Directed Nickel‐Catalyzed pseudo‐Anomeric C−H Alkynylation of Glycals as an Approach towards C‐Glycoconjugate Synthesis

Abstract

The synthesis of complex C‐glycoconjugates is presented here using a key directed nickel‐catalyzed C−H alkynylation step. Thanks to a bidentate amidoquinoline‐type directing group, the insertion of diverse alkynyl moieties onto the pseudo‐anomeric position of glycal substrates was performed on ten examples in moderate to good yields. These platforms were used as starting substrates in a click reaction with complex azides to form original C‐glycoconjugates. By this route, a C‐glycosylated amino acid, a C‐linked disaccharide and a C‐glycosylated biotin derivative were synthesized. Preliminary conditions to remove the directing group are also proposed.

Directed Palladium‐Catalyzed pseudo‐Anomeric C−H Functionalization of Glycal‐Type Substrates: Access to Unsymmetrical gem‐Diarylmethyl C‐Glycosides

“…To switch the reactivity to directed C1 position of glycal substrates, In 1989, Schmidt and co‐workers reported C ‐glucosides by direct 1‐ C ‐lithiation of 2‐phenylsulfinyl‐activated D‐glucals with aldehyde. 11a Recently, Ferry et al [11b,c] . demonstrated the C( sp 2 )−H functionalization at the anomeric position of C2‐amidoglycal leading to unsaturated C ‐aryl/alkynyl glycosides (Scheme 1b).…”

“…Moving attention toward sterically encumbered nitrogen‐containing amide, we performed preliminary protection of 4 a by a tert ‐butoxycarbonyl group to leverage the reactivity towards nucleophilic cleavage. Finally, transamidation [11c,18] of Boc‐protected compound 11 via treatment with pyrrolidine (1.5 equiv.) in toluene at 65 °C, accomplished the target, albeit in lower yield ( 12 , 32%) accompanied with starting material (Scheme 2).…”

Recent Advances on the Synthesis of C-Glycosides from 1,2-Glycals

“…They used the same bidentate 8-aminoquinoline (AQ) ligand as a directing group for the C–H activation of the anomeric center, enabling alkynylation at high temperature with moderate to good yields (Scheme 32 ). 78 . Some of these alkynylated C -glycosides were subjected to a click reaction leading to the formation of unique glycosylic triazoles, e.g., 82h .…”

Directed Dehydrogenative Copper‐Catalyzed C−H Thiolation in Pseudo‐Anomeric Position of Glycals using Thiol and Thiosugar Partners

“… [6c] Moreover, we proposed a few years ago that amidoquinoline‐containing glycals are suitable starting substrates for the C−H functionalization of the pseudo‐anomeric position of glycals. Palladium‐ or nickel‐catalysis has been successfully used on these substrates with aryl iodide [14] or alkynyl bromide partners [15] …”

“…Palladium-or nickel-catalysis has been successfully used on these substrates with aryl iodide [14] or alkynyl bromide partners. [15] CÀ H activation methods involving sugars have emerged very recently as a new option in the glycochemistry toolbox. [16] However, examples where the sugar is the CÀ H activated partner remain very rare due to the complexity of the sugar structure and the difficulty to target only one specified CÀ H bond.…”