[Synthesis]
To a solution of methyl acetate (45 mL) of methyl 3-methylenecyclobutanecarboxylate (Intermediate 43A) was added copper powder (2.77 g, 43.6 mmol) and zinc powder (5.70 g, 87 mmol). A solution of trichloroacetyl chloride (4.86 mL, 43.6 mmol) and trichlorophosphorus oxide (0.37 mL, 4.0 mmol) in methyl acetate (45 mL) was added dropwise to the mixture over a period of 2 hours. After 3 hours of reaction, the mixture was cooled to 0°C, additional zinc powder (5.70 g, 87 mmol) was added, and then acetic acid (22.7 mL, 400 mmol) was added dropwise at a rate that kept the temperature below 7°C. The reaction mixture was allowed to warm slowly to room temperature, stirred overnight and then filtered through Celite and rinsed with EtOAc. The filtrate was carefully washed with saturated aqueous NaHCO3 (2 x 200 mL) (note: gases will be released) and the aqueous layer was extracted with 1:1 EtOAc:Et2O (2 x 100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography using a 0%-50% EtOAc-hexane gradient elution. The grades containing the target product were combined, the solvent evaporated under reduced pressure and dried under vacuum to afford methyl 6-oxospiro[3.3]heptane-2-carboxylate (4.10 g, 61% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 2.38-2.48 (m, 2H), 2.50-2.61 (m, 2H), 3.00-3.09 (m, 2H), 3.09-3.22 (m, 3H), 3.68 (s, 3H). |