Synthesis of Urea and Carbamate Glycosides Employing Unprotected Carbohydrates

Abstract

A study of methods for the synthesis of urea and carbamate glycosides, starting with unprotective carbohydrates, led to the preparation of amino acid-carbohydrate conjugates in aqueous media.The fundamental importance of glycoconjugates in a wide range of biological processes has promoted a great deal of interest in neoglycoconjugates as tools for glycobiology as well as potential therapeutic agents. 1 Our efforts in this area have focused on the synthesis of neoglycoconjugates, in which the O-and N-glycosyl linkages are replaced with urea-glycosyl bonds. 2 Our specific interest in urea-tethered neoglycoconjugates arose during the synthetic works of the amino sugar antibiotic, glycocinnasperimicin D, which possesses a urea glycoside as a key structural unit. 3 Although a number of new synthetic methods to access urea glycosides have been developed by us 4 and others 5 the existing procedures have the drawback in their low efficiency, particularly due to the length of the synthetic routes arising from extensive use of protection/deprotection sequences. In this context, we became intrigued by a classical method for the synthesis of urea glucoside 2, which involves acid-catalyzed condensation of D-glucose (1) with urea 6 (Scheme 1). This simple process is remarkable, because urea glucoside 2 is formed from protectinggroup-free D-glucose. Stimulated by the synthetic potential of this reaction as a method for urea-tethered neoglycoconjugate synthesis, we launched an investigation to extend this process to the synthesis of N-substituted urea glycosides 3.After extensive literature browsing, we found that few precedents exist for the reaction of N-substituted urea derivatives with carbohydrates. In 1926, Helferich reported the reaction of glucose with methyl-harnstoff (1-methylurea) in aqueous HCl at 50 °C for 16 days leading to the production of D-methylurea glucoside (d-glucosemonomethylurid) 7 (Scheme 2). Following this work, Erickson investigated the reaction of long-chain octadecylurea with D-glucose. 8 Although these two early reports described the synthesis of N-substituted urea glucosides, products were characterized only by melting points, elemental analyses and optical rotations. Importantly, the structures of the products of these processes have never been elucidated completely. In addition, the yields are quite low, and the stereochemistry of the products (a/b selectivity) has not been determined. Scheme 2 Classical synthesis of d-glucose-monomethylureid by HelferichOur initial efforts focused on identifying the structure of d-glucose-monomethylureid reported by Helferich. Accordingly, we synthesized an anomeric pair of 1-methyl-3-glucosylureas by employing a method we developed previously (Scheme 3). b-Glucosyl isonitrile 5, prepared from acetyl glucoside 4 in four steps, was oxidized with pyridine N-oxide and a catalytic amount of iodine in the presence of MS 3A (anhydrous conditions) to generate the glucosyl isocyanate 6. 2 Successive treatment of 6 with methylamine provided the b-1-methyl-3-glucosylurea ...

Chemoselective Reactions for the Synthesis of Glycoconjugates from Unprotected Carbohydrates

“…Messmer and co‐workers later improved this reaction by treating glucosyl azide with triphenylphosphine to form an N‐glycosyl iminophosphorane followed by treatment with CO 2 to form the desired carbohydrate oxazolidinone (Scheme A). Glycosylureas can alternatively be synthesized by acid‐catalyzed condensation of unprotected, reducing carbohydrates with primary ureas, derived from, for example, amino acids . Glycosylureas have recently attracted considerable interest for analytical identification of N‐glycans from glycoproteins.…”

“…Glycosylureasc an alternatively be synthesized by acid-catalyzed condensationo fu nprotected, reducing carbohydrates with primary ureas, derived from,f or example, amino acids. [103] Glycosylureas have recently attracted considerable interestf or analytical identification of N-glycans from glycoproteins. To this end, N-glycansc an be released enzymatically (PNGaseF)ast heir glycosylamines and treated in situ with O-succinimidyl carbamates (e.g.,c ontaining af luorescent tag) to generate stable glycosylureap roducts for analysis.…”

Regioselective modification of unprotected glycosides

“…A review 4 and recent examples can be found elsewhere. [5][6][7][8][9][10][11][12][13] Furthermore, the modification of aminoglycoside antibiotics is not covered as reviews [14][15][16] including examples of impressive selectivities 17,18 can be found elsewhere.…”

Protecting group free synthesis of urea-linked glycoconjugates: efficient synthesis of β-urea glycosides in aqueous solution

“…This effort has led to the development of a unique and efficient protecting group free method for the synthesis of urea-linked glycoconjugates. 10 …”