Cyclic Phosphate Derivatives Research Articles

Influence of hydroxyl-terminated phosphoramidates on the flame retardancy of microfiber synthetic leather

As the ideal substitute for natural leather, microfiber synthetic leather (MSL) possesses excellent mechanical/chemical properties and have been commonly applied in our daily life. However, the flammability strictly limits its application in the field with high fire-safety requirement. Herein, three classical phosphorus-containing compounds with terminated hydroxyl groups, named as DTP-OH (dimethyl phosphate derivative), DPPC-OH (cyclic phosphate derivative) and DOPO-OH (DOPO derivative), were synthesized and served as the flame-retardant coating on microfiber synthetic leather. The influence of different phosphoramidates on the flame-retardant performance of microfiber synthetic leather was investigated by vertical flammability test (VFT) and limited oxygen index (LOI). Among them, DPPC-OH and DOPO-OH had better flame retardant efficiency with the comparable loadings. The LOI value increased from 18.1% to 25.7% and 26.1% respectively after coating with DPPC-OH and DOPO-OH, and they successfully passed the vertical burning test. Meanwhile, the thermal degradation and combustion behavior were also analyzed to further confirm the flame-retardant mechanism. It was found that these hydroxyl-terminated phosphoramidates can efficiently improve the char-forming ability of microfiber synthetic leather and the peak heat release rate (PHRR) reduced by 37% for the DPPC-OH modified microfiber synthetic leather. This work indicates that cyclic phosphate and DOPO derivatives has a good application prospect in the preparation of fire-safety microfiber synthetic leather.

Preparation of β-Amino Esters by a Chiral Brønsted Acid Catalyzed Mannich-Type Reaction

Mannich-type reactions of ketene silyl acetals with aldimines proceeded smoothly under the influence of 10 mol% of a cyclic chiral phosphate derivative derived from (R)-BINOL as a chiral Brønsted acid catalyst to furnish β-amino esters with excellent enantio­selectivities.

A proposal for a convenient notation for P-chiral nucleotide analogues. Part 3. Compounds with one nucleoside residue and nonnucleosidic derivatives

Recently, we have proposed a new DP/LP stereochemical notation for P-chiral dinucleoside monophosphate analogues that permits simple correlation between spatial arrangement of the substituents and the configuration at the phosphorus center. As an extension of this work, we present here applications of the DP/LP notation to derivatives containing only one nucleoside unit (e.g., alkyl nucleoside phosphodiesters, nucleoside phosphomonoesters, cyclic phosphate derivatives, nucleoside di-, and triphosphates) and to nonnucleosidic phosphorus compounds.

Identification of Phosphorylcholine-Substituted Peptides by Their Characteristic Mass Spectrometric Fragmentation

Phosphorylcholine (PC) substituted biomolecules are wide-spread, highly relevant antigens of parasites, since this small hapten has been found to be a potent immunomodulatory component which allows the establishment of long lasting infections of the host. Structural data, especially of protein bound PC-substituents, are still rare due to the observation that mass spectrometric analyses are mostly hampered by this zwitterionic substituent resulting in low sensitivities and unusual but characteristic fragmentation patterns. Here we investigated the fragmentation behaviour of synthetic PC-substituted peptides by matrix-assisted laser desorption/ionization mass spectrometry and electrospray ionization ion trap mass spectrometry. We could show that the predominant neutral loss of a trimethylamine unit (Hoffmann elimination) leads to cyclic phosphate derivatives which prevent further fragmentation of the peptide backbone by stabilizing the positive charge at this particular side chain. Knowledge of this PC-specific fragmentation might help to identify PC-substituted biomolecules and facilitate their structural analysis.

2,4‐Dinitrophenol as an Activating Reagent in a Facile Preparation of Cyclic Phosphate Triesters.

AbstractFor Abstract see ChemInform Abstract in Full Text.

2,4-Dinitrophenol as an activating reagent in a facile preparation of cyclic phosphate triesters

2,4-Dinitrophenol was employed with benzyloxy-bis-(diisopropylamino)phosphine to synthesise the cyclic phosphate derivatives of a series of alkane diols (HO–(CH 2) n –OH, n=2–6) in good isolated yields. Tetrazole and DNP were compared by 31P NMR spectroscopy for their ability to catalyse the cyclisation at the P(III) stage. Investigation of the phosphate triester stability under various oxidation and chromatographic conditions resulted in the optimisation of the isolation procedures of the chemically unstable cyclic compounds. Conditions for debenzylation were developed to yield the corresponding cyclic phosphodiesters quantitatively. The methodology was further applied to the preparation and isolation of the cyclic phosphate derivative of a carbohydrate.

Total synthesis of an antitumor antibiotic, Fostriecin (CI-920).

The total synthesis of an antitumor antibiotic, fostriecin (CI-920), via a highly convergent route is described. A characteristic feature of the present total synthesis is that the synthesis was achieved via a coupling procedure of three segments A, B, and C. The unsaturated lactone moiety of fostriecin, corresponding to segment A, was constructed from a known Horner-Emmons reagent, and the stereochemistry of the C-5 position was introduced by asymmetric reduction with (R)-BINAl-H. Segment B having a series of stereogenic centers was synthesized from (R)-malic acid and the stereogenic centers at the C-8 and C-9 positions were prepared by a combination of Wittig reaction and Sharpless asymmetric dihydroxylation reaction. The conjugated Z,Z,E-triene moiety of fostriecin, corresponding to segment C, was eventually constructed by Wittig reaction and Stille coupling reaction. The phosphate moiety, which is known to be essentially important for the antitumor activity, was introduced via two routes: (i) direct phosphorylation of the monohydroxyl derivative in which other hydroxyl groups are protected with silyl groups; (ii) cyclic phosphorylation and selective cleavage of the cyclic phosphate derivative. Although the former route is basically the same as those reported by other groups, the latter route is novel and more effective than the former one. The present total synthesis would serve as a versatile synthetic route to not only fostriecin, but also its various analogues including stereoisomers.

Determination of the Relative and Absolute Stereochemistry of Fostriecin (CI-920)

The absolute stereochemistry of fostriecin (1, CI-920), a potent antitumor antibiotic presently in Phase I clinical trials at NCI, was determined to be 5R,8R,9R,11R. 2D 1H−1H NMR NOE experiments conducted on the cyclic phosphate derivative 2 and acetonide 4 revealed a syn-diol stereochemical relationship between C8 and C9 and an anti-diol stereochemical relationship between C9 and C11, respectively. The 5R absolute configuration assignment was confirmed by synthesis of the degradation product 8 previously disclosed. Additional degradation studies of 1 to provide 7 and chiral-phase HPLC comparison with a sample of known chirality established the absolute stereochemistry of C11 to be R. This, along with the relative stereochemical assignments established the full set of absolute stereochemistry assignments for 1.

A synthetic study on cyclic phosphate derivatives of seconucleosides as potential antiviral agents (II): Synthesis of 3′, 5′-cyclic phosphates of 6-aza-2′-azido-secouridine

The synthesis of 6-aza-3′, 5′-p-nitrophenylphosphoryltrioxy-2′-azido-2′-deoxy-2′,3′-secouridine and 6-aza-3′,5′-phosphoryltrioxy-2′-azido-2′-deoxy-2′,3′-secouridine ammonium salt are described and they were evaluated for antiviral activity primarily against DNA and RNA viruses and found to be inactive, but no significant cytocidal effect was observed against Vero and Hela cell.

A synthetic study on cyclic phosphate derivatives of seconucleosides as potential antiviral agents (I). Synthesis of 3',5'-cyclic phosphates of 2'-substituted secouridines and secoribavirins.

The synthetic study of 3',5-cyclic phosphates of 2'-substituted 2',3'-secouridines and 2',3'-secoribavirins toward development of new antiviral agents is described. These cyclic phosphates were synthesized from their respective 4-nitrophenyl 3',5'-cyclic phosphate triesters. These triesters were prepared from the corresponding 2'-azido and 2'-bromo 2',3'-seconucleosides.

Synthesis and antiviral activity of 9-alkoxypurines. 1. 9-(3-Hydroxypropoxy)- and 9-[3-hydroxy-2-(hydroxymethyl)propoxy]purines

Reaction of hydroxyl-protected derivatives of hydroxyalkoxyamines (3a,b,c) with either 4,6-dichloro-2,5-diformamidopyrimidine (5) or 4,6-dichloro-5-formamidopyrimidine (31) and subsequent cyclization of the resultant 6-(alkoxyamino)pyrimidines (6, 17, 32, 35) by heating with diethoxymethyl acetate afforded 9-alkoxy-6-chloropurines (7, 18, 33, 36), which were converted subsequently to 9-(3-hydroxypropoxy)- and 9-[3-hydroxy-2-(hydroxymethyl)propoxy] derivatives of guanine, 2-amino-6-chloropurine, 2-amino-6-alkoxypurines, 2-aminopurine, 2,6-diaminopurine, adenine, hypoxanthine, and 6-methoxypurine (8, 12, 13, 19-21, 23-26, 34, 37-39). Carboxylic acid esters (9-11, 14-16, 27-29) and a cyclic phosphate derivative (22) of the 9-(hydroxyalkoxy)guanines (8, 21) and 2-amino-9-(hydroxyalkoxy)purines (13, 26) were also prepared. The guanine derivatives (8, 21) showed potent and selective activity against herpes simplex virus types 1 and 2 and varicella zoster virus in cell cultures and 8 is more active than acyclovir. Although without significant antiviral activity in cell cultures, the 2-aminopurines (13, 14-16, 26-29) and 2-amino-6-alkoxypurines (12, 23-25) are well absorbed after oral administration to mice and are converted efficiently to the antiviral guanine derivatives (8, 21) in vivo.

Effect of 2'-nor-cyclic GMP against guinea pig cytomegalovirus infection

Cyclic phosphate derivative of DHPG, 2'-nor-cGMP [9-[(2-hydroxy-1,3,2-dioxaphosphorinan-5-yl)oxymethyl]-guani ne phosphate-oxide] was evaluated for activity against guinea pig cytomegalovirus (GPCMV) infection in cultured guinea pig embryo cells and in guinea pigs. By virus yield reduction and plaque reduction assays, 2'-nor-cGMP was demonstrated to be 15- to 20-fold more potent against GPCMV infection than its parental drug DHPG. The selectivity index of 2-nor-cGMP was 110, which was 10-fold higher than that of DHPG. In cultured cells, 2'-nor-cGMP attained maximal antiviral activity when added to the cells within 12 h postinfection. In the studies on GPCMV infection in guinea pigs, 2'-nor-cGMP administered subcutaneously once daily (5 mg/kg per day) for 8 days, starting 24 after virus inoculation, significantly suppressed GPCMV infectivity titers in the blood, spleen, lung, and salivary gland during acute infection (10 days postinfection) as compared with sham-treated infected animals. A greater reduction of GPCMV infectivity titers in the salivary gland was noted during chronic infection (i.e., 24 days postinfection). Clinically, splenomegaly and peripheral lymphocytosis were significantly modified as compared with the sham-treated animals (P less than 0.05). The drug, administered at this dosage, was reasonably tolerated by the guinea pigs and showed clinical benefit.

Inhibition of HSV-transformed murine cells by nucleoside analogs, 2′-NDG and 2′-nor-cGMP: Mechanisms of inhibition and reversal by exogenous Nucleosides

A murine cell line transformed with HSV TK (LH-1) exhibits a greatly enhanced cytotoxicity to the nucleoside analog 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy) methyl]guanine (2′-NDG) as compared to the parental LM cell line ( I 50 LH-1 = 0.4 μ M, I 50 LM = 44.4 μ M). Toxicity of 2′-NDG for LH-1 and LM is reversed only by the addition of 100 μ M thymidine (dThd), indicating that 2′-NDG is a substrate for the viral and cellular TK. In LM(TK −) cells-murine cells expressing no TK activity, 2′-NDG cytotoxicity is partially reversed only with dGuo. A cyclic phosphate derivative of 2′-NDG, 2′-norcGMP, contains a phosphodiester bond, is also taken up by cells, and does not depend on viral TK for activation. LH-1 cells and LM(TK −) cells are inhibited by similar concentrations of this analog (5.1 and 4.1 μ M, respectively). In all three cell lines (LM, LH-1, LM(TK-)), the toxicity of 2′-nor-cGMP is significantly reversed with dGuo or cyclic dGMP. This pattern of reversal differs significantly from that observed with 2′-NDG, suggesting that 2′-nor-cGMP is metabolized as a guanosine analog, similar to acyclovir, in LM and LM(TK −) cells. These results indicate that a cyclic monophosphate analog of 2′-NDG can be activated independently of viral TK expression and that cellular metabolic pathways resulting in elevated dGTP concentrations are important for reversal of toxicity induced by guanosine-like nucleoside analogs.

HIGHLY STEREOSELECTIVE SYNTHESIS OF α-RIBONUCLEOTIDES VIA A CYCLIC PHOSPHATE

Abstract Several α-ribonucleotides are conveniently synthesized from the cyclic phosphate derivatives of ribose and nucleoside bases in highly stereoselective manner.

The enzymatic conversion of 3'-phosphate terminated RNA chains to 2',3'-cyclic phosphate derivatives.

The enzyme, RNA cyclase, has been purified from cell-free extracts of HeLa cells approximately 6000-fold. The enzyme catalyzes the conversion of 3'-phosphate ends of RNA chains to the 2',3'-cyclic phosphate derivative in the presence of ATP or adenosine 5'-(gamma-thio)triphosphate (ATP gamma S) and Mg2+. The formation of 1 mol of 2',3'-cyclic phosphate ends is associated with the disappearance of 1 mol of 3'-phosphate termini and the hydrolysis of 1 mol of ATP gamma S to AMP and thiopyrophosphate. No other nucleotides could substitute for ATP or ATP gamma S in the reaction. The reaction catalyzed by RNA cyclase was not reversible and exchange reactions between [32P]pyrophosphate and ATP were not detected. However, an enzyme-AMP intermediate could be identified that was hydrolyzed by the addition of inorganic pyrophosphate or 3'-phosphate terminated RNA chains but not by 3'-OH terminated chains or inorganic phosphate. 3'-[32P](Up)10Gp* could be converted to a form that yielded, (Formula: see text) after degradation with nuclease P1, by the addition of wheat germ RNA ligase, 5'-hydroxylpolynucleotide kinase, RNA cyclase, and ATP. This indicates that the RNA cyclase had catalyzed the formation of the 2',3'-cyclic phosphate derivative, the kinase had phosphorylated the 5'-hydroxyl end of the RNA, and the wheat germ RNA ligase had catalyzed the formation of a 3',5'-phosphodiester linkage concomitant with the conversion of the 2',3'-cyclic end to a 2'-phosphate terminated residue.

Improved Synthesis of 2′-Fluoro-2′-Deoxyadenosine and Synthesis and Carbon-13 NMR Spectrum of Its 3′,5′-Cyclic Phosphate Derivative1

Abstract Some improvements were made on synthetic method for 2′-fluoro-2′-deoxyadenosine (11). Thus 11 was obtained in an overall yield of 9.3% starting from adenosine. 2′-Fluoro-2′-deoxyadenosine 3′,5′-cyclic phosphate (13), an analogue of cAMP, was synthesized from 11. The carbon-13 NMR spectrum was measured. The sugar carbon signals can be unambiguously assigned since the C1′ C2′ and C3′ have different 13C-19F coupling constants. Comparison of the data with those of other 3′,5′-cyclic phosphate derivatives confirms the assignments of C3′ and C4′ signals previously proposed by us.

Reduction-elimination of cyclic phosphate derivatives as a route to alkenes

Reduction-elimination of cyclic phosphate derivatives as a route to alkenes

Studies on the syntheses of compounds related to adenosine 3',5'-cyclic phosphate. II. Removal of etheno group of 2-substituted 1,N6-etheno-adenosine 3',5'-cyclic phosphates.

Treatment of 2-substituted 1, N6-etheno-c-AMP (c-AMP : adenosine 3', 5'-cyclic phosphate) derivatives with N-bromosuccinimide (NBS) under mild conditions gave the corresponding 2-substituted-c-AMP. Therefore, the route (c-AMP→1, N6-etheno-c-AMP→2-substituted 1, N6-etheno-c-AMP→2-substituted c-AMP) offers an excellent way to synthesize the last compound from c-AMP. The yields of this deblocking reaction of the etheno group were increased by the adjustment of the solution to alkaline after bromination. The probable reaction mechanism involving the bromination and the subsequent hydrolysis has been proposed.

Feedback Inhibition by 6-Methylthioinosine 3',5'-Cyclic Monophosphate in Tumor Cells Resistant to the Nucleoside

The 3',5'-cyclic phosphate derivative (cMTIMP) of methylthioinosine (MTI) was shown to produce feedback inhibition of the de novo purine pathway in an Ehrlich ascites tumor subline resistant to MTI because of lack of adenosine kinase activity for the nucleoside analog.

The Synthesis of Alkenes via Reduction-Elimination of 1,2-Diol Cyclic Phosphate Derivatives

Abstract In connection with studies on the synthesis of hindered olefins we required a method for the conversion of ditertiary erythro vicinal glycols to tetrasubstituted E-alkenes, a process requiring net anti elimination of H2O2.1