Facile synthesis of a 3-deazaadenosine phosphoramidite for RNA solid-phase synthesis

Figures

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  Scheme 1. Synthesis of c3A described by Rousseau et al. in 1966 [22]. a) 1,2,3,5-Tetraacetyl-ß-D-ribofuranose, chloroacetic acid (cat.), 175 °C (melting until clear solution). b) NH3 in CH3OH, 0 °C, 14 h. c) Anhydrous hydrazine, steam bath, 1 h, not isolated. d) Raney nickel, water, reflux, 1 h.

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  Scheme 2. Synthesis of c3A described by Montgomery et al. in 1977 [23]. The final step, displacement of the 2-chlorine atom by a hydrogen atom, remains problematic [24–26]. a) 1,2,3,5-Tetraacetyl-ß-D-ribofuranose, p-toluenesulfonic acid (cat.), melt (160 °C), 5 to 10 min. b) NH3 in ethanol (saturated at −30 °C), 140 °C, 89 h [23] or NH3 (30% aq), 200 °C, 5 d, 80% [24].

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  Scheme 3. Synthesis of tribenzoylated 6-azido-3-deazapurine nucleoside 2. a) LiN3 (1.3 equiv), N,N-dimethylformamide, 120 °C, 18 h, 76%. b) 1-O-Acetyl-2,3,5-tri-O-benzoyl-ß-D-ribofuranose (1 equiv), N,O-bis(trimethylsilyl)acetamide (3.4 equiv), trimethylsilyl trifluoromethanesulfonate (3.0 equiv), 105 °C, 70 min, 71%.

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  Scheme 4. Efficient 5-step synthesis of 3-deazaadenosine phosphoramidite 8 from commercially available, affordable starting materials. (A) Reagents and conditions: a) N,O-bis(trimethylsilyl)acetamide (3.5 equiv), trimethylsilyl trifluoromethanesulfonate (3.0 equiv), in toluene, 105 °C, 3.5 h, 63%. b) CH3NH2, in water/ethanol, room temperature, 18 h, 95%. c) i) N,N-Dibutylformamide dimethyl acetal (2.3 equiv), in pyridine, ii) 4,4’-dimethoxytrityl chloride (2.7 equiv), 4-(dimethylamino)pyridine (0.3 equiv), in pyridine, room temperature, 16 h, 40%. d) Triisopropylsilyl chloride (4 equiv), AgNO3 (4 equiv), 18 h, 26%. e) 2-Cyanoethyl N,N-diisopropylchlorophosphoramidite (3 equiv), N,N-dimethylethylamine (10 equiv), in dichloromethane, room temperature, 105 min, 44%. (B) Reagents and conditions: a) aqueous ammonia, microwave, 140 °C, 2 h, 90%.