tert-butyl N-cyclopropylsulfonylcarbamate

Conditions: temp:-80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of compound 77 (500 mg, 2.26 mmol) in anhydrous THF (5 mL) at −80° C. was added nBuLi (2.26 mL, 5.65 mmol) dropwise. The mixture was stirred at −80° C. for 10 min and bromomethylbenzene (271 μL, 3.39 mmol) was added dropwise at −80° C. The mixture was then allowed to warm up to −30° C. Water was then slowly added followed by EtOAc. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (EtOAc/DCM) to yield compound 78 as a white powder in 30% yield. to warm up to −30° C Organics were dried over Na2SO4 filtered concentrated under reduced pressure purified by chromatography on silica gel (EtOAc/DCM)

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

Procedure: Under inert gas, 1.00 g of N-tert-butyloxycarbonylcyclopropanesulfonamide were initially charged in 40 ml of THF, and then, at a temperature of −78° C., 6.63 ml of a 1.5 N butyllithium solution in hexane were added dropwise and the mixture was left to stir while cooling with ice for 1 hour. After stirring at room temperature for a further 30 minutes, the mixture was cooled again to −78° C., and a solution of 0.92 ml of benzaldehyde in 4 ml of THF was added. The mixture was allowed to come to room temperature while stirring overnight. The reaction solution was diluted with 20 ml of a saturated aqueous ammonium chloride solution and extracted with 40 ml of ethyl acetate, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (880 mg) with a molecular weight of 327.4 g/mol (C15H21NO5S); MS (ESI): m/e=254 (M-tert-butanol+H+). the mixture was left while cooling with ice for 1 hour After stirring at room temperature for a further 30 minutes to come to room temperature while stirring overnight extracted with 40 ml of ethyl acetate the organic phase was dried over Na2SO4 concentrated by rotary evaporation The crude product was purified by means of normal phase chromatography concentrated by rotary evaporation

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

Procedure: BuLi 2.5 M in hexanes (7.53 ml) was added dropwise to the solution of tert-butyl (cyclopropylsulfonyl)carbamate (1.81 g) in THF (40 ml) at −78° C. This solution was stirred at −78° C. for 1 hour then 2-methoxyethoxymethyl chloride (1.85 ml) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 3 days. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. At this point, HCl (1 M) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (0.630 g) as a clear oil. LRMS (ES+) m/z 332.2 (M+Na)+. to warm to room temperature was stirred for 3 days The solvent was evaporated under reduced pressure the residue was diluted with ethyl acetate At this point, HCl (1 M) was added the mixture was extracted with ethyl acetate (3×) The combined organic layers were washed with brine dried over magnesium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes)

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

Procedure: BuLi 2.5 M in hexanes (7.53 ml) was added dropwise to the solution of tert-butyl (cyclopropylsulfonyl)carbamate (1.81 g) in THF (40 ml) at −78° C. This solution was stirred at −78° C. for 1 hour then 2-methoxyethoxymethyl chloride (1.85 ml) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 3 days. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. At this point, HCl (1 M) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (0.630 g) as a clear oil. LRMS (ES+) m/z 332.2 (M+Na)+. to warm to room temperature was stirred for 3 days The solvent was evaporated under reduced pressure the residue was diluted with ethyl acetate At this point, HCl (1 M) was added the mixture was extracted with ethyl acetate (3×) The combined organic layers were washed with brine dried over magnesium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes)

Conditions: temp:-80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of compound 77 (500 mg, 2.26 mmol) in anhydrous THF (5 mL) at −80° C. was added nBuLi (2.26 mL, 5.65 mmol) dropwise. The mixture was stirred at −80° C. for 10 min and bromomethylbenzene (271 μL, 3.39 mmol) was added dropwise at −80° C. The mixture was then allowed to warm up to −30° C. Water was then slowly added followed by EtOAc. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (EtOAc/DCM) to yield compound 78 as a white powder in 30% yield. to warm up to −30° C Organics were dried over Na2SO4 filtered concentrated under reduced pressure purified by chromatography on silica gel (EtOAc/DCM)

Conditions: temp:-80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of compound 77 (500 mg, 2.26 mmol) in anhydrous THF (5 mL) at −80° C. was added nBuLi (2.26 mL, 5.65 mmol) dropwise. The mixture was stirred at −80° C. for 10 min and bromomethylbenzene (271 μL, 3.39 mmol) was added dropwise at −80° C. The mixture was then allowed to warm up to −30° C. Water was then slowly added followed by EtOAc. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (EtOAc/DCM) to yield compound 78 as a white powder in 30% yield. to warm up to −30° C Organics were dried over Na2SO4 filtered concentrated under reduced pressure purified by chromatography on silica gel (EtOAc/DCM)

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

Procedure: To a solution of tert-butyl cyclopropylsulfonylcarbamate (885 mg, 4 mmol) in THF (20 mL) at −78° C. was added n-Butyllithium (3.36 mL, 8.40 mmol) (2.5 M in hexanes) dropwise. The formed solution was warmed up to r.t. and stirred for 1.5 h. Cooled this light yellow solution back to −78° C. 7-Bromo-1-heptene (1.219 mL, 8.00 mmol) was added dropwise. The final solution was allowed to warm up to r.t. over the period of 16 h. Quenched with sat. NH4Cl, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by Biotage column, eluted with gradient 5%˜40% EtOAc-Hexane to afford the desired product tert-butyl 1-(hept-6-enyl)cyclopropylsulfonylcarbamate (625 mg, 1.772 mmol, 44.3% yield) as a viscous oil, which solidified upon standing on bench. 1H NMR (400 MHz, CHLOROFORM-D) ppm 0.88-1.02 (m, 2 H) 1.26-1.49 (m, 6 H) 1.53 (s, 9 H) 1.60-1.71 (m, 2 H) 1.82-1.94 (m, 2 H) 2.06 (q, J=6.94 Hz, 2 H) 4.81-5.08 (m, 2 H) 5.68-5.88 (m, 1 H) 6.88 (b, NH). LC-MS (retention time: 2.76 min, Method A), MS m/z 218 (M+H-Boc). Cooled this light yellow solution back to −78° C to warm up to r.t. over the period of 16 h Quenched with sat. NH4Cl extracted with EtOAc The organic layer was washed with brine dried over MgSO4 filtered concentrated The residue was purified by Biotage column eluted with gradient 5%˜40% EtOAc-Hexane

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

Procedure: A solution of tert-butyl cyclopropylsulfonylcarbamate (4.3 g, 20 mmol) was dissolved in dry THF (100 ml) and cooled to −78° C. To this solution was added n-BuLi (17.6 ml, 44 mmol, 2.5 M in hexane) slowly. The reaction mixture was allowed to warm to room temperature over a period of 1.5 h. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 ml, 2.5M in hexane) was added, stirred for 1 h and a neat solution of methyl iodide (5.68 g, 40 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring overnight; then was quenched with aqueous saturated NH4Cl (100 ml) at room temperature. The mixture was extracted with EtOAc (100 ml). The organic layer was washed with brine; dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil which was crystallized from hexane to afford the product as a slightly yellow solid (3.1 g, 81%). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.97 (s, 1H), 1.44 (s, 12H), 1.35-1.33 (m, 2H), 0.93-0.91 (m, 2H). to warm to room temperature over a period of 1.5 h This mixture was then cooled to −78° C. to warm to room temperature with stirring overnight then was quenched with aqueous saturated NH4Cl (100 ml) at room temperature The mixture was extracted with EtOAc (100 ml) The organic layer was washed with brine dried over Na2SO4 filtered concentrated under reduced pressure to give a yellow oil which was crystallized from hexane

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

Procedure: Under inert gas, 1.00 g of N-tert-butyloxycarbonylcyclopropanesulfonamide were initially charged in 40 ml of THF, and then, at a temperature of −78° C., 6.63 ml of a 1.5 N butyllithium solution in hexane were added dropwise and the mixture was left to stir while cooling with ice for 1 hour. After stirring at room temperature for a further 30 minutes, the mixture was cooled again to −78° C., and a solution of 0.92 ml of benzaldehyde in 4 ml of THF was added. The mixture was allowed to come to room temperature while stirring overnight. The reaction solution was diluted with 20 ml of a saturated aqueous ammonium chloride solution and extracted with 40 ml of ethyl acetate, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (880 mg) with a molecular weight of 327.4 g/mol (C15H21NO5S); MS (ESI): m/e=254 (M-tert-butanol+H+). the mixture was left while cooling with ice for 1 hour After stirring at room temperature for a further 30 minutes to come to room temperature while stirring overnight extracted with 40 ml of ethyl acetate the organic phase was dried over Na2SO4 concentrated by rotary evaporation The crude product was purified by means of normal phase chromatography concentrated by rotary evaporation

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

Procedure: BuLi 2.5 M in hexanes (7.53 ml) was added dropwise to the solution of tert-butyl (cyclopropylsulfonyl)carbamate (1.81 g) in THF (40 ml) at −78° C. This solution was stirred at −78° C. for 1 hour then 2-methoxyethoxymethyl chloride (1.85 ml) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 3 days. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. At this point, HCl (1 M) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (0.630 g) as a clear oil. LRMS (ES+) m/z 332.2 (M+Na)+. to warm to room temperature was stirred for 3 days The solvent was evaporated under reduced pressure the residue was diluted with ethyl acetate At this point, HCl (1 M) was added the mixture was extracted with ethyl acetate (3×) The combined organic layers were washed with brine dried over magnesium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes)

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

Procedure: Under inert gas, 1.00 g of N-tert-butyloxycarbonylcyclopropanesulfonamide were initially charged in 40 ml of THF, and then, at a temperature of −78° C., 6.63 ml of a 1.5 N butyllithium solution in hexane were added dropwise and the mixture was left to stir while cooling with ice for 1 hour. After stirring at room temperature for a further 30 minutes, the mixture was cooled again to −78° C., and a solution of 0.92 ml of benzaldehyde in 4 ml of THF was added. The mixture was allowed to come to room temperature while stirring overnight. The reaction solution was diluted with 20 ml of a saturated aqueous ammonium chloride solution and extracted with 40 ml of ethyl acetate, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (880 mg) with a molecular weight of 327.4 g/mol (C15H21NO5S); MS (ESI): m/e=254 (M-tert-butanol+H+). the mixture was left while cooling with ice for 1 hour After stirring at room temperature for a further 30 minutes to come to room temperature while stirring overnight extracted with 40 ml of ethyl acetate the organic phase was dried over Na2SO4 concentrated by rotary evaporation The crude product was purified by means of normal phase chromatography concentrated by rotary evaporation

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

Procedure: To a solution of tert-butyl cyclopropylsulfonylcarbamate (30 g, 136 mmol) in 750 mL of THF was added dropwise butyllithium (1.6 M in hexane, 212 mL, 339 mmol) over 30 min at −78° C. and the resulting mixture was stirred at −78° C. for 1 h. Formaldehyde gas was generated from para-formaldehyde (by heating at 180° C.) and was purged into the above reaction mass for 30 min at −30° C. The reaction was stirred at the same temperature for 1 h, then allowed to warm to room temperature. The reaction was quenched with aqueous ammonium chloride solution and diluted with water. The resulting mass was washed with ethyl acetate and the aqueous layer was acidified to pH˜2 and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and evaporated under reduced pressure to get desired compound (27 g, 79%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.90 (sb, 1H), 4.95 (sb, 1H), 3.75 (s, 2H), 1.42 (s, 9H), 1.27 (m, 2H), 1.08 (m, 2H). was purged into the above reaction mass for 30 min at −30° C The reaction was stirred at the same temperature for 1 h to warm to room temperature The reaction was quenched with aqueous ammonium chloride solution diluted with water The resulting mass was washed with ethyl acetate extracted with ethyl acetate The combined organics were dried over sodium sulfate filtered evaporated under reduced pressure