Synthesis of Novel Iso-4‘-thionucleosides Using the Mitsunobu Reaction

A novel class of isomeric 4‘-thionucleosides with the base moiety at the 2‘-position was synthesized from d-glucose. The coupling of 1,4-anhydro-4-thioarabitol (13) with various nucleobases using the Mitsunobu reaction was investigated. With both purines and N3-benzoyluracils, the reaction predominantly gave β-isomers, suggesting that these were produced via an episulfonium intermediate. The β-anomers produced by the reaction of N3-benzoyluracils included both N- and O-alkylated derivatives. Interestingly, only the reaction of N3-benzoyluracil gave a mixture of N-alkylated adduct (20d) and O-alkylated bipyrimidinyl adduct (22), the structure of which was unambiguously determined by NMR spectroscopic data including HMBC and NOE. Deprotection of the Mitsunobu reaction products gave the desired iso-4‘-thionucleosides

A New Entry to Carbocyclic Nucleosides: Oxidative Coupling Reaction of Cycloalkenylsilanes with a Nucleobase Mediated by Hypervalent Iodine Reagent

A novel method for synthesizing carbocyclic nucleosides was developed. The new synthesis includes a direct coupling reaction of cycloalkenylsilanes with a silylated nucleobase catalyzed by a hypervalent iodine reagent. By applying the method, a novel carbocyclic cytidine derivative having bis(hydroxymethyl)cyclohexene as a pseudosugar moiety, designed as a potential anti-HIV agent, was successfully synthesized

New Synthesis of (±)-Isonucleosides

A novel method for synthesizing isonucleosides, a new class of anti-HIV nucleosides, is described. 2,2-Dimethyl-1,3-dioxan-5-one was converted into a dioxabicyclohexane derivative in six steps. After cleaving the epoxide group with thiophenol, the resulting product was subjected to the Mitsunobu reaction in the presence of a nucleobase to give the desired isonucleoside derivative via migration of the thiophenyl group. Removal of the thiophenyl group under radical conditions followed by deprotection led to the 4‘-substituted 2‘,3‘-dideoxyisonucleosides as a racemic mixture

Lithiation at the 6-Position of Uridine with Lithium Hexamethyldisilazide: Crucial Role of Temporary Silylation

Lithium hexamethyldisilazide (LiHMDS) can mediate silylation at the 6-position of uridine, although LiHMDS alone is not able to generate the C-6-lithiated uridine. Experimental results showed that temporary silylation of O-4 (or N-3) of the uracil ring triggers the C-6 lithiation with LiHMDS. This finding allowed us to develop an efficient intramolecular alkylation of 5‘-deoxy-5‘-iodouridine to furnish 6,5‘-C-cyclouridine

Solubility and Supersaturation-Dependent Protein Misfolding Revealed by Ultrasonication

Although alcohols are useful cosolvents for producing amyloid fibrils, the underlying mechanism of alcohol-dependent fibrillation is unclear. We studied the alcohol-induced fibrillation of hen egg-white lysozyme at various concentrations of ethanol, 2,2,2-trifluoroethanol (TFE), and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). Under the conditions where the alcohol-denatured lysozyme retained metastability, ultrasonication effectively triggered fibrillation. The optimal alcohol concentration depended on the alcohol species. HFIP showed a sharp maximum at 12–16%. For TFE, a broad maximum at 40–80% was observed. Ethanol exhibited only an increase in fibrillation above 60%. These profiles were opposite to the equilibrium solubility of lysozyme in water/alcohol mixtures. The results indicate that although fibrillation is determined by solubility, supersaturation prevents conformational transitions and ultrasonication is highly effective in minimizing an effect of supersaturation. We propose an alcohol-dependent protein misfolding funnel useful for examining amyloidogenicity. This misfolding funnel will apply to fibrillation under physiological conditions where biological environments play important roles in decreasing the solubility

Novel Stereoselective Entry to 2‘-β-Carbon-Substituted 2‘-Deoxy-4‘-thionucleosides from 4-Thiofuranoid Glycals

2‘-β-Methyl- and 2‘-β-hydroxymethyl-2‘-deoxy-4‘-thionucleosides have been synthesized through PhSeCl-mediated electrophilic glycosidation using 4-thiofuranoid glycals having carbon substituents at the C2-position as a glycosyl donor. Preparation of these glycals were carried out by means of the C2 lithiation of 1-chloro-4-thiofuranoid glycal with LTMP followed by the Birch reduction of the chlorine atom

Design and Synthesis of Isonucleosides Constructed on a 2-Oxa-6-thiabicyclo[3.2.0]heptane Scaffold

A novel method for the design and synthesis of an isonucleoside containing a 2-oxa-6-thiobicyclo[3.2.0]heptane skeleton is described. 2,2-Dimethyl-1,3-dioxan-5-one 13 was converted into a dioxabicyclohexane derivative in six steps. After cleavage of the epoxide group with a thiol (thiophenol or PMB mercaptan), the resulting product was subjected to the Mitsunobu reaction in the presence of a nucleobase. The reaction proceeded via the migration of the thiosulfide groups and gave the desired isonucleoside derivatives. In the case of a phenyl sulfide derivative, radical desulfurization followed by deprotection gave 4′-substituted 2′,3′-dideoxyisonucleosides. A PMB sulfide derivative, on the other hand, was converted into the corresponding dimesylate, which was then treated with mercury acetate and trifluoroacetic acid to remove the PMB group. The resulting thiol derivative was treated with DBU to give the desired isonucleoside constructed on a 2-oxa-6-thiobicyclo[3.2.0]heptane scaffold after deprotection. The optimized conformer of the isonucleoside was calculated using DFT at the B3LYP/6-31G** level and was compared with that of lamivudine using model compounds

Nucleosides and Nucleotides. 177. 9-(6,7-Dideoxy-β-d-<i>a</i><i>llo</i>-hept-5- ynofuranosyl)adenine: A Selective and Potent Ligand for P₃ Purinoceptor-like Protein

Nucleosides and Nucleotides. 177. 9-(6,7-Dideoxy-β-d-allo-hept-5- ynofuranosyl)adenine:  A Selective and Potent Ligand for P3 Purinoceptor-like Protei

An Access to the β-Anomer of 4′-Thio-C-ribonucleosides: Hydroboration of 1-<i>C</i>-Aryl- or 1-<i>C</i>-Heteroaryl-4-thiofuranoid Glycals and Its Regiochemical Outcome

We have developed a novel method for the synthesis of the β-anomer of 4′-thio-C-ribonucleosides from 3,5-O-(di-tert-butylsilylene)-4-thiofuranoid glycal. Palladium-catalyzed coupling of 1-tributylstannyl-4-thiofuranoid glycal with iodobenzene or a heteroaryl halide gave 1-C-phenyl- or 1-C-heteroaryl-glycals. Hydroboration of these glycals proceeded at the α-face, and subsequent alkaline hydrogen peroxide treatment of the resulting 2′-α-borane furnished the respective β-anomer of 4′-thio-C-ribonucleosides. These results demonstrate that this synthetic method has a wider scope in terms of heterocyclic base structure. During this study, unexpected Markovnikov-oriented hydroboration has been observed to lead to the respective 1′-α-boranes. These 1′-boranes were converted into either the ring-opened structure or the 2′-deoxy derivatives depending upon their stability

A Novel Synthesis of New Antineoplastic 2‘-Deoxy-2‘-substituted-4‘-thiocytidines

A Novel Synthesis of New Antineoplastic 2‘-Deoxy-2‘-substituted-4‘-thiocytidine