The preparation of 2'-deoxy-2'-fluoro-1',2'-seconucleosides as potential antiviral agents

Abstract

The preparation of (R,R)-1,3-dibenzyl-4-fluorobutane-1,2,3-triol (6) from D-isoascorbic acid and subsequent chloromethylation of this chiron made possible the synthesis of a series of 2'-deoxy-2'-fluoro-1',2'-seconucleosides. Among them were the uridine (10), thymidine, (11), 5-iodouridine (14), ribavirin (17), and guanosine (19) analogues. They were evaluated for antiviral activity primarily against RNA viruses and found to be inactive. In addition to the aforementioned acyclonucleosides, the 3',5'-cyclic phosphates of the uridine (22) and thymidine (23) analogues were prepared from their respective 4-nitrophenyl 3',5'-cyclic phosphate triesters. The triesters were also examined for antiviral activity, but like their nucleoside counterparts exhibited only marginal activity.

Synthesis of Phosphonate Isosteres of 2‘-Deoxy-1‘,2‘-seco-nucleotides

“…Chloromethylation of 1 − 5 was carried out with paraformaldehyde and hydrogen chloride gas in dry dichloromethane (CH 2 Cl 2 ) at 0 °C. If desired, the percent purity of 1a − 5a (Scheme ) can be determined from the characteristic OC H 2 Cl resonance typically at δ 5.6 in their respective 1 H NMR spectra . In most cases, they were used immediately in the alkylation of the desired nucleobase.…”

Synthesis of 1‐[(3‐Halo‐1‐Hydroxy‐2‐Propoxy)methyl]uracil and Thymine as Potential Antiviral Agents

“…The lower dark layer was separated ancI washed with aqueos NaHS03 (5%) several timesfapproxirnately 10 mL x 3) until the upper layer was colorless. The chloroform solution was dried over anhydrous MgS04, filtered and concentrated under diminished pressure to afford an oily residue, 9 (18.7 General Procedure for the Preparation of I.Benzyloxy-3-halogen-2-chloromethoxypropane (10)(11)(12)(13) I-Benzyloxy-3-halogcn-2-propanoI6-9 (20 mmol) and paraformaldehyde (1.2 g) were added to dry 1,2-dichloroethane (100 mL, distilled from P20S) respectively. The mixture was cooled in an icc bath and bubbled with dry Hel gas which was generated from NaCi and H2S04 (95-98%), and stirred at 0°C for 6 h; the solution became clear at the end of reaction.…”

“…Anhydrous eaCh was added; the solution was stirred, and allowed to warm to room temperature; the solution was collected by filtration. The filtrate was concentrated at reduced pressure to furnish 1-benzyloxy-3-Iluoro-Z-chloromethoxy-propaue (10), I-benzyloxyl-3-chloro-2-chloromethoxypropane (11), 1-benzyloxy-3-bromo-2-chloromethoxypropane (12), and I-benzyloxy-3-iodo-2-chloromethoxypropane (13), as syrups respectively. Due to their instability, these syrups were directly used for the next reaction without further purification.…”

Synthesis of Chiral Acyclic Pyrimidine Nucleosides with a Sulfur‐Containing Side Chain via Enantioselective Tandem Conjugate Addition/Protonation

“…Conventional routes to synthesize chiral pyrimidine acyclic nucleosides are based on a chiral pool strategy in which a prepared chiral side chain is coupled with a pyrimidine nucleobase . Representative routes for this approach are as follows: i) alkylation reaction of pyrimidines with halogenated chiral side chains; ii) epoxide ring‐opening reaction of pyrimidines to chiral epoxides; iii) Mitsunobu reaction of pyrimidines with chiral hydroxyl materials; iv) allylic amination reaction of pyrimidines with chiral allylic carbonates . Nevertheless, the generation of these chiral side chains often requires multi‐step reactions from chiral starting materials.…”