Current Organic Chemistry, 2008, 12, 1071-1092 1071 1385-2728/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Synthetic Approaches to Carbohydrate-Based Ureas Pietro Spanu* and Fausta Ulgheri Istituto di Chimica Biomolecolare del Consiglio Nazionale delle Ricerche, Trav. La Crucca 3, 07040, Sassari, Italy Abstract: The last decade has witnessed an increasing interest in sugar urea derivatives because of their biological prop- erties. Consequently, new synthetic procedures that explore reactivity differences of the sugar units for the synthesis of molecules bearing urea moiety linked to sugars architecture, have been investigated. The main routes involve isocyanate species, also obtained from the oxidation of isocyanides, by direct reaction with amines or aminosugars or more recently by aza-Wittig reaction with sugar-derived phosphinimines. Other important strategies are based on the reaction of sugar- derived oxazolidinones and carbamates with amines, and modified Curtius rearrangement of sugar carboxylic acids or re- action of sugar-derived phosphinimines with carbon dioxide and amines. This review provides a comprehensive survey of synthetic approach to carbohydrate-based ureas with a focus on the recent procedures. 1. INTRODUCTION In the last decade urea and its derivatives have received a great deal of attention because of their significant chemical and biological properties [1]. In the carbohydrate field some glycosylureas aroused interest around the 80 th years when glycocinnamoylspermidines pseudooligosaccharides incor- porating an urea–glycosyl linkage [2] or ureido monosaccha- rides as CV-1 and N-carbamoylglucosamine SF-1993 [3] have shown antibiotic activity. Recently, several ureido monosaccharides have been syn- thesised and have shown a widely spectra of new and sig- nificant biological properties as inhibitors of glycosidase [4], ligases distinguishing between NAD + and ATP-dependent ligases [5], filarial glutathione-S-transferases [6], glycogen phosphorylase [7], and finally Trypanosoma Burcei hexose transporter [8]. Furthermore, the interest in the synthesis of new molecules based on sugar ureas architecture arises also from the possibility to use urea linkage to anchor carbohy- drate moieties into biomolecules via nonnative glycosidic linkages. Recent publications report the synthesis of new urea-tethered neoglycoconjugates and pseudooligosaccha- rides based on this alternative method of glycosylation. The increasing interest, derived from the wide biological poten- tial of sugar ureas, has stimulated chemists to find new syn- thetic strategies that, although relatively scarce so far, show Address correspondence to this author at the Istituto di Chimica Biomoleco- lare del CNR, Trav. La Crucca 3, 07040, Sassari, Italy; Tel: +39 079 3961033; Fax +39 079 3961036; E-mail: p.spanu@icb.cnr.it an increasing trend. We present here a first comprehensive treatment of this topic with a focus on recent approaches to sugar ureas synthesis [9]. Over the last few years the synthesis of carbohydrate- based ureas are mainly based on the condensation of sugar- derived isocyanates, with amines or on the reaction of ami- nosugars with alkyl- or aryl isocyanates [10]. Other strate- gies involve hydrolysis of sugar-derived carbodiimides, con- densation of sugar-derived oxazolidinones and carbamates with amines, oxidation of sugar-derived isocyanides and their reaction with amines, modified Curtius rearrangement of sugar carboxylic acids, and reaction of sugar-derived phosphinimines with carbon dioxide and amines. These topics represent the principal sections of the present review, and within each section we have organized them depending on the monosaccharides, polysaccharides and glyco- conjugates sugar urea synthesised. While cyclic ureas linked to a carbohydrate but not directly involved in a bicyclic sugar architecture as well as all the simple transformations of sugar-thio ureas into sugar ureas have been excluded from this review. 2. SYNTHESIS OF UREIDO SUGARS BY REACTION OF AMINOSUGARS WITH ALKYL- AND ARLYL ISOCYANATES The first studies on the synthesis of sugar ureas exploit- ing the direct reaction of amino-deoxysugars with isocyantes started in the early twentieth century [11]. While readily available unprotected 1-amino-glycopyranosyl derivatives 1 were reported to react with alkyl- and aryl isocyanates in anhydrous pyridine to furnish in good yield the correspond- ing N-glycopyranosyl-N'-alkyl ureas 2 (Scheme 1) [12], di- rect coupling of unprotected 2-amino-2-deoxy-glycopy- ranose with isocyanates does not lead to the corresponding 2-ureido-2-deoxy-pyranose [12, 13]. Alternatively, 2-ureido- 2-deoxy-D-glucopyranose can be obtained in low yield from the reaction of the protected per-O-acetyl-2-amino-2-deoxy- or -D-glucopyranose hydrohalides 3 with silver cyanate [13b, 14] or alkyl(aryl) isocyanates [13b-d,13f,15] followed by deprotection. Fig. (1). Glycocinnaspermicin D O HO NH OH H N H N O NH 2 O HN O CH 3 HO NH 2 NH O N H O NH H 2 N