tert-butyl (2R)-2-(2,2-dibromoethenyl)pyrrolidine-1-carboxylate

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

Procedure: In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.

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

Procedure: In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.

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

Procedure: Butyl lithium (48 mL, 0.08 mol) was added at -78° C. to a stirred solution of (R)-t-butyl 2-(2,2-dibromoethenyl)-1-pyrrolidinecarboxylate (14.2 g, 0.04 mol) in dry THF (300 mL). The color turned to dark yellow. After 15 min. methanol (10 mL) and ethyl acetate (10 mL) were added and the solution was allowed to warm to room temperature. The solvent was removed and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was concentrated and applied to a silica gel column. Elution with ethyl acetate:Skellysolve B (1:10) gave 6.9 g (88%) of product as a yellow oil. The solvent was removed the residue was partitioned between ethyl acetate and water The ethyl acetate phase was concentrated Elution with ethyl acetate:Skellysolve B (1:10)

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

Procedure: Carbon tetrabromide (49.2 g, 0.15 mol) in methylene chloride (150 mL) was added at 0° C. to a stirred solution of triphenyl phosphine (78.2 g, 0.30 mol) in methylene chloride (600 mL) under nitrogen. The solution was stirred at 0° C. for 1 hr. and (R)-t-butyl 2-formyl-1-pyrrolidinecarboxylate (21.9 g, 0.10 mol) was added. After 30 min. a solution of sodium carbonate (75 g, 0.75 mol) in water (300 mL) was added. The phases were separated and the aqueous phase was reextracted with methylene chloride (200 mL). The organic phase was washed with water (40 mL), and the majority of solvent was removed under reduced pressure leaving the material in a minimum of methylene chloride. Ethyl acetate (500 mL) was added and the resulting precipitate of triphenylphosphine oxide was filtered off. The mother liquors were evaporated and filtered repeatedly to remove additional triphenylphosphine oxide. The residual solid in ethyl acetate was then concentrated and applied to a silica gel column. Elution with ethyl acetate:Skellysolve B (1:10) gave 31.6 g (91%) of product. This was crystallized from petroleum ether to give 25.8 g of product, m.p. 64°-67° C. The analytical sample was recrystallized from ethyl acetate:Skellysolve B. [α]D -21° (c 0.81, MeOH). The phases were separated The organic phase was washed with water (40 mL) the majority of solvent was removed under reduced pressure leaving the material in a minimum of methylene chloride the resulting precipitate of triphenylphosphine oxide was filtered off The mother liquors were evaporated filtered repeatedly to remove additional triphenylphosphine oxide The residual solid in ethyl acetate was then concentrated Elution with ethyl acetate:Skellysolve B (1:10)

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

Procedure: In according with Scheme I, N-α-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M boran-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4 Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.

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

Procedure: In according with Scheme I, N-α-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M boran-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4 Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.

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

Procedure: In according with Scheme I, N-α-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M boran-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4 Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.

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

Procedure: In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.

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

Procedure: In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.

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

Procedure: In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl (2R)-2-(2,2-dibromovinyl)pyrrolidine-1-carboxylate (Intermediate XXXVIII, 8.1 g, 22.8 mmol) was dissolved in dry THF (200 mL) and cooled to −78° C. Then added sec-butyllithium 1.4M in cyclohexane (32.6 mL, 45.6 mmol) over 30 minutes and continued mixing an additional 30 minutes before quenching with 20% ammonium chloride solution (200 mL). The mixture was warmed to rt and diluted with ethyl ether (200 mL). The organic phase was separated, washed with brine, dried in vacuo and purified on a silica gel column using a 100% to 99:1 gradient of methylene chloride to methanol as mobile phase to yield pure tert-buty (2R)-2-ethynylpyrrolidine-1-carboxylate. LC-MS m/z (minus t-butyl+1)=220. 1H NMR (CD3OD, 400 Mhz) 4.44 ppm (s, 1H), 3.44-3.37 (m, 1H), 3.34-3.25 (m, 1H), 2.61 (s, 1H), 2.08-1.85 (m, 4H), 1.47 (s, 9H). continued mixing an additional 30 minutes before quenching with 20% ammonium chloride solution (200 mL) The mixture was warmed to rt diluted with ethyl ether (200 mL) The organic phase was separated washed with brine dried in vacuo purified on a silica gel column

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl (2R)-2-(2,2-dibromovinyl)pyrrolidine-1-carboxylate (Intermediate XXXVIII, 8.1 g, 22.8 mmol) was dissolved in dry THF (200 mL) and cooled to −78° C. Then added sec-butyllithium 1.4M in cyclohexane (32.6 mL, 45.6 mmol) over 30 minutes and continued mixing an additional 30 minutes before quenching with 20% ammonium chloride solution (200 mL). The mixture was warmed to rt and diluted with ethyl ether (200 mL). The organic phase was separated, washed with brine, dried in vacuo and purified on a silica gel column using a 100% to 99:1 gradient of methylene chloride to methanol as mobile phase to yield pure tert-buty (2R)-2-ethynylpyrrolidine-1-carboxylate. LC-MS m/z (minus t-butyl+1)=220. 1H NMR (CD3OD, 400 Mhz) 4.44 ppm (s, 1H), 3.44-3.37 (m, 1H), 3.34-3.25 (m, 1H), 2.61 (s, 1H), 2.08-1.85 (m, 4H), 1.47 (s, 9H). continued mixing an additional 30 minutes before quenching with 20% ammonium chloride solution (200 mL) The mixture was warmed to rt diluted with ethyl ether (200 mL) The organic phase was separated washed with brine dried in vacuo purified on a silica gel column