Lewis Acid Mediated Reductive Ring Opening of 2-Methoxyethylidene Acetals: A New Approach to 2-Methoxyethyl (MOE) Ethers of cis-Diols

Abstract

The reductive opening of 2-methoxyethylidene acetals of vicinal diols in uridine and 1,4-anhydro-d-ribitol in the presence of TiCl₄ and Et₃SiH was investigated. The 3′-O-(2-methoxyethyl) ether of uridine and the 2′-O-(2-methoxyethyl) ether of 1,4-an­hydro-d-ribitol were isolated and characterized. The results were rationalized based on coordination effects involving proximal substituents.

Key words

acetal - reductive opening - nucleoside - antisense

References

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  Typical Procedure 10 → 11 → 12.
  Compound 11: to a mixture of 10 (4.5 g, 9.32 mmol) and PTSA (90 mg, 0.466 mmol) in toluene (65 mL) was added methoxyacetaldehyde dimethyl acetal (1.95 mL, 27.35 mmol). The mixture was stirred at 125 °C for 1 h, cooled to r.t. and concentrated. The crude product was purified by flash chromatography (5:1, EtOAc-hexane) to afford 11 (3.7 g, 6.87 mmol, 75%) as a white solid. R _f = 0.46 (5:1, EtOAc-hexane); mp 60-63 °C; [α]_D +4.9 (c 0.45, MeOH).
  Compound 12: to 11 (50 mg, 0.092 mmol) in CH₂Cl₂ (1.5 mL) at -78 °C was added TiCl₄ (0.92 mL, 0.92 mmol, 1 M CH₂Cl₂). The mixture was stirred at this temperature for 10 min, followed by the addition of Et₃SiH (0.6 mL, 3.68 mmol). The mixture was then slowly brought to r.t. over a period of 18 h. Then, H₂O (1.5 mL) and CH₂Cl₂ (1.5 mL) were added and the mixture and stirred for 10 min. The two phases were separated, the aqueous phase was extracted with CH₂Cl₂ (2 × 2 mL) and the organic phase was washed with NaCl (5 mL) and dried over Na₂SO₄. The organic layer was then concentrated and purified by flash chromatography (5:1, EtOAc-hexane) to afford 12 as a colorless oil (38 mg, 0.070 mmol, 76%). R _f = 0.19 (5:1, EtOAc-hexane);
  [α]_D +0.78 (c 7.00, MeOH).

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11

We have also used a combination of ZnCl₂/L-Selectride, BF₃·OEt₂/Et₃SiH, however, no opening of the acetal was observed under these conditions.

12

Decomposition was observed when MeCN and nitromethane were used as solvent.