Robust perfluorophenylboronic acid-catalyzed stereoselective synthesis of 2,3-unsaturated O-, C-, N- and S-linked glycosides

  1. ORCID Logo ,
  2. ,
  3. and
School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, 62 Nanyang Drive, N1.2–B1-14, Singapore 637459, Tel.: +65-6790-6738; Fax: +65-6794-7553
  1. Corresponding author email
Associate Editor: S. Flitsch
Beilstein J. Org. Chem. 2019, 15, 1275–1280.
Received 06 Mar 2019, Accepted 22 May 2019, Published 11 Jun 2019
Full Research Paper
cc by logo


A convenient protocol was developed for the synthesis of 2,3-unsaturated C-, O-, N- and S-linked glycosides (enosides) using 20 mol % perflurophenylboronic acid catalyst via Ferrier rearrangement. Using this protocol, D-glucals and L-rhamnals reacted with various C-, O-, N- and S-nucleophiles to give a wide range of glycosides in up to 98% yields with mainly α-anomeric selectivity. The perflurophenylboronic acid successfully catalyzed a wide range of substrates (both glucals and nucleophiles) under very mild reaction conditions.


2,3-Unsaturated glycosides, also known as pseudo-glycosides or enosides, are an important class of natural products with many biological activities and capacity to serve as substrates for further reactions [1-3]. They are involved in biochemical processes such as molecular recognition, cell–cell interaction, immunological recognition and transmission of biological information [4-6]. They are easily transformed into important bioactive compounds such as oligosaccharides, glycopeptides, nucleosides, antibiotics, uronic acids and other natural products [1-3].

The Ferrier rearrangement is one of the most useful processes to synthesize pseudo-glycosides in a direct and stereoselective fashion. Several classes of catalysts have been successfully applied in the Ferrier rearrangement including Brønsted acids [7-13], Lewis acids [14-19], redox reagents [20] and metal catalysts [21-23]. However, many of these catalysts have limited substrate scope, give variable selectivities and yields, require harsh reaction conditions and an excess amount of catalysts that are typically expensive, toxic and moisture/air sensitive. The majority of the reported catalysts are metal-based, and in pharmaceutical manufacturing, traces of metals pose a major challenge for their removal to acceptable limits. Therefore, the discovery of efficient, metal-free and mild catalysts for the Ferrier rearrangement is still challenging and desirable especially if such catalysts work well with a wide range of C-, O-, N- and S-nucleophiles under mild conditions. We also noted that the use of organocatalysts to catalyze the Ferrier rearrangement is scarcely reported.

Recently, organoboron-catalysis emerged as a mild and effective strategy for activation of alcohols [24], epoxide opening [25,26], Friedel–Crafts alkylations [27], dehydrative glycosylation [28] and many other reactions [29-31]. The robustness and mildness of organoboronic acid catalysts in comparison to traditional strong Lewis and Brønsted acid catalysts inspired us to investigate them as promoters for the Ferrier rearrangement. We envisioned that organoboronic acids can activate the allylic acetate of glycals making them susceptible to nucleophilic attacks under conditions favoring a strong polarization of the allylic acetate moiety (see Figure 4).

Herein, we report a phenylboronic acid-catalyzed synthesis of 2,3-unsaturated C-, O-, N- and S-glycosides via Ferrier rearrangement under very mild conditions. We also demonstrate the scope of the reaction using a wide range of glycals and C-, O-, N- and S-nucleophiles.

Results and Discussion

We began our study by investigating the reaction of 3,4,6-tri-O-acetyl-D-glucal (1a) with benzyl alcohol (2) in the presence of 20 mol % of arylboronic acids in different solvents (Table 1, entries 1–6). Phenylboronic acid failed to promote the reaction in several solvents and the starting glucal 1a was recovered unchanged (Table 1, entry 1). This is attributed to its low acidity. Gratifyingly, the more acidic perflurophenylboronic acid successfully promoted the reaction to give 4,6-di-O-acetyl-2,3-unsaturated glucoside 3a in CH3CN or CH3NO2 solvents (Table 1, entries 3 and 4). It gave better 92% yield of glucoside 3a in CH3NO2 over a shorter reaction time (Table 1, entries 4 vs 3). Under the same conditions, the reaction did not proceed in THF or DCM due to the lower polarity of these solvents in comparison to CH3CN and CH3NO2 (Table 1, entry 2 vs 3 and 4). Attempts to reduce the amount of perfluorophenylboronic acid to 5 mol % resulted in a reduction of the yield of glucoside 3a despite various attempts to promote the reaction by increasing the temperature and time (Table 1, entries 5 and 6). In all the cases, the α:β ratio of glucoside 3a was 90:10. Conditions in Table 1, entry 4 were considered as optimum. The structure of glucoside 3a was confirmed by the 1H NMR spectra where the anomeric proton (H1) appeared at δ 5.16 ppm (for glucal 1a it appears at δ 6.47 ppm) and the protons of the new double bond (H2, H3) appeared at δ 5.90–5.88 ppm [19]. The corresponding protons in the β-isomer appeared at δ 5.22 (H1) and δ 6.01 (H2, H3) [19,21].

Table 1: Optimization of the arylboronic acid-catalyzed reaction of 3,4,6-tri-O-acetyl-D-glucal (1a) with benzyl alcohol (2).

[Graphic 1]
Entry Arylboronic acid (mol %) Solvent Time (h) / T (°C) 3a Yield (%) (α:β)b
1 phenylboronic acid (20) CH3CN or DCM or THF or CH3NO2 10/40 NDc
2 perfluorophenylboronic acid (20) DCM or THF 10/40 ND
3 perfluorophenylboronic acid (20) CH3CN 10/40 70 (90:10)
4 perfluorophenylboronic acid (20) CH3NO2 6/40 92 (90:10)
5 perfluorophenylboronic acid (10) CH3NO2 6/60 88 (90:10)
6 perfluorophenylboronic acid (5) CH3NO2 12/60 60 (90:10)

a3,4,6-Tri-O-acetyl-D-glucal (1a, 1 equiv) reacted with benzyl alcohol (2, 1.1 equiv). bIsolated yields. α:β ratio calculated from NMR after column chromatography purification. cND: not detected.

Using the optimized conditions in Table 1, entry 4, we then examined the substrate scope. Therefore, glucal 1a was reacted with various O-nucleophiles (using primary, secondary, tertiary, allyl, propargyl alcohols and sugars), C-nucleophiles (using trimethylsilyl cyanide and trimethyl(propargyl)silane), S-nucleophiles (using thiophenol and p-toluenethiol) and N-nucleophiles (methane sulfonamide and p-toluene sulfonamide) (Figure 1). In all the cases, the reactions successfully gave the respective 2,3-unsaturated glycosides 3au in up to 92% yield with mainly α-anomeric selectivity (Table 1). Noteworthy, the reaction also gave disaccharide 3n and 3o smoothly with complete α-anomeric selectivity albeit in a moderate yield. Likewise, reaction using Et3SiH gave the desired 2,3-unsaturated sugar 3i in 74% yield. These results testify to the robustness of the perflurophenylboronic acid as a versatile organocatalyst for the Ferrier rearrangement reaction. We noted that the yields of the disaccharides 3n and 3o and sulfonamides 3t and 3u can be increased with increase in the temperature (60 °C) and extension of the reaction time. The results in Table 1 are superior to the results obtained using boron trifluoride diethyl etherate [32].


Figure 1: Perfluorophenylboronic acid-catalyzed reaction between 3,4,6-tri-O-acetyl-D-glucal 1a and O-, C-, S-, N-nucleophiles.

We then applied the perfluorophenylboronic acid catalyst to promote the reaction between 2,3,4,6-tetra-O-acetyl-D-glucal (4a) and O- and S-nucleophiles (Figure 2). The Ferrier-catalyzed rearrangements of 2-substituted sugars such as 2,3,4,6-tetra-O-acetyl-D-glucal (4a) to enosides are limited in the literature and pose special challenges including low product yields and selectivities, the need for a large excess of the catalyst and formation of by-products such as furaldehydes and enones [1,33-35]. Enosides are important building blocks especially for natural product synthesis [36-40]. Therefore, we used the perfluorophenyl boronic acid catalyst in the reaction between 2,3,4,6-tetra-O-acetyl-D-glucal (1a) and benzyl alcohol, n-butyl alcohol, cyclohexyl alcohol and p-toluenethiol (Figure 2). Gratifyingly, the reaction proceeded smoothly under mild and catalytic conditions to give the respective 2-acetoxy-2,3-unsaturated glycosides (enosides) 5ad in 62–78% yields albeit with moderate α-selectivity. No byproducts were detected and no further attempts were made to optimize the yield and selectivity of this reaction. The yields and selectivities are similar to those reported using HClO4·SiO2 [33].


Figure 2: Perfluorophenylboronic acid-catalyzed reaction between 2,3,4,6-tetra-O-acetyl-D-glucal 4a and O- and S-nucleophiles.

Based on the excellent results obtained with the reactions of glucals 1a and 4a with O-, C-, N-, S-nucleophiles, we further extended the scope of this reaction to 3,4-di-O-acetyl-L-rhamnal (6a, Figure 3). As a demonstration, the reaction between 3,4-di-O-acetyl-L-rhamnal (6a) and selected alcohols and p-toluenethiol proceed smoothly and afforded the desired 2,3-unsaturated L-rhamnosides (enosides) 7ah in up to 89% yield with complete α-anomeric selectivity (except for 7a). Disaccharide 7g was also obtained smoothly with complete α-anomeric selectivity. The reactions using rhamnal 6a was completed at a much faster rate within 2 h at room temperature in comparison to glucals 1a and 4a which required ≈6 h at 40 °C to give the products.


Figure 3: Perfluorophenylboronic-acid-catalyzed reaction between 3,4-di-O-acetyl-L-rhamnal (6a) and O- and S-nucleophiles.

A plausible pathway of the reaction is proposed in Figure 4. Coordination of perflurophenylboronic acid to the allylic acetate moiety of glucal 1a induces polarization (structure I) and leads to the formation of an allyloxycarbenium ion (structure II) in the preferred 4H3 conformation. Addition of the nucleophiles to C1 from the α-face gives the lower energy half-chair conformer and results in the observed α-selectivity of the 2,3-unsaturated glycosides III (Figure 4) [22]. However, the addition of the nucleophiles from the β-face gives the higher energy twist-boat conformer.


Figure 4: Plausible perfluorophenylboronic acid-catalyzed activation of glycal 1a.


We developed a robust perfluorophenylboronic-acid-catalyzed protocol for the synthesis of a broad range of 2,3-unsaturated O-, C-, S- and N-linked glycosides (enosides) in high yields and mostly α-anomeric selectivity through the reactions of D-glucal 1a, 2-acetoxy D-glucal 4a and L-rhamnal 6a with various C-, O-, N- and S-nucleophiles. Application of this protocol using other glycals is underway in our laboratory.


General procedure for the synthesis of compounds 3a–u, 5a–d and 7a–h

To a stirred solution of 3,4,6-tri-O-acetyl-D-glucal (1a, 136 mg, 0.5 mmol) or 2,3,4,6-tetra-O-acetyl-D-glucal (4a, 165 mg, 0.5 mmol) or 3,4-di-O-acetyl-L-rhamnal (6a, 107 mg, 0.5 mmol) in anhydrous nitromethane (3 mL) was added the acceptor (0.55 mmol) and perfluorophenylboronic acid (0.1 mmol) at room temperature. In the case of 1a and 4a, the resulting solution was stirred at 40 °C for 6 h while in the case of 6a, it was stirred at room temperature for 2 h (monitor by TLC). The reaction mixture was evaporated under reduced pressure, and the residue was purified using silica gel column chromatography (EtOAc/hexane).

Supporting Information

Supporting Information File 1: Experimental data and copies of 1H and 13C NMR spectra of glycosides 3au, 5ad and 7ah are provided.
Format: PDF Size: 5.8 MB Download


We thank Nanyang Technological University, Singapore for financial help (RG 13/18).


  1. Varki, A. Glycobiology 2014, 24, 1086–1220. doi:10.1093/glycob/cwu087
    Return to citation in text: [1] [2] [3]
  2. Durham, T. B.; Miller, M. J. Org. Lett. 2002, 4, 135–138. doi:10.1021/ol017026v
    Return to citation in text: [1] [2]
  3. Domon, D.; Fujiwara, K.; Ohtaniuchi, Y.; Takezawa, A.; Takeda, S.; Kawasaki, H.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 8279–8283. doi:10.1016/j.tetlet.2005.09.163
    Return to citation in text: [1] [2]
  4. Davis, B. G. Chem. Rev. 2002, 102, 579–602. doi:10.1021/cr0004310
    Return to citation in text: [1]
  5. Linhardt, R. J. J. Med. Chem. 2003, 46, 2551–2564. doi:10.1021/jm030176m
    Return to citation in text: [1]
  6. Ohtsubo, K.; Marth, J. D. Cell 2006, 126, 855–867. doi:10.1016/j.cell.2006.08.019
    Return to citation in text: [1]
  7. Chen, P.; Wang, S. Tetrahedron 2013, 69, 583–588. doi:10.1016/j.tet.2012.11.019
    Return to citation in text: [1]
  8. Zhang, J.; Zhang, B.; Zhou, J.; Chen, H.; Li, J.; Yang, G.; Wang, Z.; Tang, J. J. Carbohydr. Chem. 2013, 32, 380–391. doi:10.1080/07328303.2013.809093
    Return to citation in text: [1]
  9. Zhou, J.; Zhang, B.; Yang, G.; Chen, X.; Wang, Q.; Wang, Z.; Zhang, J.; Tang, J. Synlett 2010, 893–896. doi:10.1055/s-0029-1219539
    Return to citation in text: [1]
  10. Gorityala, B. K.; Cai, S.; Lorpitthaya, R.; Ma, J.; Pasunooti, K. K.; Liu, X.-W. Tetrahedron Lett. 2009, 50, 676–679. doi:10.1016/j.tetlet.2008.11.103
    Return to citation in text: [1]
  11. Agarwal, A.; Rani, S.; Vankar, Y. D. J. Org. Chem. 2004, 69, 6137–6140. doi:10.1021/jo049415j
    Return to citation in text: [1]
  12. Misra, A. K.; Tiwari, P.; Agnihotri, G. Synthesis 2005, 260–266. doi:10.1055/s-2004-837297
    Return to citation in text: [1]
  13. Wang, J.; Deng, C.; Zhang, Q.; Chai, Y. Org. Lett. 2019, 21, 1103–1107. doi:10.1021/acs.orglett.9b00009
    Return to citation in text: [1]
  14. Narasimha, G.; Srinivas, B.; Radha Krishna, P.; Kashyap, S. Synlett 2014, 523–526. doi:10.1055/s-0033-1340552
    Return to citation in text: [1]
  15. Srinivas, B.; Reddy, T. R.; Kashyap, S. Carbohydr. Res. 2015, 406, 86–92. doi:10.1016/j.carres.2015.01.009
    Return to citation in text: [1]
  16. Reddy, T. R.; Rao, D. S.; Kashyap, S. RSC Adv. 2015, 5, 28338–28343. doi:10.1039/c5ra03328d
    Return to citation in text: [1]
  17. Battina, S. K.; Reddy, T. R.; Radha Krishna, P.; Kashyap, S. Tetrahedron Lett. 2015, 56, 1798–1800. doi:10.1016/j.tetlet.2015.02.069
    Return to citation in text: [1]
  18. Balamurugan, R.; Koppolu, S. R. Tetrahedron 2009, 65, 8139–8142. doi:10.1016/j.tet.2009.07.087
    Return to citation in text: [1]
  19. Sau, A.; Palo-Nieto, C.; Galan, M. C. J. Org. Chem. 2019, 84, 2415–2424. doi:10.1021/acs.joc.8b02613
    Return to citation in text: [1] [2] [3]
  20. Yadav, J. S.; Subba Reddy, B. V.; Kumar Pandey, S. New J. Chem. 2001, 25, 538–540. doi:10.1039/b009973m
    Return to citation in text: [1]
  21. Sau, A.; Galan, M. C. Org. Lett. 2017, 19, 2857–2860. doi:10.1021/acs.orglett.7b01092
    Return to citation in text: [1] [2]
  22. Gómez, A. M.; Lobo, F.; Uriel, C.; López, J. C. Eur. J. Org. Chem. 2013, 7221–7262. doi:10.1002/ejoc.201300798
    Return to citation in text: [1] [2]
  23. Kim, H.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 1336–1337. doi:10.1021/ja039746y
    Return to citation in text: [1]
  24. Georgiou, I.; Ilyashenko, G.; Whiting, A. Acc. Chem. Res. 2009, 42, 756–768. doi:10.1021/ar800262v
    Return to citation in text: [1]
  25. Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.; Tu, Y. Q. Angew. Chem., Int. Ed. 2004, 43, 1702–1705. doi:10.1002/anie.200353177
    Return to citation in text: [1]
  26. Zheng, H.; Ghanbari, S.; Nakamura, S.; Hall, D. G. Angew. Chem., Int. Ed. 2012, 51, 6187–6190. doi:10.1002/anie.201201620
    Return to citation in text: [1]
  27. McCubbin, J. A.; Hosseini, H.; Krokhin, O. V. J. Org. Chem. 2010, 75, 959–962. doi:10.1021/jo9023073
    Return to citation in text: [1]
  28. Manhas, S.; Taylor, M. S. Carbohydr. Res. 2018, 470, 42–49. doi:10.1016/j.carres.2018.10.002
    Return to citation in text: [1]
  29. Debache, A.; Boumoud, B.; Amimour, M.; Belfaitah, A.; Rhouati, S.; Carboni, B. Tetrahedron Lett. 2006, 47, 5697–5699. doi:10.1016/j.tetlet.2006.06.015
    Return to citation in text: [1]
  30. Zheng, H.; Hall, D. G. Tetrahedron Lett. 2010, 51, 3561–3564. doi:10.1016/j.tetlet.2010.04.132
    Return to citation in text: [1]
  31. Zheng, H.; McDonald, R.; Hall, D. G. Chem. – Eur. J. 2010, 16, 5454–5460. doi:10.1002/chem.200903484
    Return to citation in text: [1]
  32. Ferrier, R. J.; Zubkov, O. A. Org. React. 2003, 569–736. doi:10.1002/0471264180.or062.04
    Return to citation in text: [1]
  33. Gupta, P.; Kumari, N.; Agarwal, A.; Vankar, Y. D. Org. Biomol. Chem. 2008, 6, 3948. doi:10.1039/b810654a
    Return to citation in text: [1] [2]
  34. Varela, O.; de Fina, G. M.; de Lederkremer, R. M. Carbohydr. Res. 1987, 167, 187–196. doi:10.1016/0008-6215(87)80278-1
    Return to citation in text: [1]
  35. De Fina, G. M.; Varela, O.; de Lederkremer, R. M. Synthesis 1988, 891–893. doi:10.1055/s-1988-27741
    Return to citation in text: [1]
  36. Hanessian, S.; Faucher, A.-M.; Léger, S. Tetrahedron 1990, 46, 231–243. doi:10.1016/s0040-4020(01)97595-7
    Return to citation in text: [1]
  37. Isobe, M.; Ichikawa, Y.; Masaki, H.; Goto, T. Tetrahedron Lett. 1984, 25, 3607–3610. doi:10.1016/s0040-4039(01)91087-1
    Return to citation in text: [1]
  38. Isobe, M.; Ichikawa, Y.; Goto, T. Tetrahedron Lett. 1985, 26, 5199–5202. doi:10.1016/s0040-4039(00)98902-0
    Return to citation in text: [1]
  39. Ichikawa, Y.; Isobe, M.; Masaki, H.; Kawai, T.; Goto, T. Tetrahedron 1987, 43, 4759–4766. doi:10.1016/s0040-4020(01)86917-9
    Return to citation in text: [1]
  40. Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 2103–2112. doi:10.1021/jo00270a019
    Return to citation in text: [1]
Other Beilstein-Institut Open Science Activities