Synlett 2017; 28(16): 2174-2178
DOI: 10.1055/s-0036-1590829
letter
© Georg Thieme Verlag Stuttgart · New York

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: [email protected]
,
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: [email protected]
,
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: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 08 April 2017

Accepted after revision: 31 May 2017

Publication Date:
18 July 2017 (online)


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.

Supporting Information

 
  • References and Notes

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  • 17 Preparation of Pipecolamides 6a–d; General Procedure: Protected azido-lactones 4ad (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 6ad 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); Rf = 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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