Glycosyl carbodiimides

This method is also used in the synthesis of and labeled EDC, which is obtained in 57 % yield. Symmetrical and unsymmetrical glycosyl carbodiimides are also obtained in good yields in the desulfurization of the corresponding thioureas with HgO. Bis-Boc-carbodiimide is obtained similarly as an intermediate in the reaction of N,N -di (t-butoxycarbonyl)thiourea with primary amines in the presence of EtsN in DMF. " ... 

Symmetrical glycosyl cyanamides are obtained from symmetrical glycosyl carbodiimides on treatment with SnCU-... 

In an extension beyond hetaryl onium salt promoted hemiacetal activation, Ishido and coworkers have reported the carbodiimide activation of hemiacetals [141]. In the method (Scheme 3.13), the hemiacetal donor 1 is treated with a carbodiimide electrophile 83 and copper(I) chloride to provide glycosyl isourea intermediate 85. Highly susceptible to hydrolysis, the isourea 85 was not isolated but could be detected by 13C NMR and IR spectroscopy [142,143], Accordingly, the reaction between intermediate 85 and the glycosyl acceptor (NuH) provides glycoside product 3, along with urea by-product 84. 

A typical procedure calls for reaction of the hemiacetal donor with dicydohexyl carbodiimide and copper(I) chloride (0.1 equiv) at 80 °C, followed by an addition of the acceptor and continued heating. As an early demonstration of this protocol, oc-riboside 86 was prepared in moderate yield but with exclusive stereoselectivity [141]. Further measures were required for the glycosylation of monosaccharide acceptors, such as addition of p-toluenesulfonic add (0.1 equiv) to promote the formation of disaccharide 87 [144]. The method was more suitably applied to the synthesis of O-acyl glycopeptides, as evidenced by the formation of 88 in 60% yield [143,144]. Various peptides with non-nudeophilic side chains were found to be amenable to this stereoselective reaction. The [3-selectivity was suggested to arise from a preponderance of the a-isourea intermediate 85 in the activation step. 

Representative Procedure for Carbodiimide Promoted Glycosylation with Cl-Hemiacetal Donors [144]... 

Photochemical a-addition of a nitrene to 1-isocyano sugars leads to the carbodiimide which adds water yielding glycosylurea or malonic acid to form potential glycosyl-barbiturate synthons [57] (Scheme 29). 

Hemiacetals can be activated for glycosylations by reaction with carbodiimides via glycosyl isourea intermediates and different aryl glycosides were prepared this way [432]. 

Af-(D-Biotinyl)-0-(3,4,6-tri-0-acetyl-2-azido-2-deoxy-a-D-galactopyranosyl)-L-threonine te/t-Butyl Ester 23 [34], A mixture of D-biotin (150 mg, 0.6 mmol), l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC 580 mg, 3 mmol), and 1-hydroxy-benzotriazole (HOBt 540 mg, 4 mmol) in dimethylformamide (DMF 2 mL) is stirred under exclusion of moisture at 22 C. After 45 min, the biotin is dissolved, and a solution of freshly prepared glycosyl threonine ester 22 (0.3 mmol, preceding procedure) in dichloro-methane (2 mL) is added at 0°C. After stirring for 16 h at room temperature, the solvent is evaporated in vacuo, the remainder dissolved in dichloromethane (50 mL), extracted with ice-cold 0.2 N HCl (3 x 25 mL), water (25 mL), and saturated NaHCOj solution (2 x 25 mL), dried with MgSO, and concentrated in vacuo. Purification by flash chromatography on silica gel (20 g) in dichloromethane-ethanol (25 1) yields 23 200 mg (93%) [a] 96.5° (c 1, CHClj) Rf 0.29 (toluene-acetone 4 1). 

Different coupling conditions have been employed to incorporate protected glycosylated amino acids on the solid phase. Carbodiimides (e.g., DCC Fig. 6, 16) with 1-hydroxybenzotriazole (HOBt) (Fig. 6, 17) used as an auxiliary agent have been extensively employed for in situ activation of protected glycosylated amino acids in solid-phase synthesis [24-27,32,34,49,63,67]. Other coupling agents such as BOP (Fig. 6,18) [51,] BOP-HOBt (1 1) [31], TBTU (Fig. 6, 19) [17,28,54] (Fig. 6, 20) [23], PyBOP (Fig. 6, 21) [53], and PfPyU (Fig. 6, 22) [19] in the presence of A -A -diisopropylethylamine or A/ -methylmorpholine have also been used to activate the carboxyl function of protected glycoamino acids. 

Photochemical addition of a nitrene to the isonitrile (6) led to the carbodiimide (7), which added water to give urea (8) and malonic acid to give the potential glycosyl barbiturate synthon (9)... 

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