(1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.6 liters 0.5M 9-borabicyclo[3.3.1]nonane in tetrahydrofuran and 122.6 g (-)-α-pinene was heated at reflux under nitrogen for 4 hr., at which time the excess (-)-α-pinene and tetrahydrofuran were removed under vacuum to leave a thick oil. The contents of the flask were cooled to 0° C. and 80 g of 1-cyclohexyl-2-propyn-1-one, prepared according to Preparation 4, was added with stirring. The resulting mixture was allowed to warm to 23° C. and it was stirred at that temperature for 16 hr. Excess S-Alpine borane was destroyed by adding 44 ml propionaldehyde and stirring at 23° C. for 1 hr. The liberated (-)-α-pinene was removed by vacuum distillation. The resulting mixture was diluted with 400 ml tetrahydrofuran followed by 300 ml 3N sodium hydroxide. To this stirred mixture was added in dropwise fashion 300 ml 30% hydrogen peroxide over 1 hr. The mixture was heated at 40° C. for 3 hr. After cooling, the mixture was extracted with diethyl ether and this extract was dried over magnesium sulfate. Evaporation of the solvent and purification of the residue by silica gel flash chromatography using 5% ethyl acetate-hexane gave 56 g of (S)-3-cyclohexyl-1-propyn-3-ol, which by nmr analysis was shown to be 90% e.e. was heated at reflux under nitrogen for 4 hr , at which time the excess (-)-α-pinene and tetrahydrofuran were removed under vacuum to leave a thick oil according to Preparation 4 was added to warm to 23° C. it was stirred at that temperature for 16 hr Excess S-Alpine borane was destroyed by adding 44 ml propionaldehyde stirring at 23° C. for 1 hr The liberated (-)-α-pinene was removed by vacuum distillation The resulting mixture was diluted with 400 ml tetrahydrofuran To this stirred mixture was added in dropwise fashion 300 ml 30% hydrogen peroxide over 1 hr The mixture was heated at 40° C. for 3 hr After cooling the mixture was extracted with diethyl ether this extract was dried over magnesium sulfate Evaporation of the solvent and purification of the residue by silica gel flash chromatography

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (−)-α-pinene (136.2 g, 1 mole) was oxidised by bubbling in O2 in the presence of cobalt stearate (0.5 g), which is added portionwise, maintaining the temperature at approximately 5-55° C., for at least 50-60 hours. When the reaction was complete, the peroxide index was approximately 27-29%. After cooling to room temperature, the excess of peroxides was decomposed by adding to the reaction mixture an equal quantity of a hot aqueous solution (˜50° C.) of 5% ferrous sulphate and 1% sulphuric acid; the peroxide index was approximately 0 within approximately 2 hours. The organic phase was then separated and washed 2-3 times with water until a pH of 5-6 is obtained. The non-reacted (−)-α-pinene was removed by column distillation at a temperature of approximately 100° C. and at a pressure of 20-25 mmHg (2.6×10−2−3.3×10−2 bar). The distillation residue was constituted by a mixture of terpenes which was characterized by oxygenated functions (alcohol, ketone and aldehyde functions). A Bertagnini reaction was then carried out by adding to the reaction mixture a solution containing sodium sulphite (120 g, 0.954 mole), while maintaining the temperature at 55-60° C. Because the pH of the mixture gradually moved to basic values, a 50% acetic acid solution was added until the pH is neutral. When the pH remained stable at ˜7, the reaction, might be regarded as complete. The organic phase (containing the alcohols PINOCARVEOL, MIRTENOL, VERBENOL) was separated and the aqueous phase was counter-extracted 2-3 times with hexane. The aqueous solution was alkalinised to pH ˜14 and then extracted with hexane, thus obtaining the fraction containing carbonyl products (MIRTENAL AND VERBENONE). The hexane extract, washed 2-3 times with water, was concentrated to obtain a high-boiling oily residue constituted to the extent of more than 80% by VERBENONE. The residue was dissolved with methanol; the methanol solution was cooled to −5 to −1° C. and, while maintaining this temperature, sodium borohydride was added until the MIRTENAL was undetectable (monitoring by TLC). The reduction was then stopped by the addition of a small amount of acetic acid, until the solution was neutral. The methanol solution was concentrated to ⅔ the volume, then diluted with water and extracted with hexane. The hexane solution was evaporated under vacuum and the residue is distilled at 80° C./1.5 mm Hg (1.9×10−3 bar) to give VRBENONE (25 g, yield 16.6%) with [α]D2b=−217° (c=10 in ethanol). by bubbling in O2 in the presence of cobalt stearate (0.5 g), which is added portionwise for at least 50-60 hours After cooling to room temperature by adding to the reaction mixture an equal quantity of a hot aqueous solution (˜50° C.) of 5% ferrous sulphate and 1% sulphuric acid within approximately 2 hours The organic phase was then separated washed 2-3 times with water until a pH of 5-6 is obtained The non-reacted (−)-α-pinene was removed by column distillation at a temperature of approximately 100° C. and at a pressure of 20-25 mmHg (2.6×10−2−3.3×10−2 bar) The distillation residue was constituted by a mixture of terpenes which by oxygenated functions (alcohol, ketone and aldehyde functions) A Bertagnini reaction by adding to the reaction mixture a solution while maintaining the temperature at 55-60° C the reaction was separated the aqueous phase was counter-extracted 2-3 times with hexane extracted with hexane thus obtaining the fraction The hexane extract washed 2-3 times with water was concentrated to obtain a high-boiling oily residue was added until the MIRTENAL The methanol solution was concentrated diluted with water extracted with hexane The hexane solution was evaporated under vacuum the residue is distilled at 80° C./1.5 mm Hg (1.9×10−3 bar) to give

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (−)-α-pinene (136.2 g, 1 mole) was oxidised by bubbling in O2 in the presence of cobalt stearate (0.5 g), which is added portionwise, maintaining the temperature at approximately 5-55° C., for at least 50-60 hours. When the reaction was complete, the peroxide index was approximately 27-29%. After cooling to room temperature, the excess of peroxides was decomposed by adding to the reaction mixture an equal quantity of a hot aqueous solution (˜50° C.) of 5% ferrous sulphate and 1% sulphuric acid; the peroxide index was approximately 0 within approximately 2 hours. The organic phase was then separated and washed 2-3 times with water until a pH of 5-6 is obtained. The non-reacted (−)-α-pinene was removed by column distillation at a temperature of approximately 100° C. and at a pressure of 20-25 mmHg (2.6×10−2−3.3×10−2 bar). The distillation residue was constituted by a mixture of terpenes which was characterized by oxygenated functions (alcohol, ketone and aldehyde functions). A Bertagnini reaction was then carried out by adding to the reaction mixture a solution containing sodium sulphite (120 g, 0.954 mole), while maintaining the temperature at 55-60° C. Because the pH of the mixture gradually moved to basic values, a 50% acetic acid solution was added until the pH is neutral. When the pH remained stable at ˜7, the reaction, might be regarded as complete. The organic phase (containing the alcohols PINOCARVEOL, MIRTENOL, VERBENOL) was separated and the aqueous phase was counter-extracted 2-3 times with hexane. The aqueous solution was alkalinised to pH ˜14 and then extracted with hexane, thus obtaining the fraction containing carbonyl products (MIRTENAL AND VERBENONE). The hexane extract, washed 2-3 times with water, was concentrated to obtain a high-boiling oily residue constituted to the extent of more than 80% by VERBENONE. The residue was dissolved with methanol; the methanol solution was cooled to −5 to −1° C. and, while maintaining this temperature, sodium borohydride was added until the MIRTENAL was undetectable (monitoring by TLC). The reduction was then stopped by the addition of a small amount of acetic acid, until the solution was neutral. The methanol solution was concentrated to ⅔ the volume, then diluted with water and extracted with hexane. The hexane solution was evaporated under vacuum and the residue is distilled at 80° C./1.5 mm Hg (1.9×10−3 bar) to give VRBENONE (25 g, yield 16.6%) with [α]D2b=−217° (c=10 in ethanol). by bubbling in O2 in the presence of cobalt stearate (0.5 g), which is added portionwise for at least 50-60 hours After cooling to room temperature by adding to the reaction mixture an equal quantity of a hot aqueous solution (˜50° C.) of 5% ferrous sulphate and 1% sulphuric acid within approximately 2 hours The organic phase was then separated washed 2-3 times with water until a pH of 5-6 is obtained The non-reacted (−)-α-pinene was removed by column distillation at a temperature of approximately 100° C. and at a pressure of 20-25 mmHg (2.6×10−2−3.3×10−2 bar) The distillation residue was constituted by a mixture of terpenes which by oxygenated functions (alcohol, ketone and aldehyde functions) A Bertagnini reaction by adding to the reaction mixture a solution while maintaining the temperature at 55-60° C the reaction was separated the aqueous phase was counter-extracted 2-3 times with hexane extracted with hexane thus obtaining the fraction The hexane extract washed 2-3 times with water was concentrated to obtain a high-boiling oily residue was added until the MIRTENAL The methanol solution was concentrated diluted with water extracted with hexane The hexane solution was evaporated under vacuum the residue is distilled at 80° C./1.5 mm Hg (1.9×10−3 bar) to give

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.6 liters 0.5M 9-borabicyclo[3.3.1]nonane in tetrahydrofuran and 122.6 g (-)-α-pinene was heated at reflux under nitrogen for 4 hr., at which time the excess (-)-α-pinene and tetrahydrofuran were removed under vacuum to leave a thick oil. The contents of the flask were cooled to 0° C. and 80 g of 1-cyclohexyl-2-propyn-1-one, prepared according to Preparation 4, was added with stirring. The resulting mixture was allowed to warm to 23° C. and it was stirred at that temperature for 16 hr. Excess S-Alpine borane was destroyed by adding 44 ml propionaldehyde and stirring at 23° C. for 1 hr. The liberated (-)-α-pinene was removed by vacuum distillation. The resulting mixture was diluted with 400 ml tetrahydrofuran followed by 300 ml 3N sodium hydroxide. To this stirred mixture was added in dropwise fashion 300 ml 30% hydrogen peroxide over 1 hr. The mixture was heated at 40° C. for 3 hr. After cooling, the mixture was extracted with diethyl ether and this extract was dried over magnesium sulfate. Evaporation of the solvent and purification of the residue by silica gel flash chromatography using 5% ethyl acetate-hexane gave 56 g of (S)-3-cyclohexyl-1-propyn-3-ol, which by nmr analysis was shown to be 90% e.e. was heated at reflux under nitrogen for 4 hr , at which time the excess (-)-α-pinene and tetrahydrofuran were removed under vacuum to leave a thick oil according to Preparation 4 was added to warm to 23° C. it was stirred at that temperature for 16 hr Excess S-Alpine borane was destroyed by adding 44 ml propionaldehyde stirring at 23° C. for 1 hr The liberated (-)-α-pinene was removed by vacuum distillation The resulting mixture was diluted with 400 ml tetrahydrofuran To this stirred mixture was added in dropwise fashion 300 ml 30% hydrogen peroxide over 1 hr The mixture was heated at 40° C. for 3 hr After cooling the mixture was extracted with diethyl ether this extract was dried over magnesium sulfate Evaporation of the solvent and purification of the residue by silica gel flash chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (−)-α-pinene (5.80 g, 42.6 mmol) in THF (10 mL) was cooled to 0° C. and a solution of borane-Me2S (10N, 1.5 mL, 15 mmol) was added. The mixture was stirred for 4 h at 0° C. and benzyl cyclopent-3-enecarboxylate (3.5 g, 17 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was cooled to 0° C. again and quenched with water (2 mL) and aqueous NaOH (3N, 15 mL). Then 30% hydrogen peroxide (20 mL) was added dropwise. The mixture was stirred for 1 h at 0° C. and diluted with water (20 mL) and EtOAc (50 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:4) to afford benzyl 3-hydroxycyclopentanecarboxylate (1.4 g, 37% yield). to warm to ambient temperature stirred overnight The mixture was cooled to 0° C. again quenched with water (2 mL) and aqueous NaOH (3N, 15 mL) Then 30% hydrogen peroxide (20 mL) was added dropwise The mixture was stirred for 1 h at 0° C. diluted with water (20 mL) and EtOAc (50 mL) The two layers were separated the aqueous phase was extracted with EtOAc (50 mL×3) The combined organic phases were washed with brine (200 mL×3) dried over anhydrous sodium sulfate concentrated The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:4)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (−)-α-pinene (5.80 g, 42.6 mmol) in THF (10 mL) was cooled to 0° C. and a solution of borane-Me2S (10N, 1.5 mL, 15 mmol) was added. The mixture was stirred for 4 h at 0° C. and benzyl cyclopent-3-enecarboxylate (3.5 g, 17 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was cooled to 0° C. again and quenched with water (2 mL) and aqueous NaOH (3N, 15 mL). Then 30% hydrogen peroxide (20 mL) was added dropwise. The mixture was stirred for 1 h at 0° C. and diluted with water (20 mL) and EtOAc (50 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:4) to afford benzyl 3-hydroxycyclopentanecarboxylate (1.4 g, 37% yield). to warm to ambient temperature stirred overnight The mixture was cooled to 0° C. again quenched with water (2 mL) and aqueous NaOH (3N, 15 mL) Then 30% hydrogen peroxide (20 mL) was added dropwise The mixture was stirred for 1 h at 0° C. diluted with water (20 mL) and EtOAc (50 mL) The two layers were separated the aqueous phase was extracted with EtOAc (50 mL×3) The combined organic phases were washed with brine (200 mL×3) dried over anhydrous sodium sulfate concentrated The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:4)

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

Procedure: In the same manner as in Example 2, the title compound was prepared by hydrogenating (E)-(R)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al which was synthesized from (1S,5S)-α-pinene having an optical purity varying from 50% e.e. to 92% e.e.

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

Procedure: In a 100 ml stainless steel autoclave were charged 3.84 g (0.02 mol) of (E)-(R)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1yl)-2-buten-1-al synthesized from (1S,5S)-α-pinene having an optical purity of 97% e.e. (available from Aldrich) in a conventional manner, 38.4 mg (0.04 mmol) of RuCl2 (PPh3)3, 4 ml of a 0.02M 1,3-diaminopropane (0.08 mmol) solution in isopropyl alcohol, and 12 ml of a 0.1M potassium hydroxide (1.2 mmol) solution in isopropyl alcohol in a nitrogen atmosphere, and the mixture was stirred at 0° C. for 3 hours under a hydrogen pressure of 50 atm.

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

Procedure: In a 100 ml stainless steel autoclave were charged 3.84 g (0.02 mol) of (E)-(R)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1yl)-2-buten-1-al synthesized from (1S,5S)-α-pinene having an optical purity of 97% e.e. (available from Aldrich) in a conventional manner, 38.4 mg (0.04 mmol) of RuCl2 (PPh3)3, 4 ml of a 0.02M 1,3-diaminopropane (0.08 mmol) solution in isopropyl alcohol, and 12 ml of a 0.1M potassium hydroxide (1.2 mmol) solution in isopropyl alcohol in a nitrogen atmosphere, and the mixture was stirred at 0° C. for 3 hours under a hydrogen pressure of 50 atm.

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

Procedure: In the same manner as in Example 2, the title compound was prepared by hydrogenating (E)-(R)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al which was synthesized from (1S,5S)-α-pinene having an optical purity varying from 50% e.e. to 92% e.e.

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

Procedure: In a 100 ml stainless steel autoclave were charged 3.84 g (0.02 mol) of (E)-(R)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al synthesized from (1S,5S)-α-pinene having an optical purity of 97% e.e. (available from Aldrich) in a conventional manner, 38.4 mg (0.04 mmol) of RuCl2 (PPh3)3, 4 ml of a 0.02M 1,3-diaminopropane (0.08 mmol) solution in isopropyl alcohol, and 12 ml of a 0.1M potassium hydroxide (1.2 mmol) solution in isopropyl alcohol in a nitrogen atmosphere, and the mixture was stirred at 0° C. for 3 hours under a hydrogen pressure of 50 atm.

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At 30° C., a mixture of 7.35 g of 2-pentenoyl chloride (62 mmol) and 1.7 g of zinc chloride (12 mmol, 0.2 eq.) in 85 ml ethylene chloride was treated dropwise within 20 min. with a solution of 19.4 g of (−)-alpha-pinene (142 mmol, 2 eq.) in 20 ml ethylene dichloride. The reaction mixture was then stirred at 30° C. for 30 min., then at 50° C. for 2 h, and finally at 80° C. for 1 h. After cooling, the reaction mixture was washed with aq. sat. NaCl soln. and aq. sat. NaHCO3 soln. The aq. phases were extracted with Et2O, dried (Na2SO4), and concentrated. FC (SiO2, hexane/Et2O 20:1) of the crude (26 g) gave 1.74 g (13%) of compound 2. The boiling point of the end product is 95° C. at 0.06 torr (0.08 mbar). at 50° C. for 2 h finally at 80° C. for 1 h After cooling the reaction mixture was washed with aq. sat. NaCl soln The aq. phases were extracted with Et2O dried (Na2SO4) concentrated