Neighboring Group Participation Research Articles

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.

Influence of Remote Picolinyl and Picoloyl Stereodirecting Groups for the Stereoselective Glycosylation

AbstractSugar compounds generally consist of several hydroxyl groups, responsible for the generation of complex oligosaccharides and are discriminated against or manipulated by using protecting groups. The protecting groups in carbohydrate chemistry adopt a central position in controlling stereoselectivity of glycosylation reaction. In all, picoloyl (Pico) and picolinyl (Pic) group are scrutinize as admirable protecting groups for the evaluation of efficient and convenient glycosyl donors which in turn, synthesize both 1,2‐cis‐ and 1,2‐trans‐linked complex and challenging oligosaccharides stereoselectively either through hydrogen bond mediated aglycone delivery (HAD) or by neighbouring group participation. This review explores the recent advances in the use of picoloyl (Pico) and picolinyl (Pic) as stereo‐directing groups for high facial α‐ or β‐stereoselectivity and its applications in the synthesis of biologically important oligosaccharides.

Synthesis and Conformational Analysis of Fluorinated Uridine Analogues Provide Insight into a Neighbouring-Group Participation Mechanism.

Fluorinated nucleoside analogues have attracted much attention as anticancer and antiviral agents and as probes for enzymatic function. However, the lack of direct synthetic methods, especially for 2′,3′-dideoxy-2′,3′-difluoro nucleosides, hamper their practical utility. In order to design more efficient synthetic methods, a better understanding of the conformation and mechanism of formation of these molecules is important. Herein, we report the synthesis and conformational analysis of a 2′,3′-dideoxy-2′,3′-difluoro and a 2′-deoxy-2′-fluoro uridine derivative and provide an insight into the reaction mechanism. We suggest that the transformation most likely diverges from the SN1 or SN2 pathway, but instead operates via a neighbouring-group participation mechanism.

Improved α-Sialylation through the Synergy of 5-N,4-O-Oxazolidinone Protection and Exocyclic C-1 Neighboring Group Participation.

Stereoselective construction of α-sialyl linkages is one of the most significant challenges in carbohydrate chemistry. In this research, we developed a novel strategy for stereoselective synthesis of α-linked sialosides by protecting the 5-N,4-O-positions of a sialyl donor with an oxazolidinone group and its C-1 carboxylic functionality with a cyanoethyl ester to promote α-glycosylation. We also adopted the more electrophilic N-bromosuccinimide as a promoter to readily activate p-tolyl thiosialoside at -78 °C. The sialylation using this sialyl donor gave excellent yields and α-selectivity. The new synthetic method was used to successfully construct naturally occurring α-sialosides having sialic acid linked to the 6-O- or 3-O-position of galactoside, or 8-O-position of another sialic acid, respectively, as well as other α-linked sialosides.

An Overview of Water‐Mediated Alkyne Functionalization by Neighboring Group Participation of Carbonyl Groups

AbstractReviewed herein, the progress employing the assistance of a neighboring carbonyl group for alkyne functionalization reactions that are mediated by water. Proper arrangement of these transformations is synthetically worthwhile because it will allow chemists to design straightforward synthetic routes for the construction of complex architectures with perfect regio‐ and chemoselectivity. Researchers must understand the mechanism before aiming a new idea based on these types of transformations as they proceed through a different way in comparison to the strategies that employ carbonyl groups as a directing group for C−H functionalization reactions. In general, an oxygen transposition event occurs in the presence of an alkyne activator. In an aim to expose the molecular diversity that can now be accessed employing intramolecular carbonyl assistance, all the precedents are organized systematically for the first time and can be expected to serve as a comprehensive reference work. Therefore, the key arrangement of this review is schemes accompanied by a concise explanatory text describing both advantages and limitations along with the mechanism. Different transformations are ordered in sections according to the chemical structure of the assisted groups. The overall objective of this review is to promote the application of carbonyl‐assisted reactions beyond the methodologies dedicated to the regioselective synthesis of carbonyl derivatives and hence, serving it as a valuable reaction archetype in modern‐day research for the synthesis of carbo‐ and heterocycles.magnified image

Anomeric configuration-dependence of the Lattrell-Dax epimerization from D-glucose to synthetically useful D-allose derivatives.

D-Allose and its derivatives play important roles in the field of health care and food nutrition. Pure and well-defined D-allose derivatives can facilitate the elucidation of their structure-activity relationship as an essential step for drug design. The Lattrell-Dax epimerization, refers to the triflate inversion using nitrite reagent, is known as valuable method for the synthesis of rare D-allose derivatives. Here, the influence of protecting group patterns on the transformation efficiency of D-glucose derivatives into synthetically useful D-alloses and D-allosamines via the Lattrell-Dax epimerization was studied. For C3 epimerization of D-glucose derivatives bearing O2-acyl group, an anomeric configuration-dependent acyl migration from O2 to O3 was found. In addition, a neighbouring group participation effect-mediated SN1 nucleophilic substitution of the D-glucosamine bearing C2 trichloroacetamido (TCA) group in the Lattrell-Dax epimerization was dependent upon anomeric configuration. Thus, the effect of anomeric configuration on the Lattrell-Dax epimerization of D-glucose suggests that β-D-glucosides with low steric hindrance at C2 should be better substrates for the synthesis of D-allose derivatives. Significantly, the efficient synthesis of the orthogonally protected D-allose 13 and D-allosamine 18 will serve well for further assembly of complex glycans.

Palladium-Catalyzed O - and N -Glycosylation with Glycosyl Chlorides

Despite the significant progress in carbohydrate chemistry, there remains a pressing need for efficient and practical glycosylation methods using simple glycosyl donors and with high atom economy. ...

Revisiting the ‘Phenonium Phenomenon’: Regiodivergent Opening of Nonsymmetrical Phenonium Ions with Halide Nucleophiles

Formation of phenonium ions through anchimeric assistance (neighboring-group participation) of aryl rings has been known since 1949. Although these reactive intermediates have been studied extensively by physical organic chemists, their potential as control elements in synthesis is underutilized. Presented here are our laboratory’s recently reported first examples of regiodivergent openings of nonsymmetrical phenonium ions with chloride nucleophiles. The selectivity of these processes is under reagent control. The reactions are operationally simple and permit the stereospecific synthesis of complex chiral building blocks from readily accessible epoxide starting materials.1 Introduction2 Select Examples of Phenonium Ion Methodology3 Regiodivergent Opening of Nonsymmetrical Phenonium Ions4 Summary and Outlook

The Cyclic Nitronate Route to Pharmaceutical Molecules: Synthesis of GSK's Potent PDE4 Inhibitor as a Case Study.

An efficient asymmetric synthesis of GlaxoSmithKline’s potent PDE4 inhibitor was accomplished in eight steps from a catechol-derived nitroalkene. The key intermediate (3-acyloxymethyl-substituted 1,2-oxazine) was prepared in a straightforward manner by tandem acylation/(3,3)-sigmatropic rearrangement of the corresponding 1,2-oxazine-N-oxide. The latter was assembled by a (4 + 2)-cycloaddition between the suitably substituted nitroalkene and vinyl ether. Facile acetal epimerization at the C-6 position in 1,2-oxazine ring was observed in the course of reduction with NaBH3CN in AcOH. Density functional theory (DFT) calculations suggest that the epimerization may proceed through an unusual tricyclic oxazolo(1,2)oxazinium cation formed via double anchimeric assistance from a distant acyloxy group and the nitrogen atom of the 1,2-oxazine ring.

Effects of H-bonding and structural constituents on the acidity and potential "anticancer activity" of D-mandelonitrile-β-D-glucuronic acid by density functional theory

Laetrile (D-mandelonitrile-β-D-glucuronic acid, 1COOH) is being promoted, more and more, as an alternate cancer treatment, in many countries. Here we show how intramolecular long-range hydrogen bonding (ILRHB) affects proton affinity (PA) of 1COOH and turns it into a rather strong acid at M06/6–311 + + G(d,p) level of theory. The ILRHB between carboxylate and the –CN of 1COOH activates the cyanide and provides a form of neighboring group participation (anchimeric assistance) in which the rate of the cyanide release is increased. The released cyanide is reported to kill cancer cells more rigorously than the normal ones. Constituents (–CN, –ph and –OH) effects on 1COOH acidity are probed. The –OH groups show the highest impact on increasing the relative acidity in H2O, DMSO and gas phase. The 1COOH and its derivatives appear more acidic in DMSO than in water. Quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO) analysis and the polarized continuum mode (PCM) are used for calculation of the pKa values.

Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions

Controlling the chemical glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-trans glycosidic linkages can be installed using neighboring group participation, the construction of 1,2-cis linkages is difficult and has no general solution. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using infrared ion spectroscopy, DFT computations, and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochemical outcome of a glycosylation reaction, and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconjugates to fuel biological research.

Using Neighboring-Group Participation for Acyclic Stereocontrol in Diastereoselective Substitution Reactions of Acetals.

Neighboring-group participation of an ester enabled stereocontrol in substitution reactions of acyclic acetals. The ester group formed a trans-fused dioxolenium ion intermediate, which underwent a substitution reaction at the acetal carbon atom to afford the product with high diastereoselectivity. Neighboring-group participation was confirmed by isolating dioxolane products resulting from nucleophilic addition at C-2 of a 1,3-dioxolenium ion intermediate. Using a pivaloate ester as the participating group in combination with strong nucleophiles produced substitution products with diastereoselectivities of ≥90:10.

Regio- and Stereoselective Synthesis of Highly Functionalized Tetrasubstituted Olefins by Iodine-Mediated Iodofunctionalization of Ferrocene-Containing Allenylphosphonates.

An iodine-mediated iodofunctionalization of ferrocene-containing allenylphosphonates with various carboxylic acids, alcohols, and phenols has been established, affording a series of highly functionalized tetrasubstituted alkenylphosphonate derivatives with high regio- and stereoselectivities in moderate to good yields. This approach provides an opportunity to the useful but not readily available tetrasubstituted olefins. The stereoselectivity of the reaction may be controlled by the neighboring group participation of the oxygen atom of the phosphate group.

Highly Diastereoselective Anodic Fluorination of Organosulfur Compounds Based on Neighboring Participation

Highly diastereoselective and efficient anodic α-fluorination of phenyl, p-chlorophenyl, and 2-naphthyl 3,3,3-trifluoro-2-methoxypropyl sulfides was successfully carried out at platinum electrodes in Et3N-nHF (n = 3-5)/MeCN to provide the corresponding α-fluorinated products in good yields, whereas the corresponding p-methoxyphenyl sulfide derivative gave much lower diastereoselectivity. On the basis of such marked substituent effects on the diastereoselectivity and a previous study of anodic methoxylation of related sulfides,1) as well as the X-ray analysis of the configuration of the major diastereomer of the electrochemically fluorinated alph-naphthyl derivative, it was clarified that the high diastereoselectivity is attributable to the neighboring MeO group participation to the anodically generated cationic intermediate destabilized by an electron-withdrawing CF3 group.2)

Tert‐Butyl Nitrite Mediated Nitro‐Nitratosation of Internal Alkenes

In an oxygen atmosphere tert‐butyl nitrite (TBN) reacts with unsymmetrical internal benzylic alkenes giving nitro‐nitratosation product exclusively. The γ‐diaryl‐substituted styrenes provided better yields compared to γ‐alkyl‐aryl‐substituted styrenes. The higher yields for the former type of substrates is possibly dictated by the additional stability of benzylic radical due to the anchimeric assistance imparted by the γ‐substituted phenyl ring. During oxidative nitration, the nitro (NO2) group adds at the non‐benzylic site, whereas the nitrato group (ONO2) is attached at the relatively stable benzylic position. Under similar reaction conditions, α,β‐unsaturated carboxylic acids, afforded nitroalkenes as the sole product.

Anchimerically Assisted Selective Cleavage of Acid-Labile Aryl Alkyl Ethers by Aluminum Triiodide and N,N-Dimethylformamide Dimethyl Acetal.

Aluminum triiodide is harnessed by N,N-dimethylformamide dimethyl acetal (DMF-DMA) for the selective cleavage of ethers via neighboring group participation. Various acid-labile functional groups, including carboxylate, allyl, tert-butyldimethylsilyl (TBS), and tert-butoxycarbonyl (Boc), suffer the conditions intact. The method offers an efficient approach to cleaving catechol monoalkyl ethers and to uncovering phenols from acetal-type protecting groups such as methoxymethyl (MOM), methoxyethoxymethyl (MEM), and tetrahydropyranyl (THP) chemoselectively.

An Epoxide Intermediate in Glycosidase Catalysis.

Retaining glycoside hydrolases cleave their substrates through stereochemical retention at the anomeric position. Typically, this involves two-step mechanisms using either an enzymatic nucleophile via a covalent glycosyl enzyme intermediate or neighboring-group participation by a substrate-borne 2-acetamido neighboring group via an oxazoline intermediate; no enzymatic mechanism with participation of the sugar 2-hydroxyl has been reported. Here, we detail structural, computational, and kinetic evidence for neighboring-group participation by a mannose 2-hydroxyl in glycoside hydrolase family 99 endo-α-1,2-mannanases. We present a series of crystallographic snapshots of key species along the reaction coordinate: a Michaelis complex with a tetrasaccharide substrate; complexes with intermediate mimics, a sugar-shaped cyclitol β-1,2-aziridine and β-1,2-epoxide; and a product complex. The 1,2-epoxide intermediate mimic displayed hydrolytic and transfer reactivity analogous to that expected for the 1,2-anhydro sugar intermediate supporting its catalytic equivalence. Quantum mechanics/molecular mechanics modeling of the reaction coordinate predicted a reaction pathway through a 1,2-anhydro sugar via a transition state in an unusual flattened, envelope (E3) conformation. Kinetic isotope effects (kcat/KM) for anomeric-2H and anomeric-13C support an oxocarbenium ion-like transition state, and that for C2-18O (1.052 ± 0.006) directly implicates nucleophilic participation by the C2-hydroxyl. Collectively, these data substantiate this unprecedented and long-imagined enzymatic mechanism.

Dehydroxylated C-3 Alkylation of Indole Accompanied by 1,2-Sulfur Migration.

A metal-free sulfur neighboring group participation C-3 alkylation method between β-sulfur-α-alcohol and indole is documented. Due to its considerable generality and excellent selectivity, this method has been provided a facile access to synthetically useful α-indole-β-functions. Meanwhile, unlike traditional Friedel-Crafts and Mitsunobu reactions, the unique chemoselectivity and regioselectivity may be attributed to a synergetic mechanism with simultaneous C-O cleavage, C-S migration, and C-C formation occurring in the developed reaction.

Synthesis of Glycosyl Chlorides and Bromides by Chelation Assisted Activation of Picolinic Esters under Mild Neutral Conditions.

A general method has been developed for the formation of glycosyl chlorides and bromides from picolinic esters under mild and neutral conditions. Benchtop stable picolinic esters are activated by a copper(II) halide species to afford the corresponding products in high yields with a traceless leaving group. Rare β glycosyl chlorides are accessible via this route through neighboring group participation. Additionally, glycosyl chlorides with labile protecting groups previously not easily accessible can be prepared.

Advances in Protecting Groups for Oligosaccharide Synthesis.

Carbohydrates contain numerous hydroxyl groups and sometimes amine functionalities which lead to a variety of complex structures. In order to discriminate each hydroxyl group for the synthesis of complex oligosaccharides, protecting group manipulations are essential. Although the primary role of a protecting group is to temporarily mask a particular hydroxyl/amino group, it plays a greater role in tuning the reactivity of coupling partners as well as regioselectivity and stereoselectivity of glycosylations. Several protecting groups offer anchimeric assistance in glycosylation. They also alter the solubility of substrates and thereby influence the reaction outcome. Since oligosaccharides comprise branched structures, the glycosyl donors and acceptors need to be protected with orthogonal protected groups that can be selectively removed one at a time without affecting other groups. This minireview is therefore intended to provide a discussion on new protecting groups for amino and hydroxyl groups, which have been introduced over last ten years in the field of carbohydrate synthesis. These protecting groups are also useful for synthesizing non-carbohydrate target molecules as well.