Facile access to C-glycosyl amino acids and peptides via Ni-catalyzed reductive hydroglycosylation of alkynes

Abstract

C-Glycosyl peptides/proteins are metabolically stable mimics of the native glycopeptides/proteins bearing O/N-glycosidic linkages, and are thus of great therapeutical potential. Herein, we disclose a protocol for the syntheses of vinyl C-glycosyl amino acids and peptides, employing a nickel-catalyzed reductive hydroglycosylation reaction of alkyne derivatives of amino acids and peptides with common glycosyl bromides. It accommodates a wide scope of the coupling partners, including complex oligosaccharide and peptide substrates. The resultant vinyl C-glycosyl amino acids and peptides, which bear common O/N-protecting groups, are amenable to further transformations, including elongation of the peptide and saccharide chains.

Catalytic Multicomponent Synthesis ofC‐Acyl Glycosides by Consecutive Cross‐Electrophile Couplings

“…The resulting products may be further transformed to an assortment of useful C ‐glycopeptides through established routes (see Scheme 1A). These examples illustrate the potential viability of the method in site‐specific peptide functionalization to modify biologically active proteins or develop carbohydrate‐based peptidomimetics [37, 64–69] …”

Recent Advances in the Development and Synthesis of Carbohydrate‐Based Molecules with Promising Antibacterial Activity

“…[68] Indeed, given their lower susceptibility to chemical and enzymatic hydrolysis by endogenous glycosidases, [69,70] many C-glycosides with promising therapeutic potential have been synthesized over the past few years in the hope of achieving compounds with enhanced bioactivity and improved chemical and enzymatic stability, as well as improved target selectivity and drug-like profile compared with their corresponding O-glycosides or aglycones, [7][8][9]13,25,71,72] despite being generally much more challenging to prepare. [73][74][75] From all the compounds synthesized by Janetka and coworkers, compounds 65 and 66 (Scheme 8) were among the best in inhibiting FimH adhesive function (EC 90 0.031 μM and 0.006 μM, respectively) in an assay using uropathogenic E. coli Scheme 8. Synthetic route towards C-mannosides 65 and 66, published by Janetka and co-workers.…”

“…The physicochemical and pharmacokinetic parameters measured for this therapeutic lead were greatly improved compared to the original unsubstituted compound, furthermore pointing towards good oral availability. [75] Regarding its synthesis, 71 was prepared from the commercially available peraceylated α-d-mannose (72) as the glycosyl donor for the O-glycosylation of 2-chloro-4-iodophenol promoted by BF 3 •OEt 2 , [79] affording intermediate 73 in 76 % yield (Scheme 9). Next, a copper iodide-mediated and microwaveassisted aromatic coupling reaction with 2,3,5,6-tetrafluorobenzonitrile gave the acetyl-protected mannoside 74 in 66 % yield.…”

“…In 2016, Janetka and co‐workers rationally designed and synthesized a series of aromatic C‐ α‐ d ‐mannosides with improved stability and overall pharmacokinetic properties due to the O → C bioisosteric replacement in the anomeric position [68] . Indeed, given their lower susceptibility to chemical and enzymatic hydrolysis by endogenous glycosidases, [69,70] many C ‐glycosides with promising therapeutic potential have been synthesized over the past few years in the hope of achieving compounds with enhanced bioactivity and improved chemical and enzymatic stability, as well as improved target selectivity and drug‐like profile compared with their corresponding O ‐glycosides or aglycones, [7–9,13,25,71,72] despite being generally much more challenging to prepare [73–75] …”

Catalytic Multicomponent Synthesis ofC‐Acyl Glycosides by Consecutive Cross‐Electrophile Couplings

“…These examples illustrate the potential viability of the method in site-specific peptide functionalization to modify biologically active proteins or develop carbohydrate-based peptidomimetics. [37,[64][65][66][67][68][69] Access to metabolically stable mimics of naturally occurring saccharides [70][71][72] can also be realized using multicomponent cross-coupling as a key step. Preparation of architecturally sophisticated (1!2)-linked C-glycosidic ketodisaccharides [69][70][71][72] was attained by reacting glycosyl chlorides and isobutyl chloroformate with sugar-derived alkenyl iodides (Table 3B).…”