Mohamad B. Ksebati

Synthesis of aza-C-disaccharides - a new class of sugar mimics

Abstract Synthesis of a novel aza- C -disaccharide is described using a Suzuki coupling of the alkyl boron reagent 8 and vinyl bromide 7 as the key step.

Synthesis of phosphonate derivatives of methylenecyclopropane nucleoside analogues by alkylation–elimination method and unusual opening of cyclopropane ring

Abstract The synthesis of phosphonates of methylenecyclopropane nucleoside analogues 15a–18a , 15b–18b and 15c–18c by alkylation–elimination approach is described. In a foreshortened series, methanesulfonate 19 was transformed by Michaelis–Becker reaction with diethyl or diisopropyl phosphite to methylenecyclopropane phosphonates 20a or 20b . The latter were converted to vicinal dibromides 21a and 21b which were then used for alkylation–elimination of nucleic acid bases (adenine) or precursors (2-amino-6-chloropurine and N4-acetylcytosine). The intermediary Z+E-isomers 22a + 23a and 22b + 23b were dealkylated with bromo- of iodotrimethylsilane to free phosphonic acids 15a , 16a and phosphonate with an open cyclopropane ring 25 which were separated by ion exchange chromatography on Dowex 1. Phosphonate diesters 22c and 23c were separated by chromatography on silica gel, they were hydrolyzed to guanine derivatives 22d and 23d which were then dealkylated to give target analogues 15b , 16b and products of addition of hydrogen bromide or iodide across the double bond 26a or 26b . The E+Z-isomers 22e + 23e were converted to cytosine phosphonates 15c + 16c and cyclic phosphonate with an open cyclopropane ring 27a . In a homologous series of phosphonates, dibromocyclopropane 34 was converted to intermediate 31 by reaction with diisopropyl methyl phosphonate and subsequent β-elimination. Compound 31 was transformed to vicinal dibromide 36 , a key component for alkylation–elimination of nucleic acid bases. The rest of the synthetic sequence followed the scheme described for the series of lower homologues to give the Z-isomeric phosphonates 17a , 17b , E-isomers 18a , 18b and E+Z-isomers 17c + 18c as the final products. All methylenecyclopropane phosphonates were devoid of antiviral activity with the exception of guanine derivative 15b which inhibited the replication of varicella zoster virus (VZV) and it was non-cytotoxic.

15N NMR and electronic properties of S-nitrosothiols.

Investigation of the 15N NMR of S-nitrosothiols showed that primary and tertiary RSNOs have distinct 15N chemical shifts around 730 and 790 ppm, respectively. Using 15N NMR technique, the equilibrium constant of NO transfer between SNAP and GSH was found to be 0.74. For primary RSNOs, linear relationships exist among 15N NMR chemical shifts, reduction potentials, and the pK(a)s of their parent thiols.

Expeditious syntheses of two carbohydrate-linked cisplatin analogs

The syntheses of two carbohydrate-linked cisplatin analogs, namely lacto- and alpha-Gal-cisplatin, are described. A fusion enzymatic approach was used to create the diazido-alpha-Gal trisaccharide intermediate in the synthesis of alpha-Gal-cisplatin.

Synthesis of (Z)- and (E)-9-[(2-hydroxyethylidene)cyclopropyl]adenine--new methylenecyclopropane analogues of adenosine and their substrate activity for adenosine deaminase.

Abstract Synthesis of Z- and E-methylenecyclopropane analogues of adenosine 3 and 4 by alkylation of adenine with novel alkylating agent 5 is described. The E-isomer 4 is a substrate for adenosine deaminase. Compounds 3 and 4 were tested for antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1.

Conformational analysis of an α-galactosyl trisaccharide epitope involved in hyperacute rejection upon xenotransplantation

alpha-Galactosyl epitopes are carbohydrate structures bearing an alpha-Gal-(1-->3)-Gal terminus (alpha-Gal epitopes). The interaction of these epitopes on the surface of animal cells with anti alpha-Gal antibodies in human serum is believed to be the main cause in antibody-mediated hyperacute rejection in xenotransplantation. In this paper, conformational analysis of an N-linked alpha-D-Galp-(1-->3)-beta-D-Galp-(1-->4)-beta-D-Glcp trisaccharide epitope was conducted in terms of each monosaccharide residue conformation, primary hydroxymethyl group configuration, and interglycosidic conformations. Selective 2D J-delta INEPT experiments have been carried out at three different temperatures to evaluate three-bond, long-range 13C-1H coupling constants for the crucial alpha-(1-->3) linkage. The NMR experimental data were complemented by theoretical calculations. The flexibility and dynamics of the trisaccharide have been studied by Metropolis Monte Carlo simulations. Ensemble-averaged three-bond, long-range 13C-1H coupling constants and nuclear Overhauser effects were in good agreement with the experimental data. The alpha-(1-->3) glycosidic linkage has shown a restricted flexibility as indicated by NMR spectroscopy and molecular modeling.

Synthesis and conformational analysis of di-13C-labeled farnesyl diphosphate analogs

Abstract Two di- 13 C-labeled farnesyl diphosphates ( 2 and 4 ) have been prepared using modified versions of the isoprenoid triflate route previously developed in this laboratory. The 3 J C C coupling constants for the precursor alcohols 1 and 3 are 1.6 Hz and 3.6 Hz, respectively, in CDCl 3 , and very similar results were obtained for 2 and 4 in D 2 O. This indicates a skew or gauche conformation about the C 3 C 4 bond and a trans conformation about the C 4 C 5 bond in both farnesol and FPP.

Ytterbium(III) triflate-catalyzed electrophilic cyclization of glyoxalate-derived unsaturated imines

Ytterbium(III) triflate was found to catalyze the electrophilic cyclization of some glyoxalate-derived unsaturated imines. The cyclization reactions gave exclusively fused amino γ-lactone products with good stereoselectivity. Moreover, a solid-phase version of the lanthanide-catalyzed reaction featured a lactonization with simultaneous cleavage of the product from the solid support.

Synthesis and antiviral activity of methylenedifluorocyclopropane analogues of nucleosides.

Synthesis and antiviral activity of methylenedifluorocyclopropane analogues 8a, 8b and 9a, 9b are described.

Synthesis, transformations and biological activity of chloro enamines and ynamines derived from chloroalkenyl- and alkynyl-N-substituted purine and pyrimidine bases of nucleic acids

Reactions of nucleic acid bases and related heterocycles 1–5, 18 and 22 with tetra-, tri- and dichloroethylenes 6–9 in hexamethylphosphoric triamide gave the corresponding N-trichloro-, -dichloro- and -chloro- enamines 11–17, 19, 20, 23 and 24 in high regioselectivity (N9 for purines and N1 for pyrimidines). Bases 1, 5, 18, 22 and trichloroethylene 7 gave the respective E-dichloro enamines 15, 16, 20 and 24. Compounds 16 and 20 were identical with the products obtained by addition of bases 1 and 18 to dichloroacetylene. Thymine 18 and compound 7 gave N1,N3-bisdichloro enamine 21 as the major product. The latter exists at room temperature as a mixture of rotamers 28 and 29(ΔG‡≅ 18 kcal mol–1). The reaction of adenine 1 with (Z)-1,2- or 1,1-dichloroethylene 8 or 9 furnished Z-chloro enamine 17 whereas thymine 18 and tetrachloroethylene 6 in dimethyl sulfoxide afforded a reduction product 20. Benzoylation of N9-(trichlorovinyl)adenine 11 gave N6,N6-dibenzoyl derivative 26. The reaction of N1-(dichlorovinyl)cytosine 24 with N,N-dimethylformamide dimethyl acetal afforded amidine 25. Interaction of (E)-N9-(dichlorovinyl)adenine 16 with sodium methoxide gave exclusively E-enamine 27. Trichloro enamines 11–14, 19, 23 and 26 were transformed to ynamines 30–35. Hydrogenation of compounds 30 and 35 furnished N9-ethyladenine 36 and N1-ethylthymine 37. Alkylation of ynamine 30 with acetone 38 gave only carbinol 41 whereas cyclohexanone 39 gave both compound 42 and cyclic ketal 43. The reaction of ynamines 30 and 35 with ketone 40 afforded only ketals 44 and 45. The reaction of compound 30 with N,N-dimethylformamide dimethyl acetal led to N-dimethylaminomethylene derivative 46. Ynamine 30 is a substrate for adenosine deaminase.