(3aS,6aR)-3,3a,6,6a-tetrahydrocyclopenta[b]furan-2-one

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of lithium diisopropylamide, prepared by adding nBuLi (2.5 M sol. in hexanes, 1.36 mL, 3.39 mmol) to diisopropylamine (477 μL, 3.39 mmol) in THF (15 mL) at 0° C., was added a pre-cooled solution of known (3aS,6aR)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one (+)-115 (350 mg, 2.82 mmol) in THF (5 mL+3 mL rinse) at −78° C., dropwise. The reaction mixture was stirred at this temperature for 30 min, then methyl iodide (352 μL, 5.65 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 6 h. The reaction mixture was quenched with 2 M aqueous HCl. The aqueous phase was extracted with Et2O (×3). The combined organic layer was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexanes/Et2O (5:1) to yield lactone 116 (369 mg, 95%) as a brown oil. TLC: Rf=0.54 (hexanes/EtOAc=2:1); [α]D20+54.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 5.74 (m, 1H), 5.59 (m, 1H), 5.12 (t, J=5.6 Hz, 1H), 3.13 (dd, J=3.8, 1.8 Hz, 1H), 2.65 (m, 2H), 2.52 (q, J=7.6 Hz, 1H), 1.33 (d, J=7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 180.0, 130.9, 129.4, 81.3, 53.8, 39.9, 39.2, 17.4. the reaction mixture was stirred at −78° C. for 6 h The reaction mixture was quenched with 2 M aqueous HCl The aqueous phase was extracted with Et2O (×3) The combined organic layer was dried (Na2SO4) filtered concentrated under vacuum The residue was purified by column chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of lithium diisopropylamide, prepared by adding nBuLi (2.5 M sol. in hexanes, 1.36 mL, 3.39 mmol) to diisopropylamine (477 μL, 3.39 mmol) in THF (15 mL) at 0° C., was added a pre-cooled solution of known (3aS,6aR)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one (+)-115 (350 mg, 2.82 mmol) in THF (5 mL+3 mL rinse) at −78° C., dropwise. The reaction mixture was stirred at this temperature for 30 min, then methyl iodide (352 μL, 5.65 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 6 h. The reaction mixture was quenched with 2 M aqueous HCl. The aqueous phase was extracted with Et2O (×3). The combined organic layer was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexanes/Et2O (5:1) to yield lactone 116 (369 mg, 95%) as a brown oil. TLC: Rf=0.54 (hexanes/EtOAc=2:1); [α]D20+54.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 5.74 (m, 1H), 5.59 (m, 1H), 5.12 (t, J=5.6 Hz, 1H), 3.13 (dd, J=3.8, 1.8 Hz, 1H), 2.65 (m, 2H), 2.52 (q, J=7.6 Hz, 1H), 1.33 (d, J=7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 180.0, 130.9, 129.4, 81.3, 53.8, 39.9, 39.2, 17.4. the reaction mixture was stirred at −78° C. for 6 h The reaction mixture was quenched with 2 M aqueous HCl The aqueous phase was extracted with Et2O (×3) The combined organic layer was dried (Na2SO4) filtered concentrated under vacuum The residue was purified by column chromatography on silica gel

Conditions: temp:74.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100 mL round bottomed flask was charged (3aS, 6aR)-3, 3a, 6, 6a-tetrahydro-2H-cyclopenta[b]furan-2-one 49 (3.85 g, 31 mmol, prepared as described in Corey et al. J. Med Chem. 1993, 36, 243), paraformaldehyde (3.0 g), glacial acetic acid (30 mL), and concentrated sulfuric acid (1 mL). The mixture was heated to 74° C. for 24 hours. To the solution was added sodium acetate (4 g). The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL). The solution was washed with saturated sodium bicarbonate solution until no gas evolution was observed. The organic phase was dried over sodium sulfate and concentrated in vacuo to give the crude product (4.1 g). The crude product was purified by silica gel column chromatography to provide the title compound (3.1 g, 39%). The solution was concentrated in vacuo the residue was dissolved in ethyl acetate (200 mL) The solution was washed with saturated sodium bicarbonate solution until no gas evolution The organic phase was dried over sodium sulfate concentrated in vacuo to give the crude product (4.1 g) The crude product was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of lithium diisopropylamide, prepared by adding nBuLi (2.5 M sol. in hexanes, 1.36 mL, 3.39 mmol) to diisopropylamine (477 μL, 3.39 mmol) in THF (15 mL) at 0° C., was added a pre-cooled solution of known (3aS,6aR)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one (+)-115 (350 mg, 2.82 mmol) in THF (5 mL+3 mL rinse) at −78° C., dropwise. The reaction mixture was stirred at this temperature for 30 min, then methyl iodide (352 μL, 5.65 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 6 h. The reaction mixture was quenched with 2 M aqueous HCl. The aqueous phase was extracted with Et2O (×3). The combined organic layer was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexanes/Et2O (5:1) to yield lactone 116 (369 mg, 95%) as a brown oil. TLC: Rf=0.54 (hexanes/EtOAc=2:1); [α]D20+54.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 5.74 (m, 1H), 5.59 (m, 1H), 5.12 (t, J=5.6 Hz, 1H), 3.13 (dd, J=3.8, 1.8 Hz, 1H), 2.65 (m, 2H), 2.52 (q, J=7.6 Hz, 1H), 1.33 (d, J=7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 180.0, 130.9, 129.4, 81.3, 53.8, 39.9, 39.2, 17.4. the reaction mixture was stirred at −78° C. for 6 h The reaction mixture was quenched with 2 M aqueous HCl The aqueous phase was extracted with Et2O (×3) The combined organic layer was dried (Na2SO4) filtered concentrated under vacuum The residue was purified by column chromatography on silica gel