The first total synthesis of amino sugar antibiotic glycocinnasperimicin D (1) has been achieved by a convergent, three-component coupling strategy. The key steps involve the Heck-Mizoroki reaction by using the iodophenyl glycoside 50 and acryl amide 32 to furnish the right core structure of 1, and the construction of the urea glycoside employing the reaction of glycosyl isocyanate 8 with amino sugar 9. Glycosyl isocyanate 8 was prepared by the oxidation of isonitrile 10, which displayed excellent reactivity in the coupling event. Synthetic roadblocks, encountered during this synthetic effort, have led to the development of the alpha-selective, Lewis acid catalyzed phenyl glycosylation process with 2-amino-hexopyranose and a procedure for acetonide deprotection without affecting the silyl ethers.
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 ...
A method for the protecting group free synthesis of β-urea-linked glycoconjugates has been developed. The one step process, involving reactions between urea and D-glucose, N-acetyl-D-glucosamine or D-xylose in acidic aqueous solution, furnishes the corresponding β-urea glycosides in modest yields. This simple and efficient procedure is applicable to the synthesis of β-urea tethered amino acid-carbohydrate conjugates.
Protecting Group Free Synthesis of Urea-Linked Glycoconjugates: Efficient Synthesis of -Urea Glycosides in Aqueous Solution. -The title method is applicable to the synthesis of -urea tethered amino acid-carbohydrate conjugates, such as (IX). -(ICHIKAWA*, Y.; MINAMI, T.; KUSABA, S.; SAEKI, N.; TONEGAWA, Y.; TOMITA, Y.; NAKANO, K.; KOTSUKI, H.; MASUDA, T.; Org. Biomol. Chem. 12 (2014) 23, 3924-3931, http://dx.doi.org/10.1039/c3ob42452a ; Fac. Sci., Kochi Univ., Akebono, Kochi 780, Japan; Eng.) -M. Paetzel 45-219
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