Glycosyl ortho‐Methoxybenzoates: Catalytically Activated Glycosyl Donors with an Easily Removable and Recyclable Leaving Group

Abstract

We describe the β‐ortho‐methoxybenzoate as a shelf stable and practical C‐1 nucleofuge for catalytic chemical glycosylation in which the benzoic acid by‐product can be easily removed, reisolated, and potentially recycled after the glycosylation reaction. This new type of glycosyl donor can be efficiently activated by a range of promoters, including Bi(OTf)3, Fe(OTf)3, TMSOTf (TMS = trimethylsilyl), and triflic acid, with low (<10 mol‐%) catalyst loadings. The donor shows higher reactivity than analogous benzoate, p‐methoxybenzoate and p‐cyano‐o‐methoxybenzoate donors. In glycosylation reactions with o‐methoxybenzoate donors, the yields of disaccharide products were good to excellent for various glycosyl acceptors, including a carbohydrate‐based secondary alcohol. Furthermore, β‐selective mannosylation was achieved with a Crich‐type donor at 0 °C to ambient temperature, without donor preactivation. The donor was also used for the first step of a one‐pot two‐step glycosylation to obtain a trisaccharide; the second coupling involved activation of a thioglycoside with NIS/TMSOTf (NIS = N‐iodosuccinimide). We believe that this offers a good alternative to current protocols.

Palladium-Catalyzed C–S Bond Formation as a Tool for Latent–Active Glycosylation

“…Based on previous studies with anomeric benzoates as C-1 leaving groups, we have found that a second coordination center (o-OMe) significantly increases the glycosyl donor reactivity. 29 We wanted to explore whether a similar trend would be present among one of the most used glycosyl donor types, the thioglycosides.…”

“…In oligosaccharide synthesis, the glycosyl donor leaving group determines the mode of activation, which basically refers to the choice of Lewis acid (e.g., halophilic, thiophilic, hard or soft). Based on previous studies with anomeric benzoates as C-1 leaving groups, we have found that a second coordination center ( o -OMe) significantly increases the glycosyl donor reactivity . We wanted to explore whether a similar trend would be present among one of the most used glycosyl donor types, the thioglycosides.…”

“…Noticeably, the results in Scheme demonstrate the compatibility of the Cu­(OTf) 2 /TTBP promoter system with various protecting groups such as esters ( 7b and 7l ) and acid-labile acetals ( 7c , 7e , and 7i ). Acetylated donors, however, proved too unstable for Cu­(OTf) 2 activation, which is in accordance with previous results by us and Yu and co-workers using similar promoter systems.…”

Stereoselective oxidative glycosylation of anomeric nucleophiles with alcohols and carboxylic acids

“…1 . Of these, the most widely applied methods capitalize on reactions of glycosyl donors in which the C2 position is capped with a carbonyl-based participating group (e.g., OAc, OBz, NPhth) 7 – 10 . For example, activation of 2- O -acyl thioglycoside with an oxidant and triflate salt leads to the formation of the dioxolenium ion intermediate 4 which is quenched with an alcohol to provide glycoside 1 in high 1,2- trans selectivity (Fig.…”

Nucleofuge Generating Glycosidations by the Remote Activation of Hydroxybenzotriazolyl Glycosides

“…Donor-regenerative glycosidations is an emerging trend in the chemical glycosidation field. The concept has been investigated by Demchenko using −OFox imidate donors, by Wan through an interrupted Pummerer reaction using 2-(2-propylthiol)­benzyl (PTB) glycosides and by Jensen utilizing o -methoxybenzoates.…”