A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain‐Permeable OGA Inhibitors

Pyrrolidine‐based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O‐GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O‐GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O‐GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.     

Synthetic Routes to Imidates and Their Applications in Organic Transformation: Recent Progress

Recent synthetic approaches and diverse applications of imidates are presented in this review. These motifs are successfully used as intermediates in organic transformations, such as the synthesis of N-heterocycles, natural products and metal complexes with a potential catalytic effect. Consequently, many attempts have been made for the development of efficient and facile synthetic methods of imidates in the past few years, as a continuum of previous paths. A wide range of organic compounds can be used as starting materials for these syntheses, including nitriles, isocyanides, amides etc. which through simple and flexible processes are converted to the desired imidates. Herein, an exploration of the recent synthetic routes of imidates and their diverse applications in organic transformations has been categorized and summarized.     

The effect of intramolecular‐hydrogen bonds in the synthesis of novel imidates from a 13‐membered dioxadithia crown ether diester

The synthesis and structural properties of three novel imidates, 11,13‐bis‐(2‐amino‐ethylimino)‐1,10‐dioxa‐4,7‐dithiacyclotridecane ( 2 ), 11,13‐bis‐(3‐aminopropylimino)‐1,10‐dioxa‐4,7‐dithiacyclotridecane, ( 3 ) and 2,11‐dioxa‐5,8‐dithia‐13,16,19,22‐tetraazabicyclo[10.10.1]tricosa‐1(22),12‐diene, ( 4 ) have been described. These compounds were synthesized by treating 1,10‐dioxa‐4,7‐dithiacyclotridecane‐11,13‐diester ( 1 ) with the appropriate diamine under N₂ and their structures have been characterised by elemental analyses, ¹H‐ and ¹³C‐nmr, ir, and mass spectral studies. Elemental analyses and spectroscopic data support the proposed imidate structures. In addition, total energy and heat of formation (Figure 2) calculated for imidates 2a‐4a and 2b‐4b by the semiempirical AM1 calculations have shown that imidates 2b‐4b having intramolecular hydrogen bonds are more stable (5‐10 kcal/mol) than compounds 2a‐4a .     

Stereoselective Synthesis of (Z)‐4‐(2‐Bromovinyl)benzene‐sulfonyl Azide and Its Synthetic Utility for the Transformation to (Z)‐N‐[4‐(2‐Bromovinyl)benzenesulfonyl]imidates

A novel method for the stereoselective synthesis of (Z)‐4‐(2‐bromovinyl)benzenesulfonyl azide by simultaneous azidation and debrominative decarboxylation of anti‐2,3‐dibromo‐3‐(4‐chlorosulfonylphenyl)propanoic acid using NaN₃ only was developed. Facile transformation of (Z)‐4‐(2‐bromovinyl)benzenesulfonyl azide to (Z)‐N‐[4‐ (2‐bromovinyl)benzenesulfonyl]imidates was also achieved by Cu‐catalyzed three‐component coulping of (Z)‐4‐(2‐bromovinyl)benzenesulfonyl azide, terminal alkynes and alcohols/phenols.     

Hydrogen‐Bond‐Mediated Aglycone Delivery (HAD): A Highly Stereoselective Synthesis of 1,2‐cis α‐D‐Glucosides from Common Glycosyl Donors in the Presence of Bromine

Described herein is the expansion of the picoloyl protecting‐group assisted H‐bond mediated aglycone delivery (HAD) method recently introduced by our laboratory. At first it was noticed that high α‐stereoselectivity is only obtained with S‐ethyl glycosyl donors and only in the presence of dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST), in high dilution, and low temperature. Combining the mechanistic studies of the HAD reaction and bromine‐promoted glycosylations allowed a very effective method to be devised that allows for highly stereoselective α‐glycosidation of practically all common leaving groups (S‐phenyl, S‐tolyl, S/O‐imidates) at regular concentrations and ambient temperature.     

Reaction of cyclic imidates with α,β‐unsaturated esters: Synthesis of new pyrrolo[2,1‐b]‐1,3‐oxazine and pyrido[2,1‐b]‐1,3‐oxazine derivatives

The cycloaddition reaction of cyclic imidates, 2‐benzyl‐5,6‐dihydro‐4H‐1,3‐oxazines 1a , 1b , 1c , 1d , 1e , 1f , with dimethyl acetylenedicarboxylate 2 , trimethyl ethylenetricarboxylate 4 , or dimethyl 2‐(methoxymethylene)malonate 6 afforded new fused heterocyclic compounds, such as methyl (6‐oxo‐3,4‐dihydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐ylidene)acetates 3a , 3b , 3c , 3d , 3e , 3f (71–79%), dimethyl 2‐(6‐oxo‐3,4,6,7‐tetrahydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐yl)malonates 5b , 5c , 5d , 5e , 5f (43–71%), or methyl 6‐oxo‐3,4‐dihydro‐2H,6H‐pyrido[2,1‐b]‐1,3‐oxazine‐7‐carboxylates 7a , 7b , 7c , 7d , 7e , 7f (32–59%), respectively. In these reactions, 1a , 1b , 1c , 1d , 1e , 1f (cyclic imidates, iminoethers) functioned as their N,C‐tautomers (enaminoethers) 2 to α,β‐unsaturated esters 2 , 4, and 6 to give annulation products 3 , 5 , and 7 following to the elimination of methanol, respectively. J. Heterocyclic Chem., (2011).     

Thermolysis of Imidates: A New Method for the Generation of Carbonyl Ylides

Thermolysis of dimethyl 2‐[(3‐oxo‐3H‐isoindol‐1‐yl)oxy]malonate ( 8 ) promotes a [1,4]‐H shift in the imidic ? N?C? O? CH? fragment of the starting molecule, which leads to a reactive carbonyl ylide. This carbonyl ylide can be trapped by the C?N bond of imidates and imines, as well as the C?O bond of benzaldehyde. The corresponding cycloadducts 11, 14 , and 16 are formed regioselectively in good yields (60–95%) and with high stereoselectivity. In the case of 11 , the minor cycloadduct in solution undergoes an isomerization to give the more stable stereoisomer. The structures of two cycloadducts, i.e., 11a and 14a , have been established by X‐ray crystallography.     

N-Pyridinium imidates as new sources of 2-aminoimidazole and imidazoline derivatives

New 2-aminoimidazole (2-AI) and imidazoline derivatives were obtained in three steps through the reduction of N-pyridinium imidates into 1,2-dihydropyridine imidates and oxidative addition of guanidine derivatives. Among the possible transformations, imidate substitution allows selectivity in the last deprotection step, leading to an original 2-aminoimidazolo-imidazoline skeleton.     

Boyd Group Electronegativity Influence on the Parr Global Electrophilicity of Vilsmeier Reagent‐Derived Imidates: New Insights toward Improving Mitsunobu Chemistry

Reactivities of 19 methylated imidate analogs were examined using B3LYP and M06‐2X DFT methods. The resulting HOMO and LUMO energies of each optimized structure were used to calculate corresponding Parr global electrophilicity (ω) values. When the resulting quantities were compared against Boyd group electronegativity (X_G) values, a clear correlation was observed, suggesting that electron‐withdrawing effects influence the reactivity of imidates. These findings represent an important first step in developing a novel method toward improving traditional Mitsunobu functionalization reactions.     

Reaction of Alkyl(dialkoxyphosphoryl)alkanimidates with Phenyl Isothiocyanate

A slow reaction of C-phosphorylated imidates with phenyl isothiocyanate proceeds selectively via nucleophilic addition by the carbon-nitrogen double bond, involving the = N-H group, to form thiourea derivatives in yields of up to 77%. The reaction accelerates in the presence of triethylamine. Reaction kinetics were studied. It was found the the rate constants vary in parallel with basicity (pK _a) of the starting imidates.     

2,4,4-trisubstituted 5-amino-4h-imidazoles. A new synthetic approach and reactivity

The scope and limitations of the reaction between imidates and α,α-disubstituted α-aminoacetonitriles to give 5-amino-4H-imidazoles are studied. The reactivity of compounds 1a-b has been explored.     

Silver(I)‐Catalyzed N‐Trifluoroethylation of Anilines and O‐Trifluoroethylation of Amides with 2,2,2‐Trifluorodiazoethane

A straightforward N‐trifluoroethylation of anilines has been developed based on silver‐catalyzed N? H insertions with 2,2,2‐trifluorodiazoethane (CF₃CHN₂). Mechanistically, the reaction is proposed to involve migratory insertion of a silver carbene as the key step. In contrast, when amides are employed as the substrates under similar reaction conditions, O‐trifluoroethylation occurs to afford trifluoroethyl imidates.     

Highly Regio‐ and Stereoselective Intermolecular Seleno‐ and Thioamination of Alkynes

By using N‐fluorobenzenesulfonimide as both the oxidant and the amination reagent, we have realized the first example of the intermolecular chalcogenative amination of alkynes, which grants facile, highly regio‐ and stereoselective access to chalcogenated enamides. The reaction features mild conditions, high yields and selectivities, remarkably broad substrate scope, and excellent functional group tolerance. Mechanistic studies indicate the in situ generated chalcogen imidates to be the actual reactive species, which in turn, has clarified the mechanism of related transformations. These reactions represent significant additions to the development of the highly selective amino bisfunctionalization of alkynes.     

Molecular Interrogation to Crack the Case of O-GlcNAc

The O-linked β-N-acetylglucosamine (O-GlcNAc) modification, termed O-GlcNAcylation, is an essential and dynamic post-translational modification in cells. O-GlcNAc transferase (OGT) installs this modification on serine and threonine residues, whereas O-GlcNAcase (OGA) hydrolyzes it. O-GlcNAc modifications are found on thousands of intracellular proteins involved in diverse biological processes. Dysregulation of O-GlcNAcylation and O-GlcNAc cycling enzymes has been detected in many diseases, including cancer, diabetes, cardiovascular and neurodegenerative diseases. Here, recent advances in the development of molecular tools to investigate OGT and OGA functions and substrate recognition are discussed. New chemical approaches to study O-GlcNAc dynamics and its potential roles in the immune system are also highlighted. It is hoped that this minireview will encourage more research in these areas to advance the understanding of O-GlcNAc in biology and diseases.     

Reactivity studies of ethyl(Z)‐N‐(2‐amino‐1,2‐dicyanovinyl) formimidate with carbonyl compounds in the presence of base

The reaction of ethyl(Z)‐N‐(2‐amino‐1,2‐dicyanovinyl)formimidate 6 with carbonyl compounds in the presence of triethyl amine occurs with formation of the Schiff s base and intramolecular hydrolysis of the adjacent cyano group to give the alkylideneamino derivatives 8a‐f . When the α‐carbon of the ketone has at least one proton, the prolonged contact of 8a‐f with triethylamine causes intramolecular cyclization between this carbon and the imidate carbon atom to form a seven membered ring. This is followed by cyclization of the cyano and amido groups, leading to the pyrrolo[4,3‐b][1,4]diazepines 9 . If a strong base is used the first ring to be formed is the pyrrole ring as evidenced in the reaction of 8a with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene leading to 14 . The subsequent addition of methyl amine to the reaction mixture, caused cleavage of the alkylideneamino unit and formation of the amidine function from the imi date ( 15 ). The addition of acid to the imidates 8a and 8f led to the diazepine compounds 10a and 10f respectively. A suspension of compound 8e in ethanol and triethylamine evolved to a pyrazinone structure 12 under kinetic conditions (4 hours, room temperature) and to the pyrrolo[4,3‐b][1,4]diazepine 9e under thermodynamic conditions (48 hours, room temperature).     

Ferrocenylimidazoline palladacycles as efficient catalysts for the aza‐Claisen rearrangement reaction of allylic imidates

Chloride‐bridged palladacycle dimers 1 have been evaluated as catalysts for the aza‐Claisen rearrangement of allylic imidates 2 to the corresponding allyl amides 3 . Cyclopalladated complexes 1b–e bearing electron‐donating substituents on imidazoline ring were identified as being superior catalysts because excellent yields were obtained without using silver salts for activation. In addition, a correlation between substituents on the imidazoline ring and catalytic activity of palladacycles was established. The electron‐deficient ligands and good solubility of catalysts in the reaction solution increase the catalytic activity. Copyright © 2008 John Wiley & Sons, Ltd.     

The Flash Vacuum Thermolysis of N-Acyl Imidates

In the flash vacuum thermolysis of methyl N-acyl imidates, the loss of methanol is consistent with the intermediacy of an N-acylketenimine. Recombination and further reactions may lead to the array of products observed in these thermal reactions. An attempt to trap the intermediate N-acylketenimine by an intramolecular [2 + 2] cycloaddition was unsuccessful.     

Controlled acid hydrolysis and kinetics of flavone C-glycosides from trollflowers

Acid hydrolysis mechanisms of orientin-2"-O-galactopyranoside(OGA),orientin and other flavone C-glycosides in the trollflowers[Trollius chinensis Bunge) were studied in this report for the first time.Hydrolysis parameters including temperature,acidity,solvent and reaction time were comprehensively investigated.OGA could be hydrolyzed to orientin,followed by an isomerization to isoorientin via a reversible Wessely-Moser rearrangement reaction under stronger acidic conditions.A first-order kinetic model fitted the hydrolysis process of OGA well.Under the optimal hydrolysis conditions of 80 ℃,1.0 mol/L H~+ and 7 h reaction time,about 77%OGA was transformed to orientin with no detectable isoorientin.These results could be helpful for better understanding of the acid hydrolysis kinetics of flavone C-glycosides,as well as the preparation of these valuable components under controlled acid hydrolysis conditions.     

Chemistry of amino acid thionoester derivatives. An unexpected change in the reaction course between heterocyclic-2-carboxylic acid hydrazides and N-substituted thionoglycinates. Preferential formation of 4-amino-1,2,4-triazole adducts over 1,3,4-oxadiazole products

The reaction between benzoic acid hydrazides and ethyl N-carbobenzyloxythionoglycinate produces the expected 2-aminomethyl-1,3,4-oxadiazoles in good yield. Heterocyclic carboxylic acid hydrazides give similar products when the hydrazide moiety is located at either the three or four position (relative to the heteroatom) in the ring. However, when heterocyclic-2-carboxylic acid hydrazides are utilized, oxadiazole formation is dramatically reduced. Instead, the intermediate imidates are usually isolated as the major products of the reaction from one equivalent of these hydrazides. These imidate products are accompanied by significant amounts of 4-amino-1,2,4-triazole derivatives which arise from incorporation of two equivalents of the hydrazide. The structure of these unexpected 4-aminotriazole products was confirmed by nmr and mass spectral data as well as an X-ray analysis. In the presence of a stoichiometric amount of these hydrazides, the 4-aminotriazoles become the major products of the reaction. This phenomenon was found to be general for 2-thienyl, 2-furoic, picolinic, and pyrazinoic acid hydrazides. The intermediate imidates for each of these systems were isolated, characterized and found to have a remarkable thermal stability. Conversion of these imidates to the corresponding 1,3,4-oxadiazoles could only be accomplished in hot acetic anhydride. A mechanistic rationale is presented which suggests that some stabilization of the intermediate imidate must occur in these examples which allows an intermolecular process to compete so effectively with an intramolecular cyclization. Since the cyclization to oxadiazole is presumed to be acid catalyzed, this stabilization is proposed to occur specifically by the formation of a hydrogen bond between the ring heteroatom and the proton-ated imino nitrogen present in the imidate prior to cyclization. The formation of such a hydrogen bond removes the carboxylate oxygen from its opportune position for cyclization, while the protonated imino nitrogen can still activate the imidate for subsequent reaction with a second equivalent of hydrazide. In all cases where this heteroatom is capable of hydrogen bond formation, 4-aminotriazoles predominate. The relative amount of 4-aminotriazole product is directly correlatable with the donor capability of the ring hetero-atom. This proposed model was tested by examining a system where steric congestion would be expected to prevent hydrogen bond formation. Indeed, when N-methyl-2-pyrrole carboxylic acid hydrazide was utilized in the reaction, the corresponding 1,3,4-oxadiazole was formed as expected in high yield. Conversely, an acyclic aliphatic hydrazide specifically bearing a beta heteroatom (N-carbobenzyloxyglycine hydrazide) produced the expected 4-aminotriazole adduct in high yield. This therefore appears to be a general phenomenon which provides a useful synthetic entry to several new unsymmetrically substituted 4-amino-1,2,4-triazole derivatives.