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

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

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)

Pd-Catalyzed Selective Synthesis of Cyclic Sulfonamides and Sulfinamides Using K₂S₂O₅ as a Sulfur Dioxide Surrogate

A variety of cyclic sulfonamides and sulfinamides could be selectively synthesized under Pd catalysis using haloarenes bearing amino groups and a sulfur dioxide (SO₂) surrogate. The amount of base was key in determining the selectivity. Mechanistic studies revealed that sulfinamides were initially formed via an unprecedented formal insertion of sulfur monoxide and were oxidized to sulfonamides in the presence of an iodide ion and DMSO

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

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

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

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