bicyclo[3.3.1]nonane-3,7-dione

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

Procedure: 386.6 mg (2.54 mmoles) of bicyclo[3.3.1]nonane-3,7-dione is dissolved in 5 mL of methanol and treated with sodium borohydride (100 mg, 2.64 mmoles) at 0° C. for 2 hours. The solution is treated with 5 mL of saturated aqueous sodium bicarbonate for 1 hour at 25° C. and extracted with 3×10 mL portions of chloroform. The combined chloroform extracts are combined, dried over sodium sulfate, stripped of solvent in vacuo, and purified by column chromatography (silica, eluant=50% hexanes, 50% ethyl acetate) yielding 343 mg (88%) of the desired product. 1HNMR (CDCl3, 500 Mhz): d 1.563 (d, 2H), 1.70-1.76 (m, 1H), 1.788 (d, 2H, J=11.1 Hz), 1.839 (d, 2H, J=13.1 Hz), 1.925 (d, 2H, J=13.0 Hz), 2.310 (s, 2H), 2.690 (s, 1H), 4.283 (s, 1H). extracted with 3×10 mL portions of chloroform dried over sodium sulfate purified by column chromatography (silica, eluant=50% hexanes, 50% ethyl acetate)

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

Procedure: Zn solid was activated just prior to perform Reformatsky reaction as followed: Zn dust was stirred at r.t. in 2 M aqueous HCl solution until the bubbling ceased (≈40 min for 15 g Zn). The solid was then filtered and washed with water (50 mL), the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated using an air gun under vacuum to complete drying. Reformasky reaction: to a suspension of such activated Zn* solid (2.29 g, 35 mmol) in dry THF (70 mL) warmed to reflux temperature under argon was added dropwise through the condenser over 40 min a mixture of ethylbromoacetate (1.75 mL, 15 mmol) and diketone (1) (0.761 g, 5 mmol) in dry THF (125 mL). The green mixture was stirred at reflux temperature for 5 h, then cooled to r.t. and hydrolyzed by quite slow addition of saturated aqueous NH4Cl solution (until pH=5-6): the resulting colorless solution with the Zn solid floating around was stirred for 10 min at r.t. before extraction with DCM (3×80 mL). The combined org. layers were washed with saturated solution of NaHCO3 (80 mL), then brine (80 mL), then water (80 mL), dried with MgSO4 and concentrated under reduced pressure to afford an orange oil. This crude product was then filtered trough a plug of silica gel and washed with AcOEt/cyclohexane mixtures, then with pure AcOEt to afford the desired acetal (2) as yellow oil pure enough to carry on the synthesis. A purer product can be obtained as white crystals (1.044 g, 87%) after flash chromatography (AcOEt/cyclohexane 4/6, v/v). reaction The solid was then filtered washed with water (50 mL) the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated to complete drying Reformasky reaction warmed to reflux temperature under argon was added dropwise through the condenser over 40 min at reflux temperature for 5 h layers were washed with saturated solution of NaHCO3 (80 mL) brine (80 mL), then water (80 mL), dried with MgSO4 concentrated under reduced pressure to afford an orange oil This crude product was then filtered trough a plug of silica gel washed with AcOEt/cyclohexane mixtures

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

Procedure: Zn solid was activated just prior to perform Reformatsky reaction as followed: Zn dust was stirred at r.t. in 2 M aqueous HCl solution until the bubbling ceased (≈40 min for 15 g Zn). The solid was then filtered and washed with water (50 mL), the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated using an air gun under vacuum to complete drying. Reformasky reaction: to a suspension of such activated Zn* solid (2.29 g, 35 mmol) in dry THF (70 mL) warmed to reflux temperature under argon was added dropwise through the condenser over 40 min a mixture of ethylbromoacetate (1.75 mL, 15 mmol) and diketone (1) (0.761 g, 5 mmol) in dry THF (125 mL). The green mixture was stirred at reflux temperature for 5 h, then cooled to r.t. and hydrolyzed by quite slow addition of saturated aqueous NH4Cl solution (until pH=5-6): the resulting colorless solution with the Zn solid floating around was stirred for 10 min at r.t. before extraction with DCM (3×80 mL). The combined org. layers were washed with saturated solution of NaHCO3 (80 mL), then brine (80 mL), then water (80 mL), dried with MgSO4 and concentrated under reduced pressure to afford an orange oil. This crude product was then filtered trough a plug of silica gel and washed with AcOEt/cyclohexane mixtures, then with pure AcOEt to afford the desired acetal (2) as yellow oil pure enough to carry on the synthesis. A purer product can be obtained as white crystals (1.044 g, 87%) after flash chromatography (AcOEt/cyclohexane 4/6, v/v). reaction The solid was then filtered washed with water (50 mL) the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated to complete drying Reformasky reaction warmed to reflux temperature under argon was added dropwise through the condenser over 40 min at reflux temperature for 5 h layers were washed with saturated solution of NaHCO3 (80 mL) brine (80 mL), then water (80 mL), dried with MgSO4 concentrated under reduced pressure to afford an orange oil This crude product was then filtered trough a plug of silica gel washed with AcOEt/cyclohexane mixtures

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of tetramethyl 3,7-dihydroxybicyclo[3.3.1]nona-2,6-diene-2,4,6,8-tetracarboxylate (19.2 g, 50 mmol) in an aqueous solution of 10 M HCl (50 mL), water (50 mL) and glacial acetic acid (100 mL) was heated at 130° C. for 6 h. After cooling at room temperature, the reaction mixture was poured onto crushed ice (200 mL) and extracted with DCM (4×200 mL). The combined organic layers were washed with an aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4, and concentrated under reduced pressure to give an orange solid. This crude product was dissolved in acetone and the salts which precipitated were filtered. Concentration of the filtrate and washing with Et2O afford the desired diketone (1) as a white solid (6.5 g, 85%). After cooling at room temperature the reaction mixture was poured extracted with DCM (4×200 mL) The combined organic layers were washed with an aqueous saturated solution of NaHCO3 The organic layer was dried over MgSO4 concentrated under reduced pressure to give an orange solid the salts which precipitated were filtered Concentration of the filtrate and washing with Et2O

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

Procedure: Zn solid was activated just prior to perform Reformatsky reaction as followed: Zn dust was stirred at r.t. in 2 M aqueous HCl solution until the bubbling ceased (≈40 min for 15 g Zn). The solid was then filtered and washed with water (50 mL), the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated using an air gun under vacuum to complete drying. Reformasky reaction: to a suspension of such activated Zn* solid (2.29 g, 35 mmol) in dry THF (70 mL) warmed to reflux temperature under argon was added dropwise through the condenser over 40 min a mixture of ethylbromoacetate (1.75 mL, 15 mmol) and diketone (1) (0.761 g, 5 mmol) in dry THF (125 mL). The green mixture was stirred at reflux temperature for 5 h, then cooled to r.t. and hydrolyzed by quite slow addition of saturated aqueous NH4Cl solution (until pH=5-6): the resulting colorless solution with the Zn solid floating around was stirred for 10 min at r.t. before extraction with DCM (3×80 mL). The combined org. layers were washed with saturated solution of NaHCO3 (80 mL), then brine (80 mL), then water (80 mL), dried with MgSO4 and concentrated under reduced pressure to afford an orange oil. This crude product was then filtered trough a plug of silica gel and washed with AcOEt/cyclohexane mixtures, then with pure AcOEt to afford the desired acetal (2) as yellow oil pure enough to carry on the synthesis. A purer product can be obtained as white crystals (1.044 g, 87%) after flash chromatography (AcOEt/cyclohexane 4/6, v/v). reaction The solid was then filtered washed with water (50 mL) the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated to complete drying Reformasky reaction warmed to reflux temperature under argon was added dropwise through the condenser over 40 min at reflux temperature for 5 h layers were washed with saturated solution of NaHCO3 (80 mL) brine (80 mL), then water (80 mL), dried with MgSO4 concentrated under reduced pressure to afford an orange oil This crude product was then filtered trough a plug of silica gel washed with AcOEt/cyclohexane mixtures

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

Procedure: Zn solid was activated just prior to perform Reformatsky reaction as followed: Zn dust was stirred at r.t. in 2 M aqueous HCl solution until the bubbling ceased (≈40 min for 15 g Zn). The solid was then filtered and washed with water (50 mL), the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated using an air gun under vacuum to complete drying. Reformasky reaction: to a suspension of such activated Zn* solid (2.29 g, 35 mmol) in dry THF (70 mL) warmed to reflux temperature under argon was added dropwise through the condenser over 40 min a mixture of ethylbromoacetate (1.75 mL, 15 mmol) and diketone (1) (0.761 g, 5 mmol) in dry THF (125 mL). The green mixture was stirred at reflux temperature for 5 h, then cooled to r.t. and hydrolyzed by quite slow addition of saturated aqueous NH4Cl solution (until pH=5-6): the resulting colorless solution with the Zn solid floating around was stirred for 10 min at r.t. before extraction with DCM (3×80 mL). The combined org. layers were washed with saturated solution of NaHCO3 (80 mL), then brine (80 mL), then water (80 mL), dried with MgSO4 and concentrated under reduced pressure to afford an orange oil. This crude product was then filtered trough a plug of silica gel and washed with AcOEt/cyclohexane mixtures, then with pure AcOEt to afford the desired acetal (2) as yellow oil pure enough to carry on the synthesis. A purer product can be obtained as white crystals (1.044 g, 87%) after flash chromatography (AcOEt/cyclohexane 4/6, v/v). reaction The solid was then filtered washed with water (50 mL) the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated to complete drying Reformasky reaction warmed to reflux temperature under argon was added dropwise through the condenser over 40 min at reflux temperature for 5 h layers were washed with saturated solution of NaHCO3 (80 mL) brine (80 mL), then water (80 mL), dried with MgSO4 concentrated under reduced pressure to afford an orange oil This crude product was then filtered trough a plug of silica gel washed with AcOEt/cyclohexane mixtures

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of tetramethyl 3,7-dihydroxybicyclo[3.3.1]nona-2,6-diene-2,4,6,8-tetracarboxylate (19.2 g, 50 mmol) in an aqueous solution of 10 M HCl (50 mL), water (50 mL) and glacial acetic acid (100 mL) was heated at 130° C. for 6 h. After cooling at room temperature, the reaction mixture was poured onto crushed ice (200 mL) and extracted with DCM (4×200 mL). The combined organic layers were washed with an aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4, and concentrated under reduced pressure to give an orange solid. This crude product was dissolved in acetone and the salts which precipitated were filtered. Concentration of the filtrate and washing with Et2O afford the desired diketone (1) as a white solid (6.5 g, 85%). After cooling at room temperature the reaction mixture was poured extracted with DCM (4×200 mL) The combined organic layers were washed with an aqueous saturated solution of NaHCO3 The organic layer was dried over MgSO4 concentrated under reduced pressure to give an orange solid the salts which precipitated were filtered Concentration of the filtrate and washing with Et2O

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

Procedure: 386.6 mg (2.54 mmoles) of bicyclo[3.3.1]nonane-3,7-dione is dissolved in 5 mL of methanol and treated with sodium borohydride (100 mg, 2.64 mmoles) at 0° C. for 2 hours. The solution is treated with 5 mL of saturated aqueous sodium bicarbonate for 1 hour at 25° C. and extracted with 3×10 mL portions of chloroform. The combined chloroform extracts are combined, dried over sodium sulfate, stripped of solvent in vacuo, and purified by column chromatography (silica, eluant=50% hexanes, 50% ethyl acetate) yielding 343 mg (88%) of the desired product. 1HNMR (CDCl3, 500 Mhz): d 1.563 (d, 2H), 1.70-1.76 (m, 1H), 1.788 (d, 2H, J=11.1 Hz), 1.839 (d, 2H, J=13.1 Hz), 1.925 (d, 2H, J=13.0 Hz), 2.310 (s, 2H), 2.690 (s, 1H), 4.283 (s, 1H). extracted with 3×10 mL portions of chloroform dried over sodium sulfate purified by column chromatography (silica, eluant=50% hexanes, 50% ethyl acetate)

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

Procedure: Zn solid was activated just prior to perform Reformatsky reaction as followed: Zn dust was stirred at r.t. in 2 M aqueous HCl solution until the bubbling ceased (≈40 min for 15 g Zn). The solid was then filtered and washed with water (50 mL), the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated using an air gun under vacuum to complete drying. Reformasky reaction: to a suspension of such activated Zn* solid (2.29 g, 35 mmol) in dry THF (70 mL) warmed to reflux temperature under argon was added dropwise through the condenser over 40 min a mixture of ethylbromoacetate (1.75 mL, 15 mmol) and diketone (1) (0.761 g, 5 mmol) in dry THF (125 mL). The green mixture was stirred at reflux temperature for 5 h, then cooled to r.t. and hydrolyzed by quite slow addition of saturated aqueous NH4Cl solution (until pH=5-6): the resulting colorless solution with the Zn solid floating around was stirred for 10 min at r.t. before extraction with DCM (3×80 mL). The combined org. layers were washed with saturated solution of NaHCO3 (80 mL), then brine (80 mL), then water (80 mL), dried with MgSO4 and concentrated under reduced pressure to afford an orange oil. This crude product was then filtered trough a plug of silica gel and washed with AcOEt/cyclohexane mixtures, then with pure AcOEt to afford the desired acetal (2) as yellow oil pure enough to carry on the synthesis. A purer product can be obtained as white crystals (1.044 g, 87%) after flash chromatography (AcOEt/cyclohexane 4/6, v/v). reaction The solid was then filtered washed with water (50 mL) the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated to complete drying Reformasky reaction warmed to reflux temperature under argon was added dropwise through the condenser over 40 min at reflux temperature for 5 h layers were washed with saturated solution of NaHCO3 (80 mL) brine (80 mL), then water (80 mL), dried with MgSO4 concentrated under reduced pressure to afford an orange oil This crude product was then filtered trough a plug of silica gel washed with AcOEt/cyclohexane mixtures

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of tetramethyl 3,7-dihydroxybicyclo[3.3.1]nona-2,6-diene-2,4,6,8-tetracarboxylate (19.2 g, 50 mmol) in an aqueous solution of 10 M HCl (50 mL), water (50 mL) and glacial acetic acid (100 mL) was heated at 130° C. for 6 h. After cooling at room temperature, the reaction mixture was poured onto crushed ice (200 mL) and extracted with DCM (4×200 mL). The combined organic layers were washed with an aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4, and concentrated under reduced pressure to give an orange solid. This crude product was dissolved in acetone and the salts which precipitated were filtered. Concentration of the filtrate and washing with Et2O afford the desired diketone (1) as a white solid (6.5 g, 85%). After cooling at room temperature the reaction mixture was poured extracted with DCM (4×200 mL) The combined organic layers were washed with an aqueous saturated solution of NaHCO3 The organic layer was dried over MgSO4 concentrated under reduced pressure to give an orange solid the salts which precipitated were filtered Concentration of the filtrate and washing with Et2O

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

Procedure: Zn solid was activated just prior to perform Reformatsky reaction as followed: Zn dust was stirred at r.t. in 2 M aqueous HCl solution until the bubbling ceased (≈40 min for 15 g Zn). The solid was then filtered and washed with water (50 mL), the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated using an air gun under vacuum to complete drying. Reformasky reaction: to a suspension of such activated Zn* solid (2.29 g, 35 mmol) in dry THF (70 mL) warmed to reflux temperature under argon was added dropwise through the condenser over 40 min a mixture of ethylbromoacetate (1.75 mL, 15 mmol) and diketone (1) (0.761 g, 5 mmol) in dry THF (125 mL). The green mixture was stirred at reflux temperature for 5 h, then cooled to r.t. and hydrolyzed by quite slow addition of saturated aqueous NH4Cl solution (until pH=5-6): the resulting colorless solution with the Zn solid floating around was stirred for 10 min at r.t. before extraction with DCM (3×80 mL). The combined org. layers were washed with saturated solution of NaHCO3 (80 mL), then brine (80 mL), then water (80 mL), dried with MgSO4 and concentrated under reduced pressure to afford an orange oil. This crude product was then filtered trough a plug of silica gel and washed with AcOEt/cyclohexane mixtures, then with pure AcOEt to afford the desired acetal (2) as yellow oil pure enough to carry on the synthesis. A purer product can be obtained as white crystals (1.044 g, 87%) after flash chromatography (AcOEt/cyclohexane 4/6, v/v). reaction The solid was then filtered washed with water (50 mL) the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated to complete drying Reformasky reaction warmed to reflux temperature under argon was added dropwise through the condenser over 40 min at reflux temperature for 5 h layers were washed with saturated solution of NaHCO3 (80 mL) brine (80 mL), then water (80 mL), dried with MgSO4 concentrated under reduced pressure to afford an orange oil This crude product was then filtered trough a plug of silica gel washed with AcOEt/cyclohexane mixtures

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of tetramethyl 3,7-dihydroxybicyclo[3.3.1]nona-2,6-diene-2,4,6,8-tetracarboxylate (19.2 g, 50 mmol) in an aqueous solution of 10 M HCl (50 mL), water (50 mL) and glacial acetic acid (100 mL) was heated at 130° C. for 6 h. After cooling at room temperature, the reaction mixture was poured onto crushed ice (200 mL) and extracted with DCM (4×200 mL). The combined organic layers were washed with an aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4, and concentrated under reduced pressure to give an orange solid. This crude product was dissolved in acetone and the salts which precipitated were filtered. Concentration of the filtrate and washing with Et2O afford the desired diketone (1) as a white solid (6.5 g, 85%). After cooling at room temperature the reaction mixture was poured extracted with DCM (4×200 mL) The combined organic layers were washed with an aqueous saturated solution of NaHCO3 The organic layer was dried over MgSO4 concentrated under reduced pressure to give an orange solid the salts which precipitated were filtered Concentration of the filtrate and washing with Et2O