Ethyl (1R,2S)-1-[[(1,1-dimethylethoxy)carbonyl]amino]-2-ethenylcyclopropanecarboxylate

The substrate (2 g, 6.1 mmol)Was dissolved in anhydrous dichloromethane (24 mL), Triethylamine (0.85 mL) was slowly added, The reaction solution becomes viscous;Then Boc2O (1.4 g, 6.1 mmol) was added, The reaction solution was stirred at room temperature for 17 hours, LTC shows complete reaction.The reaction solution was transferred to a separatory funnel, Followed by water (4 mL), Saturated sodium bicarbonate solution (4 mL), And saturated brine (4 mL)The organic phase was dried over anhydrous sodium sulfate, filter, The filtrate was concentrated to give 1.84 g of a yellow oil, The column chromatography gave 1.32 g (84.6percent) of pure product as a colorless oil.Intermediate C5: (1R, 2S)-ethyl 1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate Resolution BTo 0.5 mL 100 mM Heps.Na buffer (pH 8.5) in a well of a 24 well plate (capacity: 10 mL/well), 0.1 mL of Savinase 16.0 L (protease from Bacillus clausii) (Novozymes North America Inc.) and a solution of (1R, 2S)/(1S, 2R)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (10 mg) in 0.1 mL of DMSO were added. The plate was sealed and incubated at 250 rpm at 40° C. After 18 hours, enantio-excess of the ester was determined to be 44.3percent using the following procedure: 0.1 mL of the reaction mixture was removed and mixed well with 1 mL ethanol. After centrifugation, 10 microliter (pL) of the supernatant was analyzed with the chiral HPLC. To the remaining reaction mixture, 0.1 mL of DMSO was added, and the plate was incubated for additional 3 days at 250 rpm at 40° C., after which 4 mL of ethanol was added to the well. After centrifugation, 10 μL of the supernatant was analyzed with the chiral HPLC and enantio-excess of the ester was determined to be 100percent.Resolution CTo 0.5 mL 100 mM Heps.Na buffer (pH 8.5) in a well of a 24 well plate (capacity: 10 mL/well), 0.1 mL of Esperase 8.0 L, (protease from Bacillus halodurans) (Novozymes North America Inc.) and a solution of (1R, 2S)/(1S, 2R) N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (10 mg) in 0.1 mL of DMSO were added. The plate was sealed and incubated at 250 rpm at 40° C. After 18 hours, enantio-excess of the ester was determined to be 39.6percent using the following procedure: 0.1 mL of the reaction mixture was removed and mixed well with 1 mL ethanol; after cenrifugation, 10 μL of the supernatant was analyzed with the chiral HPLC. To the remaining reaction mixture, 0.1 mL of DMSO was added, and the plate was incubated for additional 3 days at 250 rpm at 40° C., after which 4 mL of ethanol was added to the well. After centrifugation, 10 μL of the supernatant was analyzed with the chiral HPLC and enantio-excess of the ester was determined to be 100percent.A solution of 0.3M sodium phosphate buffer (pH 8, 5 L) at 38° C. in a 20 L jacked reactor was stirred at 130 rpm and treated with 4 L of Alcalase 2.4 L (Novozymes North America Inc.) and 1 L of DI water. When the temperature of the mixture approached 38° C. the pH was adjusted to 7.8 with 10N NaOH. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R) 1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (500 grams) in 5 L DMSO was added to the reactor over a period of 1 hour via addition funnel. The reaction temperature was adjusted to 48° C. and stirred for 21 hours, at which time the enantio-excess of the ester reached 99.3percent. Heating was stopped at 24 hours and the reaction was slowly cooled to room temperature (about 25° C.) and stirred overnight. The pH of the reaction mixture was adjusted to 8.5 with 10N NaOH and the mixture was extracted with MTBE (2.x.4 L). The combined MTBE extracts were washed with 5percent NaHCOA solution of 5 L of 0.2M sodium borate buffer (pH 9) at 45° C. in a 20 L jacked reactor stirred at 400 rpm was treated with 3 L of DI water and 4 L of Savinase 16 L, type EX (Novozymes North America Inc.). When the temperature of the mixture closed to 45° C., the pH was adjusted to 8.5 with 10N NaOH. A solution of (1R, 2S)/(1S, 2R)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (200 grams) in 2 L DMSO was added to the reactor over a period of 40 minutes via addition funnel. The reaction temperature was then adjusted to 48° C. After 2 hours, the pH was adjusted to pH 9.0 with 10N NaOH. At 18 hours, enantio-excess of the ester reached 72percent and the pH was adjusted to 9.0 with 10N NaOH. At 24 hours the temperature was lowered to 35° C. At 42 hours the temperature was raised to 48° C. and the pH was adjusted to 9.0 with 10N NaOH. Heating was stopped at 48 hours and the reaction was slowly cooled down to room temperature (about 25° C.) and stirred overnight. At 66 hours, the pH of the reaction mixture was 8.6. The mixture was extracted with MTBE (2.x.4 L). The combined MTBE extracts were washed with 5percent NaHCO5 L of 0.2 M sodium borate buffer (pH 9) was maintained at 45° C. in a 20 liter jacked reactor, stirred at 400 rpm. Three liter of DI water and four liters of Savinase 16 L, type EX (Novozymes North America Inc.) were added to the reactor. When temperature of the mixture closed to 45° C., pH was adjusted to 8.5 with 10 N NaOH. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (200 grams) in 2 liters DMSO was added to the reactor over a period of 40 min, via an addition funnel. The reaction temperature was then adjusted to 48° C. After 2 hours, pH was adjusted to pH 9.0 with 10 N NaOH. At 18 hour, enantio-excess of the ester reached 72percent, pH was adjusted to 9.0 with 10 N NaOH. At 24 hour, temperature was lowered to 35° C. At 42 hour, temperature was raised to 48° C. and pH was adjusted to 9.0 with 10 N NaOH. Heating was stopped at 48 hour and the reaction was slowly cooled down to room temperature (about 25° C.) and stirred overnight. At 66 hour, pH of the reaction mixture was 8.6. The mixture was extracted with MTBE (2.x.4 L). The combined MTBE extract was washed with 5percent NaHCO3 (6.x.300 ml) and water (3.x.300 ml), and evaporated to give enantiomerically pure N-Boc-(1R, 2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow crystal (101 A g; purity: 95.9percent (at)210 nm, containing no acid; 98.6percent ee).To 0.5 ml 100 mM Heps.Na buffer (pH 8.5) in a well of a 24 well plate (capacity: 10 mL/well), 0.1 ml of Esperase 8.0 L, (protease from Bacillus halodurans) (Novozymes North America Inc.) and a solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (10 mg) in 0.1 mL of DMSO were added. The plate was sealed and incubated at 250 rpm at 40° C. After 18 hour, enantio-excess of the ester was determined to be 39.6percent as following: 0.1 mL of the reaction mixture was removed and mixed well with 1 mL ethanol; after cenrifugation, 10 μl of the supernatant was analyzed with the chiral HPLC. To the remaining reaction mixture, 0.1 mL of DMSO was added, and the plate was incubated for additional 3 days at 250 rpm at 40° C., after which four mL of ethanol was added to the well. After centrifugation, 10 μl of the supernatant was analyzed with the chiral HPLC and enantio-excess of the ester was determined to be 100percent.Resolution A To an aqueous solution of sodium phosphate buffer (0.1 M, 4.25 liter (L), pH 8) housed in a 12 Liter jacked reactor, maintained at 39° C., and stirred at 300 rpm was added 511 grams of Alcalase 2.4 L (about 425 mL) (Novozymes North America Inc.). When the temperature of the mixture reached 39° C., the pH was adjusted to 8.0 by the addition of a 50percent NaOH in water. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (85 g) in 850 mL of DMSO was then added over a period of 40 min. The reaction temperature was then maintained at 40° C. for 24.5 h during which time the pH of the mixture was adjusted to 8.0 at the 1.5 h and 19.5 h time points using 50percent NaOH in water. After 24.5 h, the enantio-excess of the ester was determined to be 97.2percent, and the reaction was cooled to room temperature (26° C.) and stirred overnight (16 h) after which the enantio-excess of the ester was determined to be 100percent. The pH of the reaction mixture was then adjusted to 8.5 with 50percent NaOH and the resulting mixture was extracted with MTBE (2.x.2 L). The combined MTBE extract was then washed with 5percent NaHCO3 (3.x.100 mL), water (3.x.100 mL), and evaporated in vacuo to give the enantiomerically pure N-Boc-(1R, 2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow solid (42.55 g; purity: 97percent (210 nm, containing no acid; 100percent enantiomeric excess (ee). The aqueous layer from the extraction process was then acidified to pH 2 with 50percent H2SO4 and extracted with MTBE (2.x.2 L). The MTBE extract was washed with water (3.x.100 mL) and evaporated to give the acid as light yellow solid (42.74 g; purity: 99percent (210 nm, containing no ester).; Resolution D L of 0.3 M sodium phosphate buffer (pH 8) was maintained at 38° C. in a 20 Liter jacked reactor, stirred at 130 rpm. Four liters of Alcalase 2.4 L (Novozymes North America Inc.) and 1 liter of DI water were added to the reactor. When temperature of the mixture closed to 38° C., pH was adjusted to 7.8 with 10 N NaOH. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (500 grams) in 5 liters DMSO was added to the reactor over a period of 1 hour via an addition funnel. The reaction temperature was then adjusted to 48° C. After 21 hours, enantio-excess of the ester reached 99.3percent. Heating was stopped at 24 hour and the reaction was slowly cooled down to room temperature (about 25° C.) and stirred overnight. pH of the reaction mixture was adjusted to 8.5 with 10 N NaOH and the mixture was extracted with MTBE (2.x.4 L). The combined MTBE extract was washed with 5percent NaHCO3 (3.x.400 ml) and water (3.x.400 ml), and evaporated to give enantiomerically pure N-Boc-(1R, 2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow crystal (259 g; purity: 96.9percent (at) 210 nm, containing no acid; 100percent ee).; Resolution E 10 L of 0.1 M sodium phosphate buffer (pH 8) was maintained at 40° C. in a 20 Liter jacked reactor, stirred at 360 rpm. 1.5 liters of Alcalase 2.4 L (Novozymes North America Inc.) was added to the reactor. When temperature of the mixture closed to 38° C., pH was adjusted to 8.0 with 10 N NaOH. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (200 grams) in 2 liters DMSO was added to the reactor over a period of 1 hour via an addition funnel. The reaction temperature was then adjusted to 40° C. After 3 hours, pH was adjusted to 8.0 with 10 N NaOH. After 21 hours, the reaction was cooled down to 25° C. pH of the reaction mixture was adjusted to 8.5 with 10 N NaOH and the mixture was extracted with MTBE (2.x.5 L). The combined MTBE extract was washed with 5percent NaHCO3 (3.x.500 ml) and water (3.x.200 ml), and evaporated to give 110 gram of yellow oil. The oil was set at room temperature under house vacuum and gave enantiomerically pure N-Boc-(1R, 2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as colorless long rod crystal (101 g; purity: 97.9percent (at) 210 nm, containing no acid; 100percent ee). The crystal structure enantiomerically pure N-Boc-(1R, 2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester has been characterized by single crystal analysis (X-ray NBNo.: 52795-093, refcode: 634592N1). The absolute configuration is not established for lack of a known chiral center or heavier atom(s). A chain structure along the crystallographic a-axis is formed via intermolecular hydrogen bonding between the amide group and the carbonyl oxygen atom (N . . . O 3.159 ).To 0.5 mL 100 mM Heps.Na buffer (pH 8.5) in a well of a 24 well plate (capacity: 10 ml/well), 0.1 mL of Savinase 16.0 L (protease from Bacillus clausii) (Novozymes North America Inc.) and a solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (10 mg) in 0.1 mL of DMSO were added. The plate was sealed and incubated at 250 rpm at 40° C. After 18 h, enantio-excess of the ester was determined to be 44.3percent as following: 0.1 mL of the reaction mixture was removed and mixed well with 1 mL ethanol; after centrifugation, 10 microliter (μl) of the supernatant was analyzed with the chiral HPLC. To the remaining reaction mixture, 0.1 mL of DMSO was added, and the plate was incubated for additional 3 days at 250 rpm at 40° C., after which four mL of ethanol was added to the well. After centrifugation, 10 μl of the supernatant was analyzed with the chiral HPLC and enantio-excess of the ester was determined to be 100percent.To an aqueous solution of sodium phosphate buffer (0.1M, 4.25 L, pH 8) housed in a 12 Liter jacked reactor, maintained at 39° C., and stirred at 300 rpm, was added 511 grams of Alcalase 2.4 L (about 425 mL) (Novozymes North America Inc.). When the temperature of the mixture reached 39° C., the pH was adjusted to 8.0 by the addition of 50percent NaOH in water. A solution of (1R, 2S)/(1S, 2R)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (85 g) in 850 mL of DMSO was then added over a period of 40 minutes. The reaction temperature was maintained at 40° C. for 24.5 hours during which time the pH of the mixture was adjusted to 8.0 at the 1.5 hour and 19.5 hour time points using 50percent NaOH in water. After 24.5 hours, the enantio-excess of the ester was determined to be 97.2percent, and the reaction was cooled to room temperature (26° C.) and stirred overnight (16 hours) at which time the enantio-excess of the ester was determined to be 100percent. The pH of the reaction mixture was then adjusted to 8.5 with 50percent NaOH and the resulting mixture was extracted with MTBE (2.x.2 L). The combined MTBE extract was washed with 5percent NaHCO10 L of 0.1 M sodium phosphate buffer (H 8) was maintained at 40° C. in a 20 liter jacked reactor, stirred at 360 rpm. 1.5 liters of Alcalase 2.4L (Novozymes North America Inc.) was added to the reactor. When the temperature of the mixture closed to 38° C., the pH was adjusted to 8.0 with 10 N NaOH. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (200 grams) in 2 liters DMSO was added to the reactor over a period of 1 hour via an addition funnel. The reaction temperature was then adjusted to 40° C. After 3 hours, the pH was adjusted to 8.0 with 10 N NaOH. After 21 hours, the reaction was cooled down to 25° C., the pH of the reaction mixture was adjusted to 8.5 with 10 N NaOH and the mixture was extracted with MTBE (2.x.5 L). The combined MTBE extract was washed with 5percent NaHCOTo 0.5 mL 100 mM HepsNa buffer (pH 8.5) in a well of a 24 well plate (capacity: 10 ml/well), 0.1 mL of Savinase 16.0 L (protease from Bacillus clausii) (Novozymes North America Inc.) and a solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (10 mg) in 0.1 mL of DMSO were added. The plate was sealed and incubated at 250 rpm at 40° C. After 18 h, enantio-excess of the ester was determined to be 44.3percent as following: 0.1 mL of the reaction mixture was removed and mixed well with 1 mL ethanol; after centrifugation, 10 microliter (μl) of the supernatant was analyzed with the chiral HPLC. To the remaining reaction mixture, 0.1 mL of DMSO was added, and the plate was incubated for additional 3 days at 250 rpm at 40° C., after which four mL of ethanol was added to the well. After centrifugation, 10 μl of the supernatant was analyzed with the chiral HPLC and enantio-excess of the ester was determined to be 100percent.To an aqueous solution of sodium phosphate buffer (0.1 M, 4.25 liter (L), pH 8) housed in a 12 Liter jacked reactor, maintained at 39° C., and stirred at 300 rpm was added 511 grams of Alcalase 2.4 L (about 425 mL) (Novozymes North America Inc.). When the temperature of the mixture reached 39° C., the pH was adjusted to 8.0 by the addition of a 50percent NaOH in water. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (85 g) in 850 mL of DMSO was then added over a period of 40 min. The reaction temperature was then maintained at 40° C. for 24.5 h during which time the pH of the mixture was adjusted to 8.0 at the 1.5 h and 19.5 h time points using 50percent NaOH in water. After 24.5 h, the enantio-excess of the ester was determined to be 97.2percent, and the reaction was cooled to room temperature (26° C.) and stirred overnight (16 h) after which the enantio-excess of the ester was determined to be 100percent. The pH of the reaction mixture was then adjusted to 8.5 with 50percent NaOH and the resulting mixture was extracted with MTBE (2.x.2 L). The combined MTBE extract was then washed with 5percent NaHCO3 (3.x.100 mL), water (3.x.100 mL), and evaporated in vacuo to give the enantiomerically pure N-Boc-(1R, 2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow solid (42.55 g; purity: 97percent (210 nm, containing no acid; 100percent enantiomeric excess (ee). The aqueous layer from the extraction process was then acidified to pH 2 with 50percent H2SO4 and extracted with MTBE (2.x.2 L). The MTBE extract was washed with water (3.x.100 mL) and evaporated to give the acid as light yellow solid (42.74 g; purity: 99percent (210 nm, containing no ester)To 0.5 ml 100 mM HepsNa buffer (pH 8.5) in a well of a 24 well plate (capacity: 10 mL/well), 0.1 ml of Esperase 8.0 L, (protease from Bacillus halodurans) (Novozymes North America Inc.) and a solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (10 mg) in 0.1 mL of DMSO were added. The plate was sealed and incubated at 250 rpm at 40° C. After 18 hour, enantio-excess of the ester was determined to be 39.6percent as following: 0.1 mL of the reaction mixture was removed and mixed well with 1 mL ethanol; after centrifugation, 10 μl of the supernatant was analyzed with the chiral HPLC. To the remaining reaction mixture, 0.1 mL of DMSO was added, and the plate was incubated for additional 3 days at 250 rpm at 40° C., after which four mL of ethanol was added to the well. After centrifugation, 10 μl of the supernatant was analyzed with the chiral HPLC and enantio-excess of the ester was determined to be 100percent. Samples analysis was carried out in the following manner: 1) Sample preparation: About 0.5 ml of the reaction mixture was mixed well with 10 volume of EtOH. After centrifugation, 10 μl of the supernatant was injected onto HPLC column. 2) Conversion determination: Column: YMC ODS A, 4.6.x.50 mm, S-5 μm Solvent: A, 1 mM HCl in water; B, MeCN Gradient: 30percent B for 1 min; 30percent to 45percent B over 0.5 min; 45percent B for 1.5 min; 45percent to 30percent B over 0.5 min. Flow rate: 2 ml/min UV Detection: 210 nm Retention time: acid, 1.2 min; ester, 2.8 min. 3) Enantio-excess determination for the ester: Column: CHIRACEL OD-RH, 4.6.x.150 mm, S-5 μm Mobile phase: MeCN/50 mM HClO10 L of 0.1 M sodium phosphate buffer (pH 8) was maintained at 40° C. in a 20 Liter jacked reactor, stirred at 360 rpm. 1.5 liters of Alcalase 2.4 L (Novozymes North America Inc.) was added to the reactor. When temperature of the mixture closed to 38° C., pH was adjusted to 8.0 with 10 N NaOH. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (200 grams) in 2 liters DMSO was added to the reactor over a period of 1 hour via an addition funel. The reaction temperature was then adjusted to 40° C. After 3 hours, pH was adjusted to 8.0 with 10 N NaOH. After 21 hours, the reaction was cooled down to 25° C. pH of the reaction mixture was adjusted to 8.5 with 10 N NaOH and the mixture was extracted with MTBE (2.x.5 L). The combined MTBE extract was washed with 5percent NaHCO3 (3.x.500 ml) and water (3.x.200 ml), and evaporated to give 110 gram of yellow oil. The oil was set at room temperature under house vacuum and gave enantiomerically pure N-Boc-(1R, 2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as colorless long rod crystal (101 g; purity: 97.9percent (210 nm, containing no acid; 100percent ee). The crystal structure enantiomerically pure N-Boc-(1R, 2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester has been characterized by single crystal analysis (X-ray NBNo.: 52795-093, refcode: 634592N1). The absolute configuration is not established for lack of a known chiral center or heavier atom(s). A chain structure along the crystallographic a-axis is formed via intermolecular hydrogen bonding between the amide group and the carbonyl oxygen atom (N, O 3.159 ).5 L of 0.3 M sodium phosphate buffer (pH 8) was maintained at 38° C. in a 20 Liter jacked reactor, stirred at 130 rpm. Four liters of Alcalase 2.4 L (Novozymes North America Inc.) and 1 liter of DI water were added to the reactor. When temperature of the mixture closed to 38° C., pH was adjusted to 7.8 with 10 N NaOH. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (500 grams) in 5 liters DMSO was added to the reactor over a period of 1 hour via an addition funel. The reaction temperature was then adjusted to 48° C. After 21 hours, enantio-excess of the ester reached 99.3percent. Heating was stopped at 24 hour and the reaction was slowly cooled down to room temperature (about 25° C.) and stirred overnight. pH of the reaction mixture was adjusted to 8.5 with 10 N NaOH and the mixture was extracted with MTBE (2.x.4 L). The combined MTBE extract was washed with 5percent NaHCO3 (3.x.400 ml) and water (3.x.400 ml), and evaporated to give enantiomerically pure N-Boc-(1R, 2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow crystal (259 g; purity: 96.9percent (210 nm, containing no acid; 100percent ee).5 L of 0.2 M sodium borate buffer (pH 9) was maintained at 45° C. in a 20 liter jacked reactor, stirred at 400 rpm. Three liter of DI water and four liters of Savinase 16L, type EX (Novozymes North America Inc.) were added to the reactor. When temperature of the mixture closed to 45° C., pH was adjusted to 8.5 with 10 N NaOH. A solution of the racemic N-Boc-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (200 grams) in 2 liters DMSO was added to the reactor over a period of 40 min, via an addition funel. The reaction temperature was then adjusted to 48° C. After 2 hours, pH was adjusted to pH 9.0 with 10 N NaOH. At 18 hour, enantio-excess of the ester reached 72percent, pH was adjusted to 9.0 with 10 N NaOH. At 24 hour, temperature was lowered to 35° C. At 42 hour, temperature was raised to 48° C. and pH was adjusted to 9.0 with 10 N NaOH. Heating was stopped at 48 hour and the reaction was slowly cooled down to room temperature (about 25° C.) and stirred overnight. At 66 hour, pH of the reaction mixture was 8.6. The mixture was extracted with MTBE (2.x.4 L). The combined MTBE extract was washed with 5percent NaHCO3 (6.x.300 ml) and water (3.x.300 ml), and evaporated to give enantiomerically pure N-Boc-(1R, 2 S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow crystal (101A g; purity: 95.9percent (210 nm, containing no acid; 98.6percent ee).The compound 37C (1 g) was resolved by SFC to give two isomers. SFC method: Column: AY(250mm *30mm, 1 Oum) Mobile phase: A: CO7 13:0.1 percentNH3H2O ETOH; Gradient: 15percent of B; Flow rate: 6OmL/inin.The compound 37C was separated by SFC to give compound 371) (500 mg, yield:49.9percent) (Rt 149 mm) and compound 37E (450 mg, yield: 259percent) (Rt == 2.68 mm) both asyellow oil. ‘1-1 NMR (400MHz, DMSO-d6) 764 (s, IH), 567- 554 (m, 1FF). 5.21 (hr d, J::::17.2 Hz, 1H), 5.07-5.01 (m, 1H), 4.10- 394 (rn, 2H), 2.08 (q, J:::: 8.7 Hz, lET), 157- 1.44(m, 1H), 1.38- 1.31 (m, 9H), 127- 123 (m, 1H), 1.18- 1.10 (m, 3H). MS (ESI m/z (M100Y 155.8.‘HMR (400’llTz, DMSO-d6) 5 7.64 (s, 1H), 5.67- 5.54 (m, IH), 5.21 (hr d, J=17.0 Hz, 1H), 5.04 (dd, J= 1.7, 10.3 Hz, 1H), 4.11 —3.95 (m, 2H), 2.08 (q, J= 8.8 Hz, IH), 1.54 (brdd, J= 5.4, 7.2 Hz, IH), 1.38- 1.31 (m, 9H), 1.27 -1.23 (m, IH), 1.19- 1.10 (m, 3H). MS (ESI) m/ (M-i00 1559..

Molecular Weight:255.31
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:7
Exact Mass:255.14705815
Monoisotopic Mass:255.14705815
Topological Polar Surface Area:64.6
Heavy Atom Count:18
Complexity:359
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes