dichlorophosphorylmethane

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

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

Procedure: tert-Butyl 4-[2-hydroxy-1-(hydroxymethyl)ethyl]benzoate (440 mg, 1.74 mmol) and TEA (510 μl, 3.66 mmol) were taken up in CH2Cl2 (20 mL) and cooled to 0° C. Methylphosphonic dichloride (193 μl, 2.09 mmol) in CH2Cl2 (10 mL) was added dropwise over 30 minutes. The reaction was then allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) allowed separation of residual starting material from the diastereomeric products, but the diastereomers coeluted. Flash chromatography of the mixed diastereomers with 25-100% EtOAc/hexanes slowly eluted the first diastereomer, and the same column was flushed with 2-10% MeOH/CH2Cl2 to push off the second diastereomer (both were obtained as colorless solids). 1H NMR (CDCl3, 600 MHz) Diastereomer 1: δ 7.95 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 4.70-4.65 (m, 2H), 4.24-4.17 (m, 2H), 3.54-3.47 (m, 1H), 1.63 (d, J=18.0 Hz, 3H), 1.56 (s, 9H). Diastereomer 2: δ 7.97 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 4.66-4.59 (m, 2H), 4.36-4.30 (m, 2H), 3.50-3.45 (m, 1H), 1.62 (d, J=17-3 Hz, 3H), 1.57 (s, 9H). MS: cal'd 313 (MH+), exp 313 (MH+). to warm to room temperature extracted with CH2Cl2 (2×) The combined organic layers were washed with brine dried (MgSO4) evaporated separation Flash chromatography of the mixed diastereomers with 25-100% EtOAc/hexanes slowly eluted the first diastereomer the same column was flushed with 2-10% MeOH/CH2Cl2 both were obtained as colorless solids)

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

Procedure: Et3N (943 μL, 6.76 mmol) and tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate (790 mg, 3.22 mmol) were combined in CH2Cl2 (25 mL) and cooled to 0° C. A solution of methylphosphonic dichloride (428 mg, 3.22 mmol) in CH2Cl2 (20 mL) was added dropwise over 1 h. The reaction was then allowed to warm to room temperature over 1 h. It was subsequently diluted with saturated NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated to give the desired product as a colorless solid that was used without purification. MS: cal'd 306 (MH+), exp 306 (MH+). to warm to room temperature over 1 h extracted with CH2Cl2 (2×) The combined organic layers were washed with brine dried (MgSO4) evaporated

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

Procedure: To a vigorously stirred solution of methylphosphonic dichloride (6.65 g, 50 mmol) in THF (100 mL) at −78° C. was added vinylmagnesium chloride (1.6 M in THF, 66 mL, 105 mmol) dropwisely over 30 min. After the addition is completed, the reaction mixture was warmed to 0° C. over 1 hour, and to it was added benzylamine (6.43 g, 60 mmol) and methanol (100 mL). The reaction mixture was then refluxed for 36 hours. After cooled to room temperature, the reaction mixture was poured into a separation funnel containing saturated aqueous ammonium chloride (100 mL), ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (100 mL) twice. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as white crystalline solid (5.69 g, 51%). LCMS ESI(+) m/z: 224 (M+1). After the addition The reaction mixture was then refluxed for 36 hours After cooled to room temperature the reaction mixture was poured into a separation funnel The organic layer was separated the aqueous layer was extracted with methylene chloride (100 mL) twice The combined organic layer and extracts were dried over anhydrous magnesium sulfate filtered concentrated The residue was purified by flash chromatography eluting with 20% methanol in dichloromethane

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

Procedure: To a vigorously stirred solution of methylphosphonic dichloride (6.65 g, 50 mmol) in THF (100 mL) at −78° C. was added vinylmagnesium chloride (1.6 M in THF, 66 mL, 105 mmol) dropwisely over 30 min. After the addition is completed, the reaction mixture was warmed to 0° C. over 1 hour, and to it was added benzylamine (6.43 g, 60 mmol) and methanol (100 mL). The reaction mixture was then refluxed for 36 hours. After cooled to room temperature, the reaction mixture was poured into a separation funnel containing saturated aqueous ammonium chloride (100 mL), ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (100 mL) twice. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as white crystalline solid (5.69 g, 51%). LCMS ESI(+) m/z: 224 (M+1). After the addition The reaction mixture was then refluxed for 36 hours After cooled to room temperature the reaction mixture was poured into a separation funnel The organic layer was separated the aqueous layer was extracted with methylene chloride (100 mL) twice The combined organic layer and extracts were dried over anhydrous magnesium sulfate filtered concentrated The residue was purified by flash chromatography eluting with 20% methanol in dichloromethane

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

Procedure: A solution of N-acetyl-colchicinol (0.36 g; 1.0 mmol) in THF (40 ml) under argon was cooled to 0° C. and treated with a 1.0M solution of lithiumHMDS in THF (1.1 ml; 1.1 mmol). The mixture was stirred at 0° C. for 1 hour and then added in portions over about 2 hours to a solution of methylphosphonic dichloride (0.53 mg; 4.0 mmol) in THF (150 ml). The mixture was stirred at ambient temperature for 15 minutes. After addition of water (200 ml) the THF was removed by evaporation. After removal of the insoluble material by filtration, the filtrate was purified on HP20 SS resin eluting with a gradient of 0–60% methanol/water. The methanol was removed by evaporation and the mixture was adjusted to pH7.14 with sodium hydroxide (0.1 M). The appropriate fractions were freeze-dried to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl hydrogen methylphosphonate as a beige solid (180 mg). The mixture was stirred at ambient temperature for 15 minutes was removed by evaporation After removal of the insoluble material by filtration the filtrate was purified on HP20 SS resin eluting with a gradient of 0–60% methanol/water The methanol was removed by evaporation The appropriate fractions were freeze-dried

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

Procedure: To a flask containing 1H-tetrazole (˜0.002 g, 0.028 mmol) was added a solution of n-butanol (0.041 g, 0.55 mmol) in 0.33 mL of DCM, followed by a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.33 mL of DCM. The resulting clear solution was cooled to 0° C. then added, under an atmosphere of N2, a solution of methylphosphonic dichloride (0.073 g, 0.55 mmol) in 0.33 mL of DCM. The resulting white suspension was stirred to ambient temperature overnight. To a cooled (0° C.) solution of rapamycin (0.1 g, 0.11 mmol) in 0.5 mL of DCM was added a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.5 mL of DCM, followed immediately by the phosphorylating reagent (yellow solution with white precipitate) and a 1.0 mL DCM wash. The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS). The cold (0° C.) reaction solution was diluted with ˜20 mL EtOAc then transferred to a separatory funnel containing EtOAc (120 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 0.25:10:3:3 then 0.5:10:3:3 MeOH/DCM/EtOAc/hexane) then RP HPLC (85% MeOH/H2O) to provide 0.063 g of a white solid (˜2:1 diastereomeric mixture): 1H NMR (300 MHz, CDCl3) 4.15 (m, 1Ha, 1Hb), 4.11-3.89 (m, 3Ha, 3Hb), 3.04 (m, 1Ha, 1Hb); 31P NMR (121 MHz, CDCl3) □32.1, 29.9; 1071 m/z (M+Na). then added, under an atmosphere of N2 a 1.0 mL DCM wash The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS) The cold (0° C.) reaction solution then transferred to a separatory funnel Upon removing the aqueous layer the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL) dried over MgSO4 concentrated The crude product was purified by silica gel flash chromatography ( eluted with 0.25:10:3:3

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

Procedure: To a flask containing 1H-tetrazole (˜0.002 g, 0.028 mmol) was added a solution of n-butanol (0.041 g, 0.55 mmol) in 0.33 mL of DCM, followed by a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.33 mL of DCM. The resulting clear solution was cooled to 0° C. then added, under an atmosphere of N2, a solution of methylphosphonic dichloride (0.073 g, 0.55 mmol) in 0.33 mL of DCM. The resulting white suspension was stirred to ambient temperature overnight. To a cooled (0° C.) solution of rapamycin (0.1 g, 0.11 mmol) in 0.5 mL of DCM was added a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.5 mL of DCM, followed immediately by the phosphorylating reagent (yellow solution with white precipitate) and a 1.0 mL DCM wash. The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS). The cold (0° C.) reaction solution was diluted with ˜20 mL EtOAc then transferred to a separatory funnel containing EtOAc (120 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 0.25:10:3:3 then 0.5:10:3:3 MeOH/DCM/EtOAc/hexane) then RP HPLC (85% MeOH/H2O) to provide 0.063 g of a white solid (˜2:1 diastereomeric mixture): 1H NMR (300 MHz, CDCl3) 4.15 (m, 1Ha, 1Hb), 4.11-3.89 (m, 3Ha, 3Hb), 3.04 (m, 1Ha, 1Hb); 31P NMR (121 MHz, CDCl3) □32.1, 29.9; 1071 m/z (M+Na). then added, under an atmosphere of N2 a 1.0 mL DCM wash The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS) The cold (0° C.) reaction solution then transferred to a separatory funnel Upon removing the aqueous layer the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL) dried over MgSO4 concentrated The crude product was purified by silica gel flash chromatography ( eluted with 0.25:10:3:3

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

Procedure: To a flask containing 1H-tetrazole (˜0.002 g, 0.028 mmol) was added a solution of n-butanol (0.041 g, 0.55 mmol) in 0.33 mL of DCM, followed by a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.33 mL of DCM. The resulting clear solution was cooled to 0° C. then added, under an atmosphere of N2, a solution of methylphosphonic dichloride (0.073 g, 0.55 mmol) in 0.33 mL of DCM. The resulting white suspension was stirred to ambient temperature overnight. To a cooled (0° C.) solution of rapamycin (0.1 g, 0.11 mmol) in 0.5 mL of DCM was added a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.5 mL of DCM, followed immediately by the phosphorylating reagent (yellow solution with white precipitate) and a 1.0 mL DCM wash. The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS). The cold (0° C.) reaction solution was diluted with ˜20 mL EtOAc then transferred to a separatory funnel containing EtOAc (120 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 0.25:10:3:3 then 0.5:10:3:3 MeOH/DCM/EtOAc/hexane) then RP HPLC (85% MeOH/H2O) to provide 0.063 g of a white solid (˜2:1 diastereomeric mixture): 1H NMR (300 MHz, CDCl3) d 4.15 (m, 1Ha, 1Hb), 4.11–3.89 (m, 3Ha, 3Hb), 3.04 (m, 1Ha, 1Hb); 31P NMR (121 MHz, CDCl3) d 32.1, 29.9; 1071 m/z (M+Na). then added, under an atmosphere of N2 a 1.0 mL DCM wash The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS) The cold (0° C.) reaction solution then transferred to a separatory funnel Upon removing the aqueous layer the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL) dried over MgSO4 concentrated The crude product was purified by silica gel flash chromatography ( eluted with 0.25:10:3:3

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

Procedure: To a flask containing 1H-tetrazole (˜0.002 g, 0.028 mmol) was added a solution of n-butanol (0.041 g, 0.55 mmol) in 0.33 mL of DCM, followed by a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.33 mL of DCM. The resulting clear solution was cooled to 0° C. then added, under an atmosphere of N2, a solution of methylphosphonic dichloride (0.073 g, 0.55 mmol) in 0.33 mL of DCM. The resulting white suspension was stirred to ambient temperature overnight. To a cooled (0° C.) solution of rapamycin (0.1 g, 0.11 mmol) in 0.5 mL of DCM was added a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.5 mL of DCM, followed immediately by the phosphorylating reagent (yellow solution with white precipitate) and a 1.0 mL DCM wash. The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS). The cold (0° C.) reaction solution was diluted with ˜20 mL EtOAc then transferred to a separatory funnel containing EtOAc (120 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 0.25:10:3:3 then 0.5:10:3:3 MeOH/DCM/EtOAc/hexane) then RP HPLC (85% MeOH/H2O) to provide 0.063 g of a white solid (˜2:1 diastereomeric mixture): 1H NMR (300 MHz, CDCl3) d 4.15 (m, 1Ha, 1Hb), 4.11–3.89 (m, 3Ha, 3Hb), 3.04 (m, 1Ha, 1Hb); 31P NMR (121 MHz, CDCl3) d 32.1, 29.9; 1071 m/z (M+Na). then added, under an atmosphere of N2 a 1.0 mL DCM wash The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS) The cold (0° C.) reaction solution then transferred to a separatory funnel Upon removing the aqueous layer the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL) dried over MgSO4 concentrated The crude product was purified by silica gel flash chromatography ( eluted with 0.25:10:3:3

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

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

Procedure: To a flask containing 1H-tetrazole (˜0.002 g, 0.028 mmol) was added a solution of n-butanol (0.041 g, 0.55 mmol) in 0.33 mL of DCM, followed by a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.33 mL of DCM. The resulting clear solution was cooled to 0° C. then added, under an atmosphere of N2, a solution of methylphosphonic dichloride (0.073 g, 0.55 mmol) in 0.33 mL of DCM. The resulting white suspension was stirred to ambient temperature overnight. To a cooled (0° C.) solution of rapamycin (0.1 g, 0.11 mmol) in 0.5 mL of DCM was added a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.5 mL of DCM, followed immediately by the phosphorylating reagent (yellow solution with white precipitate) and a 1.0 mL DCM wash. The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS). The cold (0° C.) reaction solution was diluted with ˜20 mL EtOAc then transferred to a separatory funnel containing EtOAc (120 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 0.25:10:3:3 then 0.5:10:3:3 MeOH/DCM/EtOAc/hexane) then RP HPLC (85% MeOH/H2O) to provide 0.063 g of a white solid (˜2:1 diastereomeric mixture): 1H NMR (300 MHz, CDCl3) d 4.15 (m, 1Ha, 1Hb), 4.11–3.89 (m, 3Ha, 3Hb), 3.04 (m, 1Ha, 1Hb); 31P NMR (121 MHz, CDCl3) d 32.1, 29.9; 1071 m/z (M+Na). then added, under an atmosphere of N2 a 1.0 mL DCM wash The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS) The cold (0° C.) reaction solution then transferred to a separatory funnel Upon removing the aqueous layer the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL) dried over MgSO4 concentrated The crude product was purified by silica gel flash chromatography ( eluted with 0.25:10:3:3