Neighboring Group Participation Research Articles

Double neighbouring group participation for ultrafast exchange in phthalate monoester networks

We introduce here the rapid transesterification of phthalate monoester-based covalent adaptable networks thanks to a double neighbouring group participation effect.

Recent advances in β-l-rhamnosylation.

l-Rhamnose forms the key components of important antigenic oligo- and polysaccharides of a variety of pathogens. Obtaining 1,2-cis stereoselectivity in the glycosylation of l-rhamnoside is quite challenging due to the unavailability of neighboring group participation and disfavoring of the anomeric effect and stereoelectronic effect of the substituents on the C-2 axial position. Nevertheless, various methodologies have been developed exploiting diverse pathways for obtaining β-stereoselectivity in the glycosylation of l-rhamnose. This review describes the recent advances in β-l-rhamnosylation and its applications in the total synthesis of β-l-rhamnose-containing biologically important oligosaccharides.

Diastereoselective synthesis and conformational analysis of 4,5-difluoropipecolic acids.

Stereoselectively-fluorinated analogs of pipecolic acid have been investigated through a combined theoretical and experimental approach. Three of the four possible diastereoisomers of 4,5-difluoropipecolic acid were successfully synthesized via deoxyfluorination chemistry, navigating a complex reaction network that included neighboring group participation, rearrangement, and elimination pathways. A DFT-based conformational study, supported by NMR J-based analysis, revealed that the different diastereoisomers of 4,5-difluoropipecolic acid preferentially adopt different puckers of the six-membered ring. These findings could have future relevance for the conformational control of biologically active peptides.

Iodine-mediated hydration of alkynes on keto-functionalized scaffolds: mechanistic insight and the regiospecific hydration of internal alkynes

An iodine-mediated hydration reaction of alkynes serves as a green alternative to metal-catalyzed procedures. Previous work has shown that this method works well with terminal alkynes on keto-functionalized scaffolds, including 1,3-dicarbonyls and their heteroatom analogues. It was hypothesized that the reaction proceeds through a 5-exo-dig neighboring group participation (NGP) cyclization and an α-iodo intermediate. The work described herein probes the existence of the intermediate through NMR investigations and explores the scope of the hydration process with internal alkynes. The NMR experiments confirm the existence of the α-iodo intermediate, and methodology studies demonstrate that alkyl-capped, asymmetric, internal alkynes undergo a regiospecific hydration, also via the 5-exo-dig NGP pathway.

Selection of Neighboring Group Participation Intermediates of Fully Acylated Donors around the Glycosylation Sites in Oligosaccharide Acceptors.

Stereo- and regioselective formation of glycosidic linkages is a challenging topic in oligosaccharide syntheses. The stereoselective construction of 1,2-trans-glycosides generally involves neighboring group participation, which is less successful when synthesizing β-1,3-linked oligosaccharides. The combined steric effect of a 2-O-substituent and an aglycon moiety in acceptors increases the efficiency of glycosylation via neighboring group participation. This steric effect was reduced by using vicinal polyol acceptors and was demonstrated in the synthesis of 1,3-linked branched oligosaccharides.

Hanessian-Hullar reaction in the synthesis of highly substituted trans-3,4-dihydroxypyrrolidines: Rhamnulose iminosugar mimics inhibit α-glucosidase

The key step in the syntheses of highly substituted trans-3,4-dihydroxypyrrolidines is introduction of bromide by stereospecific and regiospecific Hanessian-Hullar reactions; benzylidene lactones of l-rhamnonolactone and 6-deoxy-this should be small unnpercase d not l why can I not correct this-gulonolactone allow introduction of N at C2 with inversion or retention of configuration. Initially a protecting group, the benzylidene acetal then provides a bromide at C5 to allow formation of the pyrrolidine ring. With silyl protecting groups, bromide was introduced at C5 with inversion of configuration whereas benzoyl protection gave a mixture of retention and inversion, indicative of neighbouring group participation in a Hanessian-Hullar reaction. Four stereoisomeric pyrrolidines - iminosugar mimics of α- and β-l-rhamnulose and α- and β-6-deoxy-d-sorbose were prepared. Only the α-l-rhamnulose mimic showed moderate inhibition of rhamnosidase but some were good inhibitors of α-glucosidases; none inhibited rhamnose isomerase and they had a small effect as synthetic inducers of the rhamnose catabolic operon in E. coli.

The CuAAC: Principles, Homogeneous and Heterogeneous Catalysts, and Novel Developments and Applications.

The copper-catalyzed azide/alkyne cycloaddition reaction (CuAAC) has emerged as the most useful "click" chemistry. Polymer science has profited enormously from CuAAC by its simplicity, ease, scope, applicability and efficiency. Basic principles of the CuAAC are reviewed with a focus on homogeneous and heterogeneous catalysts, ligands, anchimeric assistance, and basic chemical principles. Recent developments of ligand design and acceleration are discussed.

Dual-Participation Protecting Group Solves the Anomeric Stereocontrol Problems in Glycosylation Reactions.

The 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) group permits, via robust neighboring group participation (NGP) or long distance participation (LDP) effects, the stereocontrolled 1,2-trans, 1,2-cis, as well as β-2,6-dideoxy glycosidic bond generation, while suppressing the undesired orthoester byproduct formation. The robust stereocontrol capability of the DMNPA is due to the dual-participation effect from both the ester functionality and the nitro group, verified by control reactions and DFT calculations and further corroborated by X-ray spectroscopy.

Catalytic amidation of natural and synthetic polyol esters with sulfonamides

Triacylglycerides are naturally abundant and renewable feedstock for biofuels and chemicals. In this report, these seemingly stable compounds are shown to be reactive toward a variety of sulfonamides under Lewis acid catalysis. In these reactions, alkyl C(sp3)–O bonds are cleaved and C–N bonds constructed, providing functionalized value-added products directly from renewables. Mechanistic and scope study demonstrate that the origin of the reactivity could be the synergy of Lewis acid catalysis and neighboring group participation by the 2- or 3-acyloxy or acylamido group with respect to the reactive site. Since poly(ethylene terephthalate) (PET), a widely available consumer polyester, also contains 1,2-diol diester group as the repeating unit in the main chain, this chemistry can also be applied to efficient depolymerization of PET.

Biochemical characteristics and crystallographic evidence for substrate-assisted catalysis of a β-N-acetylhexosaminidase in Akkermansia muciniphila

In this paper, we characterized Am2136 as a β-N-acetylhexosaminidase from Akkermansia muciniphila to perform the biochemical characteristics and the crystal structure of selenomethionine-labeled Am2136 with GlcNAc complex. Crystallographic evidence suggests that an oxazolinium ion was formed intermediately by the 2-acetamido group during the substrate-assisted catalytic procedure. Structural and kinetic analysis of native Am2136 and D412A, E413A mutants were investigated and the results revealed substantial difference. The Kcat/Km value of D412A was decreased 4297-fold compared to native Am2136 revealed that mutation of Asp-412 results in preventing the 2-acetamido substituent from providing anchimeric assistance and thus reducing the catalytic efficiency. Moreover, Am2136 has a wide dependence on pH and temperature, while sensitive to divalent metal ions such as Ca2+ and Mn2+. These biochemical and crystallographic results provide evidences that Asp-412 residue assists to orient the 2-acetamido group for catalysis. Based on crystallographic evidence and sequence alignment with other GH family 20 enzymes, Asp-412 residue is possibly fundamental for Am2136 during substrate-assisted catalysis.

Dual demeanour of norcantharidin derived dicarboxamides in acidic media: An insight

The hydrolytic stability of norcantharidine derived conformationally constrained diamides in acidic media is solely governed by the type of amide. Tertiary diamides underwent smooth acid catalyzed hydrolysis due to anchimeric assistance whereas other diamides were stable. This was corroborated from conformational proximity of the amide groups for anchimeric assistance based on single crystal X-ray structure analysis. Theoretical calculations on the diamide structures also predict the similar proximity of the diamides in those conformations. Thus norcantharidine based diamides could probably serve as promising systems for delayed release of certain types of drugs which possess secondary amine component as exemplified by the release of m-chlorophenylpiperazine at a pH range of 1–2.

Site-Selective Debenzylation of C-Allyl Iminosugars Enables Their Stereocontroled Structure Diversification at the C-2 Position.

A C-2 regioselective debenzylative cycloetherification/reductive elimination sequence applied to perbenzylated C-allyl iminosugars is described. This NIS/TMSOTf-triggered deprotection was successfully applied to five-, six-, and seven-membered C-allyl iminosugars including 1,2 cis and 1,2 trans stereoisomers. It allows rapid introduction of structural diversity at the key C-2 position in a stereoselective manner exploiting the anchimeric assistance of the intracyclic N-benzyl group, giving access to the 2-acetamido and 2-fluoro d-gluco configured C-allyl iminosugars and to the epimeric d-manno derivative.

Synthesis and Conformation of Pentopyranoside Nucleoside Phosphonates.

In contrast to natural nucleosides, where the nucleobase is positioned at the anomeric center, we report the synthesis of pentopyranoside nucleosides with a phosphonate functionality at the 1'-anomeric oxygen. Starting from l-arabinose, key functionalized l- glycero- and l- erythro-pentopyranose carbohydrate synthons were prepared and further elaborated into the final six-membered ring nucleosides via nucleobase incorporation and phosphonomethylation reactions. NMR analysis demonstrated that these nucleoside phosphonates exist in solution as conformers predominantly adopting a chair structure in which the base moiety is equatorially positioned. Such conformation prevents unfavorable 1,3-diaxial steric and electronic interactions. Notably, the stereochemical outcome of the Vorbrüggen glycosylation step utilized en route to the thymine analogue clearly suggests the absence of anchimeric assistance, as opposed to what is usually observed during nucleoside synthesis using protected furanose precursors. The finding that the diphosphates of the compounds developed in this study are recognized by DNA polymerases is important in view of the future selection of artificial genetic systems and dedicated polymerases as well as applications in therapy.

An Unexpected FeCl3/C-Catalyzed β-Stereoselective Glycosylation in the Presence of the C(2)-Benzyl Group

An efficient and completely β-stereoselective glycosylation that did not rely on neighboring group participation is described using 2–20 mol% FeCl3/C as the catalyst and benzylated propargyl glycosides as the donors to reach yields up to 96% under mild condition. With an octatomic-ring intermediate at the α-face of FeCl3/C with alkyne of propargyl glycosides, a panel of aglycones comprising aliphatic, alicyclic, unsaturated alcohols, halogenated alcohols, and phenols with different substitution were examined successfully for the exclusive β-stereoselective glycosylation reaction.

Catalytic, Enantioselective 1,2-Difluorination of Cinnamamides.

The enantio- and diastereoselective synthesis of 1,2-difluorides via chiral aryl iodide-catalyzed difluorination of cinnamamides is reported. The method uses HF-pyridine as a fluoride source and mCPBA as a stoichiometric oxidant to turn over catalyst, and affords compounds containing vicinal, fluoride-bearing stereocenters. Selectivity for 1,2-difluorination versus a rearrangement pathway resulting in 1,1-difluorination is enforced through anchimeric assistance from a N- tert-butyl amide substituent.

One-Pot Synthesis of the Repeating Unit of Type VII Group B Streptococcus Polysaccharide and the Dimer.

The first synthesis of the hexasaccharide repeating unit of type VII group B Streptococcus capsular polysaccharide was achieved by a one-pot glycosylation strategy. The dimer of this repeating unit was also synthesized by one-pot glycosylation to achieve the backbone hexasaccharide first followed by one-pot dual glycosylations with the side-chain trisaccharide donor. All glycosylation reactions gave excellent stereoselectivity, which took advantage of a new stereospecific α-glucosylation method and the neighboring group participation effect for 1,2- trans glycosylations.

Stereo- and Regioselective Synthesis of Molecular Baskets.

We describe a stereoselective method for obtaining multigram quantities of molecular basket 1 syn in overall 11% yield, using inexpensive cyclopentadiene and diethyl fumarate as starting materials. First, an asymmetric synthesis of enantioenriched bromo(trimethylstannyl)alkene (-)-8 was accomplished by the stereoselective bromination of dibromonorbornene (+)-4 guided by anchimeric assistance and subsequent syn- exo-elimination of tetrabromonorbornane (-)-5a as the key steps. Subsequent Cu(I)-catalyzed cyclotrimerization of (-)-8 was optimized to give 1 syn/ anti in 85% yield and 1:1 ratio of diastereomers. Importantly, the results of our mechanistic experiments were in line with the cyclotrimerization occurring in a chain-type fashion with racemization of a Cu(I) homochiral dimeric intermediate, reducing the stereoselectivity of the transformation. Enabled by more facile access to molecular baskets of type 1 syn, a range of recognition studies can now be completed for producing novel supramolecular catalysts, organophosphorus scavengers, and nanostructured materials.

Lewis acid promoted double bond migration in O-allyl to Z-products by Ru-H complexes

In catalytic double bond migration reaction, E-configuration olefins were normally generated as the dominant product because E-configuration was thermodynamically favored. However, Z-configuration products are sometimes desired in pharmaceutical chemistry owing to the structure-activity relationship. In this paper, we have demonstrated a new strategy that Lewis acid promoted an widely employed and convenient ruthenium(II) complex for the catalytic isomerization of O-allylethers, leading to thermodynamic-unfavored Z-product under mild conditions. The model substrate of allyl phenyl ether can be simply scaled up to 20 mmol to produce Z-product with TON of 2453 and TOF of 13,430 h−1 at 40–60 °C. The system of Ru(II)/Lewis Acid catalysts was suitable for various substituted O-allylethers and other types of substrates. Through mechanism study including kinetic study, ligand inhibition effect and molecular spectroscopy, the dissociation of PPh3 ligand by the addition of Lewis acid, and the formation a five-membered Ru complex from anchimeric assistance were both recognized as essential steps to improve the reactivity and to control the stereoselectivity of catalytic double bond migration reaction through metal hydride addition-elimination mechanism. This new strategy may provide a new opportunity to produce thermodynamic-unfavored product in heterocyclic compounds for pharmaceutical chemistry.

Boron‐Catalyzed C−C Functionalization of Allyl Alcohols

AbstractTris(pentafluorophenyl)borane‐catalyzed C−C bond functionalization of arylallyl alcohols using donor‐acceptor carbenes is presented. The allylic hydroxyl group is found to assist the product formation by neighboring group participation providing a clue towards mechanistic understanding. This method can also be employed to effect homologation of allyl alcohols to homoallyl alcohols. Overall, this metal‐free transformation presents a novel disconnection strategy towards carbon‐carbon bond scission and formation.magnified image

Copper-Driven Deselenization: A Strategy for Selective Conversion of Copper Ion to Nanozyme and Its Implication for Copper-Related Disorders.

Synthetic organic molecules, which can selectively convert excess intracellular copper (Cu) ions to nanozymes with an ability to protect cells from oxidative stress, are highly significant in developing therapeutic agents against Cu-related disorder like Wilson's disease. Here, we report 1,3-bis(2-hydroxyethyl)-1 H-benzoimidazole-2-selenone (1), which shows a remarkable ability to remove Cu ion from glutathione, a major cytosolic Cu-binding ligand, and thereafter converts it into copper selenide (CuSe) nanozyme that exhibits remarkable glutathione peroxidase-like activity, at cellular level of H2O2 concentration, with excellent cytoprotective effect against oxidative stress in hepatocyte. Cu-driven deselenization of 1, under physiologically relevant conditions, occurred in two steps. The activation of C═Se bond by metal ion is the crucial first step, followed by cleavage of the metal-activated C═Se bond, initiated by the OH group of N-(CH2)2OH substituent through neighboring group participation (deselenization step), resulted in the controlled synthesis of various types of Cu2-xSe nanocrystals (NCs) (nanodisks, nanocubes, and nanosheets) and tetragonal Cu3Se2 NCs, depending upon the oxidation state of the Cu ion used to activate the C═Se bond. Deselenization of 1 is highly metal-selective. Except Cu, other essential metal ions, including Mn2+, Fe2+, Co2+, Ni2+, or Zn2+, failed to produce metal selenide under identical reaction conditions. Moreover, no significant change in the expression level of Cu-metabolism-related genes, including metallothioneines MT1A, is observed in liver cells co-treated with Cu and 1, as opposed to the large increase in the concentrations of these genes observed in cells treated with Cu alone, suggesting the participation of 1 in Cu homeostasis in hepatocyte.