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Pure and Applied Chemistry

The Scientific Journal of IUPAC

Ed. by Burrows, Hugh / Stohner, Jürgen

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Volume 86, Issue 3


Stereoselective C-glycosylation of furanosyl halides with arylzinc reagents

Sébastien Lemaire
  • Corresponding author
  • Janssen Pharmaceutica, API Small Molecule Development, Turnhoutseweg 30, 2340 Beerse, Belgium
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/ Amandine Xolin
  • Janssen Pharmaceutica, API Small Molecule Development, Turnhoutseweg 30, 2340 Beerse, Belgium
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/ Charlotte Gozlan
  • Janssen Pharmaceutica, API Small Molecule Development, Turnhoutseweg 30, 2340 Beerse, Belgium
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/ Vittorio Farina
  • Janssen Pharmaceutica, API Small Molecule Development, Turnhoutseweg 30, 2340 Beerse, Belgium
  • Other articles by this author:
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Published Online: 2014-03-04 | DOI: https://doi.org/10.1515/pac-2013-1029


Were are reporting a highly diastereoselective, transition-metal-free approach of C-aryl glycosides in the pyranoside and furanoside series by the direct coupling of glycosyl halides with diarylzinc reagents in a toluene/di-n-butyl ether solvent mixture.

Keywords: C–C bond formation; C-glycosylation; OMCOS-17; organometallic chemistry; solvent effects; zinc


C-Glycosides are attractive skeletons for the medicinal chemist because they are more resistant to enzymatic hydrolysis than O-glycosides, and therefore are considered potential drug candidates [1]. Especially important is the new class of SGLT-2 inhibitors, used for the treatment of type 2 diabetes, which includes, i.a., Canagliflozin, Dapagliflozin, Ipragloflozin, Empagliflozin [2]. To complement the classical synthesis of C-glycosides from sugar lactones, the direct and highly diastereoselective arylation of furanosyl and pyranosyl halides is highly desirable and efforts in this direction have been recently reported [3]. For example, Gagné and Cossy have developed a direct C-glycosylation in presence of transition-metal catalysts.

The elegant solution reported by Gagné describes a Ni-catalyzed coupling of organozinc reagents with glycosyl bromides (Scheme 1). The coupling product phenyl tetreaacetylglucosyl 2 is obtained with good stereoselectivity (α/β ratio of 1:12). For the mannoside derivative, the α isomer is obtained as major product (α/β ratio of 20:1). The reaction was shown to proceed via a radical pathway, where “catalyst control” dictates the α/β ratio at the anomeric center. More recently, Cossy has demonstrated efficient C-glycosylation with Co(aca)3/tmeda in presence of Grignard reagents. High diastereoselectivity for the α isomer is obtained in presence of the tetraacetylmannosyl bromide substrates. Nevertheless starting from tetraacetyl glycosyl bromide, an average selectivity of 3/1 is obtained in favor of the α isomer. The Cossy methodology is a good complementar to the Gagné work in the case of the glucose derivative. While these methods give excellent selectivities, a transition metal free method was pursued in our laboratories for large scale production purposes.

Transition-metal catalyst C-glycosylation.
Scheme 1

Transition-metal catalyst C-glycosylation.

We herein report the development of a transition-metal-free C-glycosylation. Our method employs diarylzinc reagents and glycosyl bromides in a toluene/di-n-butyl ether solvent mixture, which provide C-glycosides with excellent stereoselectivity [4]. The selectivity is explained by anchimeric assistance of the neighboring pivaloyl group (Scheme 2).

Diastereoselective arylation of glucosyl bromides.
Scheme 2

Diastereoselective arylation of glucosyl bromides.

Coupling reactions of arylzinc reagents with pyranosyl bromides

We have developed a simple protocol for the coupling of glycosyl bromides with aryzinc species. Upon lithiation of the arene or aryl halide in toluene and transmetalation with ZnBr2.LiBr, the pivaloyl-protected bromo sugar 1 is added to the reaction mixture. Metalation can also be achieved with a magnesate species or n-butyllithium, which then smoothly transmetalates to the arylzinc species. The judicious choice of solvents is critical, as many ethereal co-solvents (especially THF) proved incompatible with these coupling conditions. Upon heating, the desired β-C-glycoside product is produced as a single diastereoisomer in good yield (Scheme 3). With para-substituted aryl derivatives bearing electron-donating substituents (2a–2d), fair to good yields are obtained. Yields are affected negatively by electron-withdrawing groups (2e, 2f) even at elevated temperatures (>100 °C). Ortho-substitution is well tolerated and the formation of coupled products (2g–2i) proceeds in fair to good yields. Heteroaryl species such as thienyl- (2j) and furylzinc (2k) are also successfully coupled. Interestingly, pyridylzinc species do not couple under our conditions.

Scope of the arylation of glucosyl bromide (with isolated yield and coupling temp.).
Scheme 3

Scope of the arylation of glucosyl bromide (with isolated yield and coupling temp.).

Coupling reactions of arylzinc reagents with furanosyl chlorides

In order to extend the methodology to other important carbohydrate derivatives, we have applied our methodology to the formation of C-furanosides. Direct C-arylation methodologies of C-furanosides are better established than those leading to C-pyranosides. Various organometallic species such as Grignard reagents [5], arylzinc species [6], aryl aluminates [7], silyl enol ethers [8] have all proven to be somewhat effective, and intramolecular rearrangement of O- to C-glycosides [9] has also been reported. In the case of the arylzinc species, while diastereoselectivity is consistently good (usually >20:1), the yields are often poor [3a, 6], primarily due to the competitive hydrolysis of the furanoside halides [3a]. Very recently, Cossy’s cobalt catalyzed system was demonstrated to be highly effective toward C-glycosylation of furanoside halides providing products in good yields and distereoselectivities >1/9 [10].

Armed with our experience in the pyranoside series, we have extended the methodology to aryl furanosides. All attempts at preparing furanoside bromide derivatives failed due to the modest stability of the halogenated products. To our delight, the chloro derivatives 3 proved excellent partners in the coupling reaction. Our C-glycosylation methodology in the toluene/di-n-butyl ether solvent mixture proved quite general. Furanosyl chlorides exhibit higher reactivity than the pyranoside halides, and the reaction proceeded best at lower temperature, typically at 60 °C, yielding the desired C-furanosides in fair to good yields (Scheme 4).

Coupling with furanosyl chlorides.
Scheme 4

Coupling with furanosyl chlorides.

In all cases, the desired C-furanoside was detected as a single diastereoisomer, with the aryl group delivered anti to the neighboring ester group. The chloro derivative 3a afforded the β isomer in good yields, the best yields observed with electron-rich aryl groups (4a–c). The chloroaryl derivative 4d was detected only in traces by LC-MS. In this case, the degradation of furanosyl chloride 3a is apparently faster than the coupling reaction. Replacement of pivalate protecting groups with benzoates (3c) negatively affects the yield (4e, 52 %). The arabinosyl chloride 3b affords a good yield (4f) of the α-C-glycoside.

Coupling reactions of alkynylzinc reagents

Finally, to expand the range of useful nucleophiles, alkynylzinc reagents were subjected to the reaction conditions (Scheme 5) [11]. To our surprise, the bicyclic species 5a was isolated in 79 % yield as a single diastereoisomer, both with the furanosyl chloride 3a and with the glucosyl bromide 1.

Coupling with alkynylzinc derivatives.
Scheme 5

Coupling with alkynylzinc derivatives.

This result suggests that the size of the nucleophile is a determining parameter for site selectivity. The formation of these compounds indirectly supports the proposed anchimeric assistance mechanism which governs the high anti-selectivity of the C-glycosylation in presence of diaryl zinc reagents (Scheme 1).


In conclusion, we have developed an efficient and stereoselective coupling of arylzinc derivatives with both pyranosyl and furanosyl halides [12]. The steric and electronic effects relative to the aryl component were studied, and indirect evidence for an ionic mechanism involving anchimeric participation was provided. It is important to note that the success of this methodology is due to the use of a solvent mixture that includes an apolar solvent with small amount of an ether co-solvent. The ethereal solvent of choice is di-n-butyl ether. We are currently exploring the extension of this methodology to other organozinc derivatives and carbohydrate substrates of biological interest, and these results will be reported in due course.


  • [1]

    (a) T. Bililign, B. R. Griffith, J. S. Thorson. Nat. Prod. Rev. 22, 742 (2005); (b) W. C. Simons. Synthesis 17, 1533 (2004); (c) J. Stanbasky, M. Hocek, P. Kosovsky. Chem. Rev. 109, 6729 (2009).CrossrefGoogle Scholar

  • [2]

    E. C. Chao, R. R. Henry. Nature 9, 537 (2010).Google Scholar

  • [3]

    (a) H. Gong, M. R. Gagné. J. Am. Chem. Soc. 130, 12177 (2008); (b) L. Nicholas, P. Angibaud, I. Stansfield, P. Bonnet, L. Meerpoel, S. Reymond, J. Cossy. Angew. Chem. Int. Ed. 51, 11101 (2012).Google Scholar

  • [4]

    S. Lemaire, I. N. Houpis, T. Xiao, J. Li, E. Digard, C. Gozlan, R. Liu, A. Gavryushin, C. Diene, Y. Wang, V. Farina, P. Knochel. Org. Lett. 14, 1480 (2012).Google Scholar

  • [5]

    M. Cai, S. Peng, L. Li, D. Chen. Acta Chim. Sin. 43, 645 (1985); M. Yokoyama, H. Toyoshima, M. Shimizu, J. Mito, H. Togo. Synthesis 12, 409 (1998).Google Scholar

  • [6]

    N. C. Chaudhuri, E. T. Kool. Tetrahedron Lett. 36, 1795 (1995).Google Scholar

  • [7]

    G. H. Posner, S. R. Haines. Tetrahedron Lett. 26, 1823 (1985); S. J. F. Macdonald, W. B. Huizinga, T. C. McKenzie. J. Org. Chem. 53, 3373 (1988).CrossrefGoogle Scholar

  • [8]

    Y. Araki, N. Kobayashi, S. Hishido, J. Nagasawa. Carbohydr. Res. 171, 125 (1971).Google Scholar

  • [9]

    T. Matsumoto, M. Katsuki, K. Suzuki. Tetrahedron Lett. 29, 6935 (1988); T. Matsumoto, T. Hosoya, K. Suzuki. Synlett 12, 709, (1991).CrossrefGoogle Scholar

  • [10]

    L. Nicolas, E. Izquierdo, P. Angibaud, I. Stansfield, L. Meerpoel, S. Reymond, J. Cossy. J. Org. Chem. 78, 11807 (2013).CrossrefGoogle Scholar

  • [11]

    D. Zhai, W. Zhai, R. M. Williams. J. Am. Chem. Soc. 110, 2501 (1988).Google Scholar

  • [12]

    General procedure: In a Schlenk tube with magnetic stirring, the halogenated derivative (1.1eq.) is dissolved in dry toluene (8 mL/g) under N2. After cooling to 0 °C, (Bu)3MgLi (0.38eq.) is added dropwise. After complete conversion (one night), ZnBr2-LiBr (0.61eq, 25 % in DBE) is added dropwise at 0° C. The halogenated pyranoside (1eq.) is added in one portion and the reaction mixture is heated to 90 °C, or the chlorinated furanoside (1eq.) is added dropwise to the reaction mixture at 60 °C. After complete conversion, the reaction mixture is quenched with NH4Cl (33 w/w%, 4 mL/g) at 50 °C, the two layers are separated and the solvent is evaporated under reduced pressure at 30 °C.Google Scholar

Article note

A collection of invited papers based on presentations at the 17th International IUPAC Conference on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS-17), Fort Collins, Colorado, USA, 28 July–1 August, 2013.

About the article

Corresponding author: Sébastien Lemaire, Janssen Pharmaceutica, API Small Molecule Development, Turnhoutseweg 30, 2340 Beerse, Belgium, e-mail: slemaire@ist.jnj.com

Published Online: 2014-03-04

Published in Print: 2014-03-20

Citation Information: Pure and Applied Chemistry, Volume 86, Issue 3, Pages 329–333, ISSN (Online) 1365-3075, ISSN (Print) 0033-4545, DOI: https://doi.org/10.1515/pac-2013-1029.

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