Cycloaddition Reactions of Sugar-Based Olefins, Nitrones and Nitrile Oxides: En Route to Saccharidic Spiroisoxazoli(di)nes

  • Nadia Pellegrini-MoïseEmail author
  • Mylène RichardEmail author
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 57)


Isoxazoline- and isoxazolidine-containing compounds are privileged structures of interest, notably in synthetic and medicinal chemistry. These heterocycles can be obtained by 1,3-dipolar cycloaddition reactions between an olefin and a nitrile oxide or a nitrone. This reaction generates one C–C and one C–O bond and up to three chiral centres in one step. In the present chapter, we aim to summarize and discuss reports of these cycloadditions on sugar olefins, with a focus on exo-methylene sugars or activated exo-glycals, leading to saccharidic spiroisoxazoli(di)nes with high regio- and stereocontrol. Additional examples of cycloaddition reactions involving chiral nitrone, sugar nitrile oxide, sugar nitrone and two chiral sugar partners will also be discussed. Due to the importance of the spiro structure in several biologically active compounds, these spiroheterocycles can be regarded as spironucleoside analogues, mimics of natural building blocks or multicyclic sugar scaffolds suitable for selective derivatization. Some of them thus showed promising biological properties as antibacterial agents or enzyme inhibitors. Moreover, the labile nature of the N–O bond in the isoxazolidine ring makes it an attractive target for synthetic chemists. The reactivity of this scaffold has therefore been widely studied, and the cycloadducts have been converted to other classes of compounds of interest. Examples of the biological relevance and synthetic use and reactivity of these spiro-sugars will be given in this chapter.


Cycloaddition Nitrile oxides Nitrones Spiroisoxazoli(di)nes Sugar-based olefins 


  1. 1.
    Berthet M, Cheviet T, Dujardin G, Parrot I, Martinez J (2016) Isoxazolidine: a privileged scaffold for organic and medicinal chemistry. Chem Rev 116:15235–15283PubMedGoogle Scholar
  2. 2.
    Tufariello JJ (1984) Nitrones. 1,3-Dipolar cycloadditions in chemistry. Wiley, New York, pp 83–168Google Scholar
  3. 3.
    Confalone PN, Huie EM (2004) The [3 + 2] nitrone–olefin cycloaddition reaction. Organic reactions. American Cancer Society, Atlanta, pp 1–173Google Scholar
  4. 4.
    Padwa A, Pearson WH (eds) (2002) Synthetic applications of 1,3-dipolar cycloaddition chemistry toward heterocycles and natural products. Wiley, New YorkGoogle Scholar
  5. 5.
    Gothelf KV (2001) Asymmetric metal-catalyzed 1,3-dipolar cycloaddition reactions. Cycloaddition reactions in organic synthesis. Wiley, Weinheim, pp 211–247Google Scholar
  6. 6.
    Kaur K, Kumar V, Sharma AK, Gupta GK (2014) Isoxazoline containing natural products as anticancer agents: a review. Eur J Med Chem 77:121–133PubMedGoogle Scholar
  7. 7.
    Frederickson M (1997) Optically active isoxazolidines via asymmetric cycloaddition reactions of nitrones with alkenes: applications in organic synthesis. Tetrahedron 53:403–425Google Scholar
  8. 8.
    Gothelf KV, Jørgensen KA (1998) Asymmetric 1,3-dipolar cycloaddition reactions. Chem Rev 98:863–910PubMedGoogle Scholar
  9. 9.
    Giuliano RM (1992) Cycloaddition reactions in carbohydrate chemistry. An overview. ACS Symp Ser 494:1–23Google Scholar
  10. 10.
    Paton RM (1998) The nitrile oxide/isoxazoline route to C-disaccharides. In: Chapleur Y (ed) Carbohydrate mimics. Wiley, Hoboken, pp 49–66Google Scholar
  11. 11.
    Osborn HMI, Gemmell N, Harwood LM (2002) 1,3-Dipolar cycloaddition reactions of carbohydrate derived nitrones and oximes. J Chem Soc Perkin Trans 1:2419–2438Google Scholar
  12. 12.
    Das SN, Chowdhury A, Tripathi N, Jana PK, Mandal SB (2015) Exploitation of in situ generated sugar-based olefin keto-nitrones: synthesis of carbocycles, heterocycles, and nucleoside derivatives. J Org Chem 80:1136–1148PubMedGoogle Scholar
  13. 13.
    Taillefumier C, Chapleur Y (2004) Synthesis and uses of exo-glycals. Chem Rev 104:263–292PubMedGoogle Scholar
  14. 14.
    Pellegrini-Moïse N, Richard M, Chapleur Y (2014) Chapter 6. Exo -glycals as useful tools for anomeric functionalization of sugars. In: Pilar Rauter A, Lindhorst T, Queneau Y (eds) Carbohydrate chemistry, vol 40. Royal Society of Chemistry, Cambridge, pp 99–117Google Scholar
  15. 15.
    Rajan Babu TV, Reddy GS (1986) 1-Methylene sugars as C-glycoside precursors. J Org Chem 51:5458–5461Google Scholar
  16. 16.
    Colinas PA, Jäger V, Lieberknecht A, Bravo RD (2003) Nitrile oxide cycloadditions to olefinated sugars. Tetrahedron Lett 44:1071–1074Google Scholar
  17. 17.
    Benltifa M, Vidal S, Gueyrard D, Goekjian PG, Msaddek M, Praly J-P (2006) 1,3-Dipolar cycloaddition reactions on carbohydrate-based templates: synthesis of spiro-isoxazolines and 1,2,4-oxadiazoles as glycogen phosphorylase inhibitors. Tetrahedron Lett 47:6143–6147Google Scholar
  18. 18.
    Benltifa M, Hayes JM, Vidal S, Gueyrard D, Goekjian PG, Praly JP, Kizilis G, Tiraidis C, Alexacou KM, Chrysina ED, Zographos SE, Leonidas DD, Archontis G, Oikonomakos NG (2009) Glucose-based spiro-isoxazolines: a new family of potent glycogen phosphorylase inhibitors. Bioorg Med Chem 17:7368–7380PubMedGoogle Scholar
  19. 19.
    Krimm I, Lancelin J-M, Praly J-P (2012) Binding evaluation of fragment-based scaffolds for probing allosteric enzymes. J Med Chem 55:1287–1295PubMedGoogle Scholar
  20. 20.
    Goyard D, Kónya B, Chajistamatiou AS, Chrysina ED, Leroy J, Balzarin S, Tournier M, Tousch D, Petit P, Duret C, Maurel P, Somsák L, Docsa T, Gergely P, Praly JP, Azay-Milhau J, Vidal S (2016) Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition. Eur J Med Chem 108:444–454PubMedGoogle Scholar
  21. 21.
    Somsák L, Bokor É, Czibere B, Czifrák K, Koppány C, Kulcsár L, Kun S, Szilágyi E, Tóth M, Docsa T, Gergely P (2014) Synthesis of C-xylopyranosyl- and xylopyranosylidene-spiro-heterocycles as potential inhibitors of glycogen phosphorylase. Carbohydr Res 399:38–48PubMedGoogle Scholar
  22. 22.
    Goyard D, Telligmann SM, Goux-Henry C, Boysen MMK, Framery E, Gueyrard D, Vidal S (2010) Carbohydrate-based spiro bis(isoxazolines): synthesis and evaluation in asymmetric catalysis. Tetrahedron Lett 51:374–377Google Scholar
  23. 23.
    Li X, Takahashi H, Ohtake H, Ikegami S (2003) Synthesis of ketosyl spiro-isoxazolidine by 1,3-dipolar cycloaddition of 1-methylenesugars with nitrones - a new access to C-glycosyl amino acids. Heterocycles 59:547–571Google Scholar
  24. 24.
    Ikegami S, Namme R (2009) Chemistry of 1-methylenesugars: synthetic utilizations to 1′-C-methyl-saccharides and related carbohydrates. Heterocycles 78:19–44Google Scholar
  25. 25.
    Li X, Wang R, Wang Y, Chen H, Li Z, Ba C, Zhang J (2008) Stereoselective synthesis and biological activity of novel spiro-oxazinanone-C-glycosides. Tetrahedron 64:9911–9920Google Scholar
  26. 26.
    Gallos JK, Koftis TV, Koumbis AE, Moutsos VI (1999) A novel carbocyclic ring closure of hex-5-enopyranosides and pent-4-enofuranosides. Synlett 1999:1289–1291Google Scholar
  27. 27.
    Gallos JK, Demeroudi SC, Stathopoulou CC, Dellios CC (2001) Expeditious synthesis of seven-membered iminocyclitols. Tetrahedron Lett 42:7497–7499Google Scholar
  28. 28.
    Gallos JK, Koftis TV (2001) Carbocyclic ring closure of hex-5-enopyranosides and pent-4-enofuranosides: a nitrile oxide approach. J Chem Soc Perkin Trans 1:415–423Google Scholar
  29. 29.
    Lakhrissi M, Chapleur Y (1996) Wittig olefination of lactones. Angew Chem Int Ed Engl 35:750–752Google Scholar
  30. 30.
    Enderlin G, Taillefumier C, Didierjean C, Chapleur Y (2005) Cycloaddition reactions on activated exo-glycals. Tetrahedron Asymmetry 16:2459–2474Google Scholar
  31. 31.
    Taillefumier C, Enderlin G, Chapleur Y (2005) Cycloaddition of nitrones and nitrile oxides to activated exo-glycals. Lett Org Chem 2:226–230Google Scholar
  32. 32.
    Salgado H, Jiménez R, Pérez L, Tamariz J, Salgado H (1993) 1,3-Dipolar cycloaddition reactions involving captodative olefins. Heterocycles 35:591–598Google Scholar
  33. 33.
    Nakajima M, Itoi K, Takamatsu Y, Kinoshita T, Okazaki T, Kawakubo K, Shindo M, Honma T, Tohjigamori M, Haneishi T (1991) Hydantocidin: a new compound with herbicidal activity from Streptomyces hygroscopicus. J Antibiot (Tokyo) 44:293–300Google Scholar
  34. 34.
    Richard M, Chapleur Y, Pellegrini-Moïse N (2016) Spiro sugar-isoxazolidine scaffold as useful polyfunctional building block for peptidomimetics design. Carbohydr Res 422:24–33PubMedGoogle Scholar
  35. 35.
    Novoa A, Pellegrini-Moïse N, Bechet D, Barberi-Heyob M, Chapleur Y (2010) Sugar-based peptidomimetics as potential inhibitors of the vascular endothelium growth factor binding to neuropilin-1. Bioorg Med Chem 18:3285–3298PubMedGoogle Scholar
  36. 36.
    Richard M, Chateau A, Jelsch C, Didierjean C, Manival X, Charron C, Maigret B, Barberi-Heyob M, Chapleur Y, Boura C, Pellegrini-Moïse N (2016) Carbohydrate-based peptidomimetics targeting neuropilin-1: synthesis, molecular docking study and in vitro biological activities. Bioorg Med Chem 24:5315–5325PubMedGoogle Scholar
  37. 37.
    Gong C, Valduga J, Chateau A, Richard M, Pellgrini-Moïse N, Barberi-Heyob M, Chastagner P, Boura C (2018) Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1. Oncotarget 9:15312–15325PubMedPubMedCentralGoogle Scholar
  38. 38.
    Li X, Takahashi H, Ohtake H, Ikegami S (2004) 1,3-Dipolar cycloaddition of exo -methylenesugars with nitrone: approach to new amino-C-ketosyl disaccharides. Tetrahedron Lett 45:4123–4126Google Scholar
  39. 39.
    Oukani H, Pellegrini-Moïse N, Jackowski O, Chrétien F, Chapleur Y (2013) The 1,3-dipolar cycloaddition reaction of chiral carbohydrate-derived nitrone and olefin: towards long-chain sugars. Carbohydr Res 381:205–214PubMedGoogle Scholar
  40. 40.
    Vasella A, Voeffray R (1982) Total Synthese von Nojirimycin. Helv Chim Acta 65:1134–1144Google Scholar
  41. 41.
    Vasella A, Voeffray R, Pless J, Huguenin R (1983) Synthesis of D- and L-5-oxaproline and of a new captopril analogue. Helv Chim Acta 66:1241–1252Google Scholar
  42. 42.
    Tronchet JMJ, Mihaly E (1972) C-glycosylic derivatives. VII. Synthesis and reactions of sugar nitrones. Helv Chim Acta 55:1813–1815Google Scholar
  43. 43.
    Torrente S, Noya B, Paredes MD, Alonso R (1997) Intramolecular 1,3-dipolar cycloadditions of sugar ketonitrones: a convenient method for stereoselective formation of nitrogenated quaternary centers. J Org Chem 62:6710–6711Google Scholar
  44. 44.
    Kishi Y, Aratani M, Fukuyama T, Nakatsubo F, Goto T, Inoue S, Tanino H, Sugiure S, Kakoi H (1972) Synthetic studies on tetrodotoxin and related compounds. IV. Stereospecific total syntheses of DL-tetrodotoxin. J Am Chem Soc 94:9219–9221PubMedGoogle Scholar
  45. 45.
    Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL (1995) Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 268:726–731PubMedGoogle Scholar
  46. 46.
    Hossain N, Papchikhin A, Plavec J, Chattopadhyaya J (1993) Synthesis of 2′- and 3′-spiro-isoxazolidine derivatives of thymidine & their conversions to 2′,3′-dideoxy-2′,3′-didehydro-3′-C-substituted nucleosides by radical promoted fragmentation. Tetrahedron 49:10133–10156Google Scholar
  47. 47.
    Rong J, Roselt P, Plavec J, Chattopadhyaya J (1994) The synthesis and conformation of 2′- and 3′-hypermodified tricyclic nucleosides and their use in the synthesis of novel 2′- or 3′-isomeric 4(7)-substituted isoxazolidine-nucleosides. Tetrahedron 50:4921–4936Google Scholar
  48. 48.
    Torrente S, Noya B, Branchadell V, Alonso R (2003) Intra- and intermolecular 1,3-dipolar cycloaddition of sugar ketonitrones with mono-, di-, and trisubstituted dipolarophiles. J Org Chem 68:4772–4783PubMedGoogle Scholar
  49. 49.
    Yokoyama M, Yamada N, Togo H (1990) Synthesis of spiro sugar isoxazolidines via tandem michael addition-1,3-dipolar cycloaddition. Chem Lett 19:753–756Google Scholar
  50. 50.
    Yokoyama M, Sujino K, Irie M, Yamazaki N, Hiyama T, Yamada N, Togo H (1991) Additional reactions of sugar oximes, nitrile oxides and hydroximolactones. J Chem Soc Perkin Trans 1:2801–2809Google Scholar
  51. 51.
    Grigg R, Markandu J, Perrior T, Surendrakumar S, Warnock WJ (1992) X = Y - ZH systems as potential 1,3-dipoles part 35. Generation of nitrones from oximes. Class 3 processes. Tandem intramolecular Michael addition (1,3-azaprotio cyclotransfer) – intermolecular 1,3-dipolar cycloaddition reactions. Tetrahedron 48:6929–6952Google Scholar
  52. 52.
    Yokoyama M, Yamada N (1989) Synthesis of spiro and bicyclic nucleosides from ribose nitrile oxide with dimethyl acetylenedicarboxylate. Tetrahedron Lett 30:3675–3676Google Scholar
  53. 53.
    Zhang PZ, Li XL, Chen H, Li YN, Wang R (2007) The synthesis and biological activity of novel spiro-isoxazoline C-disaccharides based on 1,3-dipolar cycloaddition of exo-glycals and sugar nitrile oxides. Tetrahedron Lett 48:7813–7816Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Université de Lorraine-CNRS, UMR 7053 L2CMNancyFrance

Personalised recommendations