A Practical Synthesis of Various 2-Deoxy- N -glycosides by Using D -GlucalEuropean Journal of Organic Chemistry


Terence J. Meyerhoefer, Sonia Kershaw, Nadia Caliendo, Sumeia Eltayeb, Emi Hanawa-Romero, Polina Bykovskaya, Victor Huang, Cecilia H. Marzabadi, Michael De Castro
Physical and Theoretical Chemistry / Organic Chemistry


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Job/Unit: O50001 /KAP1 Date: 25-02-15 14:36:47 Pages: 7


DOI: 10.1002/ejoc.201500001

A Practical Synthesis of Various 2-Deoxy-N-glycosides by Using D-Glucal

Terence J. Meyerhoefer,[a] Sonia Kershaw,[a] Nadia Caliendo,[a] Sumeia Eltayeb,[b]

Emi Hanawa-Romero,[b] Polina Bykovskaya,[a] Victor Huang,[a] Cecilia H. Marzabadi,[b] and

Michael De Castro*[a]

Keywords: Synthetic methods / Biological activity / Carbohydrates / Glycosides / Glycal

We herein report the synthesis of 2-deoxy-2-iodo-glycosylamides, glycosylurea, N-glycosylbenzotriazole, and Nglycosyl imidazole by addition reaction of trimethylsilyl amides, imidazoles, and benzotriazoles to D-glucal in the presence of N-iodosuccinimide and propionitrile at 0 °C. Two diastereomers were isolated  the α-mannose and β-gluco isomers. Reduction and substitution reaction of the iodine at


The development of new methods for the chemical synthesis of N-glycosides has attracted considerable attention because of the important role they play in carbohydrate chemistry. This includes: glycosylamides,[1] glycosylureas,[2] and N-glycosyl imidazoles,[3] as well as carbohydrate-based γ-lactams.[4] For example, glycosylamide 1 and glycosylurea 2 are potent inhibitors of glycogen phosphorylase  a regulatory enzyme of glycogen metabolism that is targeted to combat noninsulin-dependent or type 2 diabetes (Figure 1).[5] Substituted glycosyl triazoles have also been tested for their antidiabetic properties,[6] whereas substituted benzotriazole 3 has been used as a protecting group for the anomeric center.[7] N-glycosyl imidazole 4 has also been synthesized to study what has been defined as the reverse anomeric effect.[8]

The synthesis of glycosylamides and glycosylureas can be a challenging task because a mixture of α/β anomers is often obtained. Glycosylamides (α-glycosylamides) have been prepared by using a traceless Staundinger ligation with diphenylphosphanyl-phenyl ethers.[9] Glycosylamides have also been prepared by reaction of glycosylamines with carboxylic acids,[10] and by reaction of acyl glycosyl isothiocyanates with carboxylic acids catalyzed by triethylamine.[11] Several methods exist for the chemical synthesis [a] Department of Chemistry, Farmingdale State College-SUNY, 2350 Broadhollow Rd, Farmingdale, NY 11735, USA

E-mail: decastm@farmingdale.edu www.farmingdale.edu/academics/arts-sciences/chemistry/faculty-staff.shtml [b] Department of Chemistry and Biochemistry, Seton Hall

University, 400 South Orange Ave, South Orange, NJ 08079, USA

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201500001.

Eur. J. Org. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 position C-2 led to formation of various 2-deoxy-N-glycosides and 2-hydroxy-β-D-glucopyranosylamide. The newly generated compounds were screened for their inhibitory activity against various enzymes that included Nav1.7 sodium ion voltage-gated channel in HEK293 cells and the results are discussed.

Figure 1. Carbohydrate based N-glycosides. of glycosylureas.[12]Common procedures include acid-catalyzed condensation reactions of glucose with urea,[13] coupling of isocyanates with nucleophilic amines,[14] and a method developed by Nguyen and co-workers that uses glucal trichloroacetamides as starting materials.[15] The synthesis of N-glycosyl imidazoles through palladium-catalyzed decarboxylative allylation reaction with a glucal as the starting material has been recently published.[16] “Click” chemistry has been used to prepare anomeric triazoles by

CuI-catalyzed reaction of glycosyl azides with alkynes.[17]

For the preparation of benzotriazole, glycosyl azide is treated with benzyne instead.[18] Because of the various roles that such compounds play in carbohydrate chemistry, there remains a need to develop new methods for synthesizing glycosylamides and their analogues.

This study focuses on the development of an alternative method for the synthesis of the compounds shown in Figure 1 by using glucal as a single starting material and the corresponding commercially available trimethylsilylamide/ urea and N-heterocycles, respectively. We are also interested in the preparation of 2-deoxy-N-glycoside analogs as well.

Job/Unit: O50001 /KAP1 Date: 25-02-15 14:36:47 Pages: 7

M. De Castro et al.FULL PAPER

Scheme 1. Preparation of various N-glycosides from glycal precursors.

We hoped to accomplish this by using a series of 2-deoxy2-iodo-N-glycosides as precursors.

In this paper we describe the synthesis of 2-deoxy-2iodo-glycosylamides, glycosylurea, imidazole, benzotriazole, and glycosidic γ-lactam through nucleophilic addition reaction of various N-trimethylsilyl reagents to dglucal in the presence of N-iodosuccinimide (NIS). Trimethylsilylacetamide and related compounds are commonly used in the formation of silyl ethers in the derivatization of carbohydrates,[19] amino acids,[20] and alcohols[21] for GC analysis. Gin and co-workers have developed a one-pot synthesis of 2-deoxy-2-acetamido disaccharides that is particularly relevant to the work described here with respect to the use of trimethylsilylacetamide.[22,23]Hence, trimethylsilylacetamide, N,O-Bis(trimethylsilyl)acetamide, 1-(trimethylsilyl)imizadole, 1-(trimethylsilyl)-1H-benzotriazole, N,NBis (trimethylsilyl)urea, and 1-(trimethylsilyl)-2-pyrrolidinone were treated with tri-O-benzyl-d-glucal and tri-Omethyl-d-glucal in the presence of NIS and propionitrile at 0 °C (Scheme 1). Newly prepared 2-deoxy-2-iodo-glycosylamides 6 were treated with silver triflate (AgOTf) in the presence of a 1:1 mixture of water and acetonitrile to afford

N-(3,4,6-tri-O-benzyl-2-hydroxy-β-d-glucopyranosyl)-2pyrrolidinone 8 only (Scheme 1). Access to 2-deoxy-Nglycosides 7 was accomplished by using tributyltin hydride and azobisisobutyronitrile (AIBN) (Scheme 1).

Results and Discussion

Our work began with the preparation of 2-deoxy-2-iodoglycosylamides 6 (Scheme 2).