Koenigs–Knorr Glycosylation Reaction Catalyzed by Trimethylsilyl Trifluoromethanesulfonate

Abstract

The discovery that traditional silver(I)-oxide-promoted glycosidations of glycosyl bromides (Koenigs–Knorr reaction) can be greatly accelerated in the presence of catalytic trimethylsilyl trifluoromethanesulfonate (TMSOTf) is reported. The reaction conditions are very mild that allowed for maintaining a practically neutral pH and, at the same time, providing high rates and excellent glycosylation yields. In addition, unusual reactivity trends among a series of differentially protected glycosyl bromides were documented. In particular, benzoylated α-bromides were much more reactive than their benzylated counterparts under these conditions.

Defining the Scope of the Acid‐Catalyzed Glycosidation of Glycosyl Bromides

“…To rationalize the reduction in reaction rates in ethereal and other polar solvents, acetone and acetonitrile, we decided to look at possible differences in the mechanistic pathways for this reaction in different classes of solvents. Previously, we suggested the reaction mechanism by which this cooperative catalysis proceeds (Scheme ) . Silver is halophilic, therefore, the process originates by bromide complexation with Ag 2 O resulting in intermediate A that also forms in the classic Koenigs–Knorr reaction.…”

“…Also generated is unstable AgOH that undergoes the loss of water, scavenged by the molecular sieves (MS), and contributes to the regeneration of Ag 2 O and helps to maintain the overall neutral pH of the reaction medium. The proposed regeneration cycle of Ag 2 O implies that excess silver salt, 2.0 or even 3.0 equiv used in our previous study, may not be necessary . To investigate whether a successful glycosylation can be performed with as little as 0.50 equiv of Ag 2 O that is needed to produce 1 equiv AgBr, we reacted mannosyl bromide 1 with acceptor 2 in presence of Ag 2 CO 3 (0.50 equiv) and TMSOTf (0.20 equiv) in DCM.…”

“…Glycosylations of 3‐OH acceptor 6 and even very unreactive 4‐OH acceptor 8 were rapid, efficient, and clean. The respective disaccharides 7 and 9 were afforded in excellent yields of 96–97 % in 5 min (entries 3 and 4). Benzylidene protected 3‐OH acceptor 10 and diacetone galactose 6‐OH acceptor 12 were then investigated.…”

“…We feared that cyclic acetal and ketal protecting groups could be unstable in the presence of TfOH. However, the reactions in the presence of 0.30–0.35 equiv TfOH were very successful, and the respective disaccharides 11 and 13 were obtained in excellent yields of 92–94 % (entries 5 and 6). Glycosidation of donor 1 with electronically deactivated primary 6‐OH acceptor 14 and cholesterol 16 afforded disaccharide 15 and glycoside 17 in 99 % and 79 % yield, respectively (entries 7 and 8).…”

“…Some approaches require multistep synthesis of specialized activators or demand excess of toxic reagents. Recently, we reported that traditional silver(I) oxide‐promoted glycosylations can be greatly accelerated in the presence of catalytic TMSOTf . These reaction conditions are very mild and allow for maintaining neutral pH while providing high rates and excellent glycosylation yields (Scheme ).…”