Synthesis, In Silico and Kinetics Evaluation of N-(ß-d-glucopyranosyl)-2-arylimidazole-4(5)-carboxamides and N-(ß-d-glucopyranosyl)-4(5)-arylimidazole-2-carboxamides as Glycogen Phosphorylase Inhibitors.

Recently studied N-(ß-d-glucopyranosyl)-3-aryl-1,2,4-triazole-5-carboxamides have proven to be low micromolar inhibitors of glycogen phosphorylase (GP), a validated target for the treatment of type 2 diabetes mellitus. Since in other settings, the bioisosteric replacement of the 1,2,4-triazole moiety with imidazole resulted in significantly more efficient GP inhibitors, in silico calculations using Glide molecular docking along with unbound state DFT calculations were performed on N-(ß-d-glucopyranosyl)-arylimidazole-carboxamides, revealing their potential for strong GP inhibition. The syntheses of the target compounds involved the formation of an amide bond between per-O-acetylated ß-d-glucopyranosylamine and the corresponding arylimidazole-carboxylic acids. Kinetics experiments on rabbit muscle GPb revealed low micromolar inhibitors, with the best inhibition constants (Kis) of ~3-4 µM obtained for 1- and 2-naphthyl-substituted N-(ß-d-glucopyranosyl)-imidazolecarboxamides, 2b-c. The predicted protein-ligand interactions responsible for the observed potencies are discussed and will facilitate the structure-based design of other inhibitors targeting this important therapeutic target. Meanwhile, the importance of the careful consideration of ligand tautomeric states in binding calculations is highlighted, with the usefulness of DFT calculations in this regard proposed.

Design and Synthesis of 3-(ß-d-Glucopyranosyl)-4-amino/4-guanidino Pyrazole Derivatives and Analysis of Their Glycogen Phosphorylase Inhibitory Potential.

Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes. ß-d-Glucopyranosyl derivatives have provided some of the most potent GP inhibitors discovered to date. In this regard, C-ß-d-glucopyranosyl azole type inhibitors proved to be particularly effective, with 2- and 4-ß-d-glucopyranosyl imidazoles among the most potent designed to date. His377 backbone C=O hydrogen bonding and ion-ion interactions of the protonated imidazole with Asp283 from the 280s loop, stabilizing the inactive state, were proposed as crucial to the observed potencies. Towards further exploring these features, 4-amino-3-(ß-d-glucopyranosyl)-5-phenyl-1H-pyrazole (3) and 3-(ß-d-glucopyranosyl)-4-guanidino-5-phenyl-1H-pyrazole (4) were designed and synthesized with the potential to exploit similar interactions. Binding assay experiments against rabbit muscle GPb revealed 3 as a moderate inhibitor (IC50 = 565 µM), but 4 displayed no inhibition at 625 µM concentration. Towards understanding the observed inhibitions, docking and post-docking molecular mechanics-generalized Born surface area (MM-GBSA) binding free energy calculations were performed, together with Monte Carlo and density functional theory (DFT) calculations on the free unbound ligands. The computations revealed that while 3 was predicted to hydrogen bond with His377 C=O in its favoured tautomeric state, the interactions with Asp283 were not direct and there were no ion-ion interactions; for 4, the most stable tautomer did not have the His377 backbone C=O interaction and while ion-ion interactions and direct hydrogen bonding with Asp283 were predicted, the conformational strain and entropy loss of the ligand in the bound state was significant. The importance of consideration of tautomeric states and ligand strain for glucose analogues in the confined space of the catalytic site with the 280s loop in the closed position was highlighted.

Half-Sandwich Type Platinum-Group Metal Complexes of C-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities.

While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a C-glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to O-perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above C-glucosaminyl heterocycles in their O-perbenzylated, O-perbenzoylated and O-unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with p-cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with p-cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, O-benzyl groups were superior to O-benzoyl groups. The IC50 values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive Staphylococcus aureus and Enterococcus clinical isolates in the low micromolar range.

Reactive Oxygen Species Production Is Responsible for Antineoplastic Activity of Osmium, Ruthenium, Iridium and Rhodium Half-Sandwich Type Complexes with Bidentate Glycosyl Heterocyclic Ligands in Various Cancer Cell Models.

Platinum complexes are used in chemotherapy, primarily as antineoplastic agents. In this study, we assessed the cytotoxic and cytostatic properties of a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich-type complexes with bidentate monosaccharide ligands. We identified 5 compounds with moderate to negligible acute cytotoxicity but with potent long-term cytostatic activity. These structure-activity relationship studies revealed that: (1) osmium(II) p-cymene complexes were active in all models, while rhodium(III) and iridium(III) Cp* complexes proved largely inactive; (2) the biological effect was influenced by the nature of the central azole ring of the ligands-1,2,3-triazole was the most effective, followed by 1,3,4-oxadiazole, while the isomeric 1,2,4-oxadiazole abolished the cytostatic activity; (3) we found a correlation between the hydrophobic character of the complexes and their cytostatic activity: compounds with O-benzoyl protective groups on the carbohydrate moiety were active, compared to O-deprotected ones. The best compound, an osmium(II) complex, had an IC50 value of 0.70 µM. Furthermore, the steepness of the inhibitory curve of the active complexes suggested cooperative binding; cooperative molecules were better inhibitors than non-cooperative ones. The cytostatic activity of the active complexes was abolished by a lipid-soluble antioxidant, vitamin E, suggesting that oxidative stress plays a major role in the biological activity of the complexes. The complexes were active on ovarian cancer, pancreatic adenocarcinoma, osteosarcoma and Hodgkin's lymphoma cells, but were inactive on primary, non-transformed human fibroblasts, indicating their applicability as potential anticancer agents.

2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes.

Inhibition of the human O-linked ß-N-acetylglucosaminidase (hOGA, GH84) enzyme is pharmacologically relevant in several diseases such as neurodegenerative and cardiovascular disorders, type 2 diabetes, and cancer. Human lysosomal hexosaminidases (hHexA and hHexB, GH20) are mechanistically related enzymes; therefore, selective inhibition of these enzymes is crucial in terms of potential applications. In order to extend the structure-activity relationships of OGA inhibitors, a series of 2-acetamido-2-deoxy-d-glucono-1,5-lactone sulfonylhydrazones was prepared from d-glucosamine. The synthetic sequence involved condensation of N-acetyl-3,4,6-tri-O-acetyl-d-glucosamine with arenesulfonylhydrazines, followed by MnO2 oxidation to the corresponding glucono-1,5-lactone sulfonylhydrazones. Removal of the O-acetyl protecting groups by NH3/MeOH furnished the test compounds. Evaluation of these compounds by enzyme kinetic methods against hOGA and hHexB revealed potent nanomolar competitive inhibition of both enzymes, with no significant selectivity towards either. The most efficient inhibitor of hOGA was 2-acetamido-2-deoxy-d-glucono-1,5-lactone 1-naphthalenesulfonylhydrazone (5f, Ki = 27 nM). This compound had a Ki of 6.8 nM towards hHexB. To assess the binding mode of these inhibitors to hOGA, computational studies (Prime protein-ligand refinement and QM/MM optimizations) were performed, which suggested the binding preference of the glucono-1,5-lactone sulfonylhydrazones in an s-cis conformation for all test compounds.

Glycopyranosylidene-Spiro-Morpholinones: Evaluation of the Synthetic Possibilities Based on Glyculosonamide Derivatives and a New Method for the Construction of the Morpholine Ring.

Glycosylidene-spiro-morpholin(on)es are scarcely described skeletons in the literature. In this work, we have systematically explored the synthetic routes towards such morpholinones based on the reactions of O-peracylated hept-2-ulopyranosonamide derivatives of D-gluco and D-galacto configuration. Koenigs-Knorr type glycosylation of 2-chloroethanol, allylic and propargylic alcohols by (glyculosylbromide)onamides furnished the expected glycosides. The 2-chloroethyl glycosides were ring closed to the corresponding spiro-morpholinones by treatment with K2CO3. The (allyl glyculosid)onamides gave diastereomeric mixtures of spiro-5-hydroxymorpholinones by ozonolysis and 5-iodomethylmorpholinones under iodonium ion mediated conditions. The ozonolytic method has not yet been known for the construction of morpholine rings, therefore, it was also extended to O-allyl mandelamide. The 5-hydroxymorpholinones were subjected to oxidation and acid catalyzed elimination reactions to give the corresponding morpholine-3,5-dions and 5,6-didehydro-morpholin-3-ones, respectively. Base induced elimination of the 5-iodomethylmorpholinones gave 5-methyl-2H-1,4-oxazin-3(4H)-ones. O-Acyl protecting groups of all of the above compounds were removed under Zemplén conditions. Some of the D-gluco configured unprotected compounds were tested as inhibitors of glycogen phosphorylase, but showed no significant effect.

Coupling Reactions of Anhydro-Aldose Tosylhydrazones with Boronic Acids.

A catalyst-free coupling reaction between O-peracetylated, O-perbenzoylated, O-permethylated, and O-permethoxymethylated 2,6-anhydro-aldose tosylhydrazones (C-(ß-d-glycopyranosyl)formaldehyde tosylhydrazones) and aromatic boronic acids is reported. The base-promoted reaction is operationally simple and exhibits a broad substrate scope. The main products in most of the transformations were open-chain 1-C-aryl-hept-1-enitol type compounds while the expected ß-d-glycopyranosylmethyl arenes (benzyl C-glycosides) were formed in subordinate yields only. A mechanistic rationale is provided to explain how a complex substrate may change the well-established course of the reaction.

First Synthesis of 3-Glycopyranosyl-1,2,4-Triazines and Some Cycloadditions Thereof.

C-glycopyranosyl derivatives of six-membered heterocycles are scarcely represented in the chemical literature and the title 3-glycopyranosyl-1,2,4-triazines are completely unknown. In this paper, the first synthesis of this compound class is accomplished by the cyclocondensation of C-glycosyl formamidrazones and 1,2-dicarbonyl derivatives. In addition, the synthesis of C-glycopyranosyl 1,2,4-triazin-5(4H)-ones was also carried out by the transformation of the above formamidrazones with α-keto-carboxylic esters. Inverse electron demand Diels-Alder reactions of 3-glycopyranosyl-1,2,4-triazines with a bicyclononyne derivative yielded the corresponding annulated 2-glycopyranosyl pyridines.

Coupling of N-tosylhydrazones with tetrazoles: synthesis of 2-ß-D-glycopyranosylmethyl-5-substituted-2H-tetrazole type glycomimetics.

Coupling reactions of O-peracylated 2,6-anhydro-aldose tosylhydrazones (C-(ß-d-glycopyranosyl)formaldehyde tosylhydrazones) with tetrazoles were studied under metal-free conditions using thermic or microwave activation in the presence of different bases. The reactions proved highly regioselective and gave the corresponding, up-to-now unknown 2-ß-d-glycopyranosylmethyl-2H-tetrazoles in 7-67% yields. The method can be applied to get new types of disaccharide mimetics, 5-glycosyl-2-glycopyranosylmethyl-2H-tetrazoles, as well. Galectin binding studies with C-(ß-d-galactopyranosyl)formaldehyde tosylhydrazone and 2-(ß-d-galactopyranosylmethyl)-5-phenyl-2H-tetrazole revealed no significant inhibition of any of these lectins.

Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production.

Ruthenium complexes are developed as substitutes for platinum complexes to be used in the chemotherapy of hematological and gynecological malignancies, such as ovarian cancer. We synthesized and screened 14 ruthenium half-sandwich complexes with bidentate monosaccharide ligands in ovarian cancer cell models. Four complexes were cytostatic, but not cytotoxic on A2780 and ID8 cells. The IC50 values were in the low micromolar range (the best being 0.87 µM) and were similar to or lower than those of the clinically available platinum complexes. The active complexes were cytostatic in cell models of glioblastoma, breast cancer, and pancreatic adenocarcinoma, while they were not cytostatic on non-transformed human skin fibroblasts. The bioactive ruthenium complexes showed cooperative binding to yet unidentified cellular target(s), and their activity was dependent on reactive oxygen species production. Large hydrophobic protective groups on the hydroxyl groups of the sugar moiety were needed for biological activity. The cytostatic activity of the ruthenium complexes was dependent on reactive species production. Rucaparib, a PARP inhibitor, potentiated the effects of ruthenium complexes.

Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition.

The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg-1 and ∼43% at 60 mg kg-1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.

The architecture of hydrogen and sulfur σ-hole interactions explain differences in the inhibitory potency of C-ß-d-glucopyranosyl thiazoles, imidazoles and an N-ß-d glucopyranosyl tetrazole for human liver glycogen phosphorylase and offer new insights to structure-based design.

C-Glucopyranosyl imidazoles, thiazoles, and an N-glucopyranosyl tetrazole were assessed in vitro and ex vivo for their inhibitory efficiency against isoforms of glycogen phosphorylase (GP; a validated pharmacological target for the development of anti-hyperglycaemic agents). Imidazoles proved to be more potent inhibitors than the corresponding thiazoles or the tetrazole. The most potent derivative has a 2-naphthyl substituent, a Ki value of 3.2 µM for hepatic glycogen phosphorylase, displaying also 60% inhibition of GP activity in HepG2 cells, compared to control vehicle treated cells, at 100 µM. X-Ray crystallography studies of the protein - inhibitor complexes revealed the importance of the architecture of inhibitor associated hydrogen bonds or sulfur σ-hole bond interactions to Asn284 OD1, offering new insights to structure-based design efforts. Moreover, while the 2-glucopyranosyl-tetrazole seems to bind differently from the corresponding 1,2,3-triazole compound, the two inhibitors are equipotent.

Stereoselective Synthesis of Carbon-Sulfur-Bridged Glycomimetics by Photoinitiated Thiol-Ene Coupling Reactions.

Oligosaccharides and glycoconjugates are abundant in all living organisms, taking part in a multitude of biological processes. The application of natural O-glycosides in biological studies and drug development is limited by their sensitivity to enzymatic hydrolysis. This issue made it necessary to design hydrolytically stable carbohydrate mimetics, where sulfur, carbon, or longer interglycosidic connections comprising two or three atoms replace the glycosidic oxygen. However, the formation of the interglycosidic linkages between the sugar residues in high diastereoslectivity poses a major challenge. Here, we report on stereoselective synthesis of carbon-sulfur-bridged disaccharide mimetics by the free radical addition of carbohydrate thiols onto the exo-cyclic double bond of unsaturated sugars. A systematic study on UV-light initiated radical mediated hydrothiolation reactions of enoses bearing an exocyclic double bond at C1, C2, C3, C4, C5, and C6 positions of the pyranosyl ring with various sugar thiols was performed. The effect of temperature and structural variations of the alkenes and thiols on the efficacy and stereoselectivity of the reactions was systematically studied and optimized. The reactions proceeded with high efficacy and, in most cases, with complete diastereoselectivity producing a broad array of disaccharide mimetics coupling through an equatorially oriented methylensulfide bridge.

Synthesis of New Series of 2-C-(ß-D-glucopyranosyl)-Pyrimidines and Their Evaluation as Inhibitors of Some Glycoenzymes.

Despite the substantial interest in C-glycosyl heterocycles as mimetics of biologically active native glycans, the appearance of C-glycopyranosyl derivatives of six-membered heterocycles, both in synthetic and biological contexts, is rather scarce. As part of our ongoing research program aimed at preparing hitherto barely known 2-C-glycopyranosyl pyrimidines, the goal of the present study was to synthesize new 5-mono- and multiply substituted derivatives of this compound class. Thus, 2-C-(ß-D-glucopyranosyl)-5,6-disubstituted-pyrimidin-4(3H)-ones and 4-amino-2-C-(ß-D-glucopyranosyl)-5,6-disubstituted-pyrimidines were prepared by base-mediated cyclocondensations of O-perbenzylated and O-unprotected C-(ß-D-glucopyranosyl) formamidine hydrochlorides with methylenemalonic acid derivatives. The 2-C-(ß-D-glucopyranosyl)-5-substituted-pyrimidines were obtained from the same amidine precursors upon treatment with vinamidinium salts. The deprotected derivatives of these pyrimidines were tested as inhibitors of some glycoenzymes. None of them showed inhibitory activity towards glycogen phosphorylase and α- and ß-glucosidase enzymes, but some members of the sets exhibited moderate inhibition against bovine liver ß-galactosidase.

C-Glycopyranosyl Arenes and Hetarenes: Synthetic Methods and Bioactivity Focused on Antidiabetic Potential.

This Review summarizes close to 500 primary publications and surveys published since 2000 about the syntheses and diverse bioactivities of C-glycopyranosyl (het)arenes. A classification of the preparative routes to these synthetic targets according to methodologies and compound categories is provided. Several of these compounds, regardless of their natural or synthetic origin, display antidiabetic properties due to enzyme inhibition (glycogen phosphorylase, protein tyrosine phosphatase 1B) or by inhibiting renal sodium-dependent glucose cotransporter 2 (SGLT2). The latter class of synthetic inhibitors, very recently approved as antihyperglycemic drugs, opens new perspectives in the pharmacological treatment of type 2 diabetes. Various compounds with the C-glycopyranosyl (het)arene motif were subjected to biological studies displaying among others antioxidant, antiviral, antibiotic, antiadhesive, cytotoxic, and glycoenzyme inhibitory effects.

Probing the ß-pocket of the active site of human liver glycogen phosphorylase with 3-(C-ß-d-glucopyranosyl)-5-(4-substituted-phenyl)-1, 2, 4-triazole inhibitors.

Human liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a ß-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the ß-pocket. Recently, C-ß-d-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP. Here we probe the ß-pocket by studying the inhibitory effect of six different groups at the para position of 3-(ß-d-glucopyranosyl phenyl)-5-phenyl-, 1, 2, 4-triazoles in hlGP by kinetics and X-ray crystallography. The most bioactive compound was the one with an amine substituent to show a Ki value of 0.43 µM. Structural studies have revealed the physicochemical diversity of the ß-pocket providing information for future rational inhibitor design studies.

Synthesis of New C- and N-ß-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase.

The aim of the present study was to broaden the structure-activity relationships of C- and N-ß-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-ß-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated ß-d-glucopyranosyl ethynes and aryl azides. 1-ß-d-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-d-glucopyranosyl bromide. C-ß-d-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-ß-d-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-d-glucopyranosyl bromide to give N-ß-d-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-ß-d-glucopyranosyl-5-phenyltetrazole (IC50 600 µM). These studies extended the structure-activity relationships of ß-d-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety.

van der Waals interactions govern C-ß-d-glucopyranosyl triazoles' nM inhibitory potency in human liver glycogen phosphorylase.

3-(C-Glucopyranosyl)-5aryl-1,2,4-triazoles with an aryl moiety larger than phenyl have been shown to have strong inhibitory potency (Ki values in the range of upper nM) for human liver glycogen phosphorylase (hlGP), a pharmacologically relevant target for diabetes type 2. In this study we investigate in a comparative manner the inhibitory effect of the above triazoles and their respective imidazoles on hlGPa. Kinetic studies show that the imidazole derivatives are 6-8 times more potent than their corresponding triazoles. We also seek to answer how the type of the aryl moiety affects the potency in hlGPa, and by determination of the crystal structure of rmGPb in complex with the triazole derivatives the structural basis of their inhibitory efficacy is also elucidated. Our studies revealed that the van der Waals interactions between the aryl moiety and residues in a hydrophobic pocket within the active site are mainly responsible for the variations in the potency of these inhibitors.

Glucopyranosylidene-Spiro-Thiazolinones: Synthetic Studies and Determination of Absolute Configuration by TDDFT-ECD Calculations.

Reactions of O-peracylated C-(1-bromo-ß-d-glucopyranosyl)formamides with thioamides furnished the corresponding glucopyranosylidene-spiro-thiazolin-4-one. While O-debenzoylations under a variety of conditions resulted in decomposition, during O-deacetylations the addition of MeOH to the thiazolinone moiety was observed, and with EtOH and water similar adducts were isolated or detected. The structure and stereochemistry of the new compounds were established by means of NMR and electronic circular dichroism (ECD) data supported by time-dependent density functional theory ECD (TDDFT-ECD) calculations. TDDFT-ECD calculations could efficiently distinguish the proposed epimeric products having different absolute configuration in the spiro heterocyclic ring.

Decomposition of N-chloroglycine in alkaline aqueous solution: kinetics and mechanism.

The decomposition kinetics and mechanism of N-chloroglycine (MCG) was studied under very alkaline conditions ([OH(-)] = 0.01-0.10 M). The absorbance change is consistent with two consecutive first-order processes in the 220-350 nm wavelength range. The first reaction is linearly dependent on [OH(-)] and interpreted by the formation of a carbanion from MCG in an equilibrium step (KOH) and a subsequent loss of chloride ion from this intermediate: kobs1 = KOH k1 = (6.4 ± 0.1) × 10(-2) M(-1) s(-1), I = 1.0 M (NaClO4), and T = 25.0 °C. The second process is assigned to the first-order decomposition of N-oxalylglycine, which is also formed as an intermediate in this system: kobs2 = (1.2 ± 0.1) × 10(-3) s(-1). Systematic (1)H and (13)C NMR measurements were performed in order to identify and follow the concentration changes of the reactant, intermediate, and product. It is confirmed that the decomposition proceeds via the formation of glyoxylate ion and produces N-formylglycine as a final product. This compound is stable for an extended period of time but eventually hydrolyses into formate and glycinate ions. A detailed mechanism is postulated which resolves the controversies found in earlier literature results.