Glycosyl α-amino acids : Part III. Synthesis of D- and L-2-(1,2:5,6-DI-O-isopropylidene-α-D-galactofuranos-3-YL)glycine

Stereospecific hydroxylation of (E)-3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-(methoxycarbonylmethylene)-α-D-xylo-hexofuranose (2) with potassium permanganate in pyridine afforded pure 3-C-[(R)-hydroxy(methoxycarbonyl)methyl]-1,2:5,6-di-O-isopropylidene-α-D-galactofuranose (5) in 55% yield. Mesylation of the diol 5 in pyridine yielded the monomethanesulfonate 6 and, in addition, a small proportion of an unsaturated, exocyclic sulfonate 7. Treatment of 6 with sodium azide in N-N-dimethylformamide and reduction of the resultant α-azido ester 9 afforded methyl D- (and L-) 2-(1,2:5,6-di-O-isopropylidene-α-D-galactofuranos-3-yl)glycinate, (11a) and (10a), respectively. Basic hydrolysis of 11a and 10a yielded D- and L-2-(1,2:5,6-di-O-isopropylidene-α-D-galactofuranos-3-yl)glycine (11b) and (10b), respectively. The structures of the glycosyl α-amino acids were correlated with that of L-alanine by circular dichroism.     

Branched-chain glycosyl α-amino acids : Part II. Synthesis of 2-D- and 2-L-(3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-glucofuranos-3-yl)glycine. Analogs of the sugar moiety of the polyoxins

Stereospecific hydroxylation of 3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-trans-and 3-C-cis-(methoxycarbonylmethylene)-α-D-ribo-hexofuranose (2 and 3, respectively), with potassium permanganate in pyridine afforded 3-C-[S- and R-hydroxy-(methoxycarbonyl)methyl]-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, (6 and 7, respectively), in a combined yield, after chromatography, of 43%. Selective formation of monomethanesulfonates (9a and 10a) and p-toluenesulfonates (9b and 10b), followed by treatment with sodium azide and reduction of the azide, afforded the methyl 2-D-(and 2-L-)(3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-glucofuranos-3-yl)-glycinates (12a and 13a, respectively). Basic hydrolysis of the latter compounds yielded 2-D- and 2-L-(3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-glucofuranos-3-yl)glycine (12b and 13b, respectively). The structures of the glycosyl amino acids were correlated with that of L-alanine by circular dichroism.     

Synthesis,crystal structure,and conformation of 1(S)-acetoxy-3-[6(R)-O-benzyl-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl]-1-(methyl 2,3,4-tri-O-benzyl-6-deoxy-β-d-galactopyranosid-6-yl)propyne

Condensation of 6-O-benzyl-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-d-glycero-α-d-galacto-oct-7-ynopyranose with methyl 2,3,4-tri-O-benzyl-6-deoxy-β-d-galacto-heptodialdo-1,5-pyranoside afforded a 2:1 mixture of the 1S and 1R isomers (1a and 1b) of 3-[6(R)-O-benzyl-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl]-1-hydroxy-1-(methyl 2,3,4-tri-O-benzyl-6-deoxy-β-d-galactopyranosid-6-yl)propyne. A single crystal of the 1-O-acetyl derivative (1c) of 1a was investigated by X-ray diffraction methods in a four-circle diffractometer. Compound 1c crystallises in the monoclinic system, space group P2₁ (Z = 2) with cell dimensions a = 14.896(2), b = 8.295(1), c = 20.547(3) Å, and β = 102.66(1)°. The structure was solved by direct methods and refined by a full-matrix, least-squares procedure against 3839 unique reflections (F > 2σ_F), resulting in a final R = 0.045 (unit weights). The configuration at the new chiral center (C-1) was established as S(d). The galactopyranose rings have conformations ⁴C₁ (tri-O-benzylated moiety) and °S₅ + °T₂ (di-O-isopropylidenated moiety). The 1,2- and 3,4-O-isopropylidene rings have ³T₂ and ²E conformations, respectively.     

Synthesis and structural characterizations of para-bis(dialkyl/diarylphosphino)phenylenes built around tetrahalogenated benzene cores

Double deprotonation of 1,2-dibromo-4,5-difluorobenzene and 1-bromo-2-chloro-4,5-difluorobenzene by lithium diisopropylamide (LDA) in ethereal solutions is facile at very low temperatures (T < −90 °C). The organo-dilithium intermediates thus generated react readily with chlorophosphines ClPR₂ (R = Ph and/or ⁱPr), producing 1,2-dibromo-3,6-bis(diphenylphosphino)-4,5-difluorobenzene (1a), 1,2-dibromo-3,6-bis(diisopropylphosphino)-4,5-difluorobenzene (1b) and 1-bromo-2-chloro-3,6-bis(diphenylphosphino)-4,5-difluorobenzene (1c). Corresponding P-oxides 2a-c are obtained by oxidation of 1a-c with H₂O₂. Analogous reactions of 1,2-dibromo-4,5-difluorobenzene and 1-bromo-2-chloro-4,5-difluorobenzene with only 1 equiv. of LDA do not result in selective monodeprotonations, as 1a and 1c are formed preferentially after ClPPh₂ quench. All of the isolated new compounds were fully characterized by multinuclear NMR spectroscopy, elemental analysis and/or mass-spectrometry. In addition, 1a, 1c, 2a, and 2b were characterized by single crystal X-ray diffraction methods.     

Synthesis,crystal structure,and conformation of 3-O-(6-O-acetyl-2,3-anhydro-4-deoxy-α-l-ribo-hexopyranosyl)-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose

3-O-(6-O-Acetyl-2,3-anhydro-4-deoxy-α-l-ribo-hexopyranosyl)-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose has been synthesised and its monocrystal investigated by X-ray diffraction methods. The compound crystallises in the orthorhombic system, space group P2₁2₁2₁, with cell constants a = 8.790(7), b = 11.678(4), and c = 21.457(10) Å. The intensity data were collected with a four-circle CAD-4 diffractometer. From a total of 1684 intensities, 1275 were of I > 2σ_I. The structure was solved by direct methods and refined by the full-matrix, least-squares procedure, resulting in R 0.057. The 4-deoxy-2,3-anhydropyranose ring is characterised by a sofa conformation (₅E), the 1,2-O-isopropylidene ring has a hybrid conformation (E + T), and the 5,6-O-isopropylidene and the α-d-glucofuranose rings have twist (T) conformations. The φ and ψ torsion angles for the glycosidic linkage are 54(4)° and 29(4)°, respectively.     

The deamination of methyl 5-amino-5,6-dideoxy-2,3-O-isopropylidene-α-L-talo- and -β-D-allo-furanoside with nitrous acid

Deamination of methyl 5-amino-5,6-dideoxy-2,3-O-isopropylidene-α-L-talofuranoside (6) with sodium nitrite in 90% acetic acid at ≈0° gave methyl 6-deoxy-2,3-O-isopropylidene-α-L-talofuranoside (8a) and methyl 6-deoxy-2,3-O-isopropylidene-β-D-allofuranoside (9a) (combined yield, 12.3%), the corresponding 5-acetates 8b (2.9%) and 9b (26.4%), and the unsaturated sugar methyl 5,6-dideoxy-2,3-O-isopropylidene-β-D-ribo-hex-5-enofuranoside (10) (43.5%). Similar deamination of methyl 5-amino-5,6-dideoxy-2,3-O-isopropylidene-β-D-allofuranoside (7) gave 8a and 9a (combined yield, 20.4%), 8b (12.5%), 9b (25.8%), 10 (7.7%), and the rearranged products 6-deoxy-2,3-O-isopropylidene-5-O-methyl-L-talofuranose (13a, 17.5%) and the corresponding 1-acetate 13b (14.1%). A synthesis of 13a was accomplished by successive methylation and debenzylation of the conveniently prepared benzyl 6-deoxy-2,3-O-isopropylidene-α-L-talofuranoside (15b). Differences between the two sets of deamination products can be rationalized by assuming that the carbonium-ion intermediate reacts in the initial conformation assumed, before significant interconversion to other conformations occurs.     

2-Substituted fortimicins by ring opening of 2-deoxy-1,2-epimino-2-epi-fortimicin B and by nucleophilic displacements of 2-O-(methylsulfonyl)fortimicin derivatives

Opening of the aziridine ring of 2-deoxy-1,2-epimino-2-epi-fortimicin B (10) has been effected with both chloride and azide. The reactions are both stereo- and regiospecific and give 2-chloro-2-deoxyfortimicin B (2c) and 2-azido-2-deoxy-fortimicin B (2d). The nucleophilic displacements of the methanesulfonate groups of some 1-N-benzyloxycarbonyl-2-O-(methylsulfonyl)fortimicin derivatives with chloride, azide, and cyanide in N,N-dimethylformamide are dependent both on the nature of the nucleophile and the specific 1-N-benzyloxycarbonyl-2-methanesulfonate employed as the substrate. Striking differences in the stereochemistry of the azide displacements with different 2-methanesulfonates are believed to have a conformational basis. 2-Amino-2-deoxyfortimicin A (1c) and both of the 2-epimeric 2-chloro-2-deoxyfortimicins A (1b) and (5) were prepared for antibacterial assay and the in vitro results are reported.     

Über die Synthese partiell benzylierter Zucker

1,2:5,6-Di-O-isopropylidene-α-D-allofuranose (1), 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (2), and 1,2.3,4-di-O-isopropylidene-α-D-galactopyranose (3) have been separately treated in pyridine solution with trifluoromethanesulphonic anhydride, 2,2,2-trifluoroethanesulphonyl chloride, and pentaflucrobenzenesulphonyl chloride. Both 1 and 2 afforded the anticipated sulphonic esters. Although 3 also gave the 2,2,2-trifluoroethanesulphonic and pentafluorobenzenesulphonic esters, the reaction with trifluoromethanesulphonic anhydride yielded 6-deoxy-1,2:3,4-di-O isopropylidene-6-pyridino-α-D-galactopyranose trifluoromethanesulphonate.     

Synthesis,pharmacological studies and molecular modeling of some tetracyclic 1,3-diazepinium chlorides

Seven new 1,3-diazepinium chlorides exhibiting some structural similarities to the 1,4-benzodiazepines were synthesized. In a Hippocratic screen using mice, three of these salts, 3-methoxy-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8a), 3-methoxy-9-methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8c) and 3-methoxy-11-methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8e) were examined for their effect on the central nervous system, and their activities compared to that of diazepam. On their own, salts 8a, 8c and 8e solicited no sedative effects on the behaviour of the animals. However, they elicited significant effects in combination with diazepam on diazepam-induced activities such as decreased motor activity, ataxia and loss of righting reflex. Compounds 8a and 8c were fitted into the pharmacophore/receptor model developed by Cook et al. with interaction at the L₁, H₁ and A₂ sites indicating that they are potential inverse agonists of the Bz receptor. The compounds displayed some affinity for the α1 isoform of the GABA_A/BzR (L_Di interaction) but are non-selective for α5 (no L₂ interaction). Results of binding affinity studies showed that compound 8a is mildly selective for the α1 receptor although not very potent (K_i = 746.5 nM). The significant potentiation of diazepam-induced ataxia and decreased motor activity by compounds 8a and 8c in the Hippocratic screen may be associated with α1 selectivity.     

On the Use of Distance in the Taxonomic Study of Critical Plant Groups—Case Studies of Western European Orchidaceae

Four distance coefficients are compared on four data sets composed of samples coming from western European populations of the genera Dactylorhiza, Orchis and Epipactis (Orchidaceae). The performance of the distance coefficients is evaluated through: (a) the quality of clusters obtained by five classical methods (as compared to a priori classification), (b) the Mantel statistic with respect to an a priori distance matrix resulting from previous knowledge, (c) the result obtained with the k-means method, and (d) principal coordinate diagrams. It appears that: (a) the Mahalanobis distance based on the pooled dispersion matrix performs best on the whole; (b) a distance based on the recently developed Common Principal Component model, used with a log transformation, also provides useful information and performs best on the largest data set; (c) the Gölz and Reinhard taxonomic distance, widely used among orchidologists, is attractive for its simplicity, yet good performance and the valuable information it provides, despite its theoretical shortcomings. A brief taxonomic discussion is made on the results obtained for the Dactylorhiza samples, especially about samples whose identification was in doubt.     

Oxidation of 1,4-alkanediols into γ-lactones via γ-lactols using Rhodococcus erythropolis as biocatalyst

Whole cells of Rhodococcus erythropolis DSM 44534 grown on ethanol, (R)- and (S)-1,2-propanediol were used for biotransformation of racemic 1,4-alkanediols into γ-lactones. The cells oxidized 1,4-decanediol (1a) and 1,4-nonanediol (2a) into the corresponding γ-lactones 5-hexyl-dihydro-2(3H)-furanone (γ-decalactone, 1c) and 5-pentyl-dihydro-2(3H)-furanone (γ-nonalactone, 2c), respectively, with an EE(R) of 40–75%. The transient formation of the γ-lactols 5-hexyl-tetrahydro-2-furanol (γ-decalactol, 1b) and 5-pentyl-tetrahydro-2-furanol (γ-nonalactol, 2b) as intermediates was observed by GC–MS. 1,4-Pentanediol (3a) was transformed into 5-methyl-dihydro-2(3H)-furanone (γ-valerolactone, 3c) whereas (R)- and (S)-2-methyl-1,4-butanediol (4a) was converted to the methyl-substituted γ-butyrolactones 4-methyl-dihydro-2(3H)-furanone (4c₁) and 3-methyl-dihydro-2(3H)-furanone (4c₂) in a ratio of 80:20 with a yield of 55%. Also cis-2-buten-1,4-diol (5a) was transformed resulting in the formation of 2(5H)-furanone (γ-crotonolactone, 5c). At the higher pH values of 8.8 the yield of lactone formed was improved; however, the enatiomeric excesses were slightly higher at the lower pH of 5.2.     

Some aspects of the isopropylidenation of d-glucitol under neutral conditions

Isopropylidenation of d-glucitol (1) under neutral conditions, by treatment with 2,2-dimethoxypropane in 1,2-dimethoxyethane, has been studied. An improved procedure for the isolation of 1,2:5,6-di-O-isopropylidene-d-glucitol, the main equilibrium product, by direct crystallisation or via the 3,4-dibenzoate is described. Some aspects of the reaction are discussed and compared with results obtained previously from the isopropylidenation of 1 in the presence of zinc chloride.     

Analysis of the Light-harvesting Pigment-Protein Complex of Wild Type and a Chlorophyll-b-less Mutant of Barley

we have compared chloroplast lamellae isolated from a chlorophyll-b-less mutant and wild type barley (Hordeum vulgare). The results demonstrate that: (a) one of the two major polypeptides comprising the lightharvesting complex (LHC) is present in the chlorophyll-b-less mutant; (b) higher cation concentrations are required to maintain grana stacks in the mutant; and (c) cation effects on excitation energy distribution are present in the chlorophyll-b-less mutant but are reduced in amount and are dependent on higher concentrations of cations.     

The Interval-Strength Relationship in Mammalian Atrium: A Calcium Exchange Model: I. Theory

A model is developed for predicting the interval-strength relationship in mammalian atrium. The postulates underlying the model relate the intracellular and transmembrane calcium fluxes to changes in contractility. The predictions of the model agree qualitatively with the behavior of atrium for the following patterns of stimulation: (a) constant interval between stimuli, (b) a rest, or period with no stimuli, after the attainment of a steady-state force level, (c) a sudden change in the interval between stimuli, and (d) paired pulse stimulation. The effects of varying several parameters of the model on both the contraction staircases, after a rested-state contraction, and the steady-state interval-strength relationship are examined. Additional considerations are made: (a) estimates are made of the tissue calcium content available for contraction; (b) the physical meaning of the rested-state contraction is discussed; and (c) estimates are made of the proportionality constant between the maximum value of the contractile tension and the amount of calcium released before a contraction.     

Electroretinogram Characteristics and the Spectral Mechanisms of the Median Ocellus and the Lateral Eye in Limulus polyphemus

Electrical responses (ERG) to light flashes of various wavelengths and energies were obtained from the dorsal median ocellus and lateral compound eye of Limulus under dark and chromatic light adaptation. Spectral mechanisms were studied by analyzing (a) response waveforms, e.g. response area, rise, and fall times as functions of amplitude, (b) slopes of amplitude-energy functions, and (c) spectral sensitivity functions obtained by the criterion amplitude method. The data for a single spectral mechanism in the lateral eye are (a) response waveforms independent of wavelength, (b) same slope for response-energy functions at all wavelengths, (c) a spectral sensitivity function with a single maximum near 520 mµ, and (d) spectral sensitivity invariance in chromatic adaptation experiments. The data for two spectral mechanisms in the median ocellus are (a) two waveform characteristics depending on wavelength, (b) slopes of response-energy functions steeper for short than for long wavelengths, (c) two spectral sensitivity peaks (360 and 530–535 mµ) when dark-adapted, and (d) selective depression of either spectral sensitivity peak by appropriate chromatic adaptation. The ocellus is 200–320 times more sensitive to UV than to visible light. Both UV and green spectral sensitivity curves agree with Dartnall's nomogram. The hypothesis is favored that the ocellus contains two visual pigments each in a different type of receptor, rather than (a) various absorption bands of a single visual pigment, (b) single visual pigment and a chromatic mask, or (c) fluorescence. With long duration light stimuli a steady-state level followed the transient peak in the ERG from both types of eyes.     

Crystal structure and conformation of 3-O-(2,3-anhydro-4-deoxy-α-l-lyxo-hexopyranosyl)-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose

A single crystal of 3-O-(2,3-anhydro-4-deoxy-α-l-lyxo-hexopyranosyl)-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose (1), obtained from its 6-acetate, has been investigated by X-ray diffraction methods. Compound 1 crystallises in the orthorhombic system, space group P2₁2₁2P₁, with cell dimensions a = 8.556(1), b = 12.303(1), and c = 18.397(1) Å. An almost ideal half-chair conformation ⁵H_o was found for the 2,3-anhydropyranose moiety of 1.     

Diheteroarylmethyl substituted titanocenes: A novel class of possible anti-cancer drugs

From the reaction of tert-butyl lithium or n-butyl lithium with N-methylpyrrole (1a), furan (1b) or 2-bromo-thiophen (1c), 2-N-methylpyrrolyl lithium (2a), 2-furyl lithium (2b) or 2-thiophenyl lithium (2c), respectively, was obtained. When reacted with 6-(2-N-methylpyrrolyl) fulvene (3a), 6-(2-furyl) fulvene (3b) or 6-(2-thiophenyl) fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanocenes (5a-c) were obtained through transmetallation with titanium tetrachloride. When these titanocenes were tested against pig kidney epithelial (LLC-PK) cells, inhibitory concentrations (IC₅₀) of 32 μM, 140 μM, and 240 μM, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues.     

Synthesis of some C-glycosyl- and polyhydroxyalkyl-pyridazines

Photo-oxygenation of 3-hydroxymethyl-5-(2,3-O-isopropylidene-β-d-erythrofuranosyl)-2-methylfuran, 5-(1,2:3,4-di-O-isopropylidene-d-arabino-tetritol-1-yl)-3-(1-hydroxyethyl)-2-methylfuran (8a), and 2-methyl-5-(1,2,3,4-tetra-O-acetyl-d-arabino-tetritol-1-yl)-3-furoic acid (8b) yielded the corresponding endo-peroxides, which were transformed into 4-hydroxymethyl-6-(2,3-O-isopropylidene-β-d-erythrofuranosyl)-3-methylpyridazine, 6-(1,2:3,4-di-O-isopropylidene-d-arabino-tetritol-1-yl)-4-(1-hydroxyethyl)-3-methylpyridazine, and 6-(d-arabino-tetritol-1-yl)-3-methylpyridazine by treatment with hydrazine. The γ-di-ketones (Z)-1-(1,2:3,4-di-O-isopropylidene-d-arabino-tetritol-1-yl)-3-(1-hydroxyethyl)pent-2-ene-1,4-dione and d-arabino-6,7,8,9-tetraacetoxy-4-methoxynonane-2,5-dione can be obtained by reduction of the endo-peroxides 9a and 9b (derived from 8a and 8b, respectively) with dimethyl sulphide. The C → O rearrangement reported for C-glycosyl endo-peroxides was also observed for 9a.     

Synthesis of branched-chain sugar derivatives related to aldgarose

Ethynylation of 1,2:5,6-di-O-isopropylidene-α-D-ribo-hexofuranos-3-ulose (1) gave the 3-C-ethynyl allo derivative 2, together with an adduct (3) resulting from interaction of two molecules of 1 with one of acetylene. Lithium aluminum hydride reduced the acetylenes 2 and 3 to the corresponding alkenes 4 and 8; on sequential ozonolysis-borohydride reduction, these both gave 3-C-(hydroxymethyl)-1,2:5,6-di- O-isopropylidene-α-D-allofuranose (6), further characterized as its 3,3¹-cyclic carbonate 9. Ozonolysis of the acetylene 2 gave the 3¹,5-lactone (5) of the 3-C-carboxy analog, thus establishing the stereochemistry of 2, which was independently established by n.m.r. spectroscopy employing a lanthanide shift-reagent. Treatment of 2 with mercuric acetate in ethyl acetate, followed by hydrogen sulfide, gave a mixture of the 3-C-acetyl-3-O-acetyl derivative 10 and a product (11) derived from internal cyclization of 5,6-deacetonated, O-deacetylated 10. Reduction of 10 with lithium aluminum hydride gave a separable mixture of diastereoisomeric 3-C-(l-hydroxy-ethyl) derivatives (12a, 12b) that were individually converted into their corresponding 3,3¹-cyclic carbonates 13a and 13b, products that contain the branch functionality of the unusual, branched-chain sugar aldgarose.