Large neutral amino acid levels tune perinatal neuronal excitability and survival.

Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.

Stereodivergent 1,3-difunctionalization of alkenes by charge relocation.

Alkenes are indispensable feedstocks in chemistry. Functionalization at both carbons of the alkene-1,2-difunctionalization-is part of chemistry curricula worldwide1. Although difunctionalization at distal positions has been reported2-4, it typically relies on designer substrates featuring directing groups and/or stabilizing features, all of which determine the ultimate site of bond formation5-7. Here we introduce a method for the direct 1,3-difunctionalization of alkenes, based on a concept termed 'charge relocation', which enables stereodivergent access to 1,3-difunctionalized products of either syn- or anti-configuration from unactivated alkenes, without the need for directing groups or stabilizing features. The usefulness of the approach is demonstrated in the synthesis of the pulmonary toxin 4-ipomeanol and its derivatives.

Stereodivergent Synthesis of 1,4-Dicarbonyl Compounds through Sulfonium Rearrangement: Mechanistic Investigation, Stereocontrolled Access to γ-Lactones and γ-Lactams, and Total Synthesis of Paraconic Acids.

Although simple γ-lactones and γ-lactams have received considerable attention from the synthetic community, particularly due to their relevance in biological and medicinal contexts, stereoselective synthetic approaches to more densely substituted derivatives remain scarce. The in-depth study presented herein, showcasing a straightforward method for the stereocontrolled synthesis of γ-lactones and γ-lactams, builds on and considerably expands the stereodivergent synthesis of 1,4-dicarbonyl compounds by a ynamide/vinyl sulfoxide coupling. A full mechanistic and computational study of the rearrangement was conducted, uncovering the role of all of the reaction components and providing a rationale for stereoselection. The broad applicability of the developed tools to streamlining synthesis is demonstrated by concise enantioselective total syntheses of (+)-nephrosteranic acid, (+)-rocellaric acid, and (+)-nephromopsinic acid.

New Strategies for the Functionalization of Carbonyl Derivatives via α-Umpolung: From Enolates to Enolonium Ions.

ConspectusUmpolung, a term describing the reversal of innate polarity, has become an indispensable tool to unlock new chemical space by overcoming the limitations of natural polarity. Introduced by Dieter Seebach in 1979, this principle has had a tremendous impact on synthetic organic chemistry, offering previously inaccessible retrosynthetic disconnections. In contrast to the great progress made over the past decades for the generation of effective acyl anion synthons, the umpolung at the α-position of carbonyls (converting enolates into enolonium ions) has long proved challenging and only recently regained traction. Aiming to develop synthetic approaches to α-functionalization capable of complementing enolate chemistry, our group initiated, nearly 6 years ago, a program devoted to the α-umpolung of carbonyl derivatives. In this Account, following an overview of established methods, we will summarize our findings in this rapidly developing field. We focus on two distinct, yet related, topics of two carbonyl classes: (1) amides, where umpolung is enabled by electrophilic activation, and (2) ketones, where umpolung is enabled using hypervalent iodine reagents. Our group has developed several protocols to allow amide umpolung and subsequent α-functionalization, relying on electrophilic activation. Over the course of our investigations, transformations that are particularly challenging using enolate-based approaches, such as the direct α-oxygenation, α-fluorination, and α-amination of amides as well as the synthesis of 1,4-dicarbonyls from amide substrates, have been unlocked. Based on some of our most recent studies, this method has been shown to be so general that almost any nucleophile can be added to the α-position of the amide. In this Account, special emphasis will be placed on the discussion of mechanistic aspects. It is important to note that recent progress in this area has involved a shift in focus, moving even further away from the amide carbonyl, a development that shall also be detailed in a final subsection that highlights our latest investigations of umpolung-based remote functionalization of the ß- and γ-positions of amides. The second section of this Account covers our more recent work dedicated to the exploration of the enolonium chemistry of ketones, unlocked through the use of hypervalent iodine reagents. By placing our work in the context of previous pioneering achievements, which mainly focused on the α-functionalization of carbonyls, we discuss new skeletal reorganizations of enolonium ions enabled by the unique properties of incipient positive charges α to electron-deficient moieties. Transformations such as intramolecular cyclopropanations and aryl migrations are covered and supplemented by detailed insight into the unusual nature of the intermediate species, including nonclassical carbocations.

Lewis Acid-Driven Inverse Hydride Shuttle Catalysis.

Inverse hydride shuttle catalysis provides a multicomponent platform for the highly efficient synthesis of alkaloid frameworks with exquisite diastereoselectivity. However, a number of limitations hinder this method, primarily the strict requirement for highly electron-deficient acceptors. Herein, we present a general Lewis acid-driven approach to address this constraint, and have developed two broad strategies enabling the modular synthesis of complex azabicycles that were entirely unattainable using the previous method. The enhanced synthetic flexibility facilitates a streamlined asymmetric cyclization, leading to a concise total synthesis of the alkaloid (-)-tashiromine.

Deprotective Functionalization: A Direct Conversion of Nms-Amides to Carboxamides Using Carboxylic Acids.

The nature of protecting group chemistry necessitates a deprotection step to restore the initially blocked functionality prior to further transformation. As this aspect of protecting group manipulation inevitably adds to the step count of any synthetic sequence, the development of methods enabling simultaneous deprotection and functionalization ("deprotective functionalization"-distinct from "deprotection followed by functionalization") is appealing, as it has the potential to improve efficiency and streamline synthetic routes. Herein, we report a deprotective functionalization of the newly introduced Nms-amides guided by density functional theory (DFT) analysis, which exploits the inherent Nms reactivity. Mechanistic studies further substantiate and help rationalize the exquisite reactivity of Nms-amides, as other commonly used protecting groups are shown not to exhibit the same reactivity patterns. The practicality of this approach was ultimately demonstrated in selected case studies.

Sulfonium Rearrangements Enable the Direct Preparation of Sulfenyl Imidinium Salts.

Sulfenyl imidinium salts are a virtually unexplored class of intermediates in organic chemistry. Herein, we demonstrate how sulfonium rearrangements can be deployed to access these versatile synthetic intermediates, bearing three contiguous (and congested) stereogenic centers, with high levels of selectivity. The synthetic value of the scaffold was unraveled by selective transformations into a range of building blocks, including 1,4-dicarbonyl derivatives and sulfonolactones.

PyrAtes: Modular Organic Salts with Large Stokes Shifts for Fluo-rescence Microscopy.

The deployment of small-molecule fluorescent agents plays an ever-growing role in medicine and drug development. Herein, we complement the portfolio of powerful fluorophores, reporting the serendipitous discovery and development of a novel class with an imidazo[1,2-a]pyridinium triflate core, which we term PyrAtes. These fluorophores are synthesized in a single step from readily available materials (>60 examples) and display Stokes shifts as large as 240 nm, while also reaching NIR-I emissions at λmax as long as 720 nm. Computational studies allow the development of a platform for the prediction of λmax and λEm. Furthermore, we demonstrate the compatibility of these novel fluorophores with live cell imaging in HEK293 cells, suggesting PyrAtes as potent intracellular markers.

Biomimetic Cationic Cyclopropanation Enables an Efficient Chemoenzymatic Synthesis of 6,8-Cycloeudesmanes.

Cationic cyclopropanation involves the γ-elimination at carbocations to form a new σ-C-C bond through proton loss. While exceedingly rare in bulk solution, it is recognized as one of the main biosynthetic cyclopropanation pathways. Despite the rich history of bioinspired synthetic chemistry, cationic cyclopropanation has not been appropriated for the synthetic toolbox, likely due to the preference of carbocations to undergo competing E1 ß-elimination pathways. Here, we present an in-depth synthetic and computational study of cationic cyclopropanation, focusing on the 6,8-cycloeudesmanes as a platform for this investigation. We were able to apply biomimetic cationic cyclopropanation to the synthesis of several 6,8-cycloeudesmanes and non-natural analogues─in doing so, we showcase the power of this transformation in the preparation of complex cyclopropanes.

Lewis Base-assisted Arylation of Unsaturated Carbonyls.

The combination of Lewis bases with α,ß-unsaturated carbonyls allows the in-situ generation of enolates without the need for strong Brønsted bases. Recently developed synthetic methods employ this approach for arylation followed by elimination of the Lewis base, regenerating the alkene. This strategy has been deployed for formal α- or ß-C-H arylation in different contexts, namely (a) transition metal catalysis, (b) rearrangement reactions utilizing hypervalent main group elements and (c) organocatalysis. This concept article provides an overview of the developed strategies, highlighting and contextualizing their features.

Nms-Amides: An Amine Protecting Group with Unique Stability and Selectivity.

p-Toluenesulfonyl (Tosyl) and nitrobenzenesulfonyl (Nosyl) are two of the most common sulfonyl protecting groups for amines in contemporary organic synthesis. While p-toluenesulfonamides are known for their high stability/robustness, their use in multistep synthesis is plagued by difficult removal. Nitrobenzenesulfonamides, on the other hand, are easily cleaved but display limited stability to various reaction conditions. In an effort to resolve this predicament, we herein present a new sulfonamide protecting group, which we term Nms. Initially developed through in silico studies, Nms-amides overcome these previous limitations and leave no room for compromise. We have investigated the incorporation, robustness and cleavability of this group and found it to be superior to traditional sulfonamide protecting groups in a broad range of case studies.

Isothiouronium-Mediated Conversion of Carboxylic Acids to Cyanomethyl Thioesters.

We report the development of an isothiouronium salt as a reagent for the operationally simple synthesis of cyanomethyl thioesters with high functional group tolerance and avoiding the use of thiols. Additionally, we show that the products can be engaged in amide synthesis in either a two-step or one-pot fashion.

Direct Synthesis of α-Amino Acid Derivatives by Hydrative Amination of Alkynes.

α-Amino acid derivatives are key components of the molecules of life. The synthesis of α-amino carbonyl/carboxyl compounds is a contemporary challenge in organic synthesis. Herein, we report a practical method for the preparation of α-amino acid derivatives via direct hydrative amination of activated alkynes under mild conditions, relying on sulfinamides as the nitrogen source. Computational studies suggest that the reaction is enabled by a new type of sulfonium [2,3]-sigmatropic rearrangement.

Free Amino Group Transfer via α-Amination of Native Carbonyls.

We report herein a straightforward transfer of a free amino group (NH2 ) from a commercially available nitrogen source to unfunctionalized, native carbonyls (amides and ketones) resulting in direct α-amination. Primary α-amino carbonyls are readily produced under mild conditions, further enabling diverse in situ functionalization reactions-including peptide coupling and Pictet-Spengler cyclization-that capitalize on the presence of the unprotected primary amine.

Unlocking the Potential of Bio-Based Nitrogen-Rich Furanic Platforms as Biomass Synthons.

The demand for new biomass-derived fine and commodity chemicals propels the discovery of new methodologies and synthons. Whereas furfural and 5-hydroxymethylfurfural are cornerstones of sustainable chemistry, 3-acetamido-5-acetyl furan (3A5AF), an N-rich furan obtained from chitin biomass, remains unexplored, due to the poor reactivity of the acetyl group relative to previous furanic aldehydes. Here we developed a reactive 3-acetamido-5-furfuryl aldehyde (3A5F) and demonstrated the utility of this synthon as a source of bio-derived nitrogen-rich heteroaromatics, carbocycles, and as a bioconjugation reagent.

Deployment of Sulfinimines in Charge-Accelerated Sulfonium Rearrangement Enables a Surrogate Asymmetric Mannich Reaction.

ß-Amino acid derivatives are key structural elements in synthetic and biological chemistry. Despite being a hallmark method for their preparation, the direct Mannich reaction encounters significant challenges when carboxylic acid derivatives are employed. Indeed, not only is chemoselective enolate formation a pitfall (particularly with carboxamides), but most importantly the inability to reliably access α-tertiary amines through an enolate/ketimine coupling is an unsolved problem of this century-old reaction. Herein, we report a strategy enabling the first direct coupling of carboxamides with ketimines for the diastereo- and enantioselective synthesis of ß-amino amides. This conceptually novel approach hinges on the innovative deployment of enantiopure sulfinimines in sulfonium rearrangements, and at once solves the problems of chemoselectivity, reactivity, and (relative and absolute) stereoselectivity of the Mannich process. In-depth computational studies explain the observed, unexpected (dia)stereoselectivity and showcase the key role of intramolecular interactions, including London dispersion, for the accurate description of the reaction mechanism.

Taming Keteniminium Reactivity by Steering Reaction Pathways: Computational Predictions and Experimental Validations.

Keteniminium ions, the nitrogen analogues of ketenes, exhibit high reactivity toward olefins and π-systems. Previous results from the Maulide group demonstrated an unexpected propensity for an alternative intramolecular Bellus-Claisen-type rearrangement rather than an expected intramolecular (2 + 2) cycloaddition. We have conducted a cooperative density functional theory/experimental investigation of this process, seeking insights into the competition between the observed Claisen-type reaction and the historically expected (2 + 2) cyclization. Our calculations revealed a surprisingly small difference in the free energy barrier between these two intramolecular reactions. Further theoretical and experimental investigations probe the electronics of the substrate, rationalize a competing deallylation side reaction, and demonstrate the proof-of-concept for an enantioselective (2 + 2) variant.

Direct Stereodivergent Olefination of Carbonyl Compounds with Sulfur Ylides.

The reactivity of phosphorus and sulfur ylides toward carbonyl compounds constitutes a well-known dichotomy that is a common educational device in organic chemistry─the former gives olefins, while the latter gives epoxides. Herein, we report a stereodivergent carbonyl olefination that challenges this dichotomy, showcasing thiouronium ylides as valuable olefination reagents. With this method, aldehydes are converted to Z-alkenes with high stereoselectivity and broad substrate scope, while N-tosylimines provide a similarly proficient entry to E-alkenes. In-depth computational and experimental studies clarified the mechanistic details of this unusual reactivity.

Electrochemical Umpolung C-H Functionalization of Oxindoles.

Herein, we present a general electrochemical method to access unsymmetrical 3,3-disubstituted oxindoles by direct C-H functionalization where the oxindole fragment behaves as an electrophile. This Umpolung approach does not rely on stoichiometric oxidants and proceeds under mild, environmentally benign conditions. Importantly, it enables the functionalization of these scaffolds through C-O, and by extension to C-C or even C-N bond formation.

Challenges and Breakthroughs in Selective Amide Activation.

In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing to their unique structural and electronic features. However, recent decades have seen the emergence of research programmes focused on the selective activation of amides under mild conditions. In the past four years, this area has continued to rapidly develop, with new advances coming in at a fast pace. Several novel activation strategies have been demonstrated as effective tools for selective amide activation, enabling transformations that are at once synthetically useful and mechanistically intriguing. This Minireview comprises recent advances in the field, highlighting new trends and breakthroughs in what could be called a new age of amide activation.