Epimerization during the acetolysis of 3-O-acetyl-5-O-benzoyl-1,2-O-isopropylidene-3-C-methyl-α-d-ribofuranose. Synthesis of 3′-C-methylnucleosides with the β-d-ribo- and α-d-arabino configurations

Synthesis of 2′‐ and 3′‐C‐Methylribonucleosides

“…Physical and spectroscopic data for all products and intermediates have been reported (Mikhailov et al, 1983;Beigelman et al, 1987Beigelman et al, , 1988. The structure of compounds is supported by NMR spectroscopy, and elemental analysis and optical rotation were used for additional characterization.…”

“…The original publication (Mikhailov et al, 1983) describes two procedures for conversion of the 5-O-benzoyl ribofuranose intermediate S.4 to the triacetate S.6-one based on acetolysis with AcOH/Ac 2 O/H 2 SO 4 and another based on removal of the 1,2-O-isopropylidene group with trifluoroacetic acid followed by acetylation using pyridine/Ac 2 O/DMAP. Although the acetolysis reaction is faster and requires fewer manipulations, it was subsequently demonstrated that, under standard acetolysis conditions, even after initial acetylation of 3-OH in S.5, the resulting 3-C-methylribofuranose is a very good substrate for epimerization at C2, thus providing the undesired 3-C-methylarabinofuranose (Beigelman et al, 1988). It is possible to obtain only the desired fully acetylated D-ribofuranose derivative by varying the concentration of Ac 2 O during acetolysis, but using the two-step procedure outlined in this unit is recommended to avoid any possibility for formation of undesired 3-C-methylarabinofuranose side products.…”

“…The product, l,2,3-tri-O-acetyl-5-O-benzoyl-3-C-methyl-α,β-D-ribofuranose (S.6), is usually obtained as a mixture of anomers (α,β) and requires column purification. The individual β-anomer can be isolated in crystalline form (∼25% yield), but since both α and β anomers can be utilized in the synthesis of 3 -C-methylribonucleosides, it is advisable to pull appropriate fractions to give a combined yield of 83% (Beigelman et al, 1988). Materials 1,2:5,6-Di-O-isopropylidene-3-C-methyl-α-D-allofuranose (S.1; Bio et al, 2004) Acetic acid (AcOH) 1-Butanol, reagent grade Ethanol (EtOH), reagent grade Phosphorus pentoxide (P 2 O 5 ) Sodium periodate (NaIO 4 ) Sodium borohydride (NaBH 4 ) Chloroform (CHCl 3 ), reagent grade Methanol (MeOH), analytical grade Hexane, reagent grade Anhydrous pyridine Benzoyl chloride Saturated sodium bicarbonate (NaHCO 3 ) Anhydrous sodium sulfate (Na 2 SO 4 ) Toluene, reagent grade 90% trifluoroacetic acid (F 3 CCOOH) Acetic anhydride, reagent grade 4-Dimethylaminopyridine (DMAP) Silica gel: Kieselgel 60 (0.06 to 0.20 mm; Merck) 250-and 500-mL round-bottom flasks Rotary evaporator equipped with a water aspirator and an oil pump Reflux condenser Vacuum filtration system with glass filters (porosity 3) Vacuum desiccator 250-mL and 1-L separatory funnels Dropping funnel connected to a CaCl 2 protection tube Silica-coated aluminum TLC plates with fluorescent indicator (Merck silicagel 60 F 254 ) 254-nm UV lamp 3 × 20-cm sintered glass chromatography column, porosity 3 Vacuum oil pump 1,2-O- .…”