Unexpected shielding of methyl group protons in some piperidines

High resolution 1H and 13C NMR spectra of four 3-ethyl-4-hydroxy- 4-phenylpiperidines 1-4 have been recorded in CDCl3 and analysed. The conformations of phenyl and hydroxyl groups at C(4) and ethyl group at C(3) were analysed in detail. The chemical shift of the methyl protons in the ethyl group are quite surprising; they are close to TMS in CDCl(3) and even negative in DMSO-d6. These results are interpreted in terms of the magnetic anisotropy of the phenyl rings at C(2) and C(4) which, in turn, depend on the conformations of the ethyl group at C(3) and the hydroxyl group at C(4). Favoured conformations of ethyl group at C(3) and hydroxyl group at C(4) were calculated by AM1 methods.     

Synthesis of heparin saccharides III. Synthesis of derivatives of D-glucosamine as starting materials for disaccharides.

Derivatives of benzyl 2-[1-(benzyloxy)formamido]-2-deoxy-α-D-glucopyranoside with various protecting groups at C(3) (benzoyl, benzyl and N-phenylcarbamoyl) and C(6) (benzoyl, benzylsulfonyl, N-phenylcarbamoyl and tosyl) have been synthesized as starting materials for disaccharides. The C(4) and C(6) hydroxyl groups of the amino sugar were initially blocked by an acetal group. After introduction of the protecting group at C(3), the acetal group was removed by acid hydrolysis, and the C(6) hydroxyl group was selectively acylated or sulfonylated. The 3,6-di-O-benzoate has also been prepared by dimolar benzoylation of the amino sugar, whereby the 4,6-isomer was obtained as a by-product.     

Identification of the related substances of tilmicosin by liquid chromatography/ion trap mass spectrometry

Structures of seven impurities of the veterinary drug tilmicosin have been elucidated by multiple fragmentation with ion trap tandem mass spectrometry. All related compounds possess the main lactone ring of tilmicosin. The differences in their structures are due to the hydroxyl, mycaminose, 3,5-dimethylpiperidine and mycinose groups connected to C(3), C(5), C(6), C(14) of the lactone ring, respectively. The following compounds of the impurity profile of tilmicosin were identified: B - tilmicosin with a hydroxyl group at C(3); C - tilmicosin without a methyl group at the N-atom connected to C(3) of the mycaminose ring; D - tilmicosin with a hydroxyl group at C(6) of the mycaminose ring; E - tilmicosin with a methoxy group at C(3), F - desmicosin; G - 20-dihydrodesmicosin; and H - tilmicosin without a mycaminose ring. Isomers of the compounds B, C, D, E and H were identified by their mass chromatograms and retention times. The concentrations of the impurities varied in the range of 0.1% to 2.9%.     

D-葡萄糖酸衍生物C5和C6羟基保护基迁移现象研究

2-O-甲基-3,4-O-丙酮叉基-D-葡萄糖酸甲酯(6)的C6羟基用乙酰基保护、C5仲羟基用TBS保护得到化合物8,碳酸钾脱除C6-O-乙酰基时,C5-O-TBS迁移到C6羟基得到了化合物9(74%收率),没有得到目标产物12;将化合物6的C6羟基用TBS保护、C5羟基乙酰基保护的化合物10,四丁基氟化铵脱除C6-O...     

Refined Insight in Stereochemical and Directional Features of the FeI-Mediated Dehydrogenation of Tetralin

Experimental results demonstrate that, in the course of gas-phase Fe⁺-mediated dehydrogenation of tetralin, the metal ion sticks to the same plane of the hydrocarbon surface. The study of 5-substituted, labeled tetralin analogues reveal the operation of an interesting substituent effect: Steric hindrance imposed by a CH₃ group at C(5) deflects the metal to the more easily accessible region of C(1)/C(2); in contrast, a CH₃O substituent at C(5) directs the metal ion to the more congested C(3)/C(4) region which clearly points to a coordination of Fe⁺ to the MeO group in the course of the haptotropic migration.     

Structure and Reactivity of Xanthocorrinoids. Part III. The first example of a pinacol-type rearrangement in the corrin series

The transformation of the c-acetic-acid chain of hexamethyl Coα, Coβ-dicyanocobyrinate into an ethyl group (→ 2 ) as well as the synthesis of the pentadecaalkyl-cobalticorrin 6d from commercial cyanocobalamin are described. On reaction of 2 or 6d with O₂ in the presence of ascorbic acid, migration of the CH₃ group at C(5) to the vicinal position C(6) takes place concomitantly with the introduction of a carbonyl group at C(5).     

The Oxidation of the Double Bonds of β-Elemene

Peracid oxidation of β-elemene ( 6 ) occurs by attack specifically on the isolated [isopropenyl] group at C(4). The structures of the epoxides thus obtained were demonstrated by [conversion] to tetrahydrogeijerol 12 (R ? H), which was identical with the substance obtained from geijerone ( 2 ) by reduction, first catalytically, then with metal hydride. Ozonolysis of β-elemene is less specific, attack occurring on the other isopropenyl group (at C(2)) in addition to the one at C(4), and subsequently on the vinyl group (at C(1)). The structures of the ozonolysis products were confirmed by a sequence of reactions from elemol.     

Long branching in poly(vinyl acetate) and poly(vinyl alcohol). II. Polymerization of vinyl acetate in the presence of crosslinked poly(vinyl alcohol)

It is a common view that poly(vinyl acetate) has many branches at the acetyl side group, but that the corresponding poly(vinyl alcohol) has little branching. In order to study the branching in poly(vinyl acetate) and poly(vinyl alcohol) which is formed by chain transfer to polymer, the polymerization of ¹⁴C-labeled vinyl acetate in the presence of crosslinked poly(vinyl acetate), which was able to be decrosslinked to give soluble polymers, was investigated at 60°C and 0°C. This system made it possible to separate as well as to distinguish the graft polymer from the newly polymerized homopolymer. Furthermore, the degree of grafting onto the acetoxymethyl group and onto the main chain were estimated. It became clear that, in the polymerization of vinyl acetate, chain transfer to the polymer main chain takes place about 2.4 times as frequently at 60°C as that to the acetoxy group and about 4.8 times as frequently at 0°C.     

An experimental and in situ IR spectroscopic study of the lithiation-substitution of N-Boc-2-phenylpyrrolidine and -piperidine: controlling the formation of quaternary stereocenters

A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation-substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at -50 °C for 5-30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation-substitution of N-Boc-2-phenylpyrrolidine at -78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature (1)H NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) for rotation of the Boc group was found to be ～10 h at -78 °C and ～3.5 min at -50 °C. In contrast, for the piperidine, t(1/2) was determined to be ～4 s at -78 °C.     

Analysis of the phase transitions in alkyl-mica by density and pressure profiles

In a previous work [Heinz, Castelijns, and Suter, J. Am. Chem. Soc. 115, 9500 (2003)], we developed an accurate force field and simulated the phase transitions in C18-mica (octadecyltrimethylammonium-mica) as well as the absence of such transitions in 2C18-mica (dioctadecyldimethylammonium-mica) between room temperature and 100 degrees C. Here we analyze (i) average z coordinates of the carbon atoms and interdigitation of the hydrocarbon bilayers, (ii) density profiles, and (iii) pressure profiles of the structures along all Cartesian axes. In C18-mica, the standard deviation in the z coordinate for the chain atoms is high and more than doubles in the disordered phase. The order-disorder transition is accompanied by a change in the orientation of the ammonium head group, as well as decreasing tensile and shear stress in the disordered phase. In 2C18-mica, the standard deviation in the z coordinate for the chain atoms is low and does not increase remarkably on heating. The backbones display a highly regular structure, which is slightly obscured by rotations in the C18 backbones and minor head group displacements at 100 degrees C. Close contacts between the bulky head groups with sidearms cause significant local pressure which is in part not relieved at 100 degrees C. An increase of the basal-plane spacing at higher temperature is found in both systems due to larger separation between the two hydrocarbon layers and an increased z spacing between adjacent chain atoms (=decreased tilt of the chains relative to the surface normal), and, in C18-mica only, a stronger upward orientation of the C18 chain at the ammonium head group. The likelihood for chain interdigitation between the two hydrocarbon layers is 24%-30% for C18-mica, and 65%-26% for 2C18-mica (for 20-100 degrees C).     

Hydrolysis behavior of prednisolone 21-hemisuccinate/beta-cyclodextrin amide conjugate: involvement of intramolecular catalysis of amide group in drug release

Prednisolone 21-hemisuccinate/beta-cyclodextrin (beta-CyD) amide conjugate was prepared by binding prednisolone 21-hemisuccinate covalently to the amino group of mono(6-deoxy-6-amino)-beta-CyD through amide linkage. Prednisolone 21-hemisuccinate was intramolecularly transformed to prednisolone 17-hemisuccinate, and the parent drug, prednisolone, was slowly released from the 21-hemisuccinate with a half life of 69 h in pH 7.0 at 37 degrees C; the drug release at 25 degrees C was less than 10% for 48 h. In sharp contrast, the hydrolysis of prednisolone 21-hemisuccinate/beta-CyD amide conjugate was significantly faster (half life of 6.50 min at 25 degrees C) and gave prednisolone and mono(6-deoxy-6-succimino)-beta-CyD as products. The hydrolysis of the beta-CyD amide conjugate was subject to a specific-base catalysis in the alkaline region. The rapid hydrolysis of the conjugate can be ascribed to the involvement of an intramolecular nucleophilic catalysis of the amide group in the reaction. The succinic acid, bound to a drug through ester linkage at one carboxylic group and bound to a pro-moiety through amide linkage at another carboxylic group, may be useful as a spacer for construction of the immediate release type prodrugs of CyDs.     

Prolongation of the lifetime of the charge-separated state at low temperatures in a photoinduced electron-transfer system of [60]fullerene and ferrocene moieties tethered by rotaxane structures

A rotaxane tethering both fullerene (C60) and ferrocene (Fc) moieties (abbreviated as (C60;Fc)rotax+) was synthesized in a good yield by the urethane end-capping of pseudorotaxane based on the crown ether-secondary amine motif. In (C60;Fc)rotax+, the C60 group serving as an electron acceptor is attached to the crown ether wheel, through which the axle with a Fc group acting as an electron donor on its end penetrates. The intrarotaxane photoinduced energy-transfer and electron-transfer processes between C60 and Fc in (C60;Fc)rotax+ have been investigated by time-resolved transient absorption and fluorescence measurements with changing solvent polarity. Nanosecond transient absorption measurements of the rotaxane demonstrated that the charge-separated state (C60*-;Fc*+)rotax+ is formed mainly via the excited triplet state of C60 in polar solvents. The lifetime of (C60*-;Fc*+)rotax+ was evaluated to be 20 ns in dimethylformamide (DMF) at room temperature. With lowing temperature, the lifetime of (C60*-;Fc*+)rotax+ extends to 270 ns in DMF at -65 degrees C, due to the structural changes leaving C60*- and Fc*+ at a relatively long distance in the low-temperature region.     

In vitro and In vivo Antiproliferative Effect of a Combination of Ultraviolet‐A and Alkoxy Furocoumarins Isolated from Umbelliferae Medicinal Plants,in Melanoma Cells

We examined the effects of six furocoumarins with alkoxy groups at the C‐5 or C‐8 position isolated from Umbelliferae medicinal plants on cell proliferation, and their mechanisms of action against B16F10 melanoma cells or in melanin‐possessing hairless mice implanted with B16F10 cells, under UVA irradiation. Three furocoumarins with an alkoxy group at C‐5, isoimperatorin (1), oxypeucedanin (2) and oxypeucedanin hydrate (3), showed antiproliferative activity and caused G₂/M arrest at concentrations of 0.1–10.0 μm . Furthermore, three furocoumarins with an alkoxy group at C‐8, imperatorin (4), heraclenin (5) and heraclenol (6), inhibited the proliferation of melanoma cells and cell cycle at G₂/M at concentrations of 0.1–1.0 μm . UVA plus 1, 2, 3, 4 and 6 reduced tumor growth and final tumor weight in B16F10‐bearing mice at a dose of 0.3, 0.5 or 1.0 mg kg^?1 (intraperitoneal injection). UVA plus 1, 3 and 6 increased Chk1 phosphorylation and reduced cdc2 (Thr 161) phosphorylation in melanoma cells. We suggest that the antitumor actions of UVA plus furocoumarins with an alkoxy group at C‐5 or C‐8 were due to G₂/M arrest of the cell cycle by an increase in phosphor‐Chk1 and decrease in phospho‐cdc2.     

Formation of a bifunctional zirconocene complex that favours intramolecular -B(C6F5)2 addition to a Cp ring over sigma-ligand abstraction

The diphenyl-ansa-zirconocene complex 2 adds HB(C6F5)2 at the C=C double bond of its pendent Cp-allyl functional group to yield 3. During 3 days at room temperature the -B(C6F5)2 group takes part in an electrophilic substitution reaction at the adjacent Cp-ring to form 5 with formation of one equivalent of benzene. Complex 5 was characterized by X-ray diffraction.     

Benzyl group conformation in 4-benzyl-4-hydroxypiperidines

The high-resolution ¹H and ¹³C NMR spectra of eight 4-benzyl-4-hydroxypiperidines 1–8 were recorded in CDCl₃ and analyzed. In 2, the conformation of the equatorial benzyl group at C(4) was established as an equilibrium mixture of A [the phenyl group is gauche with respect to OH and C(5)] and B [the phenyl group is gauche with respect to OH and C(3)], whereas in 3-alkyl-4-benzyl-4-hydroxypiperidines 3–8, the favored conformation of the benzyl group at C(4) is A. In 1, the axial benzyl group at C(4) adopts the gauche conformations A′ [the phenyl group is gauche with respect to OH and C(3)] and B′ [the phenyl group is gauche with respect to OH and C(5)], in which the phenyl ring of the benzyl group is gauche with respect to the OH group. The HF/DFT B3LYP/6-3G* hybrid calculations of model systems 1′–3′ also support these conformations. The ¹³C data reveal that the equatorial methyl group at C(3) exerts a shielding influence on the methyl-bearing carbon and the magnitude of the α effect was found to be approximately ?1.5 ppm. The parameters of the ¹³C substituent in the benzyl group show that the the α effect of the equatorial benzyl group is considerably higher in 3-ethyl tertiary alcohol 7 than in 3-methyl tertiary alcohol 3 and 4-benzyl-t(4)-hydroxypiperidine 2. This may be explained if we take into account the different conformations of the ethyl group in t(4)-hydroxy-3-ethyl-2,6-diphenylpiperidine 12 and 3-ethyl tertiary alcohol 7.     

Importance of the isopropylidene terminal of geranylgeranyl group for the formation of tetraether lipid in methanogenic archaea

Labeling experiments using several deuterated lipids were pursued to study the biosynthesis of macrocyclic isoprenoidal lipids of thermophilic methanogenic archaea, Methanothermobacter thermautotrophicus. The isopropylidene terminal of geranylgeranyl group of monomeric precursor appeared to be important for the CC bond formation at the hydrophobic end in the macrocyclic lipids. A mechanism involving a radical trigger at the allylic methyl group is proposed for this CC bond formation.     

Two-dimensional heterospectral correlation analysis of wide-angle X-ray scattering and infrared spectroscopy for specific chemical interactions in weakly interacting block copolymers

We investigated, via two-dimensional heterospectral correlation analysis of wide-angle X-ray scattering (WAXS) and infrared (IR) spectroscopy, the specific chemical interactions existing in weakly interacting polystyrene-block-poly(n-pentyl methacrylate) copolymers (PS-PnPMA). PS-PnPMA was shown to exhibit a closed-loop-type phase behavior, where, upon heating, a lower disorder-to-order transition (LDOT) was found at lower temperatures, and an upper order-to-disorder transition (UODT) was observed at higher temperatures. The specific interaction between the PS and PnPMA blocks mainly arises from the dipole in the benzene ring of PS and the induced dipole in the PnPMA due to cluster formation with a size of 1 approximately 2 nm. We found that the synchronous 2D WAXS-IR heterospectral correlation spectrum of the ordered state was completely different from that in the two disordered states. The CH group of the main chains of PS and PnPMA did not contribute to the cluster formation in the two disordered states, indicating that the main chains of PS and PnPMA blocks were randomly distributed in the two disordered states. However, only the C=C group in the PS block contributed to the cluster at a disordered state below the LDOT, whereas both the C-C-O group in PnPMA and the entire phenyl ring and C=C group in PS contributed to cluster formation at another disordered state above the UODT. Thus, the probability that PS (and PnPMA) chains were located at their own neighboring chains at one disordered state above the UODT is larger than that at another disordered state below the LDOT.     

Three New Steroidal Glycosides from the Roots of Cynanchum auriculatum

Three new C₂₁ steroidal glycosides with a cinnamoyl group at C(12) and a 2‐methylbutanoyl group at C(20), and a straight sugar chain at C(3), namely cyanoauriculosides C–E ( 1 – 3 , resp.), together with three known steroidal derivatives, were isolated from the roots of Cynanchum auriculatum (Asclepiadaceae). Their structures were determined by spectroscopic analyses and chemical methods. The known constituents were identified as wilfoside K1N ( 4 ), cynanauriculoside II ( 5 ), and auriculoside IV ( 6 ).     

Consumption of Sinlek Rice Drink Improved Red Cell Indices in Anemic Elderly Subjects

Iron fortifications are used for the treatment of iron-deficiency anemia; however, iron dosing may cause oxidative damage to the gut lumen. Thai Sinlek rice is abundant in iron and contains phytochemicals. We aimed at evaluating the effect of an iron-rice (IR) hydrolysate drink (100 mL/serving) on neurological function, red cell indices and iron status in elders. Healthy elderly subjects were divided into three non-anemic groups and one anemic group. The non-anemic groups consumed one WR (2 mg iron/serving) and two IR drinks (15 and 27 mg iron/serving) (groups A, B and D, respectively), while the anemic group consumed one IR drink (15 mg iron serving) (group C) every day for 30 days. There were no significant differences in the MMSE Thai 2002 and PHQ9 test scores for members of all groups, while the nutrition scores and body weight values of group D subjects were significantly increased. Hemoglobin (Hb) and mean corpuscular hemoglobin concentrations increased significantly only in group C. Serum iron and transferrin saturation levels tended to increase in group A, while these levels were decreased in members of group C. Serum antioxidant activity levels were increased in all groups, and were highest in group C. Thus, consumption of an IR drink for 15 days functioned to increase Hb and antioxidant capacity levels in anemic elders.