2-phenylpropan-2-yl 2,2,2-trichloroethanimidate

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

Procedure: A solution of 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.85 g, 85 mmol) in cyclohexane (85 mL) was treated with a solution of cyclopent-3-enecarboxylic acid (4.77 g, 42.5 mmol) in methylene chloride (43 mL), and the mixture was stirred for about 16 hours at room temperature during which time a colorless solid precipitated. The precipitate was collected by filtration and rinsed with hexanes. The combined filtrates were concentrated in vacuo to yield a residue. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with a 0-5% ethyl acetate/hexanes gradient over 2 column volumes, then 5% ethyl acetate/hexanes for 2 column volumes, then a 5-40% ethyl acetate/hexanes gradient over 10 column volumes to yield 2-phenylpropan-2-yl cyclopent-3-enecarboxylate (8.84 g, 38.4 mmol, 90% yield) as a yellow oil. precipitated The precipitate was collected by filtration rinsed with hexanes The combined filtrates were concentrated in vacuo to yield a residue The residue was purified over a 330 g silica gel column eluting at 100 mL/min with a 0-5% ethyl acetate/hexanes

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

Procedure: A suspension of 60% sodium hydride in mineral oil (0.42 g, 10.50 mmol) in diethyl ether (10 mL) was treated with the dropwise addition of a solution of 2-phenylpropan-2-ol (12.02 mL, 86 mmol) in diethyl ether (30 mL). Upon completion of addition, the mixture was stirred for 30 minutes, during which time a nearly clear solution was observed. After this time, the mixture was cooled to 0° C. and then treated with the dropwise addition of trichloroacetonitrile (8.18 mL, 82 mmol), which caused the mixture to turn dark brown. The reaction was allowed to warm to room temperature over 1 hour, and then was concentrated in vacuo to yield a residue. The residue was dissolved in hexanes (10 mL) and treated with methanol (0.424 mL, 10.48 mmol), and the resulting mixture was stirred vigorously for 5 minutes. The resulting black suspension was filtered through glass fiberglass filter paper, and the collected solids were rinsed 3× with hexanes. The combined filtrates were concentrated in vacuo to yield 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.8 g, 85 mmol, 99% yield) as an amber oil which was used as-is in the next step. Upon completion of addition to warm to room temperature over 1 hour was concentrated in vacuo to yield a residue the resulting mixture was stirred vigorously for 5 minutes The resulting black suspension was filtered through glass fiberglass filter paper the collected solids were rinsed 3× with hexanes The combined filtrates were concentrated in vacuo

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

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

Procedure: A solution of 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.85 g, 85 mmol) in cyclohexane (85 mL) was treated with a solution of cyclopent-3-enecarboxylic acid (4.77 g, 42.5 mmol) in methylene chloride (43 mL), and the mixture was stirred for about 16 hours at room temperature during which time a colorless solid precipitated. The precipitate was collected by filtration and rinsed with hexanes. The combined filtrates were concentrated in vacuo to yield a residue. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with a 0-5% ethyl acetate/hexanes gradient over 2 column volumes, then 5% ethyl acetate/hexanes for 2 column volumes, then a 5-40% ethyl acetate/hexanes gradient over 10 column volumes to yield 2-phenylpropan-2-yl cyclopent-3-enecarboxylate (8.84 g, 38.4 mmol, 90% yield) as a yellow oil. precipitated The precipitate was collected by filtration rinsed with hexanes The combined filtrates were concentrated in vacuo to yield a residue The residue was purified over a 330 g silica gel column eluting at 100 mL/min with a 0-5% ethyl acetate/hexanes

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

Procedure: A suspension of 60% sodium hydride in mineral oil (0.42 g, 10.50 mmol) in diethyl ether (10 mL) was treated with the dropwise addition of a solution of 2-phenylpropan-2-ol (12.02 mL, 86 mmol) in diethyl ether (30 mL). Upon completion of addition, the mixture was stirred for 30 minutes, during which time a nearly clear solution was observed. After this time, the mixture was cooled to 0° C. and then treated with the dropwise addition of trichloroacetonitrile (8.18 mL, 82 mmol), which caused the mixture to turn dark brown. The reaction was allowed to warm to room temperature over 1 hour, and then was concentrated in vacuo to yield a residue. The residue was dissolved in hexanes (10 mL) and treated with methanol (0.424 mL, 10.48 mmol), and the resulting mixture was stirred vigorously for 5 minutes. The resulting black suspension was filtered through glass fiberglass filter paper, and the collected solids were rinsed 3× with hexanes. The combined filtrates were concentrated in vacuo to yield 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.8 g, 85 mmol, 99% yield) as an amber oil which was used as-is in the next step. Upon completion of addition to warm to room temperature over 1 hour was concentrated in vacuo to yield a residue the resulting mixture was stirred vigorously for 5 minutes The resulting black suspension was filtered through glass fiberglass filter paper the collected solids were rinsed 3× with hexanes The combined filtrates were concentrated in vacuo

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

Procedure: A solution of 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.85 g, 85 mmol) in cyclohexane (85 mL) was treated with a solution of cyclopent-3-enecarboxylic acid (4.77 g, 42.5 mmol) in methylene chloride (43 mL), and the mixture was stirred for about 16 hours at room temperature during which time a colorless solid precipitated. The precipitate was collected by filtration and rinsed with hexanes. The combined filtrates were concentrated in vacuo to yield a residue. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with a 0-5% ethyl acetate/hexanes gradient over 2 column volumes, then 5% ethyl acetate/hexanes for 2 column volumes, then a 5-40% ethyl acetate/hexanes gradient over 10 column volumes to yield 2-phenylpropan-2-yl cyclopent-3-enecarboxylate (8.84 g, 38.4 mmol, 90% yield) as a yellow oil. precipitated The precipitate was collected by filtration rinsed with hexanes The combined filtrates were concentrated in vacuo to yield a residue The residue was purified over a 330 g silica gel column eluting at 100 mL/min with a 0-5% ethyl acetate/hexanes

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

Procedure: A suspension of 60% sodium hydride in mineral oil (0.42 g, 10.50 mmol) in diethyl ether (10 mL) was treated with the dropwise addition of a solution of 2-phenylpropan-2-ol (12.02 mL, 86 mmol) in diethyl ether (30 mL). Upon completion of addition, the mixture was stirred for 30 minutes, during which time a nearly clear solution was observed. After this time, the mixture was cooled to 0° C. and then treated with the dropwise addition of trichloroacetonitrile (8.18 mL, 82 mmol), which caused the mixture to turn dark brown. The reaction was allowed to warm to room temperature over 1 hour, and then was concentrated in vacuo to yield a residue. The residue was dissolved in hexanes (10 mL) and treated with methanol (0.424 mL, 10.48 mmol), and the resulting mixture was stirred vigorously for 5 minutes. The resulting black suspension was filtered through glass fiberglass filter paper, and the collected solids were rinsed 3× with hexanes. The combined filtrates were concentrated in vacuo to yield 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.8 g, 85 mmol, 99% yield) as an amber oil which was used as-is in the next step. Upon completion of addition to warm to room temperature over 1 hour was concentrated in vacuo to yield a residue the resulting mixture was stirred vigorously for 5 minutes The resulting black suspension was filtered through glass fiberglass filter paper the collected solids were rinsed 3× with hexanes The combined filtrates were concentrated in vacuo

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

Procedure: 2-Phenylpropan-2-yl 2,2,2-trichloroacetimidate separately synthesized by a conventional method (2.17 g, 7.74 mmol) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(allyloxy)-4-oxobutanoic acid (Compound 106) (1.80 g, 4.55 mmol) in dichloromethane (40 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→65/35) to afford 4-allyl 1-(2-phenylpropan-2-yl) (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)succinate (Compound 107) (2.17 g, 93%). The reaction mixture was then concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→65/35)