Science China Chemistry

, Volume 54, Issue 1, pp 66–73 | Cite as

Pre-activation based stereoselective glycosylations: Stereochemical control by additives and solvent

  • Gilbert Wasonga
  • YouLin Zeng
  • XueFei HuangEmail author
Articles SPECIAL TOPIC The Frontiers of Chemical Biology and Synthesis


Stereochemical control is an important issue in carbohydrate synthesis. Glycosyl donors with participating acyl protective groups on 2-O have been shown to give 1,2-trans glycosides reliably under the pre-activation based reaction condition. In this work, the effects of additives and reaction solvents on stereoselectivity were examined using donors without participating protective groups on 2-O. While several triflate salt additives did not have major effects, the amount of AgOTf was found to significantly impact the reaction outcome. Excess AgOTf led to lower stereochemical control presumably due to its coordination with the glycosyl triflate intermediate and a more SN1 like reaction pathway. In contrast, the stereoselectivity could be directed by reaction solvents, with diethyl ether favoring the formation of β-glycosides and dichloromethane leading to β isomers. The trend of stereochemical dependence on reaction solvent was applicable to a variety of building blocks including the selective formation of β-mannosides.


stereoselectivity pre-activation based glycosylation additives solvent effects 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

11426_2010_4186_MOESM1_ESM.pdf (1.2 mb)
Supplementary material, approximately 340 KB.


  1. 1.
    Demchenko AV, Ed. Handbook of Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic Relevance. Weinheim: Wiley-VCH. 2008Google Scholar
  2. 2.
    Wang Z, Huang X. in: Comprehensive Glycoscience from Chemistry to Systems Biology. Kamerling JP, Ed. Elsevier, 2007. 379–413Google Scholar
  3. 3.
    Demchenko A. Stereoselective chemical 1,2-cis O-glycosylation: from ’sugar ray’ to modern techniques of the 21st century. Synlett, 2003: 1225-1240Google Scholar
  4. 4.
    Crich D, Li W, Li H. Direct chemical synthesis of the β-mannans: Linear and block syntheses of the alternating β-(1,3)-β-(1,4)-mannan common to Rhodotorula glutinis, Rhodotorula mucilaginosa, and Leptospira biflexa. J Am Chem Soc, 2004, 126: 15081–15086 and references cited thereinCrossRefGoogle Scholar
  5. 5.
    Crich D, Sun S. Direct chemical synthesis of β-mannopyranosides and other glycosides via glycosyl triflates. Tetrahedron, 1998, 54: 8321–8348CrossRefGoogle Scholar
  6. 6.
    Fairbanks AJ. Intramolecular aglycon delivery (IAD): The solution to 1,2-cis stereocontrol for oligosaccharide synthesis? Synlett, 2003: 1945–1958Google Scholar
  7. 7.
    Jung K-H, Müller M, Schmidt RR. Intramolecular O-glycoside bond formation. Chem Rev, 2000, 100: 4423–4442CrossRefGoogle Scholar
  8. 8.
    Kim J-H, Yang H, Park J, Boons G-J. A general strategy for stereoselective glycosylations. J Am Chem Soc, 2005, 127: 12090–12097 and references cited thereinCrossRefGoogle Scholar
  9. 9.
    Chao C-S, Li C-W, Chen M-C, Chang S-S, Mong K-KT. Low-concentration 1,2-trans β-selective glycosylation strategy and its applications in oligosaccharide synthesis. Chem Eur J, 2009, 15: 10972–10982CrossRefGoogle Scholar
  10. 10.
    Tanifum CT, Chang C-WT. Sonication-assisted oligomannoside synthesis. J Org Chem, 2009, 74: 634–644CrossRefGoogle Scholar
  11. 11.
    Teumelsan N, Huang X. Synthesis of branched Man5 oligosaccharides and an unusual stereochemical observation. J Org Chem, 2007, 72: 8976–8979CrossRefGoogle Scholar
  12. 12.
    Wang Z, Zhou L, El-boubbou K, Ye X-S, Huang X. Multi-component one-pot synthesis of the tumor-associated carbohydrate antigen globo-H based on preactivation of thioglycosyl donors. J Org Chem, 2007, 72: 6409–6420CrossRefGoogle Scholar
  13. 13.
    Lohman GJS, Seeberger PH. A Stereochemical surprise at the late stage of the synthesis of fully N-differentiated heparin oligosaccharides containing amino, acetamido, and N-sulfonate groups. J Org Chem, 2004, 69 4081-4093Google Scholar
  14. 14.
    Orgueira HA, Bartolozzi A, Schell P, Litjens REJN, Palmacci ER, Seeberger PH. Modular synthesis of heparin oligosaccharides. Chem Eur J, 2003, 9: 140–169CrossRefGoogle Scholar
  15. 15.
    Huang X, Huang L, Wang H, Ye X-S. Iterative one-pot oligosaccharide synthesis. Angew Chem Int Ed, 2004, 43: 5221–5224CrossRefGoogle Scholar
  16. 16.
    Lu X, Kamat M, Huang L, Huang X. Chemical synthesis of a hyaluronic acid decasaccharide. J Org Chem, 2009, 74: 7608–7617 and references cited thereinCrossRefGoogle Scholar
  17. 17.
    Sun B, Srinivasan B, Huang X. Pre-activation based one-pot synthesis of an α-(2,3)-sialylated core-fucosylated complex type Bi-antennary N-glycan dodecasaccharide. Chem Eur J, 2008, 14: 7072–7081CrossRefGoogle Scholar
  18. 18.
    Huang L, Huang X. Highly efficient syntheses of hyaluronic acid oligosaccharides. Chem Eur J, 2007, 13: 529–540CrossRefGoogle Scholar
  19. 19.
    Tokimoto H, Fujimoto Y, Fukase K, Kusumoto S. Stereoselective glycosylation using the long-range effect of a [2-(4-phenylbenzyl) oxycarbonyl] benzoyl group. Tetrahedron Assym, 2005, 16: 441–447CrossRefGoogle Scholar
  20. 20.
    Chiba H, Funasaka S, Mukaiyama T. Catalytic and stereoselective glycosylation with glucosyl thioformimidates. Bull Chem Soc Jpn, 2003, 76: 1629–1644CrossRefGoogle Scholar
  21. 21.
    Adinolfi M, Barone G, Iadonisi A, Schiattarella M. Efficient activation of glycosyl N-(phenyl)trifluoroacetimidate donors with ytterbium( iii) triflate in the glycosylation reaction. Tetrahedron Lett, 2002, 43: 5573–5577CrossRefGoogle Scholar
  22. 22.
    Jona H, Mandai H, Chavasiri W, Takeuchi K, Mukaiyama T. Protic acid catalyzed stereoselective glycosylation using glycosyl fluorides. Bull Chem Soc Jpn, 2002, 75: 291–309CrossRefGoogle Scholar
  23. 23.
    Demchenko A, Stauch T, Boons G-J. Solvent and other effects on the stereoselectivity of thioglycoside glycosidations. Synlett, 1997: 818-819Google Scholar
  24. 24.
    Huang L, Wang Z, Li X, Ye X-S, Huang X. Iterative one-pot syntheses of chitotetraoses. Carbohydr Res, 2006, 341: 1669–1679CrossRefGoogle Scholar
  25. 25.
    Crich D, Cai W. Chemistry of 4,6-O-benzylidene-D-glycopyranosyl triflates: contrasting behavior between the gluco and manno series. J Org Chem, 1999, 64: 4926–4930CrossRefGoogle Scholar
  26. 26.
    Crich D, Sun S. Are glycosyl triflates intermediates in the sulfoxide glycosylation method? A chemical and 1H, 13C, and 19F NMR spectroscopic investigation. J Am Chem Soc, 1997, 119: 11217–11223CrossRefGoogle Scholar
  27. 27.
    Zeng Y, Wang Z, Whitfield D, Huang X. Installation of electron donating protective groups, a strategy for glycosylating unreactive thioglycosyl acceptors using the pre-activation based glycosylation method. J Org Chem, 2008, 73: 7952–7962CrossRefGoogle Scholar
  28. 28.
    Crich D, Chandrasekera NS. Mechanism of 4,6-O-benzylidene-directed β-mannosylation as determined by β-deuterium kinetic isotope effects. Angew Chem Int Ed, 2004, 43: 5386–5389CrossRefGoogle Scholar
  29. 29.
    Crich D, Patel M. On the nitrile effect in L-rhamnopyranosylation. Carbohydr Res, 2006, 341: 1467–1475CrossRefGoogle Scholar
  30. 30.
    Braccini I, Derouet C, Esnault J, du Penhoat CH, Mallet J-M, Michon V, Sinaÿ P. Conformational analysis of nitrilium intermediates in glycosylation reactions. Carbohydr Res, 1993, 246: 23–41CrossRefGoogle Scholar
  31. 31.
    Schmidt RR, Behrendt M, Toepfer A. Nitriles as solvents in glycosylation reactions: highly selective β-glycoside synthesis. Synlett, 1990: 694-696Google Scholar
  32. 32.
    Bock K, Pedersen C. A study of 13CH coupling constants in hexopyranoses. J Chem Soc, Perkin Trans 2, 1974: 293-297Google Scholar
  33. 33.
    Sasai H, Hosono S, Kim W-S, Shibasaki M. Rare earth salts promoted glycosidation of glycosyl fluorides. Heterocycles, 1996, 42: 795–809CrossRefGoogle Scholar
  34. 34.
    Chang XG, Lowary LT. A glycosylation protocol based on activation of glycosyl 2-pyridyl sulfones with samarium triflate. Org Lett, 2000, 2: 1505–1508CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of ChemistryMichigan State UniversityEast LansingUSA

Personalised recommendations