Solid-Phase Synthesis of 2-Aminoethyl Glucosamine Sulfoforms

Abstract

Mono- and disaccharides of sulfonated glucosamines (GlcN sulfoforms) conjugated to 2-aminoethyl linkers were generated by solid-phase synthesis. Orthogonally protected intermediates were tethered onto tritylated polystyrene resin beads, subjected to a modular sequence of deprotection and sulfonation steps, then cleaved from solid support without degradation of N- or O-sulfate esters using solvolytic conditions, and finally purified by reverse-phase HPLC to afford the title compounds.

Sulfoform generation from an orthogonally protected disaccharide

“…2′-Azidoethyl β-glucoside tetraacetate 3 , which was prepared according to literature procedures, 15,18 was converted into glycosyl acceptor 4 in 4 steps and 61% overall yield. The azide was then converted into carboxybenzyl (Cbz) carbamate 5 in 92% yield (Scheme 1).…”

“…For the reductive cleavage of the 4,6-anisylidene acetal using BH 3 /Bu 2 BOTf, we note that the regioselectivity is temperature-dependent, and that performing the reaction at 78 °C yields exclusively the 6- O -PMB ether. 19 Orthogonally protected 2-azido-2-deoxyglucose 6 , which was also prepared according to literature procedures, 14,15 was converted into 3- O -SEM ether 7 in 91% yield, then coupled with 5 using N -iodosuccinimide (NIS)/TfOH activation to yield α-1,4-linked disaccharide 1 as the sole product in 68% yield. We also examined activation conditions using benzenesulfinyl piperidine (BSP)/Tf 2 O 13,20 and phenylsulfenyl chloride (PhSCl)/AgOTf, 21 but these were found to be less effective than NIS/TfOH activation.…”

“…13 To obtain fully deprotected sulfoforms, we have conducted modular deblocking–sulfonation conditions on orthogonally protected glucosamines (GlcNs) immobilized on tritylated polystyrene (PS) resins. 14,15 The solid-phase method can generate entire sets of mono- and disaccharide sulfoforms from a common precursor with up to three sulfate esters per GlcN, followed by mild cleavage and ion-exchange conditions to yield the final sulfoforms as sodium salts. We recently optimized this procedure to generate free GlcN sulfoforms in 8 operations or less with overall yields ranging from 41% (average yield per step: 90%) to 76% (average yield per step: >96%).…”

“…We recently optimized this procedure to generate free GlcN sulfoforms in 8 operations or less with overall yields ranging from 41% (average yield per step: 90%) to 76% (average yield per step: >96%). 15 This strategy can also produce sulfoforms with 2-aminoethyl linkers, to enable their conjugation onto activated substrates or for the preparation of neoglycolipids or neoglycoproteins.…”

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2011–2012

“…Self-assembling properties with octyl, decyl, dodecyl, tetradecyl, and hexadecyl chains under aqueous conditions 2-Aminoethyl glucosamine sulfoform intermediate MALDI Solid-phase synthesis (Liu & Wei, 2012) C-Arabinofuranosides TOF Stereospecific synthesis (Patil et al, 2012) Azido-functionalized cyclic phosphate-linked oligosaccharide analogue…”