Neighboring Group Participation Research Articles

Microwave-Assisted Aminoalkylation of Phenols via Mustard Carbonate Analogues

AbstractA microwave-assisted chlorine-free direct phenol substitution is presented, which is indicated as a key green chemistry research area for pharmaceuticals manufacturers. The reaction of β-aminocarbonates (mustard carbonates) with several substituted phenols in the presence of a polar solvent (acetonitrile or butanol) led to the related aminoalkylated products via the anchimeric assistance of the nitrogen incorporated in the organic carbonate backbone. The aminoalkylation required short reaction time (7 min) and the related products were isolated in high yields (>90%) via quick liquid-liquid extraction or column chromatography depending on the solvent employed. Furthermore, microwave irradiation also promoted the one-pot aminoalkylation of phenol in excellent yield. In this approach a β-aminoalcohol was reacted with phenol in the presence of diethyl carbonate, used for the in situ formation β-aminocarbonate, key intermediate in the consequent anchimerically driven alkylation. The resulting product, namely N,N-dimethyl-2-phenoxyethanamine, was isolated as pure in almost quantitative yield.

Photolabile 2-(2-Nitrophenyl)-propyloxycarbonyl (NPPOC) for Stereoselective Glycosylation and Its Application in Consecutive Assembly of Oligosaccharides.

A photolabile protecting group (PPG) 2-(2-nitrophenyl)-propyloxycarbonyl (NPPOC) was explored in glycosylation and applied in the consecutive synthesis of oligosaccharides. NPPOC displays a strong neighboring group participation (NGP) effect to facilitate the construction of 1,2-trans glycosides in excellent yield. Notably, NPPOC could be efficiently removed by photolysis, and the deprotection conditions are friendly to typical protecting groups. A branched and asymmetric oligomannose Man6 was rapidly prepared, and the consecutive assembly of oligosaccharides without intermediate purification was further investigated owing to the compatibility conditions between NPPPOC's photolysis and glycosylation.

Healable, Recyclable, and Programmable Shape Memory Organogels Based on Highly Malleable Catalyst-Free Carboxylate Linkages.

The development of healable and recyclable organogels possessing responsive abilities is mainly hindered by the unavailability of many dynamic covalent linkages that undergo exchange reaction below the boiling temperature of organic swelling medium. Furthermore, the exchange is desired to be effective under catalyst-free conditions to circumvent the issue of catalyst leaching during the swelling process. Especially, imparting swift reversibility to thermostable carboxylate linkages is challenging. In this approach, we have utilized the β-keto anchimeric assistance as the tool to induce swift reversibility into the conventional carboxylate linkage under mild temperature (∼70-90 °C) and catalyst-free conditions. Using this β-keto carboxylate linkage as an associative bond exchange mean, strong (tensile strength = 0.3 MPa) and stretchable (ultimate elongation ≈ 600%) covalent adaptable organogels (CAOs) with anisotropic swelling, remoldable, self-healing, and shape memory ability are derived from commercially available precursors. The shape memory ability of these samples shows dependency on the shape fixing time and can be programmed, targeting further applications. Soft actuators may be fabricated from the CAOs using temperature and solvent as the activating tools. This research demonstrates that the conventional carboxylate linkages can be made labile under mild conditions for further applications.

Photo- and Radiation-Induced One-Electron Oxidation of Methionine in Various Structural Environments Studied by Time-Resolved Techniques.

Oxidation of methionine (Met) is an important reaction that plays a key role in protein modifications during oxidative stress and aging. The first steps of Met oxidation involve the creation of very reactive and short-lived transients. Application of complementary time-resolved radiation and photochemical techniques (pulse radiolysis and laser flash photolysis together with time-resolved CIDNP and ESR techniques) allowed comparing in detail the one-electron oxidation mechanisms initiated either by ●OH radicals and other one-electron oxidants or the excited triplet state of the sensitizers e.g., 4-,3-carboxybenzophenones. The main purpose of this review is to present various factors that influence the character of the forming intermediates. They are divided into two parts: those inextricably related to the structures of molecules containing Met and those related to external factors. The former include (i) the protection of terminal amine and carboxyl groups, (ii) the location of Met in the peptide molecule, (iii) the character of neighboring amino acid other than Met, (iv) the character of the peptide chain (open vs cyclic), (v) the number of Met residues in peptide and protein, and (vi) the optical isomerism of Met residues. External factors include the type of the oxidant, pH, and concentration of Met-containing compounds in the reaction environment. Particular attention is given to the neighboring group participation, which is an essential parameter controlling one-electron oxidation of Met. Mechanistic aspects of oxidation processes by various one-electron oxidants in various structural and pH environments are summarized and discussed. The importance of these studies for understanding oxidation of Met in real biological systems is also addressed.

Dynamic Covalent Reactions Controlled by Ring‐Chain Tautomerism of 2‐Formylbenzoic Acid

AbstractDynamic covalent chemistry (DCC) is an intensive area of research as it has found utility in the creation of molecular assemblies, complex systems, and ordered frameworks. Herein we demonstrate the development of dynamic covalent reactions (DCRs) of common N‐, O‐, and S‐mononucleophiles by controlling ring‐chain tautomerism of 2‐formylbenzoic acid. The regulation of distinct dual reactivity of interconverting open aldehyde and cyclic hemiacetal forms, the thermodynamic stabilization through chelation and delocalization, as well as the kinetic effect resulting from neighboring group participation, enabled the realization of DCRs of a broad range of alcohols, thiols, primary amines, and secondary amines exhibiting high efficiency and fast equilibrium. The dynamic nature of the system was verified through component exchange, and the switch of DCRs was achieved through the manipulation of substrate selectivity. The investigation of mechanism shed insights on the dependence of reaction pathways on nucleophiles, laying the foundation for future design and application.

Bromo-lactamization of isoxazole via neighboring group participation: toward spiro-isoxazoline γ- and δ-lactams.

Spiro-heterocycles containing natural products and synthetic analogues have a broader biomedicinal application due to their rigid 3D conformation and structural implications. In this context, constructing spiro-isoxazoline systems have continued our interest in natural products and synthetic units to investigate their novel biological activities. Herein, a bromo-lactamization mediated neighboring group participation approach has been utilized on various isoxazole-amides to construct an array of spiro-isoxazoline-lactams. The easy synthesis with diverse functionalization in the periphery of a novel 3D framework could be interesting for biomedical investigation.

Total synthesis ofLentinus giganteusglycans with antitumor activitiesviastereoselective α-glycosylation and orthogonal one-pot glycosylation strategies

The accessibility to long, branched and complex glycans containing many 1,2-cis glycosidic linkages with precise structures remains a challenging task in chemical synthesis. Reported here is an efficient, stereoselective and orthogonal one-pot synthesis of a tetradecasaccharide and shorter sequences from Lentinus giganteus polysaccharides with antitumor activities. The synthetic strategy consists of: (1) newly developed merging reagent modulation and remote anchimeric assistance (RMRAA) α-(1→6)-galactosylation in a highly stereoselective manner, (2) DMF-modulated stereoselective α-(1→3)-glucosylation, (3) RMRAA stereoselective α-(1→6)-glucosylation, (4) several orthogonal one-pot glycosylations on the basis of N-phenyltrifluoroacetimidate (PTFAI) glycosylation, Yu glycosylation and ortho-(1-phenylvinyl)benzoate (PVB) glycosylation to streamline oligosaccharide synthesis, and (5) convergent [7 + 7] glycosylation for the final assembly of the target tetradecasaccharide. In particular, this new RMRAA α-galactosylation method has mild reaction conditions, broad substrate scopes and significantly shortened step counts for the heptasaccharide synthesis in comparison with 4,6-di-tert-butylsilyene (DTBS) directed α-galactosylation. Furthermore, DFT calculations shed light on the origins of remote anchimeric assistance effects (3,4-OBz > 3,4-OAc > 4-OBz > 3-OBz) of acyl groups.

The total synthesis of rhynchosporosides via orthogonal one-pot glycosylation and stereoselective α-glycosylation strategies.

The efficient and collective synthesis of rhynchosporosides causing scald diseases has been achieved, which features orthogonal one-pot glycosylation on the basis of PTFAI glycosylation, Yu glycosylation, and PVB glycosylation and merging reagent modulation and remote anchimeric assistance (RMRAA) α-glucosylation strategies. The issues inherent to the thioglycoside-based orthogonal one-pot glycosylation strategy, such as aglycone transfer, have been precluded by this orthogonal one-pot glycosylation strategy, which can streamline glycan chemical synthesis.

A Stereoselective Glycosylation Approach to the Construction of 1,2-trans-β-d-Glycosidic Linkages and Convergent Synthesis of Saponins.

Conventional syntheses of 1,2-trans-β-d- or α-l-glycosidic linkages rely mainly on neighboring group participation in the glycosylation reactions. The requirement for a neighboring participation group (NPG) excludes direct glycosylation with (1→2)-linked glycan donors, thus only allowing stepwise assembly of glycans and glycoconjugates containing this type of common motif. Here, a robust glycosylation protocol for the synthesis of 1,2-trans-β-d- or α-l-glycosidic linkages without resorting to NPG is disclosed; it employs an optimal combination of glycosyl N-phenyltrifluroacetimidates as donors, FeCl3 as promoter, and CH2 Cl2 /nitrile as solvent. A broad substrate scope has been demonstrated by glycosylations with 12 (1→2)-linked di- and trisaccharide donors and 13 alcoholic acceptors including eight complex triterpene derivatives. Most of the glycosylation reactions are high yielding and exclusively 1,2-trans selective. Ten representative, naturally occurring triterpene saponins were thus synthesized in a convergent manner after deprotection of the coupled glycosides. Intensive mechanistic studies indicated that this glycosylation proceeds by SN 2-type substitution of the glycosyl α-nitrilium intermediates. Importantly, FeCl3 dissociates and coordinates with nitrile into [Fe(RCN)n Cl2 ]+ and [FeCl4 ]- , and the ferric cationic species coordinates with the alcoholic acceptor to provide a protic species that activates the imidate, meanwhile the poor nucleophilicity of [FeCl4 ]- ensures an uninterruptive role for the glycosidation.

Self-Polymerization Promoting Monomers: In Situ Transformation of Disulfide-Linked Benzoxazines into the Thiazolidine Structure.

Polybenzoxazines obtained especially from green synthons are facing challenges of the requirement of high ring-opening polymerization (ROP) temperature of the monomer, thus affecting their exploration at the industrial front. This demands effective structural changes in the monomer itself, to mediate catalyst-free polymerization at a low energy via one-step synthesis protocol. In this regard, monomers based on disulfide-linked bisbenzoxazine were successfully synthesized using cystamine (biobased) and cardanol (agro-waste)/phenol. Reduction of the disulfide bridge in the monomer using dithiothreitol under mild conditions in situ transformed the oxazine ring in the monomer, via neighboring group participation of the -SH group in a transient intermediate monomer, into a thiazolidine structure, which is otherwise difficult to synthesize. Structural transformation of ring-opening followed by the ring-closing intramolecular reaction led to an interconversion of O-CH2-N containing a six-membered oxazine ring to S-CH2-N containing a five-membered thiazolidine ring and a phenolic-OH. The structure of the monomer with the oxazine ring and its congener with the thiazolidine ring was characterized by spectroscopic methods and X-ray analysis. Kinetics of structural transformation at a molecular level is studied in detail, and it was found that the reaction proceeded via a transient 2-aminoethanethiol-linked benzoxazine intermediate, as supported by nuclear magnetic resonance spectroscopy and density functional theory studies. The thiazolidine-ring-containing monomer promotes ROP at a substantially low temperature than the reported mono-/bisoxazine monomers due to the dual mode of facilitation of the ROP reaction, both by phenolic-OH and by ring strain. Surprisingly, both the monomer structures led to the formation of a similar polymer structure, as supported by thermogravimetric analysis and Fourier transform infrared study. The current work highlights the benefits of inherent functionalities in naturally sourced feedstocks as biosynthons for the new latest generation of benzoxazine monomers.

Fast Reprocessing of Acetal Covalent Adaptable Networks with High Performance Enabled by Neighboring Group Participation

Fast Reprocessing of Acetal Covalent Adaptable Networks with High Performance Enabled by Neighboring Group Participation

Efficient Exchange in a Bioinspired Dynamic Covalent Polymer Network via a Cyclic Phosphate Triester Intermediate.

Bond exchange via neighboring group-assisted reactions in dynamic covalent networks results in efficient mechanical relaxation. In Nature, the high reactivity of RNA toward nucleophilic substitution is largely attributed to the formation of a cyclic phosphate ester intermediate via neighboring group participation. We took inspiration from RNA to develop a dynamic covalent network based on β-hydroxyl-mediated transesterifications of hydroxyethyl phosphate triesters. A simple one-step synthetic strategy provided a network containing phosphate triesters with a pendant hydroxyethyl group. 31P solid-state NMR demonstrated that a cyclic phosphate triester is an intermediate in transesterification, leading to dissociative network rearrangement. Significant viscous flow at 60–100 °C makes the material suitable for fast processing via extrusion and compression molding.

Unimolecular, Bimolecular, and Intramolecular Hydrolysis Mechanisms of 4-Nitrophenyl β-d-Glucopyranoside.

1,2-trans-Glycosides hydrolyze through different mechanisms at different pH values, but systematic studies are lacking. Here, we report the pH-rate constant profile for the hydrolysis of 4-nitrophenyl β-D-glucoside. An inverse kinetic isotope effect of k(H3O+)/k(D3O+) = 0.65 in the acidic region indicates that the mechanism requires the formation of the conjugate acid of the substrate for the reaction to proceed, with the heterolytic cleavage of the glycosidic C-O bond. Reactions in the pH-independent region exhibit general catalysis with a single proton in flight, a normal solvent isotope effect of kH/kD = 1.5, and when extrapolated to zero buffer concentration show a small solvent isotope effect of k(H2O)/k(D2O) = 1.1, consistent with water attack through a dissociative mechanism. In the basic region, solvolysis in 18O-labeled water and H2O/MeOH mixtures allowed the detection of bimolecular hydrolysis and neighboring group participation, with a minor contribution of nucleophilic aromatic substitution. Under mildly basic conditions, a bimolecular concerted mechanism is implicated through an inverse solvent isotope effect of k(HO-)/k(DO-) = 0.5 and a strongly negative entropy of activation (ΔS‡ = -13.6 cal mol-1 K-1). Finally, at high pH, an inverse solvent isotope effect of k(HO-)/k(DO-) = 0.5 indicates that the formation of 1,2-anhydrosugar is the rate-determining step.

Covalent Adaptable Networks Using β-Amino Esters as Thermally Reversible Building Blocks.

In this study, β-amino esters, prepared by the aza-Michael addition of an amine to an acrylate moiety, are investigated as building blocks for the formation of dynamic covalent networks. While such amino esters are usually considered as thermally nondynamic adducts, the kinetic model studies presented here show that dynamic covalent exchange occurs via both dynamic aza-Michael reaction and catalyst-free transesterification. This knowledge is transferred to create β-amino ester-based covalent adaptable networks (CANs) with coexisting dissociative and associative covalent dynamic exchange reactions. The ease, robustness, and versatility of this chemistry are demonstrated by using a variety of readily available multifunctional acrylates and amines. The presented CANs are reprocessed via either a dynamic aza-Michael reaction or a catalyst-free transesterification in the presence of hydroxyl moieties. This results in reprocessable, densely cross-linked materials with a glass transition temperature (Tg) ranging from -60 to 90 °C. Moreover, even for the low Tg materials, a high creep resistance was demonstrated at elevated temperatures up to 80 °C. When additional β-hydroxyl group-containing building blocks are applied during the network design, an enhanced neighboring group participation effect allows reprocessing of materials up to 10 times at 150 °C within 30 min while maintaining their material properties.

Merging Reagent Modulation and Remote Anchimeric Assistance for Glycosylation: Highly Stereoselective Synthesis of α-Glycans up to a 30-mer.

The efficient synthesis of long, branched, and complex carbohydrates containing multiple 1,2-cis glycosidic linkages is a long-standing challenge. Here, we report a merging reagent modulation and 6-O-levulinoyl remote anchimeric assistance glycosylation strategy, which is successfully applied to the first highly stereoselective synthesis of the branched Dendrobium Huoshanense glycans and the linear Longan glycans containing up to 30 contiguous 1,2-cis glucosidic bonds. DFT calculations shed light on the origin of the much higher stereoselectivities of 1,2-cis glucosylation with 6-O-levulinoyl group than 6-O-acetyl or 6-O-benzoyl groups. Orthogonal one-pot glycosylation strategy based on glycosyl ortho-alkynylbenzoates and ortho-(1-phenylvinyl)benzoates has been demonstrated in the efficient synthesis of complex glycans, precluding such issues as aglycon transfer inherent to orthogonal one-pot synthesis based on thioglycosides.

Merging Reagent Modulation and Remote Anchimeric Assistance for Glycosylation: Highly Stereoselective Synthesis of α‐Glycans up to a 30‐mer

AbstractThe efficient synthesis of long, branched, and complex carbohydrates containing multiple 1,2‐cis glycosidic linkages is a long‐standing challenge. Here, we report a merging reagent modulation and 6‐O‐levulinoyl remote anchimeric assistance glycosylation strategy, which is successfully applied to the first highly stereoselective synthesis of the branched Dendrobium Huoshanense glycans and the linear Longan glycans containing up to 30 contiguous 1,2‐cis glucosidic bonds. DFT calculations shed light on the origin of the much higher stereoselectivities of 1,2‐cis glucosylation with 6‐O‐levulinoyl group than 6‐O‐acetyl or 6‐O‐benzoyl groups. Orthogonal one‐pot glycosylation strategy based on glycosyl ortho‐alkynylbenzoates and ortho‐(1‐phenylvinyl)benzoates has been demonstrated in the efficient synthesis of complex glycans, precluding such issues as aglycon transfer inherent to orthogonal one‐pot synthesis based on thioglycosides.

Neighboring Group Participation and Internal Catalysis Effects on Exchangeable Covalent Bonds: Application to the Thriving Field of Vitrimer Chemistry

Vitrimers constitute a fascinating class of polymer materials that make the link between the historically opposed 3D networks (thermosets) and linear polymers (thermoplastics). Their chemical resistance, reshaping ability, and unique rheological behavior upon heating make them promising for future applications in industry. However, many vitrimers require the use of high catalyst loadings, which raises concerns for their durability and limits their potential applications. To cope with this issue, internal catalysis and neighboring group participation (NGP) can be used to enhance the reshaping ability of such materials. A few studies report the effect of activating groups on the exchange reactions in vitrimers. Nevertheless, knowledge on this topic remains scarce, although research on vitrimers would greatly benefit from NGP already known in organic chemistry. The present Perspective presents the different types of exchangeable bonds implemented in vitrimers and discusses chemical groups known to have or potentially capable of an enhancing effect on exchange reactions. This analysis is underpinned by a thorough mechanistic discussion of the various exchangeable bonds presented.

Reactions of Cycloplatinated Guanidine Complexes with Hg(OC(O)CF3)2: Formation of a One-Dimensional Coordination Polymer Containing a Pt2Hg(μ2-S(O)Me2-S,O) Repeating Unit versus a Discrete Pt2Hg2 Complex.

Separate reactions of cycloplatinated 2-tolyl- and 2-anisylguanidine complexes, [Pt{κ2(C,N)}(OC(O)CF3)(S(O)Me2)] (1 and 2), with Hg(OC(O)CF3)2 in 1:0.5 and 1:1 molar ratios afforded the one-dimensional coordination polymer (1D CP) {[PtIII{κ2(C,N)}(OC(O)CF3)2]2Hg0}(μ2-S(O)Me2-S,O)·C7H8 (3·C7H8) as bright red crystals and the discrete tetrametallic complex [PtII{κ2(C,N)}(μ2-OC(O)CF3)2HgI-]2 (4) as yellow crystals in good yields. The two different products obtained in the aforementioned reactions are ascribed to the subtle differences in the N substituent of the guanidinate(1-) ligands in 1 and 2. The plausible mechanisms of formation of 3 and 4 are outlined. Complexes 3 and 4 were characterized by elemental analyses and IR and multinuclear NMR (1H, 13C{1H}, 19F, and 195Pt) spectroscopy. Complex 4 was also characterized by 199Hg NMR spectroscopy. The molecular structures of 3·C7H8 and 4 were determined by single-crystal X-ray diffraction studies. 1D CP 3·C7H8 contains a Pt(III)-Hg(0)-Pt(III)(μ2-S(O)Me2-S,O) repeating unit with a pair of unsupported Pt-Hg covalent bonds, while 4 contains a Pt(II)-Hg(I)-Hg(I)-Pt(II) chain with a pair of trifluoroacetate ligand supported Pt→Hg coordinate bonds. 1D CP 3·C7H8 falls apart into a mixture of three species, namely 6-8 and 9-11 in C6D6 and CDCl3, respectively, as revealed by multinuclear NMR spectroscopy. In CDCl3, 4 partially isomerizes to [PtII(OC(O)CF3)(μ2-OC(O)CF3){κ3μ2(C,N,O)}HgI-]2 (12), wherein each Pt→Hg coordinate bond is supported by one μ2-bridging trifluoroacetate ligand and one chelating bridging guanidinate(1-) ligand, as inferred from variable-temperature 1H and 19F NMR spectroscopy. Complex 12 is the major species and 4 is the minor species in CDCl3, while opposite situation prevails in C6D6. The observance of a mixture of two solution species for 4 is ascribed to a rapid "carboxylate shift" process induced by the oxygen atom of the ═N(C6H4(OMe)-2) unit of the guanidinate(1-) ligand through neighboring-group participation. UV-visible absorption and emission spectra of 4 were measured in CHCl3, and from the outcome of the investigation, the possible existence of [Cl2(H)C-Cl···PtII(OC(O)CF3)(μ2-OC(O)CF3){κ3μ2(C,N,O)}HgI-]2 (12″) was suggested, which is likely to have a pair of Pt-Hg covalent bonds made possible by CHCl3 coordination on the sixth site of the Pt(II) atom.

Mannich-Type Reaction of α-Sulfanyl N-tert-Butanesulfinylimidates: Diastereoselective Access to α-Mercapto-β-amino Acid Derivatives.

A series of α-mercapto-β-amino acid derivatives were synthesized diastereoselectively in good yields through the aza-enolization of α-sulfanyl N-tert-butanesulfinylimidates, followed by their nucleophilic addition to N-tosyl imines via a Mannich-type reaction. The resulting derivatives bearing a β-sulfonylamino sulfide moiety participated in further inter- and intramolecular transformations involving episulfonium ion intermediates generated through neighboring-group participation.

Protecting Groups as a Factor of Stereocontrol in Glycosylation Reactions

Synthetic oligosaccharides are objects of interest as model compounds in studies on the biological activity of natural compounds, but also as components for new drugs, glycoconjugate vaccines, carbohydrate diagnostic agents and various other products. The key stage in oligosaccharide synthesis is the glycosylation reaction, which leads to the formation of a linkage between carbohydrate fragments. This review highlights a current problem in modern glycochemistry – the methods of stereocontrol in the glycosylation reaction. Protecting groups within the structure of glycosyl donors are considered as stereocontrolling factors, affecting the reaction mechanism by means of (1) participation or anchimeric assistance, (2) deactivation, (3) intramolecular aglycone delivery. The well-established mechanism of neighboring group participation at O-2 for the synthesis of 1,2- trans glycosides is shown, as well as its modern modifications, including activating ethers, chiral protecting groups and achiral bicyclic glycosyl donors. The mechanisms of remote participation from O-3, O-4 and O-6 of the glycosyl donor are discussed in detail. In addition, approaches to stereocontrol using deactivating protection (conformation constraining and electron withdrawing groups) are described. Finally, synthetic approaches based on intramolecular aglycone delivery are considered. Both classical and novel protecting groups used to control the steric outcome of glycosylation are presented, the mechanisms underlying the presented approaches are discussed in detail, while also showing how the described strategies apply to the synthesis of complex structures.