1-O-tert-butyl 2-O-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate

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

Procedure: (2S,4R)-4-Hydroxypyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (10.0 g, 41 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. DIPEA (1.2 equiv) was added, followed by methanesulfonyl chloride (1.2 equiv). The mixture was stirred at room temperature for 48 hours, then diluted with DCM (100 mL). The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (11.9 g, 37 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C12H21NO7S, 323.4. found 324.3. cooled in an ice bath The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL) dried over Na2SO4 The solvent was evaporated

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

Procedure: Compound 112 was synthesized from N-Boc-trans-4-hydroxy-L-proline-methyl ester 111 and compound 88a as beige foam in 90% yield, following the procedure as described for compound 54c.

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

Procedure: To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (5.12 g, 20.8 mmol) in DMF (40 mL), imidazole (2.84 g, 41.7 mmol) and tert-butyldimethylchlorosilane (3.46 g, 22.9 mmol) were added sequentially and the mixture was stirred at ambient temperature for about 2 hours. The DMF was removed under reduced pressure and the residue partitioned between water (150 mL) and ether (150 mL). The organic phase was washed with 1N aqueous phosphoric acid (3×100 mL), water (2×100 mL), sodium bicarbonate saturated solution (2×100 mL) and brine (100 mL). The organic phase was dried with magnesium sulfate and concentrated to yield (2S,4R)-1-tert-butyl 2-methyl 4-(tert-butyldimethylsilyloxy)pyrrolidine-1,2-dicarboxylate (5.44 g, 15.1 mmol) as a colorless oil. RP-HPLC (Table 1, Method f) Rt 6.49 min. The DMF was removed under reduced pressure the residue partitioned between water (150 mL) and ether (150 mL) The organic phase was washed with 1N aqueous phosphoric acid (3×100 mL), water (2×100 mL), sodium bicarbonate saturated solution (2×100 mL) and brine (100 mL) The organic phase was dried with magnesium sulfate concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution containing 0.5 g of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2 mmol) in 5 mL of N,N-dimethylacetamide, was added 370 mg of carbonyl diimidazole (1.1 equiv.). The reaction was heated at 60° C. for 1 hr, then 400 mg of 4-bromoisoindole (2 mmol) was added. The reaction was continued at 60° C. overnight. After cooling down, the reaction mixture was extracted with 50 mL of EtOAc, and washed with water, brine, and dried over Na2SO4. After filtration and concentration, the residue was purified by flash column chromatography on silica gel using heptanes/EtOAc (v/v 5/2), giving white solid 745 mg (79%). LC-MS: m/z=369.2 (ES+, M+1-Boc). After cooling down the reaction mixture was extracted with 50 mL of EtOAc washed with water, brine dried over Na2SO4 After filtration and concentration the residue was purified by flash column chromatography on silica gel

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

Procedure: A solution of 1-t-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.1 g, 41.4 mmol) in DMF (90 mL) under nitrogen was cooled to 0° C. Solid 1,1′-carbonyldiimidazole (6.70 g, 41.4 mmol) was added, and the reaction mixture was warmed to RT. After 2 hours, a solution of 4-vinylisoindoline (6.00 g, 41.4 mmol) in DMF (10 mL) was added. The mixture was then heated in a 60° C. oil bath for 2 hours, cooled to RT and poured into water and 5% potassium bisulfate. The resulting mixture was extracted with EtOAc (4×250 mL). The combined organic phases were washed with brine and dried over Na2SO4; and the solvent was evaporated. Flash column chromatography (hexane/EtOAc 70/30) gave the title compound as a white foam, 13.9 g. LRMS (ESI) m/z 417 [(M+H)+; calcd for C27H29N2O6: 417]. The mixture was then heated in a 60° C. oil bath for 2 hours cooled to RT The resulting mixture was extracted with EtOAc (4×250 mL) The combined organic phases were washed with brine dried over Na2SO4 and the solvent was evaporated

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

Procedure: To a solution of (2S,4R)-BOC-4-hydroxyproline methyl ester (126.3 g, 515 mmol) in DMF (960 mL) at 0° C. was added N,N′-carbonyldiimidazole (83.51 g, 515 mmol). The reaction mixture was stirred at RT for 3 hours. 4-Bromoisoindoline hydrochloride (120 g, 515 mmol) and DIPEA (96.3 mL, 540 mmol) were added, and the reaction mixture heated to 50° C. for 6 hours. The reaction mixture was then allowed to cool to RT and stirred overnight. The reaction mixture was partitioned between EtOAc (3 L) and 10% aqueous KHSO4 (6 L), the aqueous re-extracted with EtOAc (2 L) and the combined organic phases washed with 10% aqueous NaHCO3, brine, dried over Na2SO4 and solvent evaporated to a foam (239 g). LRMS (ESI) m/z 471.0 [(M+H)+; calcd for C20H26BrN2O6: 471.1]. the reaction mixture heated to 50° C. for 6 hours to cool to RT stirred overnight The reaction mixture was partitioned between EtOAc (3 L) and 10% aqueous KHSO4 (6 L) the aqueous re-extracted with EtOAc (2 L) the combined organic phases washed with 10% aqueous NaHCO3, brine dried over Na2SO4 and solvent evaporated to a foam (239 g)

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

Procedure: To a solution of N-Boc-trans-4-hydroxyproline methyl ester (10.0 g, 41 mmol) 150 mL of anhydrous THF at 0° C. under N2 was added triphenylphosphine (12.7 g, 48 mmol) and 4-nitrophenol (6.7 g, 48 mmol). To this mixture was added diethylazodicarboxylate (7.7 mL, 48 mmol) dropwise over a 30 minute period. The mixture was warmed to room temperature. After stirring for 2 days, the solvent was removed in vacuo, and the crude oil treated successively with 200 mL portions of toluene and ether to remove triphenylphosphine oxide and diethylazodihydrazide by crystallization. The resulting oil was then chromatographed (SiO2, 15-50% ethyl acetate/hexanes) to provide 5.2 g (34%) of N-Boc-4-(cis)-(4-nitrophenoxy-L-proline methyl ester as a light yellow oil. the solvent was removed in vacuo the crude oil treated successively with 200 mL portions of toluene and ether to remove triphenylphosphine oxide and diethylazodihydrazide by crystallization The resulting oil was then chromatographed (SiO2, 15-50% ethyl acetate/hexanes)

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

Procedure: To a stirred mixture of methyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g, 17.2 mmol, 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 ml) was added DIAD (3.72 ml, 18.9 mmol) at room temperature under an atmosphere of nitrogen. After stirring over night, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600, CHCl3/EtOAc (10/1)], to give methyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g), which was used to the next reaction without further purification. the mixture was concentrated in vacuo The residue was chromatographed on silica gel [600, CHCl3/EtOAc (10/1)]

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

Procedure: To a stirred mixture of methyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g, 17.2 mmol), 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 ml) was added DIAD (3.72 ml, 18.9 mmol) at room temperature under an atmosphere of nitrogen. After stirring over night, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600 g, CHCl3/EtOAc (10/1)], to give methyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g), which was used without further purification. the mixture was concentrated in vacuo The residue was chromatographed on silica gel [600 g, CHCl3/EtOAc (10/1)]

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

Procedure: To a stirred mixture of methyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.69 g, 19.1 mmol), phenol (1.98 g, 21.0 mmol) and PPh3 (5.51 g, 21.0 mmol) in THF (80 ml) was added DIAD (4.13 ml, 21.0 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred over night. After removal of the solvent, the resulting residue was chromatographed on silica gel [700 g, CHCl3/EtOAc (10/1)], to give methyl (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylate (5.31 g, 86%) as a colorless oil. 1H-NMR (CDCl3) δ1.43 (br, 9H, one of isomers), 1.48 (br, 9H, one of isomers), 2.48 (m, 1H), 3.75 (br, 3H), 4.42-4.96 (m, 2H), 6.88-7.35 (m, 5H). After removal of the solvent the resulting residue was chromatographed on silica gel [700 g, CHCl3/EtOAc (10/1)]

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

Procedure: To a stirred mixture of methyl (2S, 4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g, 17.2 mmol), 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 ml) was added DIAD (3.72 ml, 18.9 mmol) at room temperature under an atmosphere of nitrogen. After stirring over night, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600 g, CHCl3/EtOAc (10/1)], to give methyl (2S, 4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g), which was used to the next reaction without further purification. the mixture was concentrated in vacuo The residue was chromatographed on silica gel [600 g, CHCl3/EtOAc (10/1)]

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

Procedure: To a stirred mixture of methyl (2S, 4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g, 17.2 mmol), 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 ml) was added DIAD (3.72 ml, 18.9 mmol) at room temperature under an atmosphere of nitrogen. After stirring over night, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600 g, CHCl3/EtOAc (10/1)], to give methyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g), which was used without further purification. the mixture was concentrated in vacuo The residue was chromatographed on silica gel [600 g, CHCl3/EtOAc (10/1)]