2,3,3a,4,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-one

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

Procedure: Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (478 mg, 2 mmol) was dissolved in 20 mL dichloromethane, and pyrrolidine-1-carbonyl chloride (0.276 mL, 2.5 mmol) and triethylamine (0.84 mL, 6 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred overnight at room temperature, 10% citric acid solution was then added to the mixture to adjust to pH 4. The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(pyrrolidine-1-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 8a (0.26 g, yield 58.5%) as a colorless oil. Upon completion of the addition The mixture was extracted with dichloromethane (50 mL×3) The combined organic extracts were washed with 50 mL of saturated brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (574 mg, 2.4 mmol) was dissolved in 20 mL of acetonitrile with stirring, and potassium carbonate (0.397 g, 2.88 mmol) was then added to the solution in an ice-water bath, followed by morpholine-4-carbonyl chloride (0.323 mL, 2.64 mmol). Upon completion of the addition, the reaction mixture was stirred overnight in an ice-water bath, then the solvent was evaporated, and water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(morpholine-4-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 7a (0.572 g, yield 77.3%) as a colorless oil. Upon completion of the addition the reaction mixture was stirred overnight in an ice-water bath the solvent was evaporated water (50 mL) was added to the residue The mixture was extracted with ethyl acetate (50 mL×3) The combined organic extracts were washed with 50 mL of saturated brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (717 mg, 3 mmol) was dissolved in 20 mL of dichloromethane, and 2-isocyanatopropane (9 mL, 9 mmol) and triethylamine(1.7 mL, 12 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred overnight at room temperature, water (50 mL) was then added to the mixture. The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 10% citric acid solution (50 mL) and 50 mL of saturated brine successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid isopropylamide 6a (0.3 g, yield 47.6%) as a colorless oil. Upon completion of the addition The mixture was extracted with dichloromethane (50 mL×3) The combined organic extracts were washed with 10% citric acid solution (50 mL) and 50 mL of saturated brine successively dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (717 mg, 3 mmol) was dissolved in 20 mL of acetonitrile, and acetic anhydride (0.42 mL, 4.5 mmol) and triethylamine (0.98 mL, 9 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was then stirred overnight in an ice-water bath. The solvent was evaporated, and water (50 mL) was then added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-acetyl-hexahydro-cyclopenta[c]pyrrol-5-one 5a (0.36 g, yield 72%) as a colorless oil. Upon completion of the addition The solvent was evaporated water (50 mL) was then added to the residue The mixture was extracted with ethyl acetate (50 mL×3) The combined organic extracts were washed with 50 mL of saturated brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (478 mg, 2 mmol) was dissolved in 20 mL of dichloromethane, and 1-methyl-3-(piperidine-1-carbonyl)-1H-imidazol-3-ium iodide (0.96 g, 3 mmol) and triehtylamine (0.84 mL, 6 mmol) were then added to the solution. Upon completion of the addition, the reaction mixture was stirred overnight at room temperature, 20 mL of water was then added to the mixture to quech the reaction, and the mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 10% citric acid solution (50 mL) and 50 mL of saturated brine successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(piperidine-1-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 4a (0.41 g, yield 87%) as a colorless oil. Upon completion of the addition the reaction the mixture was extracted with dichloromethane (50 mL×3) The combined organic extracts were washed with 10% citric acid solution (50 mL) and 50 mL of saturated brine successively dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (764.8 mg, 3.2 mmol) and 2-hydroxyacetic acid (267.5 mg, 3.52 mmol) were dissolved in 10 mL of acetonitrile, and hydroxyacetic acid (1.3 g, 9.6 mmol), 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride (1.23 g, 6.4 mmol) and triethylamine (1.3 mL, 9.6 mmol) were then added to the solution in an ice-water bath. The ice-water bath was then removed, and the reaction mixture was stirred overnight at 25° C. The solvent was evaporated, and 20 mL of ethyl acetate was then added to the residue. The mixture was filtered and the filtrate was washed with 20 mL of water. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(2-hydroxy-acetyl)-hexahydro-cyclopenta[c]pyrrol-5-one 3a (0.375 g, yield 64%) as a colorless oil. The ice-water bath was then removed The solvent was evaporated 20 mL of ethyl acetate was then added to the residue The mixture was filtered the filtrate was washed with 20 mL of water The combined organic extracts were dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (0.559 g, 2.34 mmol) was dissolved in 20 mL of acetonitrile, and potassium carbonate (0.646 g, 4.68 mmol) and methyl chloroformate (0.22 mL, 2.8 mmol) were then added to the solution in an ice-water bath successively. Upon completion of the addition, the reaction mixture was allowed to increase to room temperature, and stilled overnight. The solvent was evaporated, and 50 mL of water was then added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine and 50 mL of water successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid methyl ester 2a (0.25 g, yield 58.4%) as a colorless oil. Upon completion of the addition stilled overnight The solvent was evaporated 50 mL of water was then added to the residue The mixture was extracted with ethyl acetate (50 mL×3) The combined organic extracts were washed with 50 mL of saturated brine and 50 mL of water successively dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 1e (0.32 g, 1.42 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (3.27 mL, 42.7 mmol) was then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred at 0° C. for 30 minutes, then the solvent was evaporated to dryness to obtain the title compound hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f which was directly used in the further reaction. Upon completion of the addition the solvent was evaporated to dryness

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

Procedure: Reacting starting material 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (I-1a) with trifluoroacetic acid in the solvent of dichloromethane in an ice-water bath to obtain hexahydro-cyclopenta[c]pyrrol-5-one triflutate (I-1b); reacting hexahydro-cyclopenta[c]pyrrol-5-one triflutate (I-1b) with acyl chloride or ester in the presence of base to give the compounds of formula (I-1c); reacting the compounds of formula (I-1c) with equivalent amounts of different amines, sodium triacetoxyborohydride and triethylamine in the solvent of methanol at room temperature to obtain the compounds of formula (IB).

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

Procedure: reacting starting material 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (I-1a) with trifluoroacetic acid in the solvent of dichloromethane in an ice-water bath to obtain hexahydro-cyclopenta[c]pyrrol-5-one triflutate (I-1b);