Job/Unit: O50001 /KAP1 Date: 25-02-15 14:36:47 Pages: 7
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, glycosylureas, and N-glycosyl imidazoles, as well as carbohydrate-based γ-lactams. 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). Substituted glycosyl triazoles have also been tested for their antidiabetic properties, whereas substituted benzotriazole 3 has been used as a protecting group for the anomeric center. N-glycosyl imidazole 4 has also been synthesized to study what has been defined as the reverse anomeric effect.
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. Glycosylamides have also been prepared by reaction of glycosylamines with carboxylic acids, and by reaction of acyl glycosyl isothiocyanates with carboxylic acids catalyzed by triethylamine. Several methods exist for the chemical synthesis [a] Department of Chemistry, Farmingdale State College-SUNY, 2350 Broadhollow Rd, Farmingdale, NY 11735, USA
E-mail: email@example.com 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.Common procedures include acid-catalyzed condensation reactions of glucose with urea, coupling of isocyanates with nucleophilic amines, and a method developed by Nguyen and co-workers that uses glucal trichloroacetamides as starting materials. The synthesis of N-glycosyl imidazoles through palladium-catalyzed decarboxylative allylation reaction with a glucal as the starting material has been recently published. “Click” chemistry has been used to prepare anomeric triazoles by
CuI-catalyzed reaction of glycosyl azides with alkynes.
For the preparation of benzotriazole, glycosyl azide is treated with benzyne instead. 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, amino acids, and alcohols 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).