β-Selective One-Pot Synthesis of Acyl-C-Glycosides via Corey–Seebach Umpolung Reaction

Abstract

C-Glycosides are commonly used as carbohydrate mimics in drug development due to their stability against enzymatic and chemical hydrolysis. In this Synpacts article we elaborate on our fast and efficient β-selective approach towards protected and unprotected acyl glycosides. Application of a Corey–Seebach umpolung reaction enables the exclusive formation of the β-anomer of aromatic acyl-C-glycosides in good to excellent yields.1 Introduction2 C-Glycosylation of Benzylated Glycosyl Donors3 C-Glycosylation of Silylated Glycosyl Donors4 Conclusion

Efficient Copper‐Catalyzed Highly Stereoselective Synthesis of Unprotected C‐Acyl Manno‐, Rhamno‐ and Lyxopyranosides

“…This temperature was necessary to avoid the competing E2-elimination occuring when employing, for example, d-glucose donors. [28,29] Running the reaction at 0 °C gave Cacyl α-d-mannopyranoside 22α as the only C-glycosylation product in 11 % overall yield with poor reproducibility. In contrast to the previously reported β-selective method, the products of the Cu-catalyzed reactions are exclusively αconfigured (Scheme 2).…”

“…Our previous studies revealed that in the attempted one‐pot C ‐glycosylation of d ‐mannopyranose 9 , l ‐rhamnopyranose 10 or d ‐lyxopyranose 11 derivatives the formation of the iodide donors 15α ‐ 17α was successful, but nucleophilic attack of the lithiated dithiane 19 a was inhibited at the reaction temperature (‐95 °C to 0 °C). This temperature was necessary to avoid the competing E2‐elimination occuring when employing, for example, d ‐glucose donors [28,29] . Running the reaction at 0 °C gave C ‐acyl α‐ d ‐ mannopyranoside 22α as the only C ‐glycosylation product in 11 % overall yield with poor reproducibility.…”

“…We have previously reported a one-pot procedure for the βselective synthesis of C-acyl glycosidic compounds [28,29] from persilylated monosaccharides. [34,35] The procedure revolves around the one-pot generation of a α-glycosyl iodide [36,37] of several monosaccharides, which then reacts in a S N 2 reaction [38,39] with a lithiated dithiane [40][41][42][43][44][45] followed by cleavage of the TMS groups and the dithiane moiety to exclusively yield the β-anomer of the C-glycosidic compound.…”

“…[19][20][21] In all cases, the glycosyl donors for these strategies have to be synthesized in lengthy multi-step routes. While C-acyl glycosides have recently gained interest as synthetic intermediates and in drug discovery, [22][23][24][25][26][27][28][29][30][31][32] syntheses of C-acyl d-mannopyranosides have remained scarce and syntheses of unprotected C-acyl manno-type pyranosides were not reported at all. [23,24,26,31] To date, most syntheses of C-glycosidic compounds revolve around benzyl-protected d-mannopyranosyl cyanides 4 b.…”

“…If esters are employed as protective groups, the 2-OR substituent is eliminated in an E1 cb -elimination when deprotection under alkaline conditions is attempted. This unwanted reaction was reported to occur with pivaloyl, [32] acetyl [23,24] and benzyl [25][26][27][28][29][30][31] protecting groups. This problem is especially pronounced with peracetylated C-acyl α-d-mannopyranosides 8α where this elimination already occurs during purification by column chromatography.…”