Exploring the Effect of Bioisosteric Replacement of Carboxamide by a Sulfonamide Moiety on N‐Glycosidic Torsions and Molecular Assembly: Synthesis and X‐ray Crystallographic Investigation of N‐(β‐D‐Glycosyl)sulfonamides as N‐Glycoprotein Linkage Region Analogues

N‐Glycoprotein linkage region constituents, 2‐acetamido‐2‐deoxy‐β‐D ‐glucopyranose (GlcNAc) and asparagine (Asn) are conserved among all the eukaryotes. To gain a better understanding for nature’s choice of GlcNAcβAsn as linkage region constituents and inter‐ and intramolecular carbohydrate–protein interactions, a detailed systemic structural study of the linkage region conformation is essential. Earlier crystallographic studies of several N‐(β‐glycopyranosyl)alkanamides showed that N‐glycosidic torsion, ?_N, is influenced to a larger extent by structural variation in the sugar part than that of the aglycon moiety. To explore the effect of the bioisosteric replacement of a carboxamide group by a sulfonamide moiety on the N‐glycosidic torsions as well as on molecular assembly, several glycosyl methanesulfonamides and glycosyl chloromethanesulfonamides were synthesized as analogues of the N‐glycoprotein linkage region, and crystal structures of seven of these compounds have been solved. A comparative analysis of this series of crystal structures as well as with those of the corresponding alkanamido derivatives revealed that N‐glycosidic torsion, ?_N, does not alter significantly. Methanesulfonamido and chloromethanesulfonamido derivatives of GlcNAc display a different aglycon conformation compared to other sulfonamido analogues. This may be due to the cumulative effect of the direct hydrogen bonding between N1 and O1′ and C? H???O interactions of the aglycon chain, revealing the uniqueness of the GlcNAc as the linkage sugar.     

Characterization of isomers of oleuropein aglycon in olive oils by rapid‐resolution liquid chromatography coupled to electrospray time‐of‐flight and ion trap tandem mass spectrometry

In this work, rapid‐resolution liquid chromatography (RRLC) coupled to electrospray ionization time‐of‐flight mass spectrometry (ESI‐TOF‐MS) and ion trap multiple mass spectrometry (IT‐MSⁿ) has been applied to separate and characterize eleven isomers of oleuropein aglycon in fourteen Spanish extra‐virgin olive oils. After the extra‐virgin olive oil sample had been dissolved in hexane and cleaned up by a diol‐bonded phase solid‐phase extraction (SPE) cartridge, the eluting extract was resolved in methanol and analyzed on an Angilent 1200 system with a 4.6 × 150 mm, 1.8 µm Zorbax Eclipse plus C18 column. Mass spectrometry was carried out on a Bruker Daltonics microTOF mass spectrometer and a Bruker Daltonics ion trap mass spectrometer. The characterization of isomers of oleuropein aglycon was based on accurate mass data and the isotope function of characteristic fragment ions in the studied compounds by TOF‐MS, and the fragment ions were further confirmed by IT‐MSⁿ. The fragmentation pathway of oleuropein aglycon was successfully elucidated and all possible transformations among isomers of oleuropein aglycon were suggested. Copyright © 2008 John Wiley & Sons, Ltd.     

In‐chain neutral hydrocarbon loss from crocin apocarotenoid ester glycosides and the crocetin aglycon (Crocus sativus L.) by ESI‐MSn (n = 2, 3)

The stigmas of Crocus sativus L. have been used as spice and colorant agent (i.e. saffron) for more than 4000 years. For an updated structural investigation of the aglycon present in the glycosylated crocetin apocarotenoids (i.e. crocins), seven representative derivatives ranging from one up to five glucosyl‐residues with a maximum number of three monosaccharides per glycosylation site (glucose, gentiobiose, gentiotriose and neapolitanose) were isolated and purified by high‐performance liquid chromatography. The compounds selected for further mass spectrometric investigation include glucosyl‐, bis‐glucosyl‐, gentiobiosyl‐, gentiobiosyl‐glucosyl‐, bis‐gentiobiosyl‐, gentiobiosyl‐gentiotriosyl‐ and gentiobiosyl‐neapolitanosyl‐crocetin. Electrospray ionization in combination with low‐energy collision‐induced dissociation/tandem mass spectrometry of sodiated crocin precursor ions utilizing either a 3D‐ion trap (MSⁿ, n = 2, 3) or a QqTOF instrument, with the latter providing accurate mass determination with an accuracy of ±1–3 ppm or better at a resolution of 10 000 (full width at half maximum), was used. Major fragmentation pathways included loss of either one or two carbohydrate substituents leading to the sodiated aglycon without interglycosidic bond cleavage during in MS²‐experiments. All sodiated precursor ions and major product ions were accompanied by a loss of 92 Da, which was elucidated as C₇H₈‐loss from the aglycon by skeletal rearrangement via an eight‐membered transition state as previously described for intact C₄₀‐carotenoids. Copyright © 2013 John Wiley & Sons, Ltd.     

3,4‐Di­hydro‐6‐methyl‐3‐β‐d‐ribo­furan­osyl‐4,5′‐cyclo‐9H‐imidazo[1,2‐a]­purin‐9‐one hydrate

In the title compound, C₁₃H₁₃N₅O₄·H₂O (4,5′‐cyclo­wyosine·H₂O), the cyclization forces a syn arrangement of the aglycon with respect to the sugar moiety. The ribo­furan­ose part of the mol­ecule displays a β‐d configuration with an envelope C1′‐endo pucker. The mol­ecules are arranged in columns along the short a axis and are linked to water mol­ecules through O—H?O and O—H?N hydrogen bonds.     

Donor‐Bound Glycosylation for Various Glycosyl Acceptors: Bidirectional Solid‐Phase Semisynthesis of Vancomycin and Its Derivatives

The glycosidation of a polymer‐supported glycosyl donor, N‐phenyltrifluoroacetimidate, with various glycosyl acceptors is reported. The application of the polymer‐supported N‐phenyltrifluoroacetimidate is demonstrated in the synthesis of vancomycin derivatives. 2‐O‐[2‐(azidomethyl)benzoyl]glycosyl imidate was attached to a polymer support at the 6‐position by a phenylsulfonate linked with a C13 alkyl spacer. Solid‐phase glycosidation with a vancomycin aglycon, selective deprotection of the 2‐(azidomethyl)benzoyl group, and glycosylation of the resulting 2‐hydroxy group with a vancosamine unit were performed. Nucleophilic cleavage from the polymer support with acetate, chloride, azido, and thioacetate ions provided vancomycin derivatives in pure form after simple purification. The semisynthesis of vancomycin was achieved by deprotection of the acetate derivative.     

Synthesis and Structure–Activity Relationship of Vicenistatin,a Cytotoxic 20‐Membered Macrolactam Glycoside

We have developed two syntheses of vicenistatin and its analogues. Our first‐generation strategy included the rapid and sequential assembly of the macrocyclic lactam by using an intermolecular Horner–Wadsworth–Emmons reaction between the C3–C13 fragment and the C1–C2, C14–C19 fragment, followed by an intramolecular Stille coupling reaction. The second‐generation strategy utilized a ring‐closing metathesis of a hexaene intermediate to generate the desired 20‐membered macrolactam. This second‐generation strategy made it possible to prepare synthetic analogues of vicenistatin, including the C20‐ and/or C23‐demethyl analogues. Evaluation of the cytotoxic effect of these analogues indicated the importance of the fixed conformation of aglycon for determining the biological activity of the vicenistatins.     

Synthesis of (±)‐Tetrapetalone A‐Me Aglycon

The first synthesis of (±)‐tetrapetalone A‐Me aglycon is described. Key bond‐forming reactions include Nazarov cyclization, a ring‐closing metathesis promoted with complete diastereoselectivity by a chiral molybdenum‐based complex, tandem conjugate reduction/intramolecular aldol cyclization, and oxidative dearomatization.     

Synthesis and properties of polyimides derived from 9,10‐dialkyloxy‐1,2,3,4,5,6,7,8‐octahydro‐2,3,6,7‐anthracenetetracarboxylic 2,3:6,7‐dianhydrides

A series of new polyimides containing alicyclic units and alkyloxy side chains were prepared from 9,10‐dialkyloxy‐1,2,3,4,5,6,7,8‐octahydro‐2,3,6,7‐anthracenetetracarboxylic 2,3:6,7‐dianhydrides and various aromatic diamines. Their physical properties and structures were investigated. Polymers were obtained with inherent viscosities of 0.24–0.53 dL/g. In comparison with the aromatic polyimides, most polymers were readily soluble in common organic solvent such as N‐methylpyrrolidone and m‐cresol. These polymers had glass‐transition temperatures between 111 and 296 °C depending on the structure of the repeating unit and 10% weight‐loss temperatures of 418–477 °C in nitrogen. Wide‐angle X‐ray diffractometry for as‐polymerized samples revealed very low crystallinity and layered structures, which were better developed in the polymers with longer side chains. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1764–1774, 2002     

Deactivation reactions in the modeled 2,2,6,6‐tetramethyl‐1‐piperidinyloxy‐mediated free‐radical polymerization of styrene: A comparative study with the 2,2,6,6‐tetramethyl‐1‐piperidinyloxy/acrylonitrile system

The competitiveness of the combination and disproportionation reactions between a 1‐phenylpropyl radical, standing for a growing polystyryl macroradical, and a 2,2,6,6‐tetramethyl‐1‐piperidinyloxy (TEMPO) radical in the nitroxide‐mediated free‐radical polymerization of styrene was quantitatively evaluated by the study of the transition geometry and the potential energy profiles for the competing reactions with the use of quantum‐mechanical calculations at the density functional theory (DFT) UB3‐LYP/6‐311+G(3df, 2p)//(unrestricted) Austin Model 1 level of theory. The search for transition geometries resulted in six and two transition structures for the radical combination and disproportionation reactions, respectively. The former transition structures, mainly differing in the out‐of‐plane angle of the N? O bond in the transition structure TEMPO molecule, were correlated with the activation energy, which was determined to be in the range of 8.4–19.4 kcal mol^?1 from a single‐point calculation at the DFT UB3‐LYP/6‐311+G(3df, 2p)//unrestricted Austin Model 1 level. The calculated activation energy for the disproportionation reaction was less favorable by a value of more than 30 kcal mol^?1 in comparison with that for the combination reaction. The approximate barrier difference for the TEMPO addition and disproportionation reaction was slightly smaller for the styrene polymerization system than for the acrylonitrile polymerization system, thus indicating that a β‐proton abstraction through a TEMPO radical from the polymer backbone could diminish control over the radical polymerization of styrene with the nitroxide even more than in the latter system. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 232–241, 2007     

β‐Selective C‐Glycosylation and its Application in the Synthesis of Scleropentaside A

C‐Glycosides are carbohydrates that bear a C?C bond to an aglycon at the anomeric center. Due to their high stability towards chemical and enzymatic hydrolysis, these compounds are widely used as carbohydrate mimics in drug development. Herein, we report a general and exclusively β‐selective method for the synthesis of a naturally abundant acyl‐C‐glycosidic structural motif first found in the scleropentaside natural product family. A Corey–Seebach umpolung reaction as the key step in the synthesis of scleropentaside A and analogues enables the β‐selective construction of the anomeric C?C bond starting from unprotected carbohydrates in only four steps. The one‐pot approach is highly atom‐efficient and avoids the use of toxic heavy metals.     

Probing the Conformational Changes in the Enzymatic Hydrolysis of 2‐Acetamido‐2‐deoxy‐β‐D‐glucopyranosides

The isoquinuclidines 7 and 8 were synthesised and tested as inhibitors of hexosaminidases from jack beans and from bovine kidney. These isoquinuclidines mimick the ^1,4B‐conformer of a N‐acetyl‐glucosamine‐derived β‐d‐ glucopyranoside; they are competitive inhibitors with K_i values from 0.014 to 0.30 μM . The strong inhibition of these enzymes agrees with the hypothesis that the enzymatic hydrolysis of 2‐acetamido‐2‐deoxy‐β‐d‐ glucopyranosides proceeds via a boat‐like conformer with a pseudo‐axial scissile glycosidic bond and a pseudo‐axial acetamido substituent optimally oriented to effect an intramolecular substitution of the aglycon.     

A density functional theory study on diazotization and nitration of 3,5‐diamino‐1,2,4‐triazole

The reaction mechanism, thermodynamic and kinetic properties for diazotization and nitration of 3,5‐diamino‐1,2,4‐triazole were studied by a density functional theory. The geometries of the reactants, transition states, and intermediates were optimized at the B3LYP/6‐31G (d, p) level. Vibrational analysis was carried out to confirm the transition state structures, and the intrinsic reaction coordinate (IRC) method was used to explore the minimum energy path. The single‐point energies of all stagnation points were further calculated at the B3LYP (MP2)/6‐311+G (2d, p) level. The statistical thermodynamic method and Eyring transition state theory with Wigner correction were used to study the thermodynamic and kinetic characters of all reactions within 0–25°C. Two reaction channels are computed, including the diazotization and nitration of 3‐NH₂ or 5‐NH₂, and there are six steps in each channel. The reaction rate in each step is increased with temperature. The last step in each channel is the slowest step. The first, second, and fifth steps are exothermic reactions, and are favored at lower temperature in the thermodynamics. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors in Efficient Synthesis of Neu5Ac‐α‐2,3‐LacNPhth Trisaccharide

A concise approach to a Neu5Ac‐α‐2,3‐LacNPhth trisaccharide derivative was developed. First, the regio/stereoselective glycosylation between glycoside donors and glucoNPhth diol acceptors was investigated. It was found that the regioselectivity depends not only on the steric hindrance of the C2‐NPhth group and the C6‐OH protecting group of the glucosamine acceptors, but also on the leaving group and protecting group of the glycoside donors. Under optimized conditions, LacNPhth derivatives were synthesized in up to 92 % yield through a regio/stereoselective glycosylation between peracetylated‐α‐galactopyranosyl trichloroacetimidate and p‐methoxyphenyl 6‐O‐tert‐butyldiphenylsilyl‐2‐deoxy‐2‐phthalimido‐β‐d ‐glucopyranoside, avoiding the formation of glycosylated orthoesters and anomeric aglycon transfer. Then, the LacNPhth derivative was deacylated and then protected on the primary position by TBDPS to form a LacNPhth polyol acceptor. Finally, the Neu5Ac‐α‐2,3‐LacNPhth derivative was synthesized in 48 % yield through the regio/stereoselective glycosylation between the LacNPhth polyol acceptor and a sialyl phosphite donor. Starting from d ‐glucosamine hydrochloride, the target Neu5Ac‐α‐2,3‐LacNPhth derivative was synthesized in a total yield of 18.5 % over only 10 steps.     

Mode‐tracking based stationary‐point optimization

In this work, we present a transition‐state optimization protocol based on the Mode‐Tracking algorithm [Reiher and Neugebauer, J. Chem. Phys., 2003, 118, 1634]. By calculating only the eigenvector of interest instead of diagonalizing the full Hessian matrix and performing an eigenvector following search based on the selectively calculated vector, we can efficiently optimize transition‐state structures. The initial guess structures and eigenvectors are either chosen from a linear interpolation between the reactant and product structures, from a nudged‐elastic band search, from a constrained‐optimization scan, or from the minimum‐energy structures. Alternatively, initial guess vectors based on chemical intuition may be defined. We then iteratively refine the selected vectors by the Davidson subspace iteration technique. This procedure accelerates finding transition states for large molecules of a few hundred atoms. It is also beneficial in cases where the starting structure is very different from the transition‐state structure or where the desired vector to follow is not the one with lowest eigenvalue. Explorative studies of reaction pathways are feasible by following manually constructed molecular distortions. © 2015 Wiley Periodicals, Inc.     

Transition‐metal‐catalyzed Chelation‐assisted C–H Functionalization of Aromatic Substrates

In the past decade, transition‐metal‐catalyzed C–H activations have been very popular in the research field of organometallic chemistry, and have been considered as efficient and convenient strategies to afford complex natural products, functional advanced materials, fluorescent compounds, and pharmaceutical compounds. In this account, we begin with a brief introduction to the development of transition‐metal‐catalyzed C–H activation, especially the development of transition‐metal‐catalyzed chelation‐assisted C–H activation. Then, a more detailed discussion is directed towards our recent studies on the transition‐metal‐catalyzed chelation‐assisted oxidative C–H/C–H functionalization of aromatic substrates bearing directing functional groups.     

Reactions of 1‐amino‐5‐benzoyl‐4‐phenyl‐1H‐pyrimidine‐2‐one with carboxylic anhydrides: Experimental data and AM1 calculations

1‐Amino‐5‐benzoyl‐4‐phenyl‐1H‐pyrimidine‐2‐one 1 reacts with several carboxylic anhydrides 2a‐d under different conditions and gives new amide and imide derivatives. The structure of these compounds, 3a‐d , are determined by spectroscopic methods. Electronic and geometric structures of reactants, transition states, intermediates and final products of the reaction are calculated by the AM1 method. Transition states are further confirmed by vibrational analysis (computation of force constants analytically) and characterized by the corresponding imaginary vibration modes and frequencies.     

Theoretical studies on the structures and isomerization of methylene lithium‐chlorosilylenoid H2CSiLiCl

The methylene lithium‐chlorosilylenoid H₂C?SiLiCl was studied with ab initio calculations at the G2(MP2) level. Its four equilibrium structures, p‐complex, three‐membered ring, σ complex and silene, and three isomerization transition states were located. The calculations show that the nonplanar p‐complex structure is the lowest in energy among four equilibrium structures of H₂C?SiLiCl and should be experimentally detectable. The silene and σ complex structures with high energies are unstable and easy to isomerize to the most stable p‐complex structure via three‐membered ring one. Also, the geometric characteristics and bonding properties of various structures were analyzed and discussed. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002     

Gold‐Catalyzed Formal C−C Bond Insertion Reaction of 2‐Aryl‐2‐diazoesters with 1,3‐Diketones

The transition‐metal‐catalyzed formal C−C bond insertion reaction of diazo compounds with monocarbonyl compounds is well established, but the related reaction of 1,3‐diketones instead gives C−H bond insertion products. Herein, we report a protocol for a gold‐catalyzed formal C−C bond insertion reaction of 2‐aryl‐2‐diazoesters with 1,3‐diketones, which provides efficient access to polycarbonyl compounds with an all‐carbon quaternary center. The aryl ester moiety plays a crucial role in the unusual chemoselectivity, and the addition of a Brønsted acid to the reaction mixture improves the yield of the C−C bond insertion product. A reaction mechanism involving cyclopropanation of a gold carbenoid with an enolate and ring‐opening of the resulting donor–acceptor‐type cyclopropane intermediate is proposed. This mechanism differs from that of the traditional Lewis‐acid‐catalyzed C−C bond insertion reaction of diazo compounds with monocarbonyl compounds, which involves a rearrangement of a zwitterion intermediate as a key step.     

The Role of Weak Interactions in the Mechano‐induced Single‐Crystal‐to‐Single‐Crystal Phase Transition of 8‐Hydroxyquinoline‐Based Co‐crystals

Mechano‐induced single‐crystal‐to‐single‐crystal (SCSC) phase transitions in crystalline materials that change their properties have received more and more attention. However, there are still too few examples to study molecular‐level mechanisms in the mechano‐induced SCSC phase transitions, making the systematic and in‐depth understanding very difficult. We report that bis‐(8‐hydroxyquinolinato) palladium(II)‐tetracyanoquinodimethane (PdQ₂‐TCNQ) and bis‐(8‐hydroxyquinolinato) copper(II)‐tetracyanoquinodimethane (CuQ₂‐TCNQ) show very different mechano‐response behaviors during the SCSC phase transition. Phase transition in CuQ₂‐TCNQ can be triggered by pricking on the crystal surface, while in PdQ₂‐TCNQ it can only be induced by applying pressure uniformly over the whole crystal face. The crystallography data and Hirshfeld surface analysis indicate that the weak intra‐layer C?H???O, C?H???N hydrogen bonds and inter‐layer stacking interactions determine the feasibility of the SCSC phase transition by mechanical stimuli. Weaker intra‐layer interactions and looser inter‐layer stacking make the SCSC phase transition occur much more easily in the CuQ₂‐TCNQ.     

Synthesis of photosensitive and thermosetting poly(phenylene ether) based on poly[2,6‐di(3‐methyl‐2‐butenyl)phenol‐co‐2,6‐dimethyl‐phenol] and a photoacid generator

A chemically amplified photosensitive and thermosetting polymer based on poly[2,6‐di(3‐methyl‐2‐butenyl)phenol (15 mol %)‐co‐2,6‐dimethylphenol (85 mol %)] ( 3c ) and a photoacid generator [(5‐propylsulfonyloxyimino‐5H‐thiophen‐2‐ylidene)‐(2‐methylphenyl)acetonitrile] was developed. Poly[2,6‐bis(3‐methyl‐2‐butenyl)phenol]‐co‐2,6‐dimethylphenol)] ( 3 ) with high molecular weights (number‐average molecular weight ～ 24,000) was prepared by the oxidative coupling copolymerization of 2,6‐di(3‐methyl‐2‐butenyl)phenol with 2,6‐dimethylphenol in the presence of copper(I) chloride and pyridine as the catalyst under a stream of oxygen. The structures of 3 were characterized with IR, ¹H NMR, and ¹³C NMR spectroscopy. 3 was crosslinked by a thermal treatment at 300 °C for 1 h under N₂. The 5% weight loss temperatures and glass‐transition temperatures of the cured copolymers reached around 420 °C in nitrogen and 300 °C, respectively. The average refractive index of the cured copolymer ( 3c ) film was 1.5452, from which the dielectric constant at 1 MHz was estimated to be 2.6. The resist showed a sensitivity of 35 mJ cm^?2 and a contrast of 1.6 when it was exposed to 436‐nm light, postexposure‐baked at 145 °C for 5 min, and developed with toluene at 25 °C. A fine negative image featuring 8‐μm line‐and‐space patterns was obtained on a film exposed to 100 mJ cm^?2 with 436‐nm light in the contact‐printed mode. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 149–156, 2005