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

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

• References and Notes

• 1 Asano N. Curr. Top. Med. Chem. 2003; 3: 471
• 2a Iminosugars: From Synthesis to Therapeutic Applications . Compain P. Martin OR. Wiley; Weinheim: 2007
• 2b Winchester BG. Tetrahedron: Asymmetry 2009; 20: 645
• 2c Horne G. Wilson FX. Prog. Med. Chem. 2011; 50: 135
• 2d Horne G. Wilson FX. Tinsley J. Williams DH. Storer R. Drug Discovery Today 2011; 16: 107
• 3a Cipolla F. La Ferla B. Nicotra F. Curr. Top. Med. Chem. 2003; 3: 485
• 3b Horne G. Top. Med. Chem. 2014; 12: 23
• 3c Asano N. In Carbohydrate Chemistry: State of the Art and the Challenges for Drug Development . Cipolla L. Imperial College Press; London: 2016: 279
• 3d Harit VK. Namakkal G. RSC Adv. 2016; 6: 109528
• 4a Lopez O. Merino-Montiel P. Martos S. Gonzalez-Benjumea A. Carbohydr. Chem. 2012; 38: 215
• 4b Wrodnigg TM. Steiner AJ. Ueberbacher BJ. Anti-Cancer Agents Med. Chem. 2008; 8: 77
• 5a Cochi A. Pardo DG. Cossy J. Eur. J. Org. Chem. 2013; 809
• 5b Soler A. Garrabou X. Hernandez K. Guterriez ML. Busto E. Bujons J. Parella T. Joglar J. Clapes P. Adv. Synth. Catal. 2014; 356: 3007
• 5c Csatayova K. Davies SG. Fltecher AM. Ford JG. Klauber DJ. Roberts PM. Thomson JE. J. Org. Chem. 2014; 79: 10932
• 6a Romeo JT. Swain LA. Bleecker AB. Phytochemistry 1983; 22: 1615
• 6b Yuan ZX. Patel AV. Blunden G. Turner CH. Phytochemistry 1992; 31: 4351
• 6c Kunii Y. Otsuka M. Kashino T. Takeuchi H. Ohmori S. J. Agric. Food Chem. 1996; 44: 483
• 6d Kite G. Cardoso D. Lewis GP. Zartman CE. de Queiroz LP. Veitch NC. Phytochemistry 2015; 116: 198
• 7a Cenci di Bello I. Dorling P. Fellows L. Winchester B. FEBS Lett. 1984; 176: 61
• 7b Manning KS. Lynn DG. Shabanowitz J. Fellows LE. Singh M. Schrire BD. J. Chem. Soc., Chem. Commun. 1985; 127
• 8a Chavan SP. Khainar LB. Pawar KP. Chavan PN. Kawale SA. RSC Adv. 2015; 5: 50580
• 8b Chacko S. Ramapanicker R. J. Org. Chem. 2015; 80: 4776
• 8c Marjanovic J. Ferjancic Z. Saicic RN. Tetrahedron 2015; 71: 6784
• 9 Grand E. Kovensky J. Pourceau G. Toumieux S. Wadouachi A. Carbohydr. Chem. 2014; 40: 195
• 10a Bashyal BP. Chow HF. Fleet GW. J. Tetrahedron Lett. 1986; 27: 3205
• 10b Bashyal BP. Chow HF. Fellows LE. Fleet GW. J. Tetrahedron 1987; 43: 415
• 10c Bashyal BP. Chow HF. Fleet GW. J. Tetrahedron 1987; 43: 423
• 11 Matassini C. Mirabella S. Ferhati X. Faggi C. Robina I. Goti A. Moreno-Clavijo E. Moreno-Vargas AJ. Cardona F. Eur. J. Org. Chem. 2014; 5419
• 12a Rat S. Mathiron D. Michaud P. Kovensky J. Wadouachi A. Tetrahedron 2007; 63: 12424
• 12b Bosco M. Rat S. Kovensky J. Wadouachi A. Tetrahedron Lett. 2010; 51: 2553
• 12c Bosco M. Rat S. Dupré N. Hasenknopf B. Lacote E. Malacria M. Remy P. Kovensky J. Thorimbert S. Wadouachi A. ChemSusChem 2010; 3: 1249
• 12d Lu H. Drelich A. Omri M. Pezron I. Wadouachi A. Pourceau G. Molecules 2016; 21: 1301
• 12e Lu B. Vayssade M. Miao Y. Chagnault V. Grand E. Wadouachi A. Postel D. Drelich A. Egles C. Pezron I. Colloids Surf., B 2016; 145: 79
• 13 Kitahara T. Ogawa T. Naganuma T. Matsui M. Agric. Biol. Chem. 1974; 38: 2189
• 14 Caution! Azides are known to be explosive under a range of conditions, and can react violently at acidic pH to form HN₃. For safety, storage and manipulation see: http://www.ehs.ucsb.edu/files/docs/ls/factsheets/Azides_FS26.pdf.
• 15 Krulle TM. Davis B. Ardron H. Long DD. Hindle NA. Smith C. Brown D. Lane AL. Watkin DJ. Marquess DG. Fleet GW. J. Chem. Commun. 1996; 1271
• 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.
• 18a Tsukida T. Moriyama H. Inoue Y. Kondo H. Yoshino K. Nishimura SI. Bioorg. Med. Chem. Lett. 2004; 14: 1569
• 18b Moriyama H. Tsukida T. Inoue Y. Yokota K. Yoshino K. Kondo H. Miura N. Nishimura SI. J. Med. Chem. 2004; 47: 1930