Synthesis of Oligonucleotides Containing Fapy·dG (<i>N6</i>- (2-Deoxy-α,β-d-<i>e</i><i>rythro</i>-pentofuranosyl)-2,6- diamino-4-hydroxy-5-formamidopyrimidine)

Synthesis of Oligonucleotides Containing Fapy·dG (N6- (2-Deoxy-α,β-d-erythro-pentofuranosyl)-2,6- diamino-4-hydroxy-5-formamidopyrimidine

Ring Opening of 4‘,5‘-Epoxynucleosides: A Novel Stereoselective Entry to 4‘-<i>C</i>-Branched Nucleosides

Stereoselective synthesis of 4‘-α-carbon-substituted nucleosides has been accomplished through epoxidation of 4‘,5‘-unsaturated nucleosides with dimethyldioxirane (DMDO) and successive SnCl4-promoted ring opening of the resulting 4‘,5‘-epoxynucleosides with organosilicon reagents

Ring Opening of Nucleoside 1‘,2‘-Epoxides with Organoaluminum Reagents: Stereoselective Entry to Ribonucleosides Branched at the Anomeric Position

Epoxidation of 3‘,5‘-O-(di-tert-butylsilylene)-1‘,2‘-unsaturated uridine (11) with dimethyldioxirane proceeded from the α-face to give the 1‘,2‘-α-epoxide 12. Upon reacting with organoaluminum reagents, the 1‘,2‘-α-epoxide 12 underwent preferential syn-opening of the epoxide ring to yield the β-anomers of 1‘-methyl- (13β), 1‘-ethyl- (14β), 1‘-isobutyl- (15β), 1‘-ethynyl- (16β), 1‘-vinyl- (17β), and 1‘-phenyl- (18β) uridine derivatives, although the corresponding α-anomers were also formed except for the reaction with triphenylaluminum. It was found, however, that protection of the N3-position of 11 either with a benzyloxymethyl or benzoyl group led to the exclusive formation of the desired β-anomers. A possible explanation for the observed stereochemical outcome is presented. A similar strategy was found to be applicable to the synthesis of 1‘-branched adenosine analogues, which include protected angustmycin C (37)

Nucleophilic Substitution at the 4‘-Position of Nucleosides: New Access to a Promising Anti-HIV Agent 2‘,3‘-Didehydro-3‘-deoxy-4‘-ethynylthymidine

For the synthesis of 2‘,3‘-didehydro-3‘-deoxy-4‘-ethynylthymidine (8:  4‘-Ed4T), a recently reported promising anti-HIV agent, a new approach was developed. Since treatment of 1-(2,5-dideoxy-β-l-glycero-pent-4-enofuranosyl)thymine with Pb(OBz)4 allowed the introduction of the 4‘-benzoyloxy leaving group, nucleophilic substitution at the 4‘-position became feasible for the first time. Thus, reaction between the 4‘-benzoyloxy derivative (14) and Me3SiC⋮CAl(Et)Cl as a nucleophile led to the isolation of the desired 4‘-“down”-ethynyl derivative (18) stereoselectively in 62% yield. As an application of this approach, other 4‘-substituted nucleosides, such as the 4‘-allyl (24a) and 4‘-cyano (26a) derivatives, were synthesized using organosilicon reagents. In these instances, pretreatment of 14 with MeAlCl2 was necessary

Additive Pummerer Reaction of 3,5-<i>O</i>-(Di-<i>tert</i>-butyl)silylene-4-thiofuranoid Glycal: A High-Yield and β-Selective Entry to 4′-Thioribonucleosides

Upon reacting 3,5-O-(di-tert-butyl)silylene-4-thiofuranoid glycal S-oxide (6) with Ac2O/TMSOAc/BF3·OEt2 in CH2Cl2, the additive Pummerer reaction proceeded to furnish the corresponding 1,2-di-O-acetyl-4-thioribofuranose 7. Compound 7 serves as a highly β-selective glycosyl donor in the Vorbrüggen condensation carried out in the presence of TMSOTf. Thus, the 4-thio-β-d-ribofuranosyl derivatives of uracil, thymine, N-acetylcytosine, 6-chloropurine, and 2-amino-6-chloropurine were synthesized. The use of 7 can be extended to the β-selective synthesis of 4′-thio-C-ribonucleosides

Phenylsulfanylation of 3′,4′-Unsaturated Adenosine Employing Thiophenol-<i>N</i>-Iodosuccinimide Leads to 4′-Phenylsulfanylcordycepin: Synthesis of 4′-Substituted Cordycepins on the Basis of Substitution of the Phenylsulfanyl Leaving Group

Upon reaction of the 3′,4′-unsaturated adenosine derivative 2 with N-iodosuccinimide (NIS) and thiophenol, an unexpected electrophilic hydrophenylsulfanylation proceeded to provide 4′-phenylsulfanylcordycepin 7 in 79% yield with the ratio 7a/7b = 6.6/1. A study of the reaction mechanism revealed that hydrogen iodide (HI) generated from NIS and PhSH acted as an active species. On the basis of a deuterium experiment using PhSD, initial protonation occurred at the β face of the double bond to furnish the β-π complex III, which underwent anti addition of PhSH as a major pathway. Nucleophilic substitution of N6-pivaloylated 9 with various alcohols in the presence of N-bromosuccinimide (NBS) gave the respective 4′-α-alkoxycordycepins 15a–21a as the major stereoisomers. Use of DAST in place of an alcohol gave the 4′-α-fluoro analogue 23a stereoselectively. Radical-mediated carbon–carbon bond construction was also applicable to 7, giving 4′-α-allylcordycepin (24a) and 4′-α-cyanoethylcordycepin (25) derivatives

Solvent Effect Observed in Nucleophilic Substitution of 4′-(Benzoyloxy)cordycepin with AlMe₃: Stereochemical Evidence for S_Ni Mechanism

Nucleophilic substitution between the 4′-benzoyloxy derivative of cordycepin (3′-deoxyadenosine) and AlMe3 proceeds mostly with retention of configuration at the 4′-position: the 4′-benzoyloxy substrate having the β-d-configuration (8a) gave the 4′-methylated β-d-nucleoside (9a) with a high diastereomeric excess, while the substrate 8b having the opposite 4′-configuration gave the corresponding α-l-isomer (9b) with a comparatively lower stereoselectivity. The SNi mechanism is proposed for this reaction (from 8 to 9). The polarity of the solvent has a significant influence on the stereoselectivity, especially for the formation of 9b

Allylic Substitution of 3‘,4‘-Unsaturated Nucleosides: Organosilicon-Based Stereoselective Access to 4‘-<i>C</i>-Branched 2‘,3‘-Didehydro-2‘,3‘-dideoxyribonucleosides

Reactions of organosilicon reagents (such as allyltrimethylsilane, silyl enol ethers, cyanotrimethylsilane) with 3‘,4‘-unsaturated nucleosides (of uracil, N4-acetylcytosine, and hypoxanthine) having an allyl ester structure were investigated in the presence of a Lewis acid in CH2Cl2. In the cases of uracil and N4-acetylcytosine derivatives, SnCl4 appeared to be suitable, whereas the use of EtAlCl2 was necessary for the hypoxanthine derivatives. The main pathway of these reactions was found to be α-face-selective SN2‘ allylic substitution, irrespective of the configuration of 2‘-O-acyl leaving group. As a result, a new stereoselective operation for C−C bonds formation leading to 4‘-carbon-substituted 2‘,3‘-didehydro-2‘,3‘-dideoxyribonucleosides has been disclosed for the first time. Stereochemistry of these 4‘-C-branched products can be assigned on the basis of 1H NMR spectroscopy in terms of the anisotropic shift of H-5 of the pyrimidine base (or H-8 of the hypoxanthine), which is caused by the 5‘-O-(tert-butyldiphenylsilyl) protecting group

Probing the Configurations of Formamidopyrimidine Lesions Fapy·dA and Fapy·dG in DNA Using Endonuclease IV^†

The formamidopyrimidines Fapy·dA and Fapy·dG are produced in DNA as a result of oxidative stress. These lesions readily epimerize in water, an unusual property for nucleosides. The equilibrium mixture slightly favors the β-anomer, but the configurational status in DNA is unknown. The ability of endonuclease IV (Endo IV) to efficiently incise α-deoxyadenosine was used as a tool to determine the configuration of Fapy·dA and Fapy·dG in DNA. Endo IV incision of the C-nucleoside analogues of Fapy·dA was used to establish selectivity for the α-anomer. Incision of α-C-Fapy·dA follows Michaelis−Menten kinetics (Km = 144.0 ± 7.5 nM, kcat = 0.58 ± 0.21 min-1), but the β-isomer is a poor substrate. Fapy·dA incision is considerably slower than that of α-C-Fapy·dA, and does not proceed to completion. Endo IV incision of Fapy·dA proceeds further upon rehybridization, suggesting that the lesion reequilibrates and that the enzyme preferentially cleaves duplex DNA containing α-Fapy·dA. The extent of Fapy·dA incision suggests that the lesion exists predominantly (∼90%) as the β-anomer in DNA. Endo IV incises Fapy·dG to less than 5% under comparable reaction conditions, suggesting that the lesion exists almost exclusively as its β-anomer in DNA

Anti versus Syn Opening of Epoxides Derived from 9-(3-Deoxy-β-d-<i>g</i><i>lycero</i>-pent-3-enofuranosyl)adenine with Me₃Al: Factors Controlling the Stereoselectivity

Upon epoxidation with dimethyldioxirane, the 2‘,5‘-bis-O-silyl derivatives of 9-(3-deoxy-β-d-glycero-pent-3-enofuranosyl)adenine gave the respective “3‘,4‘-up” epoxides exclusively. Reaction between these epoxides and Me3Al was investigated in detail. It was found that the stereoselectivity of epoxide ring opening (anti versus syn) varied significantly upon changing the amount of Me3Al, the solvent, the O-silyl protecting group, and the reaction temperature. A possible reaction mechanism is proposed