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A new low-molecular weight dendrimer-like MRI contrast agent (Gd-D1) has been synthesized and characterized in vitro by proton and oxygen-17 relaxometry. Its pharmacokinetic parameters and biodistribution patterns were evaluated on rats. Its in vitro and in vivo properties, that is, the longitudinal relaxivity (defined as the increase of the water proton longitudinal relaxation rate induced by one millimole per liter of Gd-D1) equal to 5.6s(-1)mM(-1) at 20 MHz and 310 K, the elimination half-time equal to 85 min, and its low accumulation in liver and spleen, underline its potential as a blood-pool MRI contrast agent.

A novel synthetic approach is described to incorporate one more carbon atom at C-2 position of phospholane oxides as homologated allylic alcohol by treatment of erythro -2,3-epoxy-3-methylphospholane 1-oxides with excess of dimethylsulfonium methylide.

An x-ray crystallographic analysis was carried out for Boc-(Aib-DeltaZPhe)4-Aib-OMe (1: Boc = t-butoxycarbonyl; Aib = alpha-aminoisobutyric acid; DeltaZPhe = Z-alpha,beta-didehydrophenylalanine) to provide the precise conformational parameters of the octapeptide segment -(Aib-DeltaZPhe)4-. Peptide 1 adopted a typical 3(10)-helical conformation characterized byphi= +/-55.8 degrees (50 degrees -65 degrees),psi= +/-26.7 degrees (15 degrees -45 degrees), andomega= +/-179.5 degrees (168 degrees -188 degrees) for the average values of the -(Aib-DeltaZPhe)4- segment (the range of the eight values). The 3(10)-helix contains 3.1 residues per turn, being close to the "perfect 3(10)-helix" characterized by 3.0 residues per turn. NMR and Fourier transform infrared (FTIR) spectroscopy revealed that the 3(10)-helical conformation at the atomic resolution is essentially maintained in solution. Energy minimization of peptide 1 by semiempirical molecular orbital calculation converged to a 3(10)-helical conformation similar to the x-ray crystallographic 3(10)-helix. The preference for a 3(10)-helix in the -(Aib-DeltaZPhe)4- segment is ascribed to strong inducers of the 3(10)-helix inherent in Aib and DeltaZPhe residues-in particular, the Aib residues tend to stabilize a 3(10)-helix more effectively. Therefore, the -(Aib-DeltaZPhe)4- segment is useful to rationally design an optically inactive 3(10)-helical backbone, which will be of great importance to provide novel insights into noncovalent and covalent chiral interactions of a helical peptide with a chiral molecule.

An efficient method is described in the synthesis of several novel deoxy phospha sugar pyrimidine nucleosides in racemic form, analogs of normal sugar nucleosides, in high yields by treatment of (±)-2-aminophospholane 1-oxide with several, α-cyano-, -acetyl-, -ethoxycarbonyl-β-ethoxy-N-ethoxycarbonylacrylamides.

A new type of polyaromatic dendrimer composed of six anthracene groups was synthesized, which showed a monomeric fluorescence feature with a diminished quantum yield due to intramolecular self-quenching processes in the dendritic framework.

Novel pentofuranose analogs of phospha sugar derivatives were synthesized starting from 1-phenyl-2-phospholene 1-oxide ( 1 ). First, the allylic oxidation of 1-phenyl-2-phospholene 1-oxide ( 1 ) with CrO 3 in Ac 2 O-AcOH or 3-hydroxy-1-phenyl-2-phospholene ( 2 ) with MnO 2 afforded 1-phenyl-4-oxo-2-phospholene 1-oxide ( 3 ). The C-5 alkylation of 3 in the presence of NaH by using benzyl bromide or methyl iodide as electrophiles afforded the target title compounds.

Several novel 1-(substituted phenyl)-2-phospholene 1-oxide derivatives, which are analogs of sugars having a phosphorus atom in place of the ring oxygen of normal sugars, were synthesized from the corresponding 2-phospholenes as the starting materials. Structures of all the synthesized compounds were unequivocally confirmed by IR, 1 H, 13 C, and 31 P NMR spectral, elemental, and X-ray crystallographic analyses.

The synthesis of the novel 1-(substituted phenoxy/phenyl)-2-phospholene and phospholane 1-oxide derivatives, which are analogs of sugars having a phosphorus atom in place of the ring oxygen of normal sugars, is described. All of the synthesized derivatives are structurally characterized by multi nuclear NMR, mass, and IR spectral data, elemental and X-ray crystallographic analyses.

Allylic oxidation of 2-phospholenes gave the first successful preparation of 4-oxo-2-phospholene 1-oxide derivatives, and this synthetic approach provides a ready accessible route in the synthesis of a wide variety of pentofuranose analogs of phospha sugars, having a phosphorus atom as the sugar ring hetero atom.

Several novel phospha sugar nucleosides, analogs of normal sugar nucleosides, were synthesized from a phospholene 1-oxide derivative. Bromination of a phospholene precursor in aqueous organic medium gave regio diastereomers, the threo and erythro bromohydrins 3 (1-bromo-1,3,4-trideoxy-1,4-C-[(R,S)-phenylphosphinylidene]-glycero-tetrofuranose). Further substitution of the threo isomer 3a with sodium azide led to its corresponding azidophospholane 4 (1-azido-1,3,4-trideoxy-2-methyl-1,4-C-[(R)-phenylphosphinylidene]-beta-D-glycero-tetrofuranose). 1,3-Dipolar cycloaddition of 4 with various electron-deficient and electron-rich alkynes afforded triazole derivatives that are nucleoside analogues. The strong electron-withdrawing phosphoryl group in the hemiacetal ring exerted no effect over reaction regioselectivity of the 1,3-dipolar cycloaddition, but steric effects of the alkynes played a vital role on the selectivity, since the regioisomer ratios and the rates and yields of cycloadducts changed as the bulkiness of the substituents on the acetylene changes. Structures of all compounds were unequivocally confirmed by 1H, 13C, and 31P NMR and mass spectral studies. Single crystal X-ray crystallographic analysis of some derivatives allowed determination of configuration of the phospha sugar nucleosides.

In this paper we attempted to reveal how a large β-substituent (pyrenyl group) of dehydroresidue affects the structural and conformational preferences of (Z)-β-substituted α,α-dehydroalanine. An X-ray crystallographic analysis was carried out for Boc–L-Ala–ΔZPyr–L-Val–OMe (Boc = t-butyloxycarbonyl; OMe = methoxy) possessing a novel (Z)-β-(1-pyrenyl)dehydroalanine (ΔZPyr) residue. Single crystals were obtained by slow evaporation from an ethanol solution in the monoclinic space group P21. The bond lengths and bond angles of the ΔZPyr residue were essentially similar to other β-substituted dehydroalanines. The tripeptide took a type II β-turn conformation involving an intramolecular hydrogen bond between CO(Boc) and NH(Val), like small peptides possessing a (Z)-β-(1-naphthyl)dehydroalanine or a (Z)-β-phenyldehydroalanine residue. The similarity between ΔZPyr and other dehydroalanines in structural property and conformational preference should be responsible for the non-planarity of the ΔZPyr residue to give...

An X-ray crystallographic analysis was carried out for Boc-(Aib-ΔZPhe)2-Aib-OMe 1 and Boc-L-Pro-(Aib-ΔZPhe)2-Aib-OMe 2 (Aib = α-aminoisobutyric acid; ΔZPhe = α,β-dehydrophenylalanine; Boc = tert-butoxycarbonyl; OMe = methoxy) to provide detailed conformational data for oligopeptides possessing an -(Aib-ΔZPhe)2- segment. Both peptides adopted a typical 310-helical conformation characterized by = 52.8°, = 29.3°, and = -173.8° for the average values of the four residues of the -(Aib-ΔZPhe)2- segment in peptide 1, and = 54°, = 27°, and = -175° for those in peptide 2. The preference for a 310-helix in the -(Aib-ΔZPhe)2- segment is ascribed to the presence of Aib and ΔZPhe residues being strong inducers for the formation of a 310-helix. In peptide 2, the N-terminal L-Pro residue adopted a semiextended conformation, leading to a left-handed screw sense for the following achiral segment. This result was also supported by conformational energy calculation, in which the L-Pro residue leading to a left-handed 310-helical segment prefers a semiextended conformation rather than a right-handed helical conformation.

A new type of designed and functionalized ligand for a lanthanide ion based on dendritic architecture was synthesized. The dendrimers, which contain four and twelve glucose moieties on the molecular surfaces, were readily synthesized with good yields in every step. The NMR and GPC analyses precisely demonstrated successful constructions of the dendritic structures, while the formations of gadolinium chelates were deduced on the basis of HPLC study.

To understand how chemical structure of beta-substituted alpha, beta-dehydroalanine (particularly size and pi conjugation of beta substituent) affects conformational property, x-ray crystallographic analysis was performed on Boc-Ala-Delta(Z) Nap-Val-OMe [Boc: t-butoxycarbonyl; Delta(Z) Nap: (Z)-beta-(1-naphthyl)dehydroalanine; OMe: methoxy] having the naphthyl group as a bulky beta substituent. Single crystals were grown by slow evaporation from an ethanol solution in the triclinic space group P1 with a = 9.528 (3) A, b = 12.410(4) A, c = 5.975(2) A, alpha = 96.77(3) degrees, beta = 102. 81(2) degrees, gamma = 88.74(3) degrees, V = 684.1(4) A3, and Z = 1. Phase determination was carried out by a direct method (SHELEXS), and the final structure was refined to R = 8.1% and R(w) = 9.0% for 1964 observed reflections. The bond lengths and bond angles of the Delta(Z)Nap residue, characterized by a sp(2) hybridized C(alpha) atom, did not differ from those of other dehydroresidues such as Delta(Z) Phe, Delta(Z) Leu, and DeltaVal essentially. The peptide backbone took a type II beta-turn conformation involving an intramolecular hydrogen bond between CO(Boc) and NH(Val), similar to di- or tripeptides containing a Delta(Z) Phe or Delta(Z) Leu residue in the second positions. Here the naphthyl group was found to be nonplanar [chi(2) = 55(1) degrees ] relative to the C(alpha)==C(beta)==C(gamma) plane. The nonplanarity was supported by conformational energy calculation. The molecular packing was stabilized by two kinds of intermolecular hydrogen bonds and van der Waals interactions. Naphthyl groups were arranged in a partially overlapped face-to-face orientation with a center-to-center distance of 5.97 A. For additional information, peptide Boc-(Ala-Delta(Z) Nap-Leu)(2)-OMe was synthesized and its solution conformation was investigated by (1)H-NMR spectroscopy. The hexapeptide showed the tendency to form a 3(10)-helical conformation in solution essentially. Conformational properties of Delta(Z) Nap residue, characterized by a type II beta-turn and 3(10)-helix, were supported by a conformational energy contour map of the Delta(Z)Nap residue.

The synthesis and structure of novel glycoside and nucleoside derivatives of phospha sugar analogs from phospholenes are reported. 1-Phenyl-2-phospholene 1-oxide was regio-and diastereo-selectively converted into a 2-bromo-3-hydroxyphospholane derivative by an action of bromine in aqueous media. The reaction of the 2-bromophospholane derivative with some amines afforded 2-amino derivatives, which were N-glycosides of phospha sugar analogs. The 2-bromophospholane derivative was also converted into the corresponding azido derivative by the replacement of the 2-bromo substituent with sodium azide. 1,3-Diploar cycloaddition of the azido derivative with alkynes afforded phospha sugar nucleoside analogs which have a triazole ring as a nitrogen heterocycle.

3-Methyl-1-phenyl-2-phospholene and 1-phenyl-2-phospholene 1-oxides were converted into 2-bromo-3-hydroxy-3-methyl-1-phenylphospholane and 2-bromo-3-hydroxy-1-phenylphospholane 1-oxide (1-bromo-1,3,4-trideoxy-1,4-C-[(R, S)-phenylphosphinylidene]-glycero-tetrofuranose) by the action of bromine in aqueous medium. The bromo substituent of the phospholane was substituted by treatment with amines or an azide anion to afford novel glycoside derivatives of phosphanyl sugar analogs such as 2-amino-3-hydroxy-1-phenylphospholane (3,4-dideoxy-1,4-C-[(R, S)-phenylphosphinylidene]-glycero-tetrofuranosylamine) and 2-azido-3-hydroxy-3-methyl-1-phenylphospholane 1-oxides with retention of the configuration. The 1,3-dipolar cycloaddition of the 2-azido derivative of the phospholane with alkynes gave 3-hydroxy-3-methyl-1-phenyl-2-(triazol-1′-y1)phospholane 1-oxides as a novel triazole-derived nucleoside of phosphanyl sugar analogs. The structure of the glycoside and nucleoside derivatives of the phosphanyl sugar a...

X-ray crystallographic analyses were performed on single crystals of 1,2,3,4-tetra-O-acetyl-5-deoxy-5-C-(isopropylphosphinyl)- d -ribopyranoses, 1,2,3,4-tetra-O-acetyl-5-deoxy-5-C-(isopropylphosphinyl)- d -xylopyranoses, and 1,2,4-tri-O-acetyl-5-deoxy-3-O-methyl-5-C-(phenylphosphinyl)- d -ribopyranoses. These compounds have the (RP) configuration at the phosphorus atom with the 4C1 conformation of the pyranose ring, and the conformation supported by NMR studies.

Some phosphanyl sugar derivatives, which are analogs of sugars having a phosphorus atom in place of the ring oxygen, were synthesized from 2- and 3-phospholenes as starting materials. Catalytic cis-dihydroxylation of 2-phospholene or 3-phospholene 1-oxide derivatives with osmium(VIII) oxide in the presence of a cooxidant afforded 3-deoxy- or 1-deoxy-tetrofuranose-type phosphanyl sugar derivatives, respectively. cis- Dihydroxylation of 4-acyloxy-2-phospholene 1-oxide derivatives gave tetrofuranose type phosphanyl sugar derivatives. Some of these derivatives of phosphanyl sugars were subjected to structural analyses using 1H NMR and X-ray crystallography. 1. Presented at the XVIIIth Inlernational Carbohydrate Symposium, Milan, Italy, July 21-26, 1996.

2- And 3-phospholenes were used as the starting materials for the syntheses of sugar derivatives having a phosphorus atom in the hemiacetal ring of the sugar derivatives (phosphono sugars). Alkylation or benzyloxymethylation of 3-phospholene 1-oxides afforded phospholene derivatives with more than 5 carbon atoms. Epoxidation followed by epoxide ring opening and cis-dihydroxylation of 5-benzyloxymethyl-2-phospholene derivatives afforded four pentofuranose type phosphono sugars (arabinose, lyxose, ribose, and xylose). Some nucleosides and isonucleosides of phosphono sugars were also prepared. Some of these derivatives of phosphono sugars were subjected to structure elucidation and bioassay.

A novel method has been developed for stereospecific conversion of 2-phospholene 1-oxides into their corresponding 2,3-epoxides in high yields using sodium peroxide as a reagent.

Stereoselective reactions of 1-methoxy-3-phospholene 1-oxide gave a novel 1-deoxy phosphono sugar, whose relative configuration was confirmed by X-ray crystallography. Further reaction of the 1-deoxy phosphono sugar with phthalimide and 6-chloropurine produced novel phosphono sugar nucleosides.

Reactions of 1-phenyl- and 1-methoxy-2-phospholene 1-oxides with bromine in aqueous organic solvents or in a protic medium, such as methanol, easily afforded the corresponding 2-bromo-3-hydroxy- or 2-bromo-3-methoxyphospholane 1-oxide derivatives. The reaction mechanism was postulated based on the stereochemistry of the products.

Reaction of 2-bromo-3-hydroxy-1-methoxy-3-methylphospholane 1-oxide with silylated 2-hydroxypyridine gave a novel non-natural phosphono sugar nucleoside derivative.

Treatment of 1-alkoxy-3-phospholene 1-oxide with lithium diisopropylamide followed by novel stereoselective C-alkylation with alkyl halides afforded 2-alkyl-and 2-benzyloxymethyl-3-phospholene 1-oxides, which were subjected to osmium (VIII) oxide-catalyzed diastereoselective cis-dihydroxylation to give new C-glycoside derivatives of Furanose-type phosphono sugars, with twist conformation.

Optically active (S)-2-aminopropylphosphonic and (S)-2-amino-4-methylpentylphosphonic acids were synthesized from commercially available chiral α-amino acids [(S)-(+)-alanine and (S)-(+)-leucine] without racemization.

Reactions of 2-phospholene 1-oxides with N-bromoacetamide in aqueous organic solvent produced 2-bromo-3-hydroxyphospholane 1-oxides, which reacted with sodium salts of dialkyl phosphonates to afford novel 2-phosphinoylphospholane 1-oxide derivatives. A 4-phosphin-oyl-2-phospholene derivative was also prepared.

Treatment of 1-alkoxy-3-phospholene 1-oxide with lithium diisopropylamide followed by novel stereoselective C-alkylation with alkyl halides afforded 2-alkyl-and 2-benzyloxymethyl-3-phospholene 1-oxides, which were subjected to osmium (VIII) oxide-catalyzed diastereoselective cis-dihydroxylation to give new C-glycoside derivatives of Furanose-type phosphono sugars, with twist conformation.

Reaction of 2-bromo-3-hydroxy-1-methoxy-3-methylphospholane 1-oxide with silylated 2-hydroxypyridine gave a novel non-natural phosphono sugar nucleoside derivative.

Stereoselective reactions of 1-methoxy-3-phospholene 1-oxide gave a novel 1-deoxy phosphono sugar, whose relative configuration was confirmed by X-ray crystallography. Further reaction of the 1-deoxy phosphono sugar with phthalimide and 6-chloropurine produced novel phosphono sugar nucleosides.

Reaction of 2-benzyloxymethyl-1-methoxy-3-phospholene 1-oxide with mCPBA afforded 3,4-epoxyphospholane derivatives, whose isomerized allylic alcohols were cis-dihydroxylated by osmium(VIII) oxide-catalyzed oxidation to give ribo-, arabino-, xylo-, and lyxofuranose-type phosphono sugars. The nmr data suggest a twist conformation

Various amines and alcohols are converted into the corresponding phosphamides by the action of optically active diazacyclophosphamidic chlorides and absolute configurations of amines and alcohols are readily determined by proton and phosphorus NMR of the cyclophosphamides that are formed.

Helical aromatics, 13,14-dimethyldibenzo[b,j][4,7]phenanthroline 1 and its dihydro form 2 were synthesized via a one-step reaction, resolved into each of the enantiomers by HPLC and their single crystal structures were determined.

Allylic oxidation of 2-phospholenes gave the first successful preparation of 4-oxo-2-phospholene 1-oxide derivatives, and this synthetic approach provides a ready accessible route in the synthesis of a wide variety of pentofuranose analogs of phospha sugars, having a phosphorus atom as the sugar ring hetero atom.

Treatment of 1-phenyl-2-phospholene 1-oxide with N-bromoacetamide or bromine afforded threo and erythro bromohydrins, the latter being converted into novel N-glycosides by reaction with amines. The N-t-butyl phosphono sugar glycoside exists in the 2E conformation.

Hiroko Hasegawa, Mitsuji Yamashita,* Reiko Makita, Mayumi Yamaoka, Michio Fujie, Satoki Nakamura, Tatsuo Oshikawa, Junko Yamashita, Manabu Yamada, Mitsuru Kondo, Kazutaka Hirakawa, Mitsuo Toda, Yasuo Takehara, Kazunori Ohnishi, Haruhiko Sugimura, Sophie Laurent, and Robert N. Muller 1 Graduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan 2 Faculty of Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan 3 Department of Chemistry and Biochemistry, Numazu National College of Technology, Numazu 410-8501, Japan 4 Faculty of Medicine, University of Mons, Mons, Hainaut, Belgium

Helical aromatics (1) were synthesized via one step in good quantity by solvent-free condensation of N,N'-p-phenylenediamine (2) and various carboxylic acids in the presence of a Lewis acid. Microwave irradiation greatly facilitated the condensation reaction to furnish 1 with a 100% diastereo- and a 50% enantioselectivity, when a chiral carboxylic acid was utilized. 1f, derived from 2-methylglutaric acid, was quite stable, no racemization taking place even at 200 degrees C. The assignment of the absolute configurations to the helical aromatics has been achieved by experimental and theoretical CD spectra calculated by time-dependent density functional theory.

A novel and facile synthetic method is described in the synthesis of several deoxy phospha sugar–sugar disaccharides, analogs of normal sugar disaccharides by treatment of (±)-2-bromo-3-methoxy-1-phenylphospholane 1-oxide with several pentose and hexose sugar acetonides.

1H NMR spectroscopy of phosphorus containing hetero sugars (phospha sugars), revealed the alpha and beta configurations and chair conformations for 3-acetamido-1,4-di-O-acetyl-2,3,5-trideoxy-5-C-(isopropylphosphinyl)-alpha- and beta-D-erythro-pentopyranoses. The conformation of the title compounds was determined by 1H NMR as 1C4 in CDCl3 and the conformation was in accord with that in solid state determined by X-ray crystallographic analysis.