ABSTRACT
Hydride shuttle catalysis has emerged as a powerful synthetic platform, enabling the selective formation of C-C bonds to yield sp3-rich structures. By virtue of the compelling reactivity of sterically encumbered Lewis acids from the frustrated Lewis pair regime, hydride shuttle catalysis enables the regioselective functionalization of alkyl amines at either the α- or ß-position. In contrast to classical Lewis acid reactivity, the increased steric hindrance prevents interaction with the Lewis basic amine itself, instead leading to reversible abstraction of a hydride from the amine α-carbon. The created positive charge facilitates the occurrence of transformations before hydride rebound or a similar capture event happen. In this Perspective, we outline a broad selection of transformations featuring hydride shuttle catalysis, as well as the recently developed approach of inverse hydride shuttle catalysis. Both strategies give rise to a wide array of functionalized amines and offer elegant approaches to otherwise elusive bond formations.
ABSTRACT
The creatine transporter-1 (CRT-1/SLC6A8) maintains the uphill transport of creatine into cells against a steep concentration gradient. Cellular creatine accumulation is required to support the ATP-buffering by phosphocreatine. More than 60 compounds have been explored in the past for their ability to inhibit cellular creatine uptake, but the number of active compounds is very limited. Here, we show that all currently known inhibitors are full alternative substrates. We analyzed their structure-activity relation for inhibition of CRT-1 to guide a rational approach to the synthesis of novel creatine transporter ligands. Measurements of both, inhibition of [3H]creatine uptake and transport associated currents, allowed for differentiating between full and partial substrates and true inhibitors. This combined approach led to a refined understanding of the structural requirements for binding to CRT-1, which translated into the identification of three novel compounds - i.e. compound 1 (2-(N-benzylcarbamimidamido)acetic acid), and MIPA572 (=carbamimidoylphenylalanine) and MIPA573 (=carbamimidoyltryptophane) that blocked CRT-1 transport, albeit with low affinity. In addition, we found two new alternative full substrates, namely MIP574 (carbamimidoylalanine) and GiDi1257 (1-carbamimidoylazetidine-3-carboxylic acid), which was superior in affinity to all known CTR-1 ligands, and one partial substrate, namely GiDi1254 (1-carbamimidoylpiperidine-4-carboxylic acid). Significance Statement The creatine transporter-1 (CRT-1) is required to maintain intracellular creatine levels. Inhibition of CRT-1 has been recently proposed as a therapeutic strategy for cancer, but pharmacological tools are scarce. In fact, all available inhibitors are alternative substrates. We tested existing and newly synthesized guanidinocarboxylic acids for CRT-1 inhibition and identified three blockers, one partial and two full substrates of CRT-1. Our results support a refined structural understanding of ligand binding to CRT-1 and provide a proof-of-principle for blockage of CRT-1.
ABSTRACT
Dialkyldiazirines have emerged as a photo-reactive group of choice for interactome mapping in live cell experiments. Upon irradiation, 'linear' dialkyldiazirines produce dialkylcarbenes which are susceptible to both intramolecular reactions and unimolecular elimination processes, as well as diazoalkanes, which also participate in intermolecular labeling. Cyclobutylidene has a nonclassical bonding structure and is stable enough to be captured in bimolecular reactions. Cyclobutanediazirines have more recently been studied as photoaffinity probes based on cyclobutylidene, but the mechanism, especially with respect to the role of putative diazo intermediates, was not fully understood. Here, we show that photolysis (365 nm) of cyclobutanediazirines can produce cyclobutylidene intermediates as evidenced by formation of their expected bimolecular and unimolecular products, including methylenecyclopropane derivatives. Unlike linear diazirines, cyclobutanediazirine photolysis in the presence of tetramethylethylene produces a [2 + 1] cycloaddition adduct. By contrast, linear diazirines produce diazo compounds upon low temperature photolysis in THF, whereas diazo compounds are not detected in similar photolyses of cyclobutanediazirines. Diazocyclobutane, prepared by independent synthesis, is labile, reactive toward water and capable of protein alkylation. The rate of diazocyclobutane decomposition is not affected by 365 nm light, suggesting that the photochemical conversion of diazocyclobutane to cyclobutylidene is not an important pathway. Finally, chemical proteomic studies revealed that a likely consequence of this primary conversion to a highly reactive carbene is a marked decrease in labeling by cyclobutanediazirine-based probes relative to linear diazirine counterparts both at the individual protein and proteome-wide levels. Collectively, these observations are consistent with a mechanistic picture for cyclobutanediazirine photolysis that involves carbene chemistry with minimal formation of diazo intermediates, and contrasts with the photolyses of linear diazirines where alkylation by diazo intermediates plays a more significant role.
ABSTRACT
The deployment of fluorinated functional groups has become a widespread tool in medicinal chemistry due to the impact of fluorine on lipophilicity and metabolic stability. Among these compounds, enantiopure secondary trifluoromethylcarbinols are recurrent features in bioactive compounds. Herein, we present a diastereoselective redox-neutral process allowing the stereospecific synthesis of 1,5-carboxamido-trifluoromethylcarbinols through the formal reduction of a trifluoromethylketone into a trifluoromethylcarbinol. A combined experimental and computational investigation unveiled a network of interconnected equilibria leading to a key hydride transfer event.
ABSTRACT
Ureas stand out as potent pharmacophores in drug development, rendering them a prime focus for synthesis. Herein, we present an appealing entry point for urea synthesis from protected amines (Nms-amides) and relying on a Lossen-type rearrangement process as an elegant example of deprotective functionalisation. The method developed exhibits an exceptionally broad tolerance towards various protected amines, encompassing numerous drug derivatives, and delivers high reaction yields.
ABSTRACT
A domino difunctionalization of sulfonyl(acryl)imides to form ß-substituted α-aryl amides is reported. This transformation involves a 1,4-addition followed by a polar Truce-Smiles rearrangement process, entropically driven by release of SO2. A wide range of carbon- and heteroatom-based nucleophiles and sulfonyl imides were employed, allowing rapid access to highly functionalized amides. In contrast to related reactions with a radical pathway, unbiased substrates could be employed. Despite the usual requirement of an electron-poor migrating moiety for the SNAr event, we herein report unique and unprecedented vinylogous migrations of electron-neutral arenes. Additionally, a one-pot process toward ß-amido amides starting from acrylic acids has been developed.
ABSTRACT
Generally, the acidity of carbon-hydrogen bonds is most sensitive to functionality just one or two bonds away. Here, we present an approach to the formation of carbon-carbon σ bonds by remote proton elimination, a distinct mode of carbon-hydrogen activation enabled by distal acidification through five carbon-carbon bonds. Application of remote proton elimination to cyclodecyl cations unveiled an appealing method for the synthesis of decalins. The transformation is regioconvergent, proceeds without the need for a directing group or precious metal, and demonstrates exquisite site selectivity. An in-depth computational study illuminated the reaction mechanism. Additionally, we describe the complete stereoisomeric enrichment of the decalin products through epimerization mediated by hydrogen atom transfer.
ABSTRACT
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.
ABSTRACT
We describe the single-step formation of complex tetracyclic fused scaffolds enabled by (3 + 2) cycloaddition of azomethine ylides. Various indoles, N-protecting groups, and amino acids are well tolerated. The products are obtained in a catalyst-free manner with moderate to excellent yield and high diastereoselectivity. Representing a new scaffold that is not yet found in nature, the construction of pyrrolidine-fused cyclohepta-, azepino-, or oxepinoindoles could be found valuable in the synthesis of new pseudo-natural products.
ABSTRACT
Cobalt complexes with multiproton- and multielectron-responsive ligands are of interest for challenging catalytic transformations. The chemical and redox noninnocence of pentane-2,4-dione bis(S-methylisothiosemicarbazone) (PBIT) in a series of cobalt complexes has been studied by a range of methods, including spectroscopy [UV-vis, NMR, electron paramagnetic resonance (EPR), X-ray absorption spectroscopy (XAS)], cyclic voltammetry, X-ray diffraction, and density functional theory (DFT) calculations. Two complexes [CoIII(H2LSMe)I]I and [CoIII(LSMe)I2] were found to act as precatalysts in a Wacker-type oxidation of olefins using phenylsilane, the role of which was elucidated through isotopic labeling. Insights into the mechanism of the catalytic transformation as well as the substrate scope of this selective reaction are described, and the essential role of phenylsilane and the noninnocence of PBIT are disclosed. Among the several relevant species characterized was an unprecedented Co(III) complex with a dianionic diradical PBIT ligand ([CoIII(LSMeâ¢â¢)I]).
ABSTRACT
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 (>60â examples) and display Stokes shifts as large as 240â nm, while also reaching NIR-I emissions at λmax as long as 720â 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.
Subject(s)
Fluorescent Dyes , Humans , Fluorescent Dyes/chemistry , HEK293 Cells , Microscopy, Fluorescence , Salts/chemistry , Molecular StructureABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
A nickel-catalyzed reductive dimerization of bromocyclobutenes to produce unusual and unprecedented cyclobutene dimers was developed. In a stereoconvergent procedure, various bromocyclobutenes were readily dimerized in good yields, with good diastereoselectivities and broad functional group tolerance. Notably, the presence of a carbonyl group in the starting material appears to dictate diastereoselectivity.
ABSTRACT
Spirocyclic butyrolactones and butenolides are widespread structural motifs in bioactive substances. Despite their prevalence, a simple method ensuring their direct preparation from exocyclic alkenes, ideally in a late-stage context, remains elusive. Herein, we report direct aminolactone formation using unactivated alkenes which addresses this gap, employing cheap and readily available reactants. The method relies on the hijacking of a cationic aminoalkylation pathway and affords (spiro)aminolactones with excellent functional group tolerance and chemoselectivity. The synthetic versatility of the products is demonstrated through a range of transformations, notably exploiting stereospecific rearrangement chemistry to produce sterically congested scaffolds.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.