Formic Acid → Acetate

Participants

Reaction Conditions

Reaction Steps

4,5-dihydroisoxazol-3-yl acetate I-260a and I-260b were prepared in 3 steps according to the following procedures: racemic bromoisoxazole I-10 was (1.0 equiv) was dissolved in tetrahydrofuran (1.0 M). 1N Sodium hydroxide solution is added (4.0 equiv) followed by allyl alcohol (45 equiv). The reaction was sealed and heated to 60° C. for 3 h. The reaction mixture was allowed to cool and then transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was washed water and brine, drive over sodium sulfate and concentrated under vacuum to provide crude material which was purified using flash silica gel chromatography (gradient ethyl acetate/hexanes). The resulting allyl ether (1.0 equiv) was then dissolved in tetrahydrofuran (0.2 M). Formic acid (5.0 equiv) was added followed by palladium tetrakis (10 mol %) after which the reaction was allowed to stir for 2 h at room temperature. The reaction mixture was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and purified using flash silica gel chromatography (gradient ethyl acetate/hexanes). The resulting isoxazolidin-3-one (1.0 equiv) was dissolved in methylene chloride (0.3 M) after which N,N-dimethyamino pyridine (1.0 equiv) and acetic anhydride (1.0 equiv) were added. After stirring at room temperature for 14 h, the reaction was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was washed with 1N HCl and brine, dried over sodium sulfate and concentrated to provide the desired racemic acetate I-260. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=297.8 m/z. Activity: D

Provenance & Evidence