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Synlett 2021; 32(11): 1089-1092
DOI: 10.1055/a-1493-9078
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A Short Enantioselective Synthesis of (S)-Levetiracetam through Direct Palladium-Catalyzed Asymmetric N-Allylation of Methyl 4-Aminobutyrate

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This work was supported by the University of Cologne and the Fonds der Chemischen Industrie.
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Abstract

An exceedingly short and enantioselective synthesis of the antiepileptic drug (S)-levetiracetam was elaborated. As the chirogenic key step, a Pd-catalyzed asymmetric N-allylation of methyl 4-aminobutyrate was achieved in the presence of only 1 mol% of a catalyst prepared in situ from [Pd(allyl)Cl]2 and a tartaric acid-derived C 2-symmetric diphosphine ligand.

Key words

asymmetric catalysis - palladium catalysis - chiral ligands - amino acid derivatives - ozonolysis - levetiracetam

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Publication History

Received: 07 April 2021

Accepted after revision: 28 April 2021

Accepted Manuscript online:
28 April 2021

Article published online:
11 May 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References and Notes

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  • 16 Detailed experimental procedures and characterization data are given in the Supporting Information. 1-[(2E)-1-Ethylpent-2-en-1-yl]pyrrolidin-2-one (2) Under an atmosphere of argon, a Schlenk flask was charged with [Pd(allyl)Cl]2 (1.10 mg, 3.01 μmol, 0.50 mol%) and ligand L* (5.40 mg, 7.04 μmol, 1.17 mol%). Anhyd THF (0.6 mL) was then added and the solution was stirred for 20 min at r.t. before carbonate rac-3 (103 mg, 0.60 mmol) was added neat from a syringe. After 20 min, methyl 4-aminobutyrate hydrochloride (7; 116 mg, 0.76 mmol) and Et3N (0.11 mL, 0.79 mmol) were added, and stirring was continued for 16 h. QuadraSil AP (~50 mg) was then added to capture Pd, and the mixture was stirred for 1 h then filtered through a short pad of Celite with EtOAc. After removal of the solvent under reduced pressure, the crude product mixture of 2 and 8 was dissolved in EtOAc (1 mL) and Et3N (0.11 mL, 0.79 mmol), then heated at 80 °C for 20 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography [silica gel, cyclohexane–EtOAc (1:1)] to give a yellowish oil; yield: 78 mg (0.43 mmol; 72%); [α]λ 20 (c = 0.24, CHCl3): [α]365 –364.6, [α]436 –206.7 °, [α]546 –111.1, [α]579 –96.0, [α]589 –92.5°. 1H NMR (400 MHz, CDCl3): δ = 5.64 (dtd, 3 J = 15.5 Hz, 3 J = 6.3 Hz, 4 J = 1.3 Hz, 1 H), 5.34 (ddt, 3 J = 15.5 Hz, 3 J = 6.6 Hz, 4 J = 1.6 Hz, 1 H), 4.48 (Ψq, 3 J = 7.0 Hz, 1 H), 3.27 (Ψqt, 3 J = 9.6 Hz, 3 J = 7.0 Hz, 2 H), 2.45–2.35 (m, 2 H), 2.10–1.92 (m, 4 H), 1.68–1.46 (m, 2 H), 0.98 (t, 3 J = 7.5 Hz, 3 H), 0.86 (t, 3 J = 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 174.7, 135.0, 126.6, 54.1, 42.5, 31.6, 25.5, 24.9, 18.3, 13.7, 10.8. HRMS (ESI): m/z [M + H]+ calcd for C11H20NO: 182.1539; found: 182.1540. Methyl 2-(2-Oxopyrrolidin-1-yl)butanoate (9) A round-bottomed flask was charged with a solution of 2 (105 mg, 0.58 mmol) in CH2Cl2 (40 mL) and a 2.50 M solution of NaOH in MeOH (3.0 mL, 7.5 mmol). The clear solution was cooled to –78 °C and a weak stream of ozone was introduced until the solution turned blue (70 min). Excess ozone was removed by introducing a weak stream of oxygen for 10 min before the solution was allowed to warm to r.t. H2O (50 mL) was added, and the aqueous phase was extracted with CH2Cl2 (3 × 100 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, cyclohexane–EtOAc (1:1)] to give a yellow oil; yield: 78 mg (0.42 mmol; 73%); [α]λ 20 (c = 0.26, CHCl3): [α]365 –152.9, [α]436 –87.1, [α]546 –46.1, [α]579 –40.0, [α]589 –38.6. 1H NMR (500 MHz, CDCl3): δ = 4.69 (Ψdd, 3 J = 10.7 Hz, 4 J = 5.2 Hz, 1 H), 3.71 (s, 3 H), 3.52 (td, 3 J = 8.7, 4 J = 6.1 Hz, 1 H), 3.35 (td, 3 J = 8.8 Hz, 4 J = 5.5 Hz, 1 H), 2.44 (t, 3 J = 8.1 Hz, 2 H), 2.15–1.96 (m, 3 H), 1.69 (ddq, 3 J = 14.6 Hz, 3 J = 10.7 Hz, 3 J = 7.3 Hz, 1 H), 0.92 (t, 3 J = 7.4 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 176.0, 171.7, 55.2, 52.2, 43.6, 31.0, 22.3, 18.4, 10.9. HRMS (ESI): m/z = [M + H]+ calcd for C9H16NO3: 186.1124; found: 186.1127.