2-benzyl-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrol-4-one

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A 3-neck, 1-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at RT was charged with cyclopentenone (16.48 g, 0.20 mol) in 0.5 L of CH2Cl2. Benzyl(methoxymethyl)trimethylsilylmethylamine (5.0 grams, 21 mmol) and trifluoroacetic acid (TFA) (1.07 mL, 13.9 mmol) were added. To this mixture was added additional benzyl(methoxymethyl)-trimethylsilylmethylamine (40 g, 0.168 mol) dropwise via addition funnel over 1 hour with the reaction temperature being maintained below 25° C. (water bath). After the addition was complete, the mixture was stirred for 4 h. The mixture was washed with 1×100 mL 10% Na2CO3. The layers were separated and the organic layer was washed with 1×100 mL 23% NaCl. The organic extract was concentrated under reduced pressure to give an oil. The oil was redissolved in methyl-t-butyl ether (250 mL) and extracted into 1M H3PO4 (200 mL). The aqueous layer was basified with 50% NaOH to pH 12. The product was extracted with methyl-t-butyl ether (250 mL). The layers were separated and the organic layer was washed with 23% NaCl. The layers were separated. The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms). The mixture was stirred 5 minutes and filtered through a silica gel pad (10 grams). The filtrate was concentrated to give the title compound (35.0 grams, 81.4% of theory), which was carried on to the next step without further purification. MS (ESI/APCI) m/z 216 (M+H)+. dropwise via addition funnel over 1 hour with the reaction temperature After the addition The mixture was washed with 1×100 mL 10% Na2CO3 The layers were separated the organic layer was washed with 1×100 mL 23% NaCl The organic extract was concentrated under reduced pressure to give an oil extracted into 1M H3PO4 (200 mL) The product was extracted with methyl-t-butyl ether (250 mL) The layers were separated the organic layer was washed with 23% NaCl The layers were separated The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms) The mixture was stirred 5 minutes filtered through a silica gel pad (10 grams) The filtrate was concentrated

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

Procedure: A 3-neck, 1-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at RT was charged with cyclopentenone (16.48 g, 0.20 mol) in 0.5 L of CH2Cl2. Benzyl(methoxymethyl)trimethylsilylmethylamine (5.0 grams, 21 mmol) and trifluoroacetic acid (TFA) (1.07 mL, 13.9 mmol) were added. To this mixture was added additional benzyl(methoxymethyl)-trimethylsilylmethylamine (40 g, 0.168 mol) dropwise via addition funnel over 1 hour with the reaction temperature being maintained below 25° C. (water bath). After the addition was complete, the mixture was stirred for 4 h. The mixture was washed with 1×100 mL 10% Na2CO3. The layers were separated and the organic layer was washed with 1×100 mL 23% NaCl. The organic extract was concentrated under reduced pressure to give an oil. The oil was redissolved in methyl-t-butyl ether (250 mL) and extracted into 1M H3PO4 (200 mL). The aqueous layer was basified with 50% NaOH to pH 12. The product was extracted with methyl-t-butyl ether (250 mL). The layers were separated and the organic layer was washed with 23% NaCl. The layers were separated. The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms). The mixture was stirred 5 minutes and filtered through a silica gel pad (10 grams). The filtrate was concentrated to give the title compound (35.0 grams, 81.4% of theory), which was carried on to the next step without further purification. MS (ESI/APCI) m/z 216 (M+H)+. dropwise via addition funnel over 1 hour with the reaction temperature After the addition The mixture was washed with 1×100 mL 10% Na2CO3 The layers were separated the organic layer was washed with 1×100 mL 23% NaCl The organic extract was concentrated under reduced pressure to give an oil extracted into 1M H3PO4 (200 mL) The product was extracted with methyl-t-butyl ether (250 mL) The layers were separated the organic layer was washed with 23% NaCl The layers were separated The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms) The mixture was stirred 5 minutes filtered through a silica gel pad (10 grams) The filtrate was concentrated

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

Procedure: 2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (0.578 g, 2.68 mmol), cyclopropylamine (0.189 mL, 2.68 mmol), and acetic acid (10 mL) were combined in dichloromethane (20 mL). PS-Cyanoborohydride (1.147 g, 2.68 mmol) was added. The reaction was stirred at room temperature for 2 hours, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was applied to a silica gel column and was eluted with 1-10% methanol(2 N ammonia)/dichloromethane to give the title compounds. filtered the resin was washed with dichloromethane The solvent was removed in vacuo was eluted with 1-10% methanol(2 N ammonia)/dichloromethane

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

Procedure: 2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (0.578 g, 2.68 mmol), cyclopropylamine (0.189 mL, 2.68 mmol), and acetic acid (10 mL) were combined in dichloromethane (20 mL). PS-Cyanoborohydride (1.147 g, 2.68 mmol) was added. The reaction was stirred at room temperature for 2 hours, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was applied to a silica gel column and was eluted with 1-10% methanol(2 N ammonia)/dichloromethane to give the title compounds. filtered the resin was washed with dichloromethane The solvent was removed in vacuo was eluted with 1-10% methanol(2 N ammonia)/dichloromethane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (16.28 g, 76 mmol), titanium tetraethoxide (28.5 mL, 137 mmol), and (S)-2-methylpropane-2-sulfinamide (10.452 g, 86 mmol) were combined in tetrahydrofuran (200 mL). The reaction was heated at 60° C. overnight. The reaction was then reduced in volume to about half and poured into 150 mL of saturated aqueous ammonium chloride. The precipitate was collected by filtration and washed with ethyl acetate. The filtrate was poured into a separatory funnel and the organic layer was removed. The aqueous layer was extracted with ethyl acetate (3×100 mL). The organic washes were combined and washed with brine, dried (Na2SO4) and concentrated. The crude material was chromatographed using silica gel cartridge (Analogix®, Burlington, Wis., RS65-400) eluting with 5-100% ethyl acetate/hexanes to give (S,E)-N-((3aR,6aS)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide and (S,E)-N-((3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide. The precipitate was collected by filtration washed with ethyl acetate The filtrate was poured into a separatory funnel the organic layer was removed The aqueous layer was extracted with ethyl acetate (3×100 mL) washed with brine dried (Na2SO4) concentrated The crude material was chromatographed eluting with 5-100% ethyl acetate/hexanes

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

Procedure: A 3-neck, 1-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at RT was charged with cyclopentenone (16.48 g, 0.20 mol) in 0.5 L of CH2Cl2. Benzyl(methoxymethyl)trimethylsilylmethylamine (5.0 grams, 21 mmol) and trifluoroacetic acid (TFA) (1.07 mL, 13.9 mmol) were added. To this mixture was added additional benzyl(methoxymethyl)-trimethylsilylmethylamine (40 g, 0.168 mol) dropwise via addition funnel over 1 hour with the reaction temperature being maintained below 25° C. (water bath). After the addition was complete, the mixture was stirred for 4 h. The mixture was washed with 1×100 mL 10% Na2CO3. The layers were separated and the organic layer was washed with 1×100 mL 23% NaCl. The organic extract was concentrated under reduced-pressure to give an oil. The oil was redissolved in methyl-t-butyl ether (250 mL) and extracted into 1M H3PO4 (200 mL). The aqueous layer was basified with 50% NaOH to pH 12. The product was extracted with methyl-t-butyl ether (250 mL). The layers were separated and the organic layer was washed with 23% NaCl. The layers were separated. The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms). The mixture was stirred 5 minutes and filtered through a silica gel pad (10 grams). The filtrate was concentrated to give the title compound (35.0 grams, 81.4% of theory), which was carried on to the next step without further purification. MS (ESI/APCl) m/z 216 (M+H)+. dropwise via addition funnel over 1 hour with the reaction temperature After the addition The mixture was washed with 1×100 mL 10% Na2CO3 The layers were separated the organic layer was washed with 1×100 mL 23% NaCl The organic extract was concentrated under reduced-pressure to give an oil extracted into 1M H3PO4 (200 mL) The product was extracted with methyl-t-butyl ether (250 mL) The layers were separated the organic layer was washed with 23% NaCl The layers were separated The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms) The mixture was stirred 5 minutes filtered through a silica gel pad (10 grams) The filtrate was concentrated

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

Procedure: A 3-neck, 1-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at RT was charged with cyclopentenone (16.48 g, 0.20 mol) in 0.5 L of CH2Cl2. Benzyl(methoxymethyl)trimethylsilylmethylamine (5.0 grams, 21 mmol) and trifluoroacetic acid (TFA) (1.07 mL, 13.9 mmol) were added. To this mixture was added additional benzyl(methoxymethyl)-trimethylsilylmethylamine (40 g, 0.168 mol) dropwise via addition funnel over 1 hour with the reaction temperature being maintained below 25° C. (water bath). After the addition was complete, the mixture was stirred for 4 h. The mixture was washed with 1×100 mL 10% Na2CO3. The layers were separated and the organic layer was washed with 1×100 mL 23% NaCl. The organic extract was concentrated under reduced-pressure to give an oil. The oil was redissolved in methyl-t-butyl ether (250 mL) and extracted into 1M H3PO4 (200 mL). The aqueous layer was basified with 50% NaOH to pH 12. The product was extracted with methyl-t-butyl ether (250 mL). The layers were separated and the organic layer was washed with 23% NaCl. The layers were separated. The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms). The mixture was stirred 5 minutes and filtered through a silica gel pad (10 grams). The filtrate was concentrated to give the title compound (35.0 grams, 81.4% of theory), which was carried on to the next step without further purification. MS (ESI/APCl) m/z 216 (M+H)+. dropwise via addition funnel over 1 hour with the reaction temperature After the addition The mixture was washed with 1×100 mL 10% Na2CO3 The layers were separated the organic layer was washed with 1×100 mL 23% NaCl The organic extract was concentrated under reduced-pressure to give an oil extracted into 1M H3PO4 (200 mL) The product was extracted with methyl-t-butyl ether (250 mL) The layers were separated the organic layer was washed with 23% NaCl The layers were separated The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms) The mixture was stirred 5 minutes filtered through a silica gel pad (10 grams) The filtrate was concentrated

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

Procedure: A 3-neck, 1-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at RT was charged with cyclopentenone (16.48 g, 0.20 mol) in 0.5 L of CH2Cl2. Benzyl(methoxymethyl)trimethylsilylmethylamine (5.0 grams, 21 mmol) and trifluoroacetic acid (TFA) (1.07 mL, 13.9 mmol) were added. To this mixture was added additional benzyl(methoxymethyl)-trimethylsilylmethylamine (40 g, 0.168 mol) dropwise via addition funnel over 1 hour with the reaction temperature being maintained below 25° C. (water bath). After the addition was complete, the mixture was stirred for 4 h. The mixture was washed with 1×100 mL 10% Na2CO3. The layers were separated and the organic layer was washed with 1×100 mL 23% NaCl. The organic extract was concentrated under reduced pressure to give an oil. The oil was redissolved in methyl-t-butyl ether (250 mL) and extracted into 1M H3PO4 (200 mL). The aqueous layer was basified with 50% NaOH to pH 12. The product was extracted with methyl-t-butyl ether (250 mL). The layers were separated and the organic layer was washed with 23% NaCl. The layers were separated. The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms). The mixture was stirred 5 minutes and filtered through a silica gel pad (10 grams). The filtrate was concentrated to give the title compound (35.0 grams, 81.4% of theory), which was carried on to the next step without further purification. MS (ESI/APCI) m/z 216 (M+H)+. dropwise via addition funnel over 1 hour with the reaction temperature After the addition The mixture was washed with 1×100 mL 10% Na2CO3 The layers were separated the organic layer was washed with 1×100 mL 23% NaCl The organic extract was concentrated under reduced pressure to give an oil extracted into 1M H3PO4 (200 mL) The product was extracted with methyl-t-butyl ether (250 mL) The layers were separated the organic layer was washed with 23% NaCl The layers were separated The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms) The mixture was stirred 5 minutes filtered through a silica gel pad (10 grams) The filtrate was concentrated

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (0.578 g, 2.68 mmol), cyclopropylamine (0.189 mL, 2.68 mmol), and acetic acid (10 mL) were combined in dichloromethane (20 mL). PS-Cyanoborohydride (1.147 g, 2.68 mmol) was added. The reaction was stirred at room temperature for 2 hours, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was applied to a silica gel column and was eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compounds. filtered the resin was washed with dichloromethane The solvent was removed in vacuo was eluted with 1-10% methanol (2 N ammonia)/dichloromethane

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

Procedure: 2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (0.578 g, 2.68 mmol), cyclopropylamine (0.189 mL, 2.68 mmol), and acetic acid (10 mL) were combined in dichloromethane (20 mL). PS-Cyanoborohydride (1.147 g, 2.68 mmol) was added. The reaction was stirred at room temperature for 2 hours, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was applied to a silica gel column and was eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compounds. filtered the resin was washed with dichloromethane The solvent was removed in vacuo was eluted with 1-10% methanol (2 N ammonia)/dichloromethane