An Access to Glycoconjugate Libraries through Multicomponent Reactions

Abstract

Four-component reactions: The Ugi reaction of four suitably functionalized carbohydrate derivatives (as a per-O-benzylated amine, an aldehyde, a carboxylic acid, and an isocyanide) allow the effective assembly of diverse compound libraries. The complex glycoconjugates formed can be deprotected (see the picture for an example), and the resulting glycomimetics are of high interest for screening purposes.

Cyanide-Free Synthesis of Glycosyl Carboxylic Acids and Application for the Synthesis of Scleropentaside A

“…Similarly, the oxidation of benzoyl-protected 17 and 18 with method B, synthesized in the same sequence as that for 8 , afforded 19 and 20 , respectively, in 76% and 61% yields. Importantly, the success in the synthesis of 16 and 20 showed that our strategy could be used for the synthesis of 1,2- cis glycosyl acids, thus complementing the cyanide-based strategy. − , The synthesis of 22 , the C1 diastereomer of 9 , from aryl C-glycoside 21 further strengthened the above statement. Furhermore, the reaction is also suitable for C6-deoxygenated substrates, and 24 was obtained from rhamnose-derived 23 in an 81% yield (for the syntheses of 21 and 23 , see the Supporting Information).…”

“…Glycos-1-yl (glycosyl) carboxylic acids are a lesser-known yet valuable subclass of sugar acids. For example, they can be used as coupling reagents for biological probes and for the synthesis of oligosaccharides via multicomponent reactions . They are also versatile intermediates used in C–H activation and radical reactions , for the synthesis of C -glycosides.…”

“…Glycosyl carboxylic acids are mostly synthesized from glycosyl acetates or halides via a sequence of cyanation and hydrolysis (Scheme a) . Being reliable and general on its own, unfortunately this strategy inevitably requires superstoichiometric amounts of toxic cyanide-containing reagents (e.g., TMSCN and Hg­(CN) 2 ) and catalytic mercury salts (HgX 2 ) for the cyanation step. − , In addition to the toxicity, harsh conditions are generally required for the transformation of the cyanide group to a carboxylic acid group, rendering this reaction incompatible with most of the protecting groups. − , Furthermore, because neighboring group participation determines the stereoselectivity in the cyanation step, this strategy is only suitable for the synthesis of 1,2- trans glycosyl acids. − , …”

“…Herein, we report a general cyanide-free strategy for the synthesis of glycosyl carboxylic acids (Scheme b). Complementary to the cyanide-based strategy, − , this approach can provide 1,2- trans or 1,2- cis glycosyl acids and is compatible with common protecting groups. The key steps were recently developed, i.e., stereoselective aryl C -glycosylation − and the classical Sharpless oxidation of arenes .…”

Multicomponent Approach to Homo- and Hetero-Multivalent Glycomimetics Bearing Rare Monosaccharides

“…18 Acetyl-and benzyl-protected galactoseand fucose-derived aldehydes were used in the synthesis of a focused library of monovalent sialyl Lewis X glycomimetics. 19 Lockhoff used per-O-benzylated carbohydrate building blocks for the synthesis of a glycoconjugate library, 20 while Westermann and Dorner utilized the Ugi reaction for the synthesis of multivalent aminoglycoside mimics aimed to bind to RNA targets. 21 Main advantages of MCRs for the synthesis of multivalent glycomimetics are their convergent nature, high atom economy, and control over the structural identity of products, while β-elimination of carbohydrate-derived aldehydes, observed as a side-reaction in MCRs, and partial Nacetylation of the amine components when O-acetylated components are used, 19 present main drawbacks of the multicomponent methodology.…”