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Carbohydrates regulate an inimitable spectrum of biological functions, yet successfully leveraging this therapeutic avenue continues to be frustrated by low affinities with glycan-specific proteins. A conspicuous exception is the interaction of monosialotetrahexosylganglioside (GM1) with the carbohydrate-recognition domain of cholera toxin from Vibrio cholerae : this is one of the strongest protein-carbohydrate interactions known. To establish the importance of a long-discussed key hydrogen bond between C2 of the terminal galactose of GM1 and the B subunit pentamer of cholera toxin (CTB 5 ), the total synthesis of a selectively fluorinated GM1 epitope was conducted in 19 steps. This process of molecular editing (O δ- H → F δ- ) strategically deletes the hydrogen bond donor while retaining the localized partial charge of the substituent. Comparison of the binding affinity of F-GM1/CTB 5 with native GM1, the GM1 carbohydrate epitope, and meta -mononitrophenyl-α-galactoside (MNPG) revealed a trend that fully supports the importance of this key interaction. These NMR data suggest that F-GM1 binds in a closely similar conformation as native GM1. Crystallographic analyses of the complex also confirm that the OH → F bioisosteric exchange at C2 of the terminal galactose induces a ring conformation that eliminates key hydrogen bonds: these interactions are compensated for by inter- and intramolecular fluorine-specific interactions., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: With metabolic alterations of the tumor microenvironment (TME) contributing to cancer progression, metastatic spread and response to targeted therapies, non-invasive and repetitive imaging of tumor metabolism is of major importance. The purpose of this study was to investigate whether multiparametric chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI) allows to detect differences in the metabolic profiles of the TME in murine breast cancer models with divergent degrees of malignancy and to assess their response to immunotherapy., Methods: Tumor characteristics of highly malignant 4T1 and low malignant 67NR murine breast cancer models were investigated, and their changes during tumor progression and immune checkpoint inhibitor (ICI) treatment were evaluated. For simultaneous analysis of different metabolites, multiparametric CEST-MRI with calculation of asymmetric magnetization transfer ratio (MTR asym ) at 1.2 to 2.0 ppm for glucose-weighted, 2.0 ppm for creatine-weighted and 3.2 to 3.6 ppm for amide proton transfer- (APT-) weighted CEST contrast was conducted. Ex vivo validation of MRI results was achieved by 1 H nuclear magnetic resonance spectroscopy, matrix-assisted laser desorption/ionization mass spectrometry imaging with laser postionization and immunohistochemistry., Results: During tumor progression, the two tumor models showed divergent trends for all examined CEST contrasts: While glucose- and APT-weighted CEST contrast decreased and creatine-weighted CEST contrast increased over time in the 4T1 model, 67NR tumors exhibited increased glucose- and APT-weighted CEST contrast during disease progression, accompanied by decreased creatine-weighted CEST contrast. Already three days after treatment initiation, CEST contrasts captured response to ICI therapy in both tumor models., Conclusion: Multiparametric CEST-MRI enables non-invasive assessment of metabolic signatures of the TME, allowing both for estimation of the degree of tumor malignancy and for assessment of early response to immune checkpoint inhibition., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Enantioenriched chiral indoles are of high interest for the pharmaceutical and agrochemical industries. Herein, we present an asymmetric Fukuyama indole synthesis through a mild and efficient radical cascade reaction to access 2-fluoroalkylated 3-(α-cyanobenzylated) indoles by stereochemical control with a chiral copper-bisoxazoline complex using 2-vinylphenyl arylisocyanides as radical acceptors and fluoroalkyl iodides as C-radical precursors. Radical addition to the isonitrile moiety, 5 -exo -trig cyclization, and Cu-catalyzed stereoselective cyanation provide the targeted indoles with excellent enantioselectivity and good yields. Due to the similar electronic and steric properties of the two aryl substituents to be differentiated, the enantioselective construction of the cyano diaryl methane stereocenter is highly challenging. Mechanistic studies reveal a negative nonlinear effect which allows proposing a model to explain the stereochemical outcome. Scalability and potential utility of the enantioenriched 3-(α-cyanobenzylated) indoles as hubs for chiral tryptamines, indole-3-acetic acid derivatives, and triarylmethanes are demonstrated, and a formal synthesis of a natural product analogue is disclosed.

Catalyst-free 1,2-carboboration of ynamides is presented. Readily available aryldichloroboranes react with alkyl- or aryl-substituted ynamides in high yields with complete regio- and stereoselectivity to valuable β-boryl-β-alkyl/aryl α-aryl substituted enamides which belong to the class of trisubstituted alkenylboronates. The 1,2-carboboration reaction is experimentally easy to conduct, shows high functional group tolerance and broad substrate scope. Gram-scale reactions and diverse synthetic transformations convincingly demonstrate the synthetic potential of this method. The reaction can also be used to access 1-boraphenalenes, a class of boron-doped polycyclic aromatic hydrocarbons., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The η 2 -formyl borane system 3 is readily available by carbonylation of the vicinal P/BH frustrated Lewis pair (FLP) 1 . It serves as a frustrated C/B Lewis pair toward carbon dioxide or phenylisocyanate. In the presence of B(C 6 F 5 ) 3 , it forms the coupling product between two CO-derived units. The resulting compound 13 rearranged to a doubly O -borylated endiolate, with both of the central carbon atoms originating from carbon monoxide. The subsequent treatment with a silane gave a rare macrocyclic silicon endiolate.

Recently palladium catalysts have been discovered that enable the directing-group-free C-H activation of arenes without requiring an excess of the arene substrate, thereby enabling methods for the late-stage modification of complex organic molecules. The key to success has been the use of two complementary ligands, an N-acyl amino acid and an N-heterocycle. Detailed experimental and computational mechanistic studies on the dual-ligand-enabled C-H activation of arenes have led us to identify the catalytically active species and a transition state model that explains the exceptional activity and selectivity of these catalysts. These findings are expected to be highly useful for further method development using this powerful class of catalysts., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Hydration of alkenes using first row transition metals (Fe, Co, Mn) under oxygen atmosphere (Mukaiyama-type hydration) is highly practical for alkene functionalization in complex synthesis. Different hydration protocols have been developed, however, control of the stereoselectivity remains a challenge. Herein, highly diastereoselective Fe-catalyzed anaerobic Markovnikov-selective hydration of alkenes using nitroarenes as oxygenation reagents is reported. The nitro moiety is not well explored in radical chemistry and nitroarenes are known to suppress free radical processes. Our findings show the potential of cheap nitroarenes as oxygen donors in radical transformations. Secondary and tertiary alcohols were prepared with excellent Markovnikov-selectivity. The method features large functional group tolerance and is also applicable for late-stage chemical functionalization. The anaerobic protocol outperforms existing hydration methodology in terms of reaction efficiency and selectivity., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Light-responsive modulation of the longitudinal (T1) and transversal relaxation times of a fluorinated cyclodextrin has been achieved by host-guest complexation with arylazopyrazole-modified metal complexes in aqueous solution. This supramolecular concept can potentially be applied to the development of contrast agents for 19F magnetic resonance imaging (MRI).

Fluorinated piperidines are desirable motifs for pharmaceutical and agrochemical research. Nevertheless, general synthetic access remains out of reach. Herein, we describe a simple and robust cis -selective hydrogenation of abundant and cheap fluoropyridines to yield a broad scope of (multi)fluorinated piperidines. This protocol enables the chemoselective reduction of fluoropyridines while tolerating other (hetero)aromatic systems using a commercially available heterogenous catalyst. Fluorinated derivatives of important drug compounds are prepared, and a straightforward strategy for the synthesis of enantioenriched fluorinated piperidines is disclosed., Competing Interests: The authors declare no competing financial interest.

A dimeric ethylene-bridged PH/BH system reduced carbon monoxide to the -CH 2 -O- state. In the presence of B(C 6 F 5 ) 3 , the frustrated PH/BH Lewis pair reacted with carbon monoxide by reductive coupling of two CO molecules at the template. Removal of the B(C 6 F 5 ) 3 borane with pyridine liberated one equiv of carbon monoxide to give a cyclic five-membered P(═O)-CH 2 -B compound, the product of reductive cleavage of carbon monoxide. It reacted as a borylated Horner P(═O)CH 2 B carbon nucleophile with carbon dioxide to give a bicyclic product by P-CH 2 attack on CO 2 combined with internal P═O to boron coordination.

A trans -selective arene hydrogenation of abundant phenol derivatives catalyzed by a commercially available heterogeneous palladium catalyst is reported. The described method tolerates a variety of functional groups and provides access to a broad scope of trans -configurated cyclohexanols as potential building blocks for life sciences and beyond in a one-step procedure. The transformation is strategically important because arene hydrogenation preferentially delivers the opposite cis -isomers. The diastereoselectivity of the phenol hydrogenation can be switched to the cis -isomers by employing rhodium-based catalysts. Moreover, a protocol for the chemoselective hydrogenation of phenols to cyclohexanones was developed., Competing Interests: The authors declare no competing financial interest.

Lanthanide photocatalysts are much less investigated in synthetic chemistry than rare and expensive late transition metals. We herein introduce Gd III photocatalysis of a highly regioselective, intermolecular [2+2] photocycloaddition/ring-expansion sequence with indoles, which could provide divergent access to cyclopenta[b]indoles and indolines. A simple and commercially available Gd(OTf) 3 salt is sufficient for this visible-violet-light-induced transformation. The reaction proceeds either through a transient or start-to-end dearomatization cascade and shows excellent regioselectivity (usually >95:5 r.r.), broad scope (59 examples), good functional group tolerance and facile scale-up under mild, direct visible-light-excitation conditions. Mechanistic investigations reveal that direct excitation of the Gd(OTf) 3 /indole mixture gives an excited state intermediate, which undergoes the subsequent [2+2] cycloaddition and cyclobutane-expansion cascade., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Gaining an understanding of the conformational behavior of fluorinated compounds would allow for expansion of the current molecular design toolbox. In order to facilitate drug discovery efforts, a systematic survey of a series of diversely substituted and protected fluorinated piperidine derivatives has been carried out using NMR spectroscopy. Computational investigations reveal that, in addition to established delocalization forces such as charge-dipole interactions and hyperconjugation, solvation and solvent polarity play a major role. This work codifies a new design principle for conformationally rigid molecular scaffolds., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Thermal treatment of the bicyclo[1.1.0]tetrasilatetraamide [Si 4 {N(SiMe 3 )Dipp} 4 ] 1 resulted in the formation of a highly unsaturated six-vertex silicon cluster [Si 6 {N(SiMe 3 )Dipp} 4 ] 2 with only four amine-substituents and two ligand-free silicon atoms. In solution, a major and a minor conformer of this cluster are in equilibrium according to multinuclear NMR spectroscopy, lineshape analysis, DFT calculations and molecular dynamics simulations. The bonding situation in the highly unsaturated cluster features lone pair type character at the ligand-free silicon atoms and partial single and double bond character in the upper butterfly-shaped ring of 2 . This allows to consider 2 as the silicon analogue of a butalene isomer., (This journal is © The Royal Society of Chemistry 2020.)

Sialic acids are conspicuous structural components of the complex gangliosides that regulate cellular processes. Their importance in molecular recognition manifests itself in drug design ( e.g. Tamiflu®) and continues to stimulate the development of effective chemical sialylation strategies to complement chemoenzymatic technologies. Stereodivergent approaches that enable the α- or β-anomer to be generated at will are particularly powerful to attenuate hydrogen bond networks and interrogate function. Herein, we demonstrate that site-selective halogenation (F and Br) at C3 of the N -glycolyl units common to marine Neu2,6Glu epitopes enables pseudo-stereodivergent sialylation. α-Selective sialylation results from fluorination, whereas traceless bromine-guided sialylation generates the β-adduct. This concept is validated in the synthesis of HLG-1 and Hp-s1 analogues., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A stereodivergent synthesis of four diastereomeric 2,3,4,5-tetrafluoropentanols is disclosed. X-ray crystallographic analysis reveals conformations that manifest sequential stereoelectronic gauche effects (σ C-H/C → σ C-F *), thereby generating topological diversity via subtle C(sp 3 )-H to C(sp 3 )-F exchange. Two representative tetrafluoro arrays have been incorporated into truncated analogues of Gilenya for the management of relapsing remitting multiple sclerosis. These closely similar multivicinal fluoroalkanes have notably different physicochemical profiles and were found to be stable in the presence of human microsomes.

Fluorinated motifs have a venerable history in drug discovery, but as C(sp 3 )-F-rich 3D scaffolds appear with increasing frequency, the effect of multiple bioisosteric changes on molecular recognition requires elucidation. Herein we demonstrate that installation of a 1,3,5-stereotriad, in the substrate for a commonly used lipase from Pseudomonas fluorescens does not inhibit recognition, but inverts stereoselectivity. This provides facile access to optically active, stereochemically well-defined organofluorine compounds (up to 98 % ee). Whilst orthogonal recognition is observed with fluorine, the trend does not hold for the corresponding chlorinated substrates or mixed halogens. This phenomenon can be placed on a structural basis by considering the stereoelectronic gauche effect inherent to F-C-C-X systems (σ→σ*). Docking reveals that this change in selectivity (H versus F) with a common lipase results from inversion in the orientation of the bound substrate being processed as a consequence of conformation. This contrasts with the stereochemical interpretation of the biogenetic isoprene rule, whereby product divergence from a common starting material is also a consequence of conformation, albeit enforced by two discrete enzymes., (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Pinacol boronic esters are highly valuable building blocks in organic synthesis. In contrast to the many protocols available on the functionalizing deboronation of alkyl boronic esters, protodeboronation is not well developed. Herein we report catalytic protodeboronation of 1°, 2° and 3° alkyl boronic esters utilizing a radical approach. Paired with a Matteson-CH 2 -homologation, our protocol allows for formal anti-Markovnikov alkene hydromethylation, a valuable but unknown transformation. The hydromethylation sequence was applied to methoxy protected (-)-Δ8-THC and cholesterol. The protodeboronation was further used in the formal total synthesis of δ-( R )-coniceine and indolizidine 209B.

1-(Trimethylsilyl)propyne 2a reacts with halogenoboranes XB(C6F5)2 (X: Cl, Br) in a 1 : 1 molar ratio at r.t. to give the respective alkenylboranes 3. These undergo a subsequent 1,1-alkenylboration reaction with additional alkyne 2a to give the persubstituted 3-boryl-2,4-hexadiene products 4. The conjugated diyne bis(trimethylsilyl)butadiyne 2d reacts with ClB(C6F5)2 in a 2 : 1 molar ratio by a sequence of consecutive 1,1-carboboration reactions to give the persubstituted borylated octadiendiyne product 6.

Stable seleniranium ions were prepared from easily available stable bromiranium ions and diselenides. The solid state structure of the obtained seleniranium ions was determined by X-ray crystallographic analysis and their alkene-to-alkene transfer was investigated by NMR techniques. The rapid alkene-to-alkene transfer of the selenium group enabled the application of the seleniranium ion salts as selenenylating agents, which led to very efficient and highly diastereoselective, selenium-induced polyene-type cyclisations of terpene analogues.

Sialic acids are ubiquitous components of mammalian cell membranes and key regulators of cellular recognition events. Located at the non-reducing termini of bioactive gangliosides, these essential building blocks are fused to the polysaccharide core via a characteristic α-linkage, and rarely occur in the monomeric form. Effective chemical strategies to enable α-sialylation are urgently required to construct well-defined tools for glycomics. To complement existing chemoenzymatic strategies, an α-selective process has been devised based on the site-selective introduction of fluorine at C3 (more than 20 examples, up to 90 % yield). Predicated on localized particle charge inversion (C-H δ+ →C-F δ- ), fluorine insertion simultaneously augments the anomeric effect, enhances electrophilicity at C2 and mitigates elimination. A stereochemical induction model is postulated that spans the S N continuum and validates the role of the C-F bond in orchestrating α-selectivity., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Piperidines and fluorine substituents are both independently indispensable components in pharmaceuticals, agrochemicals and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous potential. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselective synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochemistry. That of multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report, we describe a straightforward process for the one-pot rhodium-catalysed dearomatization-hydrogenation of fluoropyridine precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly diastereoselective fashion through pyridine dearomatization followed by complete saturation of the resulting intermediates by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine substituents were successfully applied in the preparation of commercial drugs analogues. Additionally, fluorinated PipPhos as well as fluorinated ionic liquids were obtained by this dearomatization-hydrogenation process.

Catalytic transfer hydrocyanation represents a clean and safe alternative to hydrocyanation processes using toxic HCN gas. Such reactions provide access to pharmaceutically important nitrile derivatives starting with alkenes and alkynes. Herein, an efficient and practical cooperative palladium/Lewis acid-catalyzed transfer hydrocyanation of alkenes and alkynes is presented using 1-methylcyclohexa-2,5-diene-1-carbonitrile as a benign and readily available HCN source. A large set of nitrile derivatives (>50 examples) are prepared from both aliphatic and aromatic alkenes with good to excellent anti-Markovnikov selectivity. A range of aliphatic alkenes engage in selective hydrocyanation to provide the corresponding nitriles. The introduced method is useful for chain walking hydrocyanation of internal alkenes to afford terminal nitriles in good regioselectivities. This protocol is also applicable to late-stage modification of bioactive molecules.

Herein, we report the selective, non-directed and cross-dehydrogenative coupling of allylic C(sp 3 )-H bonds with C(sp 2 )-H bonds of (hetero)arenes. The methodology employs olefins and (hetero)arenes which are abundantly available chemical feedstocks, and could be applied in late-stage functionalization reactions of pharmaceuticals. Furthermore, the system exclusively delivers the allylic C-C coupling products highlighting the preservation of the olefin substitution pattern for further derivatization., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A method for remote radical C-H alkynylation at unactivated sites is reported. C-H functionalization proceeds via 1,5-hydrogen atom transfer (HAT) to amidyl radicals that are generated via an addition/fragmentation reaction. The readily installed N-allylsulfonyl moiety is used as a precursor of the N-centered radical. Unactivated secondary and tertiary as well as selected primary C-H bonds can be functionalized by this method.

The reduction of the tribromoamidosilane {N(SiMe 3 )Dipp}SiBr 3 (Dipp=2,6-iPr 2 C 6 H 3 ) with potassium graphite or magnesium resulted in the formation of [Si 4 {N(SiMe 3 )Dipp} 4 ] (1), a bicyclo[1.1.0]tetrasilatetraamide. The Si 4 motif in 1 does not adopt a tetrahedral substructure and exhibits two three-coordinate and two four-coordinate silicon atoms. The electronic situation on the three-coordinate silicon atoms is rationalized with positive and negative polarization based on EPR analysis, magnetization measurements, and DFT calculations as well as 29 Si CP MAS NMR and multinuclear NMR spectroscopy in solution. Reactivity studies with 1 and radical scavengers confirmed the partial charge separation. Compound 1 reacts with sulfur to give a novel type of silicon sulfur cage compound substituted with an amido ligand, [Si 4 S 3 {N(SiMe 3 )Dipp} 4 ] (2)., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Electrophilic halogenating agents are an important class of reagents in chemical synthesis. Herein, we show that sterically demanding bromiranium ions with weakly coordinating counterions are highly reactive electrophilic brominating agents. Despite their high reactivity these reagents are stable, in one case even under ambient conditions and can be applied in electrophilic halogenations of alkenes as well as heteroatoms., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The energy profile of a frustrated Lewis pair (FLP) dihydrogen splitting system was determined by a combined experimental kinetic and DFT study. A trimethylene-bridged phosphane-borane FLP was converted into its endothermic H2 -cleavage product by sequential H(+) /H(-) addition. The system could be handled at low temperature, and the kinetics of the H2 elimination were determined to give a rate constant of kHH,exp (299 K)=(2.87±0.1)×10(-4)  s(-1) in solution. The primary kinetic isotope effects were determined; for example, (kHH /kDD )exp =3.19. The system was accurately analyzed by DFT calculations., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

For the efficient utilization of carbon dioxide as feedstock in chemical synthesis, low-energy-barrier CO2 activation is a valuable tool. We report a metal-free approach to reversible CO2 binding under mild conditions based on simple Lewis base adducts with electron-rich phosphines. Variable-temperature NMR studies and DFT calculations reveal almost thermoneutral CO2 binding with low-energy barriers or stable CO2 adduct formation depending on the phosphines donor ability. The most basic phosphine forms an air-stable CO2 adduct that was used as phosphine transfer agent, providing a convenient access to transition-metal complexes with highly electron-rich phosphine ligands relevant to catalysis.

Fusarium fujikuroi is a member of the Gibberella fujikuroi species complex and well known for the production of gibberellins and mycotoxins including fusarins and fusaric acid. A recent genome sequencing study revealed that the fungus has the genetic potential to produce many more secondary metabolites than have been reported. This paper describes the structure elucidation of the products of the cryptic and silent PKS19 gene cluster that were recently identified (fujikurins A-D). We present the complete NMR data for the structure elucidation of the main compound fujikurin D, which shows tautomeric 1,3-diketo elements. The different tautomeric structures could be confirmed using quantum chemical calculations. Additionally, the structures of the minor compounds fujikurins A-C were elucidated by high-resolution mass spectrometric fragmentation experiments. It emerged that fujikurin A was identical to the bioactive compound CR377 of the taxonomically unclassified Fusarium strain CR377, while fujikurins B-D have not been reported from other fungi.