Synthesis of Heparan Sulfate- and Dermatan Sulfate-Related Oligosaccharides via Iterative Chemoselective Glycosylation Exploiting Conformationally Disarmed [2.2.2] l-Iduronic Lactone Thioglycosides

Abstract

Heparan sulfate (HS) and dermatan sulfate (DS) are l-iduronic acid containing glycosaminoglycans (GAGs) which are implicated in a number of biological processes and conditions including cancer and viral infection. Chemical synthesis of HS and DS is required to generate structurally defined oligosaccharides for a biological study. Herein, we present a new synthetic approach to HS and DS oligosaccharides using chemoselective glycosylation which relies on a disarmed [2.2.2] l-ido lactone motif. The strategy provides a general approach for iterative-reducing end chain extension, using only shelf-stable thioglycoside building blocks, exploiting a conformational switch to control reactivity, and thus requires no anomeric manipulation steps between glycosylations.

Developments in the Chemical Synthesis of Heparin and Heparan Sulfate

“…Gardiner and co‐workers’ described a novel approach towards the preparation of protected HS oligosaccharides bearing reducing end thioglycoside functionality (Scheme 12). [35] The authors employed a sequential chemoselective glycosylation at the reducing end, additive to their previously reported non‐reducing terminus extension via lactone‐terminated d ‐GlcN‐ l ‐IdoA intermediates [36] . This new approach introduced chemoselective activation of a reducing end l ‐IdoA‐lactone to enable iterative HS oligosaccharide synthesis, without the need to interconvert the reducing end anomeric group.…”

Conformationally Constrained Glycosyl Donors as Tools to Control Glycosylation Outcomes

“…The anomeric thioglycoside of β- 154 was not activated under NIS/AgOTf activating conditions, thereby allowing the synthesis of lactone-containing disaccharide 156 via chemoselective activation of glucoazide thioglycoside 155 . It was later shown that α- 154 was also unreactive under the same conditions with both 2-azido- and 2-trichloroacetyl-protected thioglycoside donors . This phenomenon was exploited in 2019 for the development of a strategy for the synthesis of heparan- and dermatan-sulfate-related oligosaccharides using this conformationally disarmed [2.2.2] l -iduronic lactone motif as a conformational switch to control reactivity (Scheme b) .…”

“…111 The anomeric thioglycoside of β-154 was not It was later shown that α-154 was also unreactive under the same conditions with both 2-azido-and 2-trichloroacetylprotected thioglycoside donors. 112 This phenomenon was exploited in 2019 for the development of a strategy for the synthesis of heparan-and dermatan-sulfate-related oligosaccharides using this conformationally disarmed [2.2.2] Liduronic lactone motif as a conformational switch to control reactivity (Scheme 24b). 112 Chemoselective activation of monocyclic iduronate thioglycoside disaccharides 158 and 161 could be performed over the anomeric thioglycosides of bicyclic [2.2.2] L-ido lactone containing acceptors α-157 or α-160, respectively.…”

“…112 This phenomenon was exploited in 2019 for the development of a strategy for the synthesis of heparan-and dermatan-sulfate-related oligosaccharides using this conformationally disarmed [2.2.2] Liduronic lactone motif as a conformational switch to control reactivity (Scheme 24b). 112 Chemoselective activation of monocyclic iduronate thioglycoside disaccharides 158 and 161 could be performed over the anomeric thioglycosides of bicyclic [2.2.2] L-ido lactone containing acceptors α-157 or α-160, respectively. This demonstrated that constraining the iduronate residues in the B 2 , 5 conformation, via the use of the 2,6-lactone bridge, could be used to "switch off" the reactivity of the anomeric thioglycoside.…”

Modular Synthesis of Heparan Sulfate Oligosaccharides Having N-Acetyl and N-Sulfate Moieties

“…Due to the structural diversity of HS, well-defined compounds cannot be obtained from natural sources. Several laboratories have successfully prepared HS oligosaccharides − and, although elegant, these approaches are mainly focused on the preparation of compounds composed of the same repeating unit. The enzyme-mediated synthesis of HS oligosaccharides requires significantly fewer steps but cannot provide a wide variety of structures due to the promiscuity of the biosynthetic enzymes. − As a result, structure–activity relationship studies have employed small numbers of HS oligosaccharides that cannot properly probe the ligand selectivities of HS-binding proteins. ,,− …”