One-Pot Synthesis of Glycosyl Chlorides from Thioglycosides Mediated by a Bromodiethylsulfonium Salt as a Mild Oxidant

Abstract

Conventional synthesis of glycosyl chlorides from thioglycosides relies on the two sequential oxidation and chlorination. A one-pot synthesis of glycosyl chlorides is warranted as an alternative method. Herein, we report the one-pot synthesis of glycosyl chlorides from thioglycoside precursors. The transformation was mediated at low temperature by bromodiethylsulfonium bromopentachloroantimonate (BDSB) as a mild oxidant and n-Bu4NCl as an additive. The armed thioglycosides afforded the corresponding α-glycosyl chlorides in moderate to good yields under the optimized conditions. Low conversions and yields were obtained when the less reactive disarmed thioglycosides were used. Unexpectedly, BDSB-mediated oxidation of thioglycosides without the addition of n-Bu4NCl also afforded the α-glycosyl chlorides in moderate yields. We suggest a mechanism involving the transfer of chloride ions from the non-nucleophilic bromopentachloroantimonate (SbCl5Br) anion to the oxocarbenium ion.

Glycosylation of n-pentenyl glycosides using bromodiethylsulfonium salt as an activator: interception of the glycosyl intermediate by chloride ion transfer

“…The intramolecular cyclization via 5- exo -tet of the anomeric oxygen yields the glycosyl intermediate B . These reversible processes are disrupted by chloride ion transfer from the SbCl 5 Br anion, 23,31 which could endure an S N 1-like pathway through an oxocarbenium intermediate or direct displacement of 2-(bromomethyl)tetrahydrofuran (S N 2-like pathway), generating glycosyl chloride. 32 Subsequently, nucleophilic substitution by the glycosyl acceptor forms the desired coupling product.…”

“…22 Similarly, our research group has recently observed the transfer of chloride ions during the synthesis of α-glycosyl chlorides from thioglycosides using BDSB as a mild oxidant. 23…”

“…22 Similarly, our research group has recently observed the transfer of chloride ions during the synthesis of α-glycosyl chlorides from thioglycosides using BDSB as a mild oxidant. 23 Herein, we propose to harness a unique chloride ion transfer for the activation of NPGs (Fig. 1A, pathway b).…”

Direct Synthesis of Glycosyl Chlorides from Thioglycosides

“…The generated chlorides were used in subsequent glycosylations in situ . Very recently, a very thorough study by Padungros and co-workers led to the development of a new bromodiethylsulfonium/bromopentachloroantimonate-mediated protocol (Scheme E) . This method is applicable to a broad range of substrates, but due to competing hydrolysis, the yields are moderate at this stage of the method’s development.…”

“…Very recently, a very thorough study by Padungros and co-workers led to the development of a new bromodiethylsulfonium/bromopentachloroantimonate-mediated protocol (Scheme 1E). 35 This method is applicable to a broad range of substrates, but due to competing hydrolysis, the yields are moderate at this stage of the method's development. As evident from this compendium of previous methods, a majority of existing reaction conditions are applicable for the reactive (armed) thioglycosides and very few are effective for the less reactive (disarmed) counterparts.…”