Efficient Synthesis of N-Alkyl Polyhydroxylated Pipecolamide Compounds from d-Glucurono-6,3-lactone

Alaa Kaddour; Sylvestre Toumieux; Anne Wadouachi

doi:10.1055/s-0036-1590829

Synlett, Table of Contents

Synlett 2017; 28(16): 2174-2178
DOI: 10.1055/s-0036-1590829

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Efficient Synthesis of N-Alkyl Polyhydroxylated Pipecolamide Compounds from d-Glucurono-6,3-lactone

Alaa Kaddour

Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources CNRS UMR 7378, Université de Picardie Jules Verne, Institut de Chimie de Picardie CNRS FR 3085, 33 rue Saint Leu 80039 Amiens Cedex, France Email: anne.wadouachi@u-picardie.fr

,

Sylvestre Toumieux

Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources CNRS UMR 7378, Université de Picardie Jules Verne, Institut de Chimie de Picardie CNRS FR 3085, 33 rue Saint Leu 80039 Amiens Cedex, France Email: anne.wadouachi@u-picardie.fr

,

Anne Wadouachi*

Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources CNRS UMR 7378, Université de Picardie Jules Verne, Institut de Chimie de Picardie CNRS FR 3085, 33 rue Saint Leu 80039 Amiens Cedex, France Email: anne.wadouachi@u-picardie.fr

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Abstract

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Abstract

N-Alkyl pipecolamides were efficiently synthesized from d-glucurono-6,3-lactone via a key 5-azido N-alkylamide intermediate that can be used as a scaffold for the synthesis of 4-amino and N-sulfonated pipecolamide derivatives.

Key words

carbohydrates - d-glucurono-6,3-lactones - polyhydroxylated pipecolamides - iminosugars

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References

References and Notes
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16 5-Azido-5-deoxy-N-alkyl-1,2-O-isopropylidene-β-l-idofuranuro-amides 4a–d; General Procedure: To a solution of azido lactone 3 (500 mg, 1 equiv) in anhydrous CH₂Cl₂ (10 mL), the requisite alkylamine (1.2 equiv) was added at 0 °C. The reaction mixture was then warmed to room temperature and stirred until TLC showed complete conversion. The solvent was evaporated under reduced pressure and the crude residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate, 3:1) to give the corresponding glucuronamide as a colorless oil. Compound 4a: Yield: 70% (456 mg); R_f = 0.33 (cyclohexane/EtOAc, 2:1); [α]_D ²⁰ = –39.3 (c =1, CH₂Cl₂); IR (neat): 3350, 2935, 2119, 1647, 1075 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.72 (s, 1 H, NH), 6.00 (d, J _1–2 = 3.6 Hz, 1 H, H-1), 4.59 (d, J _2–1 = 3.6 Hz, 1 H, H-2), 4.36 (d, J _5–4 = 9.2 Hz, 1 H, H-5), 4.21 (d, J _3–2 = 2.8 Hz, 1 H, H-3), 4.18 (dd, J _4–3 = 2.8 Hz, J _4–5 = 9.1 Hz, 1 H, H-4), 3.26 (m, 2 H, H-a), 1.56–1.26 (m, 10 H, H-b, H-c, 2CH₃isop), 0.93 (t, J _d–c = 7.2 Hz, 3 H, H-d). ¹³C NMR (75 MHz, CDCl₃): δ = 167.5 (C=O), 111.9 (CMe₂), 105.3 (C-1), 85.0 (C-2), 84.7 (C-4), 75.6 (C-3), 64.2 (C-5), 39.6 (C-a), 31.3 (C-b), 27.1 (CH₃isop), 26.3 (CH₃isop), 20.1 (C-c), 13.8 (C-d). HRMS (ESI): m/z [M+Na]⁺ calcd for C₁₃H₂₃O₅N₄Na: 337.14764; found: 337.14824.
17 Preparation of Pipecolamides 6a–d; General Procedure: Protected azido-lactones 4a–d (1.5 mmol) were treated with TFA/H₂O (6 mL/4 mL, v/v) at 0 °C, then the reaction mixture was warmed to room temperature and stirred until TLC showed complete conversion. The reaction was quenched with saturated aqueous NaHCO₃ and extracted with ethyl acetate. The combined organic phases were dried over Na₂SO₄, filtered, and evaporated to afford a syrup, which was dissolved in methanol and submitted to hydrogenation in an H CUBE™ until TLC showed complete conversion. The suspension was then concentrated under reduced pressure, and intermediates 6a–d were treated with 1 M HCl (10 mL/200 mg of compound) and stirred at room temperature for 10 min. DOWEX 50X8 (2 g of resin/200 mg of amine) was added to the suspension and the mixture stirred for 10 min. The mixture was filtered and washed with distilled water to pH ca. 7. Methanolic NH₃ (7 M) was added to the mixture, which was stirred for 1 h at room temperature, and then filtered, washed with methanol, evaporated and dried to give the corresponding pipecolamide. Compound 6a: Yield: 93% (315 mg); R_f = 0.45 (EtOAc/MeOH, 9:2); [α]_D ²⁰ = –44.4 (c = 1, MeOH); IR (neat): 3315, 2943, 1693, 1456, 1022 cm^–1. ¹H NMR (600 MHz, 50 °C, CD₃OD): δ = 3.90 (s, 1 H, H-3), 3.76 (m, 1 H, H-4), 3.70 (s, 1 H, H-2), 3.60 (s, 1 H, H-5), 3.24 (t, J _a–b = 6.0 Hz, 2 H, H-a), 3.10 (dd, J _6–5 = 6.0 Hz, 1 H, H-6), 2.88 (dd, J _6–5 = 6.0 Hz, 1 H, H-6), 1.54 (m, 2 H, H-b), 1.39 (m, 2 H, H-c), 0.96 (t, J _d–c =7.0 Hz, 3 H, H-d). ¹³C NMR (75 MHz, CD₃OD): δ = 173.5 (C=O), 72.3 (C-5), 72.2 (C-4), 70.5 (C-3), 59.3 (C-2), 47.7 (C-6), 40.0 (C-a), 32.5 (C-b), 21.1 (C-c), 14.1 (C-d). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₀H₂₁N₂O₄: 233.1501; found: 233.1496.

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