Methanol → 8-(1,1-Dimethylethyl) 2-methyl 3-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylate

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Reaction Steps

3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester from Step 1 (14.1 g, 62 mmol) was dissolved in cyclohexane (550 mL), to which was added dimethyl carbonate (12.4 g, 137 mmol), followed by sodium hydride (5.0 g, 125 mmol) and methanol (0.2 mL). The reaction mixture was stirred at reflux for 15 hours, then cooled to room temperature, and water (25 mL) was added. The reaction mixture was concentrated under reduced pressure to a volume of 50 mL, which was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to provide 3-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester as a light yellow oil (15.4 g, 87% yield).

Provenance & Evidence