methyl (2S,3R)-3-hydroxypyrrolidine-2-carboxylate

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

Procedure: DIAD (23.88 mmol, 1.3 eq.) was added dropwise with stirring to a solution of cis-3-hydroxyproline methyl ester# (18.36 mmol, 1 eq.) and triphenylphosphine (22.9 mmol, 1.25 eq.) in THF (100 mL) at 0° C. Then a solution of diphenylphosphoryl azide (22.9 mmol, 1.25 eq.) in THF (20 ml) was added. The reaction was slowly warmed to rt and stirred for 16 h. The solvent was then removed under vacuum, and the residue triturated with cold ether to remove triphenylphosphine oxide. Upon filtration, the filtrate was concentrated and subjected to column chromatography (SiO2, gradient 15%-20% ethyl acetate/hexanes) to give the desired trans-3-azido-proline compound. The solvent was then removed under vacuum the residue triturated with cold ether to remove triphenylphosphine oxide Upon filtration the filtrate was concentrated

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

Procedure: Reaction of cis-3-hydroxyproline methyl ester with DIAD, triphenylphosphine and diphenylphosphoryl azide provides the desired 3-azido proline methyl ester. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.

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

Procedure: To a solution of hydroxyproline compound 1F (493 mg, 3.40 mmol) in CH2Cl2 (15 mL) was added 4 Å molecular sieves (˜3.0 g), followed by isocyanate 23E (725 mg, 3.22 mmol), and the resulting mixture was stirred at rt overnight, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1) to afford the title compound (736 mg) as an off-white solid. HPLC column: YMC S-5 C18 (4.6×50 mm), 0% to 100% B, 4 min gradient, 1 min hold (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA), flow rate at 4 mL/min, UV detection at 220 nm, 1.57 min retention time (100%); MS (ES) m/z 338 [M+H]+. filtered concentrated under reduced pressure The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1)

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

Procedure: To a solution of hydroxyproline compound 1F (493 mg, 3.40 mmol) in CH2Cl2 (15 mL) was added 4 Å molecular sieves (˜3.0 g), followed by isocyanate 23E (725 mg, 3.22 mmol), and the resulting mixture was stirred at rt overnight, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1) to afford the title compound (736 mg) as an off-white solid. HPLC column: YMC S-5 C18 (4.6×50 mm), 0% to 100% B, 4 min gradient, 1 min hold (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA), flow rate at 4 mL/min, UV detection at 220 nm, 1.57 min retention time (100%); MS (ES) m/z 338 [M+H]+. filtered concentrated under reduced pressure The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1)

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

Procedure: To a solution of hydroxyproline compound 1F (493 mg, 3.40 mmol) in CH2Cl2 (15 mL) was added 4 Å molecular sieves (˜3.0 g), followed by isocyanate 23E (725 mg, 3.22 mmol), and the resulting mixture was stirred at rt overnight, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1) to afford the title compound (736 mg) as an off-white solid. HPLC column: YMC S-5 C18 (4.6×50 mm), 0% to 100% B, 4 min gradient, 1 min hold (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA), flow rate at 4 mL/min, UV detection at 220 nm, 1.57 min retention time (100%); MS (ES) m/z 338 [M+H]+. filtered concentrated under reduced pressure The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1)

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

Procedure: DIAD (23.88 mmol, 1.3 eq.) was added dropwise with stirring to a solution of cis-3-hydroxyproline methyl ester# (18.36 mmol, 1 eq.) and triphenylphosphine (22.9 mmol, 1.25 eq.) in THF (100 mL) at 0° C. Then a solution of diphenylphosphoryl azide (22.9 mmol, 1.25 eq.) in THF (20 ml) was added. The reaction was slowly warmed to rt and stirred for 16 h. The solvent was then removed under vacuum, and the residue triturated with cold ether to remove triphenylphosphine oxide. Upon filtration, the filtrate was concentrated and subjected to column chromatography (SiO2, gradient 15%-20% ethyl acetate/hexanes) to give the desired trans-3-azido-proline compound. The solvent was then removed under vacuum the residue triturated with cold ether to remove triphenylphosphine oxide Upon filtration the filtrate was concentrated

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

Procedure: DIAD (23.88 mmol, 1.3 eq.) was added dropwise with stirring to a solution of cis-3-hydroxyproline methyl ester# (18.36 mmol, 1 eq.) and triphenylphosphine (22.9 mmol, 1.25 eq.) in THF (100 mL) at 0° C. Then a solution of diphenylphosphoryl azide (22.9 mmol, 1.25 eq.) in THF (20 ml) was added. The reaction was slowly warmed to rt and stirred for 16 h. The solvent was then removed under vacuum, and the residue triturated with cold ether to remove triphenylphosphine oxide. Upon filtration, the filtrate was concentrated and subjected to column chromatography (SiO2, gradient 15%-20% ethyl acetate/hexanes) to give the desired trans-3-azido-proline compound. The solvent was then removed under vacuum the residue triturated with cold ether to remove triphenylphosphine oxide Upon filtration the filtrate was concentrated

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

Procedure: Reaction of cis-3-hydroxyproline methyl ester with DIAD, triphenylphosphine and diphenylphosphoryl azide provides the desired 3-azido proline methyl ester. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.

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

Procedure: To a solution of hydroxyproline compound 1F (493 mg, 3.40 mmol) in CH2Cl2 (15 mL) was added 4 Å molecular sieves (˜3.0 g), followed by isocyanate 23E (725 mg, 3.22 mmol), and the resulting mixture was stirred at rt overnight, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1) to afford the title compound (736 mg) as an off-white solid. HPLC column: YMC S-5 C18 (4.6×50 mm), 0% to 100% B, 4 min gradient, 1 min hold (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA), flow rate at 4 mL/min, UV detection at 220 nm, 1.57 min retention time (100%); MS (ES) m/z 338 [M+H]+. filtered concentrated under reduced pressure The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1)

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

Procedure: To a solution of hydroxyproline compound 1F (493 mg, 3.40 mmol) in CH2Cl2 (15 mL) was added 4 Å molecular sieves (˜3.0 g), followed by isocyanate 23E (725 mg, 3.22 mmol), and the resulting mixture was stirred at rt overnight, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1) to afford the title compound (736 mg) as an off-white solid. HPLC column: YMC S-5 C18 (4.6×50 mm), 0% to 100% B, 4 min gradient, 1 min hold (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA), flow rate at 4 mL/min, UV detection at 220 nm, 1.57 min retention time (100%); MS (ES) m/z 338 [M+H]+. filtered concentrated under reduced pressure The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1)

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

Procedure: DIAD (23.88 mmol, 1.3 eq.) was added dropwise with stirring to a solution of cis-3-hydroxyproline methyl ester# (18.36 mmol, 1 eq.) and triphenylphosphine (22.9 mmol, 1.25 eq.) in THF (100 mL) at 0° C. Then a solution of diphenylphosphoryl azide (22.9 mmol, 1.25 eq.) in THF (20 ml) was added. The reaction was slowly warmed to rt and stirred for 16 h. The solvent was then removed under vacuum, and the residue triturated with cold ether to remove triphenylphosphine oxide. Upon filtration, the filtrate was concentrated and subjected to column chromatography (SiO2, gradient 15%-20% ethyl acetate/hexanes) to give the desired trans-3-azido-proline compound. The solvent was then removed under vacuum the residue triturated with cold ether to remove triphenylphosphine oxide Upon filtration the filtrate was concentrated

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

Procedure: Reaction of cis-3-hydroxyproline methyl ester with DIAD, triphenylphosphine and diphenylphosphoryl azide provides the desired 3-azido proline methyl ester. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.