(3aS,5R,7aR)-tert-butyl 5-hydroxyhexahydro-1H-isoindole-2(3H)-carboxylate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.9 g of oxalyl chloride was dissolved in 250 ml of dichloromethane and cooled to −78° C. in a nitrogen atmosphere. Then a solution of 4.83 g of dimethyl sulfoxide in dichloromethane (20 ml) was dropped thereinto over 17 minutes. Subsequently, a solution of 3.73 g of 8-(tert-butoxycarbonyl)-8-azabicyclo[4.3.0]nonan-3-ol in dichloromethane (40 ml) was dropped thereinto over 10 minutes. After stirring for 10 minutes, 7.82 g of triethylamine was dropped thereinto over 10 minutes and stirring was continued for additional 1 hour. The reaction mixture was brought back to room temperature, diluted with dichloromethane, washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 3.21 g of the title compound as a colorless oily substance. over 10 minutes over 10 minutes stirring was continued for additional 1 hour was brought back to room temperature washed with water a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure The residue thus obtained was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate)

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

Procedure: To a solution of tert-butyl 5-hydroxyhexahydro-1H-isoindole-2(3H)-carboxylate (48.98 g, 203.0 mmol) in DCM (500 mL) at 0° C. was added DMP (103.31 g, 243.6 mmol) portionwise. After addition, the reaction mixture was stirred at 0° C. for 0.5 h and then moved to rt overnight, cooled down to 0° C. and washed with a mixture of NaHCO3/Na2S2O3 saturated solution (v/v, 1/1, 500 mL), then stirred at 0° C. for 0.5 h and filtered. The filter cake was washed with DCM (250 mL×3) and the filtrate was extracted with DCM (250 mL×3). The combined organic phases were washed with brine (500 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as yellow oil (48.58 g, 100%). After addition moved to rt overnight cooled down to 0° C. washed with a mixture of NaHCO3/Na2S2O3 saturated solution (v/v, 1/1, 500 mL) stirred at 0° C. for 0.5 h filtered The filter cake was washed with DCM (250 mL×3) the filtrate was extracted with DCM (250 mL×3) The combined organic phases were washed with brine (500 mL) dried over anhydrous Na2SO4 filtered concentrated in vacuo The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5)

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

Procedure: To a solution of tert-butyl 3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (48.18 g, 215.8 mmol) in THF (500 mL) was added a solution of BH3-DMS in THF (2 M in THF, 130 mL, 260.0 mmol) dropwise at 0° C. The reaction mixture was warmed slowly to rt and stirred overnight, then cooled down to 0° C. again. Methanol (120 mL) was added dropwise to the above mixture, and followed by a mixture of NaOH aqueous solution (3 M, 75 mL, 225 mmol) and H2O2 (30% in water, 75 mL). The resulting mixture was stirred at 60° C. for 1.5 h, then cooled down to rt, and diluted with Et2O (500 mL) and water (450 mL), then extracted with EtOAc (450 mL×3). The combined organic phases were washed with brine (500 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as orange oil (49.04 g, 94.2%), which was used in the next step without further purification. cooled down to 0° C. again The resulting mixture was stirred at 60° C. for 1.5 h cooled down to rt extracted with EtOAc (450 mL×3) The combined organic phases were washed with brine (500 mL) dried over anhydrous Na2SO4 filtered concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.9 g of oxalyl chloride was dissolved in 250 ml of dichloromethane and cooled to −78° C. in a nitrogen atmosphere. Then a solution of 4.83 g of dimethyl sulfoxide in dichloromethane (20 ml) was dropped thereinto over 17 minutes. Subsequently, a solution of 3.73 g of 8-(tert-butoxycarbonyl)-8-azabicyclo[4.3.0]nonan-3-ol in dichloromethane (40 ml) was dropped thereinto over 10 minutes. After stirring for 10 minutes, 7.82 g of triethylamine was dropped thereinto over 10 minutes and stirring was continued for additional 1 hour. The reaction mixture was brought back to room temperature, diluted with dichloromethane, washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 3.21 g of the title compound as a colorless oily substance. over 10 minutes over 10 minutes stirring was continued for additional 1 hour was brought back to room temperature washed with water a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure The residue thus obtained was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate)