Hydrochloric Acid → (1S,4'R,5'R,6R)-4',5'-diphenylspiro[bicyclo[4.1.0]heptane-2,2'-[1,3]dioxolane]

Participants

Reaction Steps

The zinc/copper couple was freshly prepared by quickly washing zinc dust with 1N HCl (4×100 mL), then washing with distilled water (4×120 mL), 2 mol % CuSO4 solution (2×200 mL), water (4×120 mL), EtOH (4×120 mL) and Et2O (5×100 mL). The washings were done in a flask with decanting of the liquid. The Et2O washes were poured onto a funnel and dried by vacuum filtration. The resulting solid was added to a 2 L flask and dried under vacuum at 115° C. for 30 min, then cooled to RT. The flask was fitted with an addition funnel and reflux condenser, then purged with nitrogen and kept under N2 throughout the reaction. Next, 400 mL of Et2O was added followed by I2 (0.551 g, 2.172 mmol), and the solution was stirred and heated to reflux. Once at reflux, heating was stopped and diiodomethane (87 mL, 1086 mmol) was slowly added making sure to not allow the reaction to reflux out of control. (2R,3R)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6-ene (127 g, 434 mmol) was then added in 350 mL ether, followed by an additional 0.5 eq of diiodomethane. The reaction was heated to reflux and the reaction monitored by LCMS. After 1.5 h the reaction was cooled to RT and quenched with saturated aq Na2CO3 (230 g in 900 mL water). The mixture was stirred for 30 min, then filtered through celite. The inorganics were washed with Et2O (2 L), then the combined organics were washed with saturated aq NH4Cl (1 L), saturated aq NaHCO3 (1 L), brine (1 L). The organic layers were dried over MgSO4, filtered and concentrated to afford the crude product (176.45 g). To the residue was added Et2O (250 mL) and the suspension was heated to reflux, then allowed to cool to RT to crystallize the product. The suspension was put in the freezer for 3 days, then the ether decanted off. Drying of the solids gave (1S,4′R,5′R,6R)-4′,5′-diphenylspiro[bicyclo[4.1.0]heptane-2,2′-[1,3]dioxolane] (112.5 g, 85% yield). The material was used as an intermediate without further purification.

Provenance & Evidence