1-[(2-methylpropan-2-yl)oxycarbonyl]-4-oxopiperidine-2-carboxylic acid

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

Procedure: Propyltriphenylphosphonium bromide (1.24 g, 3.22 mmol) in THF (10 mL) was added to hexane washed sodium hydride (123 mg, 3.22 mmol), in THF (10 mL) and stirred at room temperature for 3 h. Methyl ester 12a (P=Boc, m=2, P2=Me) (0.55 g, 2.15 mmol) in THF (5 mL) was added to the above reaction mixture slowly and then allowed to stir for additional 2 h. It was then poured into water and extracted with ethyl acetate (30 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated to dryness, the resulting residue was chromatographed using 20% EtOAc in hexanes to provide the product 4-propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. (0.100 g, 16%): MS (ESPOS): 284 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 5.18 (m, m), 4.60-4.93 (m, 1), 3.91 (m, 1), 3.67 (s, 3), 2.94-3.04 (m, 2), 2.40-2.48 (m, 2), 1.99-2.06 (m, 1), 1.85-1.97 (m, 2), 1.38 (bs, 9), 0.85 (t, J=5 Hz, 3). extracted with ethyl acetate (30 mL) The organic phase was dried with magnesium sulfate filtered evaporated to dryness the resulting residue was chromatographed

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

Procedure: To a stirred solution n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL) at −78° C. was added 12a (P=Boc, P2=Me, m=1) (570 mg, 2.3 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. for 2 h and then at −40° C. for an additional 1 h. EtOAc (20 mL) was added, followed by NH4Cl (5 mL, 10%) and water (10 mL). Organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by silica gel column chromatography using 50% EtOAc in hexanes as eluant to provide 4-hydroxy-4-butylproline methyl ester 12b (P=Boc, m=1, R9=n-butyl) as a colorless oil (0.52 g, 73%): 1H NMR (300 MHz, CDCl3) δ 4.33 (m, 1), 3.76 (d, J=4.8, 3), 3.62 (m, 2), 3.28 (m, 1), 2.13 (m, 1), 2.02 (m, 1), 1.57 (m, 2), 1.29 (m, 12), 0.88 (m, 3); MS (ESPOS): 324 [M+Na]+. at −40° C. for an additional 1 h Organic layer was separated dried over sodium sulfate evaporated to dryness The residue obtained was purified by silica gel column chromatography

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

Procedure: Propyltriphenylphosphonium bromide (1.24 g, 3.22 mmol) in THF (10 mL) was added to hexane washed sodium hydride (123 mg, 3.22 mmol), in THF (10 mL) and stirred at room temperature for 3 h. Methyl ester 12a (P=Boc, m=2, P2=Me) (0.55 g, 2.15 mmol) in THF (5 mL) was added to the above reaction mixture slowly and then allowed to stir for additional 2 h. It was then poured into water and extracted with ethyl acetate (30 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated to dryness, the resulting residue was chromatographed using 20% EtOAc in hexanes to provide the product 4-propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. (0.100 g, 16%): MS (ESPOS): 284 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 5.18 (m, m), 4.60-4.93 (m, 1), 3.91 (m, 1), 3.67 (s, 3), 2.94-3.04 (m, 2), 2.40-2.48 (m, 2), 1.99-2.06 (m, 1), 1.85-1.97 (m, 2), 1.38 (bs, 9), 0.85 (t, J=5 Hz, 3). extracted with ethyl acetate (30 mL) The organic phase was dried with magnesium sulfate filtered evaporated to dryness the resulting residue was chromatographed

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

Procedure: To a stirred solution n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL) at −78° C. was added 12a (P=Boc, P2=Me, m=1) (570 mg, 2.3 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. for 2 h and then at −40° C. for an additional 1 h. EtOAc (20 mL) was added, followed by NH4Cl (5 mL, 10%) and water (10 mL). Organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by silica gel column chromatography using 50% EtOAc in hexanes as eluant to provide 4-hydroxy-4-butylproline methyl ester 12b (P=Boc, m=1, R9=n-butyl) as a colorless oil (0.52 g, 73%): 1H NMR (300 MHz, CDCl3) δ 4.33 (m, 1), 3.76 (d, J=4.8, 3), 3.62 (m, 2), 3.28 (m, 1), 2.13 (m, 1), 2.02 (m, 1), 1.57 (m, 2), 1.29 (m, 12), 0.88 (m, 3); MS (ESPOS): 324 [M+Na]+. at −40° C. for an additional 1 h Organic layer was separated dried over sodium sulfate evaporated to dryness The residue obtained was purified by silica gel column chromatography

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

Procedure: To a stirred solution n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL) at −78° C. was added 12a (P=Boc, P2=Me, m=1) (570 mg, 2.3 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. for 2 h and then at −40° C. for an additional 1 h. EtOAc (20 mL) was added, followed by NH4Cl (5 mL, 10%) and water (10 mL). Organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by silica gel column chromatography using 50% EtOAc in hexanes as eluant to provide 4-hydroxy-4-butylproline methyl ester 12b (P=Boc, m=1, R9=n-butyl) as a colorless oil (0.52 g, 73%): 1H NMR (300 MHz, CDCl3) δ 4.33 (m, 1), 3.76 (d, J=4.8, 3), 3.62 (m, 2), 3.28 (m, 1), 2.13 (m, 1), 2.02 (m, 1), 1.57 (m, 2), 1.29 (m, 12), 0.88 (m, 3); MS (ESPOS): 324 [M+Na]+. at −40° C. for an additional 1 h Organic layer was separated dried over sodium sulfate evaporated to dryness The residue obtained was purified by silica gel column chromatography

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

Procedure: Propyltriphenylphosphonium bromide (1.24 g, 3.22 mmol) in THF (10 mL) was added to hexane washed sodium hydride (123 mg, 3.22 mmol), in THF (10 mL) and stirred at room temperature for 3 h. Methyl ester 12a (P=Boc, m=2, P2=Me) (0.55 g, 2.15 mmol) in THF (5 mL) was added to the above reaction mixture slowly and then allowed to stir for additional 2 h. It was then poured into water and extracted with ethyl acetate (30 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated to dryness, the resulting residue was chromatographed using 20% EtOAc in hexanes to provide the product 4-propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. (0.100 g, 16%): MS (ESPOS): 284 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 5.18 (m, m), 4.60–4.93 (m, 1), 3.91 (m, 1), 3.67 (s, 3), 2.94–3.04 (m, 2), 2.40–2.48 (m, 2), 1.99–2.06 (m, 1), 1.85–1.97 (m, 2), 1.38 (bs, 9), 0.85 (t, J=5 Hz, 3). extracted with ethyl acetate (30 mL) The organic phase was dried with magnesium sulfate filtered evaporated to dryness the resulting residue was chromatographed

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

Procedure: To a stirred solution n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL) at −78° C. was added 12a (P=Boc, P2=Me, m=1) (570 mg, 2.3 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. for 2 hr and then at −40° C. for an additional 1 hr. EtOAc (20 mL) was added, followed by NH4Cl (5 mL, 10%) and water (10 mL). Organic layer was separated, dried over sodium sulflate and evaporated to dryness. The residue obtained was purified by silica gel column chromatography using 50% EtOAc in hexanes as eluent to provide 4-hydroxy-4-butylproline methylester 12b (P=Boc, m=1, R9=n-butyl) as a colorless oil (0.52 g, 73%): 1H NMR (300 MHz, CDCl3) δ 4.33 (m, 1), 3.76 (d, J=4.8, 3), 3.62 (m, 2), 3.28 (m, 1), 2.13 (m, 1), 2.02 (m, 1), 1.57 (m, 2), 1.29 (m, 12), 0.88 (m, 3); MS (ESPOS): 324 [M+Na]+. at −40° C. for an additional 1 hr Organic layer was separated dried over sodium sulflate evaporated to dryness The residue obtained was purified by silica gel column chromatography

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

Procedure: Propyltriphenylphosphonium bromide (1.24 g, 3.22 mmol) in THF (10 mL) was added to hexane washed sodium hydride (123 mg, 3.22 mmol), in THF (10 mL) and stirred at room temperature for 3 h. Methyl ester 12a (P=Boc, m=2, P2=Me) (0.55 g, 2.15 mmol) in THF (5 mL) was added to the above reaction mixture slowly and then allowed to stir for additional 2 h. It was then poured into water and extracted with ethyl acetate (30 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated to dryness, the resulting residue was chromatographed using 20% EtOAc in hexanes to provide the product 4-propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. (0.100 g, 16%): MS (ESPOS): 284 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 5.18 (m, m), 4.60-4.93 (m, 1), 3.91 (m, 1), 3.67 (s, 3), 2.94-3.04 (m, 2), 2.40-2.48 (m, 2), 1.99-2.06 (m, 1), 1.85-1.97 (m, 2), 1.38 (bs, 9), 0.85 (t, J=5 Hz, 3). extracted with ethyl acetate (30 mL) The organic phase was dried with magnesium sulfate filtered evaporated to dryness the resulting residue was chromatographed

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

Procedure: To a stirred solution n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL) at −78° C. was added 12a (P=Boc, P2=Me, m=1) (570 mg, 2.3 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. for 2 h and then at −40° C. for an additional 1 h. EtOAc (20 mL) was added, followed by NH4Cl (5 mL, 10%) and water (10 mL). Organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by silica gel column chromatography using 50% EtOAc in hexanes as eluant to provide 4-hydroxy-4-butylproline methyl ester 12b (P=Boc, m=1, R9=n-butyl) as a colorless oil (0.52 g, 73%): 1H NMR (300 MHz, CDCl3) δ 4.33 (m, 1), 3.76 (d, J=4.8, 3), 3.62 (m, 2), 3.28 (m, 1), 2.13 (m, 1), 2.02 (m, 1), 1.57 (m, 2), 1.29 (m, 12), 0.88 (m, 3); MS (ESPOS): 324 [M+Na]+. at −40° C. for an additional 1 h Organic layer was separated dried over sodium sulfate evaporated to dryness The residue obtained was purified by silica gel column chromatography

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

Procedure: Propyltriphenylphosphonium bromide (1.24 g, 3.22 mmol) in THF (10 mL) was added to hexane washed sodium hydride (123 mg, 3.22 mmol), in THF (10 mL) and stirred at room temperature for 3 h. Methyl ester 12a (P=Boc, m=2, P2=Me) (0.55 g, 2.15 mmol) in THF (5 mL) was added to the above reaction mixture slowly and then allowed to stir for additional 2 h. It was then poured into water and extracted with ethyl acetate (30 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated to dryness, the resulting residue was chromatographed using 20% EtOAc in hexanes to provide the product 4-propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. (0.100 g, 16%): MS (ESPOS): 284 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 5.18 (m, m), 4.60-4.93 (m, 1), 3.91 (m, 1), 3.67 (s, 3), 2.94-3.04 (m, 2), 2.40-2.48 (m, 2), 1.99-2.06 (m, 1), 1.85-1.97 (m, 2), 1.38 (bs, 9), 0.85 (t, J=5 Hz, 3). extracted with ethyl acetate (30 mL) The organic phase was dried with magnesium sulfate filtered evaporated to dryness the resulting residue was chromatographed

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

Procedure: To a stirred solution n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL) at −78° C. was added 12a (P=Boc, P2=Me, m=1) (570 mg, 2.3 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. for 2 h and then at −40° C. for an additional 1 h. EtOAc (20 mL) was added, followed by NH4Cl (5 mL, 10%) and water (10 mL). Organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by silica gel column chromatography using 50% EtOAc in hexanes as eluant to provide 4-hydroxy-4-butylproline methyl ester 12b (P=Boc, m=1, R9=n-butyl) as a colorless oil (0.52 g, 73%): 1H NMR (300 MHz, CDCl3) δ 4.33 (m, 1), 3.76 (d, J=4.8, 3), 3.62 (m, 2), 3.28 (m, 1), 2.13 (m, 1), 2.02 (m, 1), 1.57 (m, 2), 1.29 (m, 12), 0.88 (m, 3); MS (ESPOS): 324 [M+Na]+. at −40° C. for an additional 1 h Organic layer was separated dried over sodium sulfate evaporated to dryness The residue obtained was purified by silica gel column chromatography