Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
Carbohydrate-spiro-heterocycles

Part of the book series: Topics in Heterocyclic Chemistry ((TOPICS,volume 57))

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Berthet M, Cheviet T, Dujardin G, Parrot I, Martinez J (2016) Isoxazolidine: a privileged scaffold for organic and medicinal chemistry. Chem Rev 116:15235–15283

    CAS  PubMed  Google Scholar 

  2. Tufariello JJ (1984) Nitrones. 1,3-Dipolar cycloadditions in chemistry. Wiley, New York, pp 83–168

    Google Scholar 

  3. Confalone PN, Huie EM (2004) The [3 + 2] nitrone–olefin cycloaddition reaction. Organic reactions. American Cancer Society, Atlanta, pp 1–173

    Google Scholar 

  4. Padwa A, Pearson WH (eds) (2002) Synthetic applications of 1,3-dipolar cycloaddition chemistry toward heterocycles and natural products. Wiley, New York

    Google Scholar 

  5. Gothelf KV (2001) Asymmetric metal-catalyzed 1,3-dipolar cycloaddition reactions. Cycloaddition reactions in organic synthesis. Wiley, Weinheim, pp 211–247

    Google Scholar 

  6. Kaur K, Kumar V, Sharma AK, Gupta GK (2014) Isoxazoline containing natural products as anticancer agents: a review. Eur J Med Chem 77:121–133

    CAS  PubMed  Google Scholar 

  7. Frederickson M (1997) Optically active isoxazolidines via asymmetric cycloaddition reactions of nitrones with alkenes: applications in organic synthesis. Tetrahedron 53:403–425

    CAS  Google Scholar 

  8. Gothelf KV, Jørgensen KA (1998) Asymmetric 1,3-dipolar cycloaddition reactions. Chem Rev 98:863–910

    CAS  PubMed  Google Scholar 

  9. Giuliano RM (1992) Cycloaddition reactions in carbohydrate chemistry. An overview. ACS Symp Ser 494:1–23

    CAS  Google Scholar 

  10. Paton RM (1998) The nitrile oxide/isoxazoline route to C-disaccharides. In: Chapleur Y (ed) Carbohydrate mimics. Wiley, Hoboken, pp 49–66

    Google Scholar 

  11. Osborn HMI, Gemmell N, Harwood LM (2002) 1,3-Dipolar cycloaddition reactions of carbohydrate derived nitrones and oximes. J Chem Soc Perkin Trans 1:2419–2438

    Google Scholar 

  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 80:1136–1148

    CAS  PubMed  Google Scholar 

  13. Taillefumier C, Chapleur Y (2004) Synthesis and uses of exo-glycals. Chem Rev 104:263–292

    CAS  PubMed  Google Scholar 

  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 99–117

    Google Scholar 

  15. Rajan Babu TV, Reddy GS (1986) 1-Methylene sugars as C-glycoside precursors. J Org Chem 51:5458–5461

    CAS  Google Scholar 

  16. Colinas PA, Jäger V, Lieberknecht A, Bravo RD (2003) Nitrile oxide cycloadditions to olefinated sugars. Tetrahedron Lett 44:1071–1074

    CAS  Google Scholar 

  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 47:6143–6147

    CAS  Google Scholar 

  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 17:7368–7380

    CAS  PubMed  Google Scholar 

  19. Krimm I, Lancelin J-M, Praly J-P (2012) Binding evaluation of fragment-based scaffolds for probing allosteric enzymes. J Med Chem 55:1287–1295

    CAS  PubMed  Google Scholar 

  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 108:444–454

    CAS  PubMed  Google Scholar 

  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 399:38–48

    PubMed  Google Scholar 

  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 51:374–377

    CAS  Google Scholar 

  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 59:547–571

    CAS  Google Scholar 

  24. Ikegami S, Namme R (2009) Chemistry of 1-methylenesugars: synthetic utilizations to 1′-C-methyl-saccharides and related carbohydrates. Heterocycles 78:19–44

    Google Scholar 

  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 64:9911–9920

    CAS  Google Scholar 

  26. Gallos JK, Koftis TV, Koumbis AE, Moutsos VI (1999) A novel carbocyclic ring closure of hex-5-enopyranosides and pent-4-enofuranosides. Synlett 1999:1289–1291

    Google Scholar 

  27. Gallos JK, Demeroudi SC, Stathopoulou CC, Dellios CC (2001) Expeditious synthesis of seven-membered iminocyclitols. Tetrahedron Lett 42:7497–7499

    CAS  Google Scholar 

  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 1:415–423

    Google Scholar 

  29. Lakhrissi M, Chapleur Y (1996) Wittig olefination of lactones. Angew Chem Int Ed Engl 35:750–752

    CAS  Google Scholar 

  30. Enderlin G, Taillefumier C, Didierjean C, Chapleur Y (2005) Cycloaddition reactions on activated exo-glycals. Tetrahedron Asymmetry 16:2459–2474

    CAS  Google Scholar 

  31. Taillefumier C, Enderlin G, Chapleur Y (2005) Cycloaddition of nitrones and nitrile oxides to activated exo-glycals. Lett Org Chem 2:226–230

    CAS  Google Scholar 

  32. Salgado H, Jiménez R, Pérez L, Tamariz J, Salgado H (1993) 1,3-Dipolar cycloaddition reactions involving captodative olefins. Heterocycles 35:591–598

    Google Scholar 

  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) 44:293–300

    CAS  Google Scholar 

  34. Richard M, Chapleur Y, Pellegrini-Moïse N (2016) Spiro sugar-isoxazolidine scaffold as useful polyfunctional building block for peptidomimetics design. Carbohydr Res 422:24–33

    CAS  PubMed  Google Scholar 

  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 18:3285–3298

    CAS  PubMed  Google Scholar 

  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 24:5315–5325

    CAS  PubMed  Google Scholar 

  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 9:15312–15325

    PubMed  PubMed Central  Google Scholar 

  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 45:4123–4126

    CAS  Google Scholar 

  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 381:205–214

    CAS  PubMed  Google Scholar 

  40. Vasella A, Voeffray R (1982) Total Synthese von Nojirimycin. Helv Chim Acta 65:1134–1144

    CAS  Google Scholar 

  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 66:1241–1252

    CAS  Google Scholar 

  42. Tronchet JMJ, Mihaly E (1972) C-glycosylic derivatives. VII. Synthesis and reactions of sugar nitrones. Helv Chim Acta 55:1813–1815

    Google Scholar 

  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 62:6710–6711

    CAS  Google Scholar 

  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 94:9219–9221

    CAS  PubMed  Google Scholar 

  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 268:726–731

    CAS  PubMed  Google Scholar 

  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 49:10133–10156

    CAS  Google Scholar 

  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 50:4921–4936

    CAS  Google Scholar 

  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 68:4772–4783

    CAS  PubMed  Google Scholar 

  49. Yokoyama M, Yamada N, Togo H (1990) Synthesis of spiro sugar isoxazolidines via tandem michael addition-1,3-dipolar cycloaddition. Chem Lett 19:753–756

    Google Scholar 

  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 1:2801–2809

    Google Scholar 

  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 48:6929–6952

    CAS  Google Scholar 

  52. Yokoyama M, Yamada N (1989) Synthesis of spiro and bicyclic nucleosides from ribose nitrile oxide with dimethyl acetylenedicarboxylate. Tetrahedron Lett 30:3675–3676

    CAS  Google Scholar 

  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 48:7813–7816

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Université de Lorraine-CNRS, UMR 7053 L2CM, Nancy, France

    Nadia Pellegrini-Moïse & Mylène Richard

Authors
  1. Nadia Pellegrini-Moïse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mylène Richard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Nadia Pellegrini-Moïse or Mylène Richard .

Editor information

Editors and Affiliations

  1. Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary

    László Somsák

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Pellegrini-Moïse, N., Richard, M. (2019). Cycloaddition Reactions of Sugar-Based Olefins, Nitrones and Nitrile Oxides: En Route to Saccharidic Spiroisoxazoli(di)nes. In: Somsák, L. (eds) Carbohydrate-spiro-heterocycles. Topics in Heterocyclic Chemistry, vol 57. Springer, Cham. https://doi.org/10.1007/7081_2019_28

Download citation

Publish with us

Policies and ethics

Search

Navigation