(1S,5R)-1-Phenyl-3-oxabicyclo[3.1.0]hexan-2-one

Synthesis

General procedure for the synthesis of 1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one from levulinic epichlorohydrin and phenylacetonitrile: 28 g of sodium amide (0.682 mol) was suspended in 400 ml of toluene, and 85.5 g of a toluene solution of phenylacetonitrile (0.729 mol) was slowly added with vigorous stirring and at 0-5 °C. The reaction mixture was stirred continuously at 0°C for at least 1 hour. Subsequently, 27 g of levulinic epichlorohydrin (0.292 mol) dissolved in 40 ml of toluene was added while the reaction temperature was controlled at 100 °C. After the addition was completed, the reaction mixture was stirred at 50°C for at least 2 hours. After completion of the reaction, the reaction solution was slowly poured into 240 ml of water for hydrolysis, keeping the temperature between 5-40°C. The hydrolyzed solution was concentrated, 115 g of 30% sodium hydroxide solution was added and the mixture was heated to 95°C to promote hydrolysis of the nitro functional groups. The reaction mixture was washed twice with 190 ml of toluene and the toluene phase was discarded. After addition of 270 ml of toluene, the aqueous phase was separated by acidification with 25% hydrochloric acid solution to the appropriate pH. Subsequently, the mixture was heated to 60°C and kept for at least 3 hours. After decantation, the toluene phase containing the target lactone was washed with 10 ml of water and neutralized with 10% sodium carbonate solution to pH 8. Finally, the toluene phase was washed with 140 ml of water and concentrated to give 38 g of intermediate lactone 3.

References

[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2834 - 2837
[2] Patent: US2012/165339, 2012, A1. Location in patent: Page/Page column 25-26
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8838 - 8858,21
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8838 - 8858
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 16, p. 6371 - 6385