which suggest that items in WM interact during active maintenance. In the present study, we report two experiments that replicate a repulsion bias between metrically similar colors during active storage in WM. We also observed that metrically similar colors were stored with lower resolution than a unique color held actively in mind at the same time. To account for these effects, we report quantitative simulations of two novel neurodynamical models of WM. In both models, the unique behavioral signatures reported here emerge directly from laterally-inhibitory neural interactions that serve to maintain multiple, distinct neural representations throughout the WM delay period. Simulation results show that the full pattern of empirical findings was only obtained with a model that included an elaborated spatial pathway with sequential encoding of memory display items. We discuss implications of our findings for theories of visual working memory more generally.

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.