Stereoelectronic Properties Research Articles

N-Glycosylation-Induced Pathologic Protein Conformations as a Tool to Guide the Selection of Biologically Active Small Molecules.

Post-translational modifications such as protein N-glycosylation, significantly influence cellular processes. Dysregulated N-glycosylation, exemplified in Grp94, a member of the Hsp90 family, leads to structural changes and the formation of epichaperomes, contributing to pathologies. Targeting N-glycosylation-induced conformations offers opportunities for developing selective chemical tools and drugs for these pathologic forms of chaperones. We here demonstrate how a specific Grp94 conformation induced by N-glycosylation, identified previously via molecular dynamics simulations, rationalizes the distinct behavior of similar ligands. Integrating dynamic ligand unbinding information with SAR development, we differentiate ligands productively engaging the pathologic Grp94 conformers from those that are not. Additionally, analyzing binding site stereoelectronic properties and QSAR models using cytotoxicity data unveils relationships between chemical, conformational properties, and biological activities. These findings facilitate the design of ligands targeting specific Grp94 conformations induced by abnormal glycosylation, selectively disrupting pathogenic protein networks while sparing normal mechanisms.

A Modular Dual-Catalytic Aryl-Chlorination of Alkenes.

Alkyl chlorides are a class of versatile building blocks widely used to generate C(sp3)-rich scaffolds through transformation such as nucleophilic substitution, radical addition reactions and metal-catalyzed cross-coupling processes. Despite their utility in the synthesis of high-value functional molecules, distinct methods for the preparation of alkyl chlorides are underrepresented. Here, we report a visible-light-mediated dual catalysis strategy for the modular synthesis of highly functionalized and structurally diverse arylated chloroalkanes via the coupling of diaryliodonium salts, alkenes and potassium chloride. A distinctive aspect of this transformation is a ligand-design-driven approach for the development of a copper(II)-based atom-transfer catalyst that enables the aryl-chlorination of electron-poor alkenes, complementing its iron(III)-based counterpart that accommodates non-activated aliphatic alkenes and styrene derivatives. The complementarity of the two dual catalytic systems allows the efficient aryl-chlorination of alkenes bearing different stereo-electronic properties and a broad range of functional groups, maximizing the structural diversity of the 1-aryl, 2-chloroalkane products.

A General Iron-Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids.

We report an iron-catalyzed decarboxylative C(sp3)-O bond-forming reaction under mild, base-free conditions with visible light irradiation. The transformation uses readily available and structurally diverse carboxylic acids, iron photocatalyst, and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) derivatives as oxygenation reagents. The process exhibits a broad scope in acids possessing a wide range of stereoelectronic properties and functional groups. The developed reaction was applied to late-stage oxygenation of a series of bio-active molecules. The reaction leverages the ability of iron complexes to generate carbon-centered radicals directly from carboxylic acids by photoinduced carboxylate-to-iron charge transfer. Kinetic, electrochemical, EPR, UV/Vis, HRMS, and DFT studies revealed that TEMPO has a triple role in the reaction: as an oxygenation reagent, an oxidant to turn over the Fe-catalyst, and an internal base for the carboxylic acid deprotonation. The obtained TEMPO adducts represent versatile synthetic intermediates that were further engaged in C-C and C-heteroatom bond-forming reactions using commercial organo-photocatalysts and nucleophilic reagents.

A General Iron‐Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids

AbstractWe report an iron‐catalyzed decarboxylative C(sp3)−O bond‐forming reaction under mild, base‐free conditions with visible light irradiation. The transformation uses readily available and structurally diverse carboxylic acids, iron photocatalyst, and 2,2,6,6‐tetramethylpiperidine 1‐oxyl (TEMPO) derivatives as oxygenation reagents. The process exhibits a broad scope in acids possessing a wide range of stereoelectronic properties and functional groups. The developed reaction was applied to late‐stage oxygenation of a series of bio‐active molecules. The reaction leverages the ability of iron complexes to generate carbon‐centered radicals directly from carboxylic acids by photoinduced carboxylate‐to‐iron charge transfer. Kinetic, electrochemical, EPR, UV/Vis, HRMS, and DFT studies revealed that TEMPO has a triple role in the reaction: as an oxygenation reagent, an oxidant to turn over the Fe‐catalyst, and an internal base for the carboxylic acid deprotonation. The obtained TEMPO adducts represent versatile synthetic intermediates that were further engaged in C−C and C‐heteroatom bond‐forming reactions using commercial organo‐photocatalysts and nucleophilic reagents.

Dienes as Versatile Substrates for Transition Metal‐Catalyzed Reactions

AbstractDienes have been of great interest to synthetic chemists as valuable substrates due to their abundance and ease of synthesis. Their unique stereoelectronic properties enable broad reactivity with a wide range of transition metals to construct molecular complexity facilitating synthesis of biologically active compounds. In addition, structural diene variation can result in substrate‐controlled reactions, providing valuable mechanistic insights into reactivity and selectivity patterns. The last decade has seen a wealth of new methodologies involving diene substrates through the power of transition metal catalysis. This review summarizes recent advances and remaining opportunities for transition metal‐catalyzed transformations involving dienes.

Dienes as Versatile Substrates for Transition Metal-Catalyzed Reactions.

Dienes have been of great interest to synthetic chemists as valuable substrates due to their abundance and ease of synthesis. Their unique stereoelectronic properties enable broad reactivity with a wide range of transition metals to construct molecular complexity facilitating synthesis of biologically active compounds. In addition, structural diene variation can result in substrate-controlled reactions, providing valuable mechanistic insights into reactivity and selectivity patterns. The last decade has seen a wealth of new methodologies involving diene substrates through the power of transition metal catalysis. This review summarizes recent advances and remaining opportunities for transition metal-catalyzed transformations involving dienes.

Boosting the π-Acceptor Property of Mesoionic Carbenes by Carbonylation with Carbon Monoxide.

We report the room temperature dimerization of carbon monoxide mediated by C4/C5-vicinal anionic dicarbenes Li(ADC) (ADC = ArC{(Dipp)NC}2 ; Dipp = 2,6-iPr2 C6 H3 ; Ar = Ph, DMP (4-Me2 NC6 H4 ), Bp (4-PhC6 H4 )) to yield (E)-ethene-1,2-bis(olate) (i.e. - O-C=C-O- = COen ) bridged mesoionic carbene (iMIC) lithium compounds COen -[(iMIC)Li]2 (COen -[iMIC]2 = [ArC{(Dipp)NC}2 (CO)]2 ) in quantitative yields. COen -[(iMIC)Li]2 are highly colored stable solids, exhibit a strikingly small HOMO-LUMO energy gap, and readily undergo 2e-oxidations with selenium, CuCl (or CuCl2 ), and AgCl to afford the dinuclear compounds COon -[(iMIC)E]2 (E = Se, CuCl, AgCl) featuring a 1,2-dione bridged neutral bis-iMIC (i.e. COon -[iMIC]2 = [ArC{(Dipp)NC}2 (C=O)]2 ). COen -[(iMIC)Li]2 undergo redox-neutral salt metathesis reactions with LiAlH4 and (Et2 O)2 BeBr2 and afford COen -[(iMIC)AlH2 ]2 and COen -[(iMIC)BeBr]2 , in which the dianionic COen -moiety remains intact. All compounds have been characterized by NMR spectroscopy, mass spectrometry, and X-ray diffraction. Stereoelectronic properties of COon -[iMIC]2 are quantified by experimental and theoretical methods.

Steigerung der π‐Akzeptoreigenschaft mesoionischer Carbene durch Carbonylierung mit Kohlenmonoxid

AbstractWir berichten über die Dimerisierung von Kohlenmonoxid bei Raumtemperatur mittels anionischer C4/C5‐Dicarbene Li(ADC) (ADC = ArC{(Dipp)NC}2; Dipp = 2,6‐iPr2C6H3; Ar = Ph, DMP (4‐Me2NC6H4), Bp (4‐PhC6H4)), wobei (E)‐Ethen‐1,2‐bis(olat) (d. h. −O−C=C−O− = COen) verbrückte mesoionische Carben (iMIC)‐Lithiumverbindungen COen‐[(iMIC)Li]2 (COen‐[iMIC]2 = [ArC{(Dipp)NC}2(CO)]2) in quantitativer Ausbeute isoliert wurden. COen‐[(iMIC)Li]2 sind farbliche, stabile Feststoffe und weisen eine bemerkenswert kleine HOMO–LUMO‐Energielücke auf. Sie untergehen mit Selen, CuCl (oder CuCl2) und AgCl 2e‐Oxidationen, um die dinuklearen Verbindungen COon‐[(iMIC)E]2 (E = Se, CuCl, AgCl) mit einem 1,2‐Dion‐verbrückten neutralen Bis‐iMIC (d. h. COon‐[iMIC]2 = [ArC{(Dipp)NC}2(C=O)]2) zu erzeugen. COen‐[(iMIC)Li]2 reagieren mit LiAlH4 und (Et2O)2BeBr2 durch redoxneutrale Salzmetathesereaktion zu COen‐[(iMIC)AlH2]2 und COen‐[(iMIC)BeBr]2, bei denen die dianionische COen‐Brücke erhalten bleibt. Alle Verbindungen wurden mittels NMR‐Spektroskopie, Massenspektrometrie und Röntgenbeugung charakterisiert. Die stereoelektronischen Eigenschaften von COon‐[iMIC]2 wurden durch experimentelle und theoretische Methoden quantifiziert.

Naturally J-aggregated F-BODIPYs: Self-assembly organization driven by substitution pattern

The development of self-assembled dyes able to display J-aggregation-induced emission has gained a renewed interest as an appealing and distinctive approach for the design of smart photoactive materials. F-BODIPY dyes have been exploited to this aim since J-type supramolecular organization has been effectively photoinduced under specific surrounding conditions (hydrophilic or constrained media) although, up to date, it has never been observed in pure organic media. Herein, we report the first systematic study of the self-assembly properties of F-BODIPYs in pure organic solvents and analyze in depth the control exerted by the substitution pattern of its carbon skeleton into the formation of emissive J-aggregates. Spontaneous J-aggregation in F-BODIPYs is evidenced by their lasing properties and supported by the analysis of their solid-state photophysics and X-ray crystalline packing as well as by molecular dynamics in solvent cages. These studies point out the key role of the stereoelectronic properties of the substituents orthogonally grafted at the dipyrrin core (meso and C-2 and C-6 positions) as the main driving force to control the molecular stacking arrangement of F-BODIPYs in common organic solvents. The understanding of the interplay between the molecular structure and the properties of the resulting aggregates sheds light on the workability of BODIPY-based self-assembly as a tool for advanced luminescent materials.

Ring-Opening of 1,3-Imidazole Based Mesoionic Carbenes (iMICs) and Ring-Closing Clicks: Facile Access to iMIC-Compounds.

Herein, ring-opening of mesoionic carbenes (iMICs) (iMIC=[ArC{N(Dipp)}2 C(SiMe3 )C:) (Dipp=2,6-iPr2 C6 H3 , Ar=Ph, 4-Me2 NC6 H4 or 4-PhC6 H4 ) based on an 1,3-imidazole scaffold to yield N-ethynylformimidamide (eFIM) derivatives as crystalline solids (eFIM={(Dipp)N=C(Ar)N(Dipp)}C≡CSiMe3 ) is reported. eFIMs are thermally stable under inert gas atmosphere and show moderate air stability (t1/2= 3 h for Ar=Ph). eFIMs are excellent surrogates of iMICs, which generally have a limited shelf-life, and readily undergo ring-closing click reactions with a variety of main-group as well as transition metal Lewis acids to form hitherto challenging iMIC-compounds in good to excellent yields. In addition to the relevance of eFIMs in the synthesis of iMIC-compounds, quantification of the stereoelectronic properties of a representative iMIC (Ar=Ph) by experimental and theoretical methods suggests remarkably σ-donor property and steric profile of these new ligand sets.

Application of N-heterocyclic carbene-Cu(I) complexes as catalysts in organic synthesis: a review.

N-Heterocyclic carbenes (NHCs) are a special type of carbenes in which the carbene carbon atom is part of the nitrogen heterocyclic ring. Due to the simplicity of their synthesis and the modularity of their stereoelectronic properties, NHCs have unquestionably emerged as one of the most fascinating and well-known species in chemical science. The remarkable stability of NHCs can be attributed to both kinetic as well as thermodynamic effects caused by its structural features. NHCs constitute a well-established class of new ligands in organometallic chemistry. Although initially NHCs were regarded as pure σ-donor ligands, later experimental and theoretical studies established the presence of a significant back donation from the d-orbital of the metal to the π* orbital of the NHC. Over the last two decades, NHC-metal complexes have been extensively used as efficient catalysts in different types of organic reactions. Of these, NHC-Cu(I) complexes found prominence for various reasons, such as ease of preparation, possibility of structural diversity, low cost, and versatile applications. This article overviews applications of NHC-Cu(I) complexes as catalysts in organic synthesis over the last 12 years, which include hydrosilylation reactions, conjugate addition, [3 + 2] cycloaddition, A3 reaction, boration and hydroboration, N-H and C(sp2)-H carboxylation, C(sp2)-H alkenylation and allylation, C(sp2)-H arylation, C(sp2)-H amidation, and C(sp2)-H thiolation. Preceding the section of applications, a brief description of the structure of NHCs, nature of NHC-metal bond, and methods of preparation of NHC-Cu complexes is provided.

Direct Access to meta‐Alkylated N‐Arylazolium Salts via Ruthenium Catalyzed Electronically Controlled Site Selective Functionalization: Scope and Mechanistic Aspect

AbstractEffective access to azolium salts with varying stereoelectronic properties has always fascinated the organometallic chemists. Herein, we described a Ru(II)‐catalyzed one‐step access to diverse meta‐alkylated N‐aryl (benz)imidazolium salts (>40 examples) via σ‐bond activation strategy starting from the readily available azolium salts using alkyl bromide. Notably, the present method is compatible with a wide range of azolium salts and secondary/tertiary alkyl bromides, including the biologically relevant motifs. Various control experiments along with the DFT calculation established the reaction pathway of orthometalated Ru(II)‐NHC complex (6) formation followed by the generation of a Ru(III)‐intermediate, which controls the observed meta‐selectivity, via single electron transfer. Crucially, detailed insight of the reaction mechanism helped to comprehend why some substrates are challenging for this methodology.

Cyclopentadienyl ring activation in organometallic chemistry and catalysis.

The cyclopentadienyl (Cp) ligand is a cornerstone of modern organometallic chemistry.Since the discovery of ferrocene, the Cp ligand and its various derivatives have become foundational motifs in catalysis, medicine and materials science. Although largely considered an ancillary ligand for altering the stereoelectronic properties of transition metal centres, there is mounting evidence that the core Cp ring structure also serves as a reservoir for reactive protons (H+), hydrides (H-) or radical hydrogen (H•) atoms. This Review chronicles the field of Cp ring activation, highlighting the pivotal role that Cp ligands can have in electrocatalytic H2 production, N2 reduction, hydride transfer reactions and proton-coupled electron transfer.

Application of alkane-diyl based chiral phosphine-aminophosphine (P-NP) and thioether-aminophosphine (S-NP) ligands in Rh-catalyzed asymmetric hydrogenation

Rhodium(I)-complexes of five new alkane-diyl based phosphine-aminophosphine (P,NP) type chiral ligands (Ph2PCH(CH3)(CH2)nCH(CH3)N(R1)PR22 (n = 0-2, R1 = Me, Et, iPr, R2 = Ph, Cy)) and a thioether-aminophosphine type compound ((S,S)-PhSCH(CH3)(CH2)CH(CH3)N(iPr)PPh2) have been synthesized. The investigation of the coordination chemistry of structurally analogous systems by NMR and IR spectroscopy and in one case by X-ray crystallography enabled the comparison of the effect of (i) the ligand backbone length, (ii) the N-substituent, (iii) the type of the coordinating functionality and (iv) the P-substituent in aminophosphine moiety on the stereo-electronic properties of the complexes. The novel Rh-compounds were tested in the asymmetric hydrogenation of a broad range of prochiral substrates including dimethyl itaconate, dehydroaminoacid derivatives and α,β-unsaturated enol ester phosphonates. Catalysts modified by the pentane-2,4-diyl based phosphine-aminophosphine ligands provided superior catalytic performance compared to the analogous butane- and hexane-diyl based systems and thioether containing compound. Most importantly, by the proper choice of the N-substituent outstanding enantioselectivities could be obtained in the asymmetric hydrogenation of acetamidocinnamic acid derivatives (up to 98% ee) and enol ester phosphonates (up to 97% ee).

O-, N- and C-bicyclopentylation using thianthrenium reagents

Rigid 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) are linear bioisosteres for para-substituted benzene rings in drug development and can lead to an improved pharmacokinetic profile. The construction of BCPs commonly requires the cumbersome use of labile [1.1.1]propellane in solution, and more stable reagents do not show the versatile reactivity of propellane itself. Here we report stable thianthrenium-based BCP reagents for practical O-, N- and C-alkylation reactions that expand the scope of bicyclopentylation beyond that of any other reagent, including [1.1.1]propellane. The redox and stereoelectronic properties of the thianthrene scaffold are relevant for both the synthesis of the BCP-thianthrenium reagents via strain release as well as their subsequent reactivity. The weak exocyclic C–S bond can undergo selective mesolytic cleavage upon single-electron reduction to produce BCP radicals that engage in transition metal-mediated C–O, C–N and C–C bond formations, even at a late stage of multistep reactions with a wide variety of functional groups present.

Optimized Baccharis dracunculifolia extract as photoprotective and antioxidant: In vitro and in silico assessment

Baccharis dracunculifolia (alecrim-do-campo) leaves contain polyphenols with antioxidant and anti-inflammatory properties and represents an alternative for the production or enhancement of sunscreen formulations. This study was designed to evaluate the photoprotective and antioxidant action of B. dracunculifolia, using in vitro and in silico methods, and correlate them with its phytochemical profile to obtain the optimized extract. The chemical composition was verified by chromatographic analysis, which confirmed the presence of flavonoids and phenolic acids. The B. dracunculifolia extract was optimized using antioxidant potential by eliminating the free radical DPPH, auto-oxidation of linoleic acid, in vitro sun protection factor (SPF), and quimiometric analysis. The optimal extraction conditions were defined, resulting in a value of SPF 18.9 and antioxidant EC50 12.9, and a total polyphenol content of 6%. The stereoelectronic properties involved with the antioxidant action and UV absorption were studied using an in silico approach. The electron donating capacity in silico was observed in the flavonoid quercetin while the greatest antioxidant capacity in phenolic acids was chlorogenic acid. The obtained results suggest the photoprotective and antioxidant effect of B. dracunculifolia and support its use in natural and multifunctional formulations against UV-induced damages.

Polarized Au(I)/Rh(I) bimetallic pairs cooperatively trigger ligand non-innocence and bond activation.

The combination of molecular metallic fragments of contrasting Lewis character offers many possibilities for cooperative bond activation and for the disclosure of unusual reactivity. Here we provide a systematic investigation on the partnership of Lewis basic Rh(I) compounds of type [(η5-L)Rh(PR3)2] (η5-L = (C5Me5)- or (C9H7)-) with highly congested Lewis acidic Au(I) species. For the cyclopentadienyl Rh(I) compounds, we demonstrate the non-innocent role of the typically robust (C5Me5)- ligand through migration of a hydride to the Rh site and provide evidence for the direct implication of the gold fragment in this unusual bimetallic ligand activation event. This process competes with the formation of dinuclear Lewis adducts defined by a dative Rh → Au bond, with selectivity being under kinetic control and tunable by modifying the stereoelectronic and chelating properties of the phosphine ligands bound to the two metals. We provide a thorough computational study on the unusual Cp* non-innocent behavior and the divergent bimetallic pathways observed. The cooperative FLP-type reactivity of all bimetallic pairs has been investigated and computationally examined for the case of N-H bond activation in ammonia.

Bulky, electron-rich, renewable: analogues of Beller's phosphine for cross-couplings.

In recent years, considerable progress has been made in the conversion of biomass into renewable chemicals, yet the range of value-added products that can be formed from biomass remains relatively small. Herein, we demonstrate that molecules available from biomass serve as viable starting materials for the synthesis of phosphine ligands, which can be used in homogeneous catalysis. Specifically, we prepared renewable analogues of Beller's ligand (di(1-adamantyl)-n-butylphosphine, cataCXium® A), which is widely used in homogeneous catalysis. Our new renewable phosphine ligands facilitate Pd-catalysed Suzuki-Miyaura, Stille, and Buchwald-Hartwig coupling reactions with high yields, and our catalytic results can be rationalized based on the stereoelectronic properties of the ligands. The new phosphine ligands generate catalytic systems that can be applied for the late-stage functionalization of commercial drugs.

Application of P‐Bridged Biaryl Phosphines in Pd‐Catalyzed α‐Arylation Reactions

AbstractThe use of catalysts derived from Pd2(dba)3 and phosphatrioxa‐adamantane framework (Cg) has been demonstrated to facilitate the effective alpha(α)‐arylation of ketones using a diverse array of aryl halides under mild reaction conditions (40 °C–80 °C). The evaluation of phosphines with dissimilar stereoelectronic properties revealed the pivotal role of fine‐tuning the ligand's steric bulk. In particular, catalysts based on the Cg‐biphenyl ligand (1) proved efficient for facile α‐arylation of electronically and sterically diverse aryl bromides and chlorides.

Tricyanoborane-Functionalized Anionic N-Heterocyclic Carbenes: Adjustment of Charge and Stereo-Electronic Properties.

The 1‐methyl‐3‐(tricyanoborane)imidazolin‐2‐ylidenate anion (2) was obtained in high yield by deprotonation of the B(CN)3‐methylimidazole adduct 1. Regarding charge and stereo‐electronic properties, anion 2 closes the gap between well‐known neutral NHCs and the ditopic dianionic NHC, the 1,3‐bis(tricyanoborane)imidazolin‐2‐ylidenate dianion (IIb). The influence of the number of N‐bonded tricyanoborane moieties on the σ‐donating and π‐accepting properties of NHCs was assessed by quantum chemical calculations and verified by experimental data on 2, IIb, and 1,3‐dimethylimidazolin‐2‐ylidene (IMe, IIa). Therefore NHC 2, which acts as a ditopic ligand via the carbene center and the cyano groups, was reacted with alkyl iodides, selenium, and [Ni(CO)4] yielding alkylated imidazoles 3 and 4, the anionic selenium adduct 5, and the anionic nickel tricarbonyl complex 8, respectively. The results of this study prove that charge, number of coordination sites, buried volume (%V bur) and σ‐donor and π‐acceptor abilities of NHCs can be effectively fine‐tuned via the number of tricyanoborane substituents.