General synthesis of sugar-pendant 1,3-propanediamines containing a C-glycoside linkage

A straightforward route to C-glycoside linked sugar-pendant 1,3-propanediamines is described. The three-step preparation procedure involves (1) C-glycosylation of an OH-protected α-glycosyl halide with malononitrile, (2) catalytic hydrogenation of the nitriles to amines, and (3) deprotection of acetyl groups via acid-catalyzed hydrolysis. In the case of the galactose derivative, excess sodiomalononitrile promotes the second addition of a carbanion in the first step. The β-anomeric configuration was confirmed by X-ray crystallography of the glycosylated intermediates. This method demonstrates a general method to access a new class of carbohydrate-pendant C-glycoside chelators.     

Synthesis and evaluation of C-glycosides as hydrotropes and solubilizing agents

This work presents expeditious synthesis of C-glycoside amphiphiles in aqueous media from unprotected di- or mono-saccharides. A Horner-Wadsworth-Emmons/Michael addition/Barbier allylation sequence led to C-glycosides that exhibit hydrotropic properties. The hydrotropic and solubilizing properties of these homoallylic alcohols including a β-C-glycoside moiety as well as additional β-C-glycosidic ketones with a short (C₇) alkyl chain are also described and compared with those of commercial O-glucoside references.     

The conformational behaviour of α,β-trehalose-like disaccharides and their C-glycosyl,imino-C-glycosyl and carbagalactose analogues depends on the chemical nature of the modification: an NMR investigation

The conformational behaviour of β-O-Gal-(1→1)-α-Man 4 and the C-glycoside, carbaglycoside and aza-C-glycoside mimics 1–3 has been studied using J/NOE NMR data, molecular mechanics and molecular dynamics. It is shown that the population distributions around the glycosidic linkages of the different analogues depend on the chemical nature of the acetal or pseudoacetal residue.     

New reactivities of deltaline analogs: an efficient O-demethylation at C-1 and an unusual extrusion of the C-14 atom

O-Demethylation at C-1 in the C₁₉-diterpenoid alkaloids is very challenging. In this paper, it was firstly observed that 10-OH group in deltaline (1) is a determining factor for the O-demethylation reaction. After removal of this hydroxyl group, 1-O-methyl group in the corresponding deltaline analogs can be readily removed by treatment with HBr–HOAc. Meanwhile, the C-14 atom in bromides 18 or 20 can be extruded under basic condition probably via a sequence, including Grob fragmentation, aerobic oxidation, deformylation, and S_N2 nucleophilic substitution, to give enone 21 (70%) and oxetane 22 (14%). The structure of compound 22 was confirmed by X-ray crystallographic analysis of its derivative 21.     

Crystal structure and conformation of N,N′-bis (3,5-dichlorosalicylidene)-2-hydroxy 1,3 diamino-2-propan

N,N′-bis(3,5-dichlorosalicylidene)-2-hydroxy-1,3-diamino-2-propan (C₁₇H₁₄Cl₄N₂O₃) was synthesized and its crystal structure determined. It crystallizes in the monoclinic space group, C2/c, with a=29.734(8), b=4.541(1), c=14.694(2) Å, β=115.85(2), R(F²)=0.048 for 1704 independent reflections. The title compound has a twofold axis passing through the central C9 atom. The intramolecular hydrogen bond occurs between the pairs of atoms N1 and O1 [2.648(5) Å] and the hydrogen atom is essentially being bonded to the nitrogen atom. There is no intermolecular proximity between molecules. Conformations of the title compound were investigated by semi-empirical quantum mechanical AM1 calculations. The optimized geometry of the molecular structure corresponding to the non-planar conformation is the most stable conformation in the theoretical calculations. The results strongly indicate that the minimum energy conformation is primarily determined by non-bonded steric interactions.     

Concise total synthesis of flavone C-glycoside having potent anti-inflammatory activity

The total synthesis of anti-inflammatory active flavone C-glycoside isolated from oolong tea extract is achieved. Introducing a C-glucosyl moiety to an aryl system and constructing a fused tetracyclic ring characteristic to this natural product were conducted based on the O-to-C rearrangement of sugar moiety and the successive intramolecular Mitsunobu reaction, respectively. This concise and efficient synthetic pathway is applicable to the large-scale synthesis of target flavone and for constructing a large library of related compounds.     

Synthesis of (+)-laurencin via ring expansion of a C-glycoside derivative

Laurencin was efficiently synthesized from a C-glycoside derivative based on ring expansion of the oxane part of the starting compound into an eight-membered cyclic ether via a ring-cleavage/ring-closing olefin metathesis process, stereoselective introduction of a bromo group at C4, and convergent construction of the side-chain part using a lithiated enyne unit.     

Synthesis of thio-C-glycosides from 2′-carbonylalkyl C-glycosides by a tandem β-elimination and intramolecular hetero-Michael addition

2′-Carbonyl 5-S-acetyl-C-glycofuranosides and 2′-carbonyl 4-S-acetyl-C-glycopyranosides were converted in good yields to respective 5-thio-C-glycopyranosides and 4-thio-C-glycofuranosides under base treatment. The transformation was resulted from β-elimination on 2′-carbonyl C-glycoside to form α,β-conjugated aldehyde (or ketone) and following intramolecular hetero-Michael addition by the thiol group.     

A concise synthesis of (3S,4S,5R)-1-(α-d-galactopyranosyl)-3-tetracosanoylamino-4,5-decanediol, a C-glycoside analogue of immunomodulating α-galactosylceramide OCH

A concise and convergent synthesis of the C-glycoside analogue 2b of immunomodulating α-galactosylceramide OCH 1b starting from readily available 2,3,4,6-tetra-O-benzyl-d-galactose 3 and l-arabinose 6 is described. The synthesis features the nucleophilic addition of an α-ethynyl sugar 5 to the phytosphingosine-precursor aldehyde 9 and would be applicable to a variety of C-glycoside analogues of interest.     

Structure and synthesis of a derivative of fasciculiferin,a novel peltogynoid from Acacia fasciculifera

The structure and synthesis of the 5-O-ethyl-2,3,10-tril-O-methyl derivative of fasciculiferin (5-hydroxypeltogynin) a natural peltogynoid which exhibits an intermediate oxidation state of the C-5 methylene function in the D-ring are described.     

Protonation Sites in Gaseous Pyrrole and Imidazole: A Neutralization–Reionization and ab initio Study

Mild gas-phase acids C₄H₉⁺ and NH₄⁺ protonate pyrrole at C-2 and C-3 but not at the nitrogen atom, as determined by deuterium labeling and neutralization–reionization mass spectrometry. Proton affinities in pyrrole are calculated by MP2/6–311G(2d, p) as 866, 845 and 786 kJ mol^-1 for protonation at C-2, C-3 and N, respectively. Vertical neutralization of protonated pyrrole generates bound radicals that in part dissociate by loss of hydrogen atoms. Unimolecular loss of hydrogen atom from C-2-and C-3-protonated pyrrole cations is preceded by proton migration in the ring. Protonation of gaseous imidazole is predicted to occur exclusively at the N-3 imine nitrogen to yield a stable aromatic cation. Proton affinities in imidazole are calculated as 941, 804, 791, 791 and 724 for the N-3, C-4, C-2, C-5 and N-1 positions, respectively. Radicals derived from protonated imidazole are only weakly bound. Vertical neutralization of N-3-protonated imidazole is accompanied by large Franck–Condon effects which deposit on average 183 kJ mol^-1 vibrational energy in the radicals formed. The radicals dissociate unimolecularly by loss of hydrogen atom, which involves both direct N-H bond cleavage and isomerization to the more stable C-2 H-isomer. Potential energy barriers to isomerizations and dissociations in protonated pyrrole and imidazole isomers and their radicals were investigated by ab initio calculations.     

Studies Toward the Syntheses of Pluramycin Natural Products. The First Total Synthesis of Isokidamycin

We report the first total synthesis of the complex C-aryl glycoside isokidamycin, the epimer of the naturally-occurring pluramycin antibiotic kidamycin. The synthesis features a highly efficient Diels-Alder reaction between a substituted naphthyne and a glycosylated furan to form the anthracene core bearing a pendent angolosamine C-glycoside. The regiochemical outcome of the Diels-Alder reaction was controlled by employing a disposable silicon tether to link the reactive naphthyne and the glycosyl furan, rendering the cycloaddition intramolecular. The benzopyranone moiety of the aromatic nucleus was appended by cyclization of a functionalized vinylogous amide onto an advanced anthrol intermediate. The vancosamine amino glycoside was introduced by an O→C-glycoside rearrangement that produced the β-anomer. Subsequent refunctionalizations then led to isokidamycin.     

Synthesis of pyrimidine-containing 3-aminobutenolides

An efficient synthesis of pyrimidine-containing butenolides is reported, starting from C-alkoxycarbonyl isoxazolidines. Two competitive reaction routes are operating: the pathway leading to homo-N,O-nucleosides, based on the reduction of an ester group at C₃, and the reaction channel leading to butenolides promoted by the removal of the hydrogen atom at C₃. The two reaction pathways can be easily controlled according to the adopted experimental conditions     

The first bis(orotato–N,O) complex: Synthesis,crystal structure,spectroscopic and thermal characterization of (chaH)2[Cu(HOr–N,O)2(cha)] · 2H2O (cha = cyclohexylamine and HOr = orotate(2−))

The novel bis(cyclohexylaminium) cyclohexylaminebis(orotate–N,O)cuprate(II) dihydrate, (C₆H₁₅N)₂[Cu(C₅H₂N₂O₄)₂(C₆H₁₄N)] · 2H₂O, has been prepared and characterized by elemental analysis, magnetic measurements, FT-IR and UV–Vis spectroscopy, thermal analysis and X-ray diffraction. The Cu(II) complex crystallizes in the monoclinic space group P2₁/c. The copper atom in the five-coordinated (chaH)₂[Cu(HOr–N,O)₂(cha)] · 2H₂O is chelated by a deprotonated pyrimidine nitrogen atom and carboxylate oxygen atom as a bis(bidentate) ligand and the cyclohexylamine ligand completes the square-pyramidal coordination. The thermal decomposition of the complex has been predicted by the help of thermal analysis (TG, DTG and DTA).     

Hydrogen migrations in mass spectrometry. II—single and double hydrogen migrations in the electron impact fragmentation of n-propyl benzoate

The sources of the migrant hydrogen atom(s) in reactions (a) and (b) in the electron impact mass spectrum of n-propyl benzoate have been investigated: (a) [C₆H₅CO₂C₃H₇]⁺ →[C₆H₅CO₂H]⁺ + C₃H₆; (b) [C₆H₅CO₂C₃H₇]⁺ → [C₆H₅CO₂H₂]⁺ + C₃H₅^sdot;. Deuterium labelling of the propyl group showed that, for reaction (a) at 70 eV ionizing energy 3 ± 1% of the hydrogen originates from C-1 of the propyl group, 86 ± 4% from C-2 and 11 ± 3% from C-3. The specificity of the transfer from C-2 increases as the internal energy of the fragmenting ions decreases, indicating that the results cannot be rationalized in terms of H/D interchanges between positions in the propyl group, but rather that the reaction involves specific, competing, H transfer reactions from each propyl position, in contrast to the high site specificity characteristic of the McLafferty rearrangement. Reaction (b) involves, almost exclusively, transfer of one hydrogen from C-2 and one from C-3 with only very minor participation of C-1 hydrogens. The [C₆H₅COOH]⁺ ion produced in reaction (a) fragments further to [C₆H₅CO]⁺ + OH. and the labelling results indicate some interchange of the carboxylic hydrogen with (ortho) ring hydrogens for those ions fragmenting in the first drift region. The extent of interchange is less than that observed for fragmentation of the same ion produced by direct ionization of benzoic acid or by reaction (a) in ethyl benzoate.     

Synthesis of 3-deoxy-d-manno-2-octulosonic acid (Kdo) and d-glycero-d-talo-2-octulosonic acid (Ko) and their α-glycosides

Reaction of 2,3:5,6-di-O-isopropylidene-d-mannofuranose 1 with C-2 lithio derivatives of glyoxylate mercaptal in the presence of MgBr₂ afforded d-glycero-d-galacto-2-octulosonates 2 and 3, respectively. Their 3-O-deoxygenation led to Kdo. N-Iodosuccinimide treatment of 3 gave thioglycoside 11 directly, which was transformed into Ko derivative 12 via epimerisation of the 3-hydroxy group. 3-O-Benzoylation of 12 and then transformation into phosphite furnished 15, an efficient glycosyl donor. Reaction of 15 with 6-O-unprotected glucosamine derivative 22 as acceptor gave α-glycoside 23, which was successfully transformed either into Kdo-disaccharide 27 or into Ko-disaccharide 29.     

Four cocrystals of thymine with phenolic coformers: influence of the coformer on hydrogen bonding

Cocrystals are molecular solids composed of at least two types of neutral chemical species held together by noncovalent forces. Crystallization of thymine [systematic name: 5‐methylpyrimidine‐2,4(1H,3H)‐dione] with four phenolic coformers resulted in cocrystal formation, viz. catechol (benzene‐1,2‐diol) giving thymine–catechol (1/1), C₅H₆N₂O₂·C₆H₆O₂, (I), resorcinol (benzene‐1,3‐diol) giving thymine–resorcinol (2/1), 2C₅H₆N₂O₂·C₆H₆O₂, (II), hydroquinone (benzene‐1,4‐diol) giving thymine–hydroquinone (2/1), 2C₅H₆N₂O₂·C₆H₆O₂, (III), and pyrogallol (benzene‐1,2,3‐triol) giving thymine–pyrogallol (1/2), C₅H₆N₂O₂·2C₆H₆O₃, (IV). The resorcinol molecule in (II) occupies a twofold axis, while the hydroquinone molecule in (III) is situated on a centre of inversion. Thymine–thymine base pairing is common across all four structures, albeit with different patterns. In (I)–(III), the base pair is propagated into an infinite one‐dimensional ribbon, whereas it exists as a discrete dimeric unit in (IV). In (I)–(III), the two donor N atoms and one carbonyl acceptor O atom of thymine are involved in thymine–thymine base pairing and the remaining carbonyl O atom is hydrogen bonded to the coformer. In contrast, in (IV), just one donor N atom and one acceptor O atom are involved in base pairing, and the remaining donor N atom and acceptor O atom of thymine form hydrogen bonds to the coformer molecules. Thus, the utilization of the donor and acceptor atoms of thymine in the hydrogen bonding is influenced by the coformers.     

Towards cyclic,conformationally constrained,fluorine-containing β-amino acid derivatives from d-glucose

Novel, potentially bioactive, fluorinated branched-chain monosaccharides were obtained by reaction of diethylaminosulphur trifluoride (DAST) with a series of methyl 3-C-cyano-3-ethoxycarbonyl-β-d-glucopyranoside derivatives, including the 4,6-O-benzylidene derivative and their 3-C-(N-protected aminomethyl) reduction products, as well as the phenyl 3-C-cyano-3-ethoxycarbonyl-1-thio-α-d-(and β-d-)glucopyranosides. The absolute configuration at C(3) was unambiguously assigned for all compounds on the basis of X-ray crystallographic analysis of methyl 4,6-O-benzylidene-3-C-cyano-3-deoxy-3-ethoxycarbonyl-β-d-glucopyranoside, corroborating the previous tentative assignment by other authors for the 4,6-unprotected compound. The course of the fluorination depended on the reaction temperature and the substitution pattern of the substrate. Thus, for methyl 3-C-cyano-3-ethoxycarbonyl-β-d-glucopyranoside, fluorination occurred exclusively at C(6), but for the phenylthio analogue, a 2-deoxy-2-phenylthio-α-d-manno-configured glycosyl fluoride and its 6-fluoro derivative were obtained, resulting from the expected rearrangement reaction, whilst starting from the phenylthio α anomer, only the unrearranged 6-fluoro compound was formed. Rearrangement was also observed in the fluorination of methyl 4,6-O-benzylidene-3-C-(N-protected aminomethyl)-β-d-glucopyranoside, which led to the 2-O-methyl-α-d-mannopyranosyl fluoride derivative as the sole product. This methodology may constitute a simple route to enantiopure conformationally constrained cyclic fluorinated β-amino acids having the α carbon atom shared with a pyranose ring, although only moderate yields were achieved, particularly in the fluorination step.     

Cocrystals of the antibiotic trimethoprim with glutarimide and 3,3‐dimethylglutarimide held together by three hydrogen bonds

The antibiotic trimethoprim [5‐(3,4,5‐trimethoxybenzyl)pyrimidine‐2,4‐diamine] was cocrystallized with glutarimide (piperidine‐2,6‐dione) and its 3,3‐dimethyl derivative (4,4‐dimethylpiperidine‐2,6‐dione). The cocrystals, viz. trimethoprim–glutarimide (1/1), C₁₄H₁₈N₄O₃·C₅H₇NO₂, (I), and trimethoprim–3,3‐dimethylglutarimide (1/1), C₁₄H₁₈N₄O₃·C₇H₁₁NO₂, (II), are held together by three neighbouring hydrogen bonds (one central N—H...N and two N—H...O) between the pyrimidine ring of trimethoprim and the imide group of glutarimide, with an ADA/DAD pattern (A = acceptor and D = donor). These heterodimers resemble two known cocrystals of trimethoprim with barbituric acid and its 5,5‐diethyl derivative. Trimethoprim shows a conformation in which the planes of the pyrimidine and benzene rings are approximately perpendicular to one another. In its glutarimide coformer, five of the six ring atoms lie in a common plane; the C atom opposite the N atom deviates by about 0.6 Å. The crystal packing of each of the two cocrystals is characterized by an extended network of hydrogen bonds and contains centrosymmetrically related trimethoprim homodimers formed by a pair of N—H...N hydrogen bonds. This structural motif occurs in five of the nine published crystal structures in which neutral trimethoprim is present.     

A general and efficient route to 3′-deoxy-3′-N-, S-, and C-substituted altropyranosyl thymines from 2′,3′-O-anhydro-mannopyranosylthymine

An efficient route to 1-(2,3-O-anhydro-4,6-O-phenylmethylene-β-d-mannopyranosyl) thymine from 1,2,4,6-tetra-O-acetyl-3-O-tosyl-β-d-glucopyranose has been devised. This newly synthesized epoxide is opened up regioselectively at the C-3′-position by N-, S-, and C-nucleophiles to afford a wide range of new 3′-deoxy-3′-substituted altropyranosyl thymines.