(1R,2S)-2-(dimethylamino)-1-phenylpropan-1-ol

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

Procedure: (-)-Narwedine (>98% ee, 0.1 g) was added to a mixture of lithium aluminium hydride (1.2 ml of a 1.0 M solution in ether), (-)-N-methylephedrine (0.23 g) and N-ethyl-2-aminopyridine (0.31 g) in ether at 0° C., and the resulting mixture was stirred at that temperature for 4 h. Sodium hydroxide solution (10 ml of a 1.0 M solution) was added and the product extracted with dichloromethane. Evaporation of the organic phase gave (-)-galanthamine (>98% ee, 85% yield) free of epigalanthamine by GC/MS analysis. the product extracted with dichloromethane Evaporation of the organic phase

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

Procedure: Lithium aluminium hydride (1M in ether, 1.2 ml, 1.20 mmol) was placed in a two necked round bottom flask fitted with a reflux condenser and nitrogen inlet. (-)-N-methylephedrine (0.23 g, 1.26 mmol) in ether (1 ml) was added dropwise and the solution was heated at reflux for 1 hour then cooled to room temperature. N-Ethyl-2-amino-pyridine (0.31 g, 2.52 mmol) in ether (1 ml) was added and the bright yellow solution was heated under reflux for a further 1 hour. The solution was cooled to -78° C. and solid racemic narwedine (0.10 g, 0.35 mmol) was added. The suspension was stirred for 3 hours at -78° C. and then allowed to warm to room temperature over 1 hour. The reaction was quenched with hydrochloric acid (3M, 2 ml). The aqueous layer was removed and basified with KOH to pH 14. The remaining mixture was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with water (5 ml) and brine (5 ml) and dried over magnesium sulphate. Filtration and evaporation gave an orange oil which was flash chromatographed on silica in dichloromethane-methanol 10:1 to yield (-)-galanthamine (50% e.e.) as a white solid (0.036 g, 36%), pure by NMR. fitted with a reflux condenser and nitrogen inlet the solution was heated at reflux for 1 hour the bright yellow solution was heated under reflux for a further 1 hour The solution was cooled to -78° C. to warm to room temperature over 1 hour The reaction was quenched with hydrochloric acid (3M, 2 ml) The aqueous layer was removed The remaining mixture was extracted with dichloromethane (3×10 ml) the combined organic layers were washed with water (5 ml) and brine (5 ml) dried over magnesium sulphate Filtration and evaporation gave an orange oil which chromatographed on silica in dichloromethane-methanol 10:1

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

Procedure: Lithium aluminium hydride (1M in ether, 1.2 ml, 1.20 mmol) was placed in a two necked round bottom flask fitted with a reflux condenser and nitrogen inlet. (-)-N-methylephedrine (0.23 g, 1.26 mmol) in ether (1 ml) was added dropwise and the solution was heated at reflux for 1 hour then cooled to room temperature. N-Ethyl-2-amino-pyridine (0.31 g, 2.52 mmol) in ether (1 ml) was added and the bright yellow solution was heated under reflux for a further 1 hour. The solution was cooled to -78° C. and solid racemic narwedine (0.10 g, 0.35 mmol) was added. The suspension was stirred for 3 hours at -78° C. and then allowed to warm to room temperature over 1 hour. The reaction was quenched with hydrochloric acid (3M, 2 ml). The aqueous layer was removed and basified with KOH to pH 14. The remaining mixture was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with water (5 ml) and brine (5 ml) and dried over magnesium sulphate. Filtration and evaporation gave an orange oil which was flash chromatographed on silica in dichloromethane-methanol 10:1 to yield (-)-galanthamine (50% e.e.) as a white solid (0.036 g, 36%), pure by NMR. fitted with a reflux condenser and nitrogen inlet the solution was heated at reflux for 1 hour the bright yellow solution was heated under reflux for a further 1 hour The solution was cooled to -78° C. to warm to room temperature over 1 hour The reaction was quenched with hydrochloric acid (3M, 2 ml) The aqueous layer was removed The remaining mixture was extracted with dichloromethane (3×10 ml) the combined organic layers were washed with water (5 ml) and brine (5 ml) dried over magnesium sulphate Filtration and evaporation gave an orange oil which chromatographed on silica in dichloromethane-methanol 10:1

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask containing Zn(OTf)2 (Zinc triflate purchased from Fluka was found to give the best results, other vendor's proved inefficient; 557 mg, 1.50 mmol) and (−)—N-methylephedrine (275 mg, 1.50 mmol) was added toluene (1.5 mL) and Et3N (209 μL, 1.50 mmol) at 23° C. under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 23° C. before but-1-en-3-ynyl-benzene (192 μL, 1.50 mmol) was added in one portion. After stirring for 15 min at 23° C., the reaction was cooled to 0° C., then acetaldehyde (168 μL, 30.0 mmol) was added at the same temperature in one portion. The resulting mixture was warmed to 23° C. and stirred for 35 h, then quenched by the addition of saturated aqueous NH4Cl (3 mL). The mixture was poured into a separatory funnel and diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (0→20% EtOAc/hexanes) afforded compound 7 (106 mg, 41%, 72% ee; the ee was determined after making the acetate ester) as a pale yellow oil. to give the best results was added in one portion the reaction was cooled to 0° C. The resulting mixture was warmed to 23° C. stirred for 35 h quenched by the addition of saturated aqueous NH4Cl (3 mL) The mixture was poured into a separatory funnel diluted with EtOAc (5 mL) The layers were separated the aqueous layer was extracted with EtOAc (3×3 mL) The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Purification of the residue via flash chromatography (0→20% EtOAc/hexanes)

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

Procedure: Ephedrine hydrochloride (30.3 g, 0.15 mol) was dissolved in warm water (60 ml) there was, then added thereto a 40% sodium hydroxide aqueous solution (15 ml, 0.15 mol) and 85% formic acid (21.7 g, 0.4 mol) and the mixture refluxed under heating, and to this solution was added dropwise at 35% formalin solution (15 g, 0.18 mol) over 20 minutes. Thereafter, refluxing under heating was continued for 3 hours and the reaction solution was concentrated to 1/2 of its original volume and then added thereto was a 40% sodium hydroxide aqueous solution to adjust the pH to about 11. The resultant precipitated crystals were filtered out and recrystallized from methanol. Yield: 23 g (84%); m.p.: 86.5°-87.5° C. [α]D20 =-29.5° (C=4.54, MeOH). added under heating Thereafter, refluxing under heating the reaction solution was concentrated to 1/2 of its original volume added The resultant precipitated crystals were filtered out recrystallized from methanol m.p.: 86.5°-87.5° C. [α]D20 =-29.5° (C=4.54, MeOH)

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

Procedure: Ephedrine hydrochloride (30.3 g, 0.15 mol) was dissolved in warm water (60 ml) there was, then added thereto a 40% sodium hydroxide aqueous solution (15 ml, 0.15 mol) and 85% formic acid (21.7 g, 0.4 mol) and the mixtures refluxed under heating, and to this solution was added dropwise a 35% formalin solution (15 g, 0.18 mol) over 20 minutes. Thereafter, refluxing under heating was continued for 3 hours and the reaction solution was concentrated to 1/2 of its original volume and then added thereto was a 40% sodium hydroxide aqueous solution to adjust the pH to about 11. The resultant precipitated crystals were filtered out and recrystallized from methanol. Yield: 23 g (84%); m.p.: 86.5°-87.5° C. [α]D20 =-29.5° (C=4.54, MeOH). added under heating Thereafter, refluxing under heating the reaction solution was concentrated to 1/2 of its original volume added The resultant precipitated crystals were filtered out recrystallized from methanol m.p.: 86.5°-87.5° C. [α]D20 =-29.5° (C=4.54, MeOH)

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask containing Zn(OTf)2 (Zinc triflate purchased from Fluka was found to give the best results, other vendor's proved inefficient; 557 mg, 1.50 mmol) and (−)-N-methylephedrine (275 mg, 1.50 mmol) was added toluene (1.5 mL) and Et3N (209 μL, 1.50 mmol) at 23° C. under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 23° C. before but-1-en-3-ynyl-benzene (192 μL, 1.50 mmol) was added in one portion. After stirring for 15 min at 23° C., the reaction was cooled to 0° C., then acetaldehyde (168 μL, 30.0 mmol) was added at the same temperature in one portion. The resulting mixture was warmed to 23° C. and stirred for 35 h, then quenched by the addition of saturated aqueous NH4Cl (3 mL). The mixture was poured into a separatory funnel and diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (0→20% EtOAc/hexanes) afforded compound 7 (106 mg, 41%, 72% ee; the ee was determined after making the acetate ester) as a pale yellow oil. to give the best results was added in one portion the reaction was cooled to 0° C. The resulting mixture was warmed to 23° C. stirred for 35 h quenched by the addition of saturated aqueous NH4Cl (3 mL) The mixture was poured into a separatory funnel diluted with EtOAc (5 mL) The layers were separated the aqueous layer was extracted with EtOAc (3×3 mL) The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Purification of the residue via flash chromatography (0→20% EtOAc/hexanes)

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

Procedure: (-)-Narwedine (>98% ee, 0.1 g) was added to a mixture of lithium aluminium hydride (1.2 ml of a 1.0 M solution in ether), (-)-N-methylephedrine (0.23 g) and N-ethyl-2-aminopyridine (0.31 g) in ether at 0° C., and the resulting mixture was stirred at that temperature for 4 h. Sodium hydroxide solution (10 ml of a 1.0 M solution) was added and the product extracted with dichloromethane. Evaporation of the organic phase gave (-)-galanthamine (>98% ee, 85% yield) free of epigalanthamine by GC/MS analysis. the product extracted with dichloromethane Evaporation of the organic phase

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

Procedure: Lithium aluminium hydride (1M in ether, 1.2 ml, 1.20 mmol) was placed in a two necked round bottom flask fitted with a reflux condenser and nitrogen inlet. (-)-N-methylephedrine (0.23 g, 1.26 mmol) in ether (1 ml) was added dropwise and the solution was heated at reflux for 1 hour then cooled to room temperature. N-Ethyl-2-amino-pyridine (0.31 g, 2.52 mmol) in ether (1 ml) was added and the bright yellow solution was heated under reflux for a further 1 hour. The solution was cooled to -78° C. and solid racemic narwedine (0.10 g, 0.35 mmol) was added. The suspension was stirred for 3 hours at -78° C. and then allowed to warm to room temperature over 1 hour. The reaction was quenched with hydrochloric acid (3M, 2 ml). The aqueous layer was removed and basified with KOH to pH 14. The remaining mixture was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with water (5 ml) and brine (5 ml) and dried over magnesium sulphate. Filtration and evaporation gave an orange oil which was flash chromatographed on silica in dichloromethane-methanol 10:1 to yield (-)-galanthamine (50% e.e.) as a white solid (0.036 g, 36%), pure by NMR. fitted with a reflux condenser and nitrogen inlet the solution was heated at reflux for 1 hour the bright yellow solution was heated under reflux for a further 1 hour The solution was cooled to -78° C. to warm to room temperature over 1 hour The reaction was quenched with hydrochloric acid (3M, 2 ml) The aqueous layer was removed The remaining mixture was extracted with dichloromethane (3×10 ml) the combined organic layers were washed with water (5 ml) and brine (5 ml) dried over magnesium sulphate Filtration and evaporation gave an orange oil which chromatographed on silica in dichloromethane-methanol 10:1