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

Synthesis and Anti-Human Immunodeficiency Virus Activity of 4‘-Branched (±)-4‘-Thiostavudines

Motivated by our recent finding that 4‘-ethynylstavudine (4) is a promising anti-human immunodeficiency virus type 1 (HIV-1) agent, we synthesized its 4‘-thio analogue, as well as other 4‘-thiostavudines having a carbon substituent at the 4‘-position, as racemates in this study. Methyl 3-oxo-tetrahydrothiophen-2-carboxylate (5) was used as a starting material to construct the requisite 4-thiofuranoid glycal (13). Introduction of a thymine base was carried out by an electrophilic addition reaction to 13 using N-iodosuccinimide (NIS) and bis(trimethylsilyl)thymine. The desired β-anomer (16β) obtained as a major product in this reaction underwent ready elimination with activated Zn to give the 4‘-carbomethoxy derivative (18). By using 18 as a common intermediate, 4‘-carbon-substituted (CH2OH, CO2Me, CONH2, CHCH2, CN, and C⋮CH) 4‘-thiostavudines were prepared. Among these six compounds, 4‘-cyano (28) and 4‘-ethynyl (29) analogues were found to show inhibitory activity against HIV-1 with ED50 values of 7.6 and 0.74 μM, respectively. The activity of 29 was comparable to that of stavudine, but 29 was not as active as 4. Optical resolution of 29 was briefly examined

5-<i>Exo</i> versus 6-<i>Endo</i> Cyclization of Nucleoside 2-Sila-5-hexenyl Radicals: Reaction of 6-(Bromomethyl)dimethylsilyl 1‘,2‘-Unsaturated Uridines

The mode of cyclization of 2-sila-5-hexen-1-yl radicals generated from 6-(bromomethyl)dimethylsilyl-1‘,2‘-unsaturated uridines was investigated. In contrast to the case of the 2‘-unsubstituted 6-silicon-tethered substrate (4), which undergoes exclusive 6-endo-cyclization, reactions of the 2‘-substituted (Me, CO2Me, OBz, and Cl) derivatives (14, 20, 22, and 24) uniformly proceeded in preferential or exclusive 5-exo-mode. The Tamao oxidation of the resulting cyclized products was also carried out to synthesize the corresponding 1‘-C-hydroxymethyl derivatives

Diastereoselective Synthesis of 6″‑(<i>Z</i>)- and 6″‑(<i>E</i>)‑Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers

A method for the diastereoselective synthesis of 6″-(<i>Z</i>)- and 6″‑(<i>E</i>)-fluorinated analogues of the anti-HBV agent entecavir has been developed. Construction of the methylenecyclopentane skeleton of the target molecules has been accomplished by radical-mediated 5-<i>exo</i>-<i>dig</i> cyclization of the selenides <b>6</b> and <b>15</b> having the phenylsulfanylethynyl structure as a radical accepting moiety. In the radical reaction of the TBS-protected precursor <b>6</b>, (<i>Z</i>)-<i>anti</i>-<b>12</b> was formed as a major product. On the other hand, TIPS-protected <b>15</b> gave (<i>E</i>)-<i>anti</i>-<b>12</b>. The sulfur-extrusive stannylation of <i>anti</i>-<b>12</b> furnished a mixture of geometric isomers of the respective vinylstannane, whereas benzoyl-protected <b>17</b> underwent the stannylation in the manner of retention of configuration. Following XeF₂-mediated fluorination, introduction of the purine base and deoxygenation of the resulting carbocyclic guanosine gave the target (<i>E</i>)- and (<i>Z</i>)-<b>3</b> after deprotection. Evaluation of the anti-HBV activity of <b>3</b> revealed that fluorine-substitution at the 6″-position of entecavir gave rise to a reduction in the cytotoxicity in HepG2 cells with retention of the antiviral activity