A Short Enantioselective Synthesis of (S)-Levetiracetam through Direct Palladium-Catalyzed Asymmetric N-Allylation of Methyl 4-Aminobutyrate

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

Publication History

Received: 07 April 2021

Accepted after revision: 28 April 2021

Accepted Manuscript online:
28 April 2021

Article published online:
11 May 2021

• References and Notes

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CCDC 2074847 contains the supplementary crystallographic data for (S)-levetiracetam (1). The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures. For earlier X-ray crystal structures of 1 determined at room temperature, see:
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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.