Convergent syntheses of Le^X analogues

Abstract

SummaryThe synthesis of three Lex derivatives from one common protected trisaccharide is reported. These analogues will be used respectively for competitive binding experiments, conjugation to carrier proteins and immobilization on gold. An N-acetylglucosamine monosaccharide acceptor was first glycosylated at O-4 with a galactosyl imidate. This coupling was performed at 40 °C under excess of BF3·OEt2 activation and proceeded best if the acceptor carried a 6-chlorohexyl rather than a 6-azidohexyl aglycon. The 6-chlorohexyl disaccharide was then converted to an acceptor and submitted to fucosylation yielding the corresponding protected 6-chlorohexyl Lex trisaccharide. This protected trisaccharide was used as a precursor to the 6-azidohexyl, 6-acetylthiohexyl and 6-benzylthiohexyl trisaccharide analogues which were obtained in excellent yields (70–95%). In turn, we describe the deprotection of these intermediates in one single step using dissolving metal conditions. Under these conditions, the 6-chlorohexyl and 6-azidohexyl intermediates led respectively to the n-hexyl and 6-aminohexyl trisaccharide targets. Unexpectedly, the 6-acetylthiohexyl analogue underwent desulfurization and gave the n-hexyl glycoside product, whereas the 6-benzylthiohexyl analogue gave the desired disulfide trisaccharide dimer. This study constitutes a particularly efficient and convergent preparation of these three Lex analogues.

Convergent Preparation of DimLex Hexasaccharide Analogues

“…Scheme 1. This represents an improvement over our reported synthesis of 7, which required five steps (64 % overall) from the analogous 3,4-O-isopropylidene p-thiotolyl galactoside. [7] Thiotolyl galactoside 7 was then converted into trichloroacetimidate donor 9 by using the same conditions as those we have described: [7] hydrolysis of the thioglycoside and conversion of the expected hemiacetal into a trichloroacetimidate. Interestingly, full 1 H NMR spectroscopic characterization of the compound formed after hydrolysis revealed that intermediate 8 carried an α-acetate at the anomeric position (δ 1-H = 6.31 ppm, J 1-H,2-H = 3.8 Hz) and a free equatorial hydroxy group at C-2 (δ 2-H = 4.22 ppm).…”

“…Indeed, dissolving-metal conditions were shown to efficiently and concurrently remove protecting groups such as benzyl, benzylidene, acyl, and tri-chloroacetamido and also reduce azido groups to amino groups. [3,7,16] After such reactions, GlcLe x Le x propyl glycoside (2) and dimLe x propyl glycoside (4) were purified by size-exclusion chromatography on a Biogel P2 column and obtained pure in 71 and 65 % yield, respectively. Fortunately, these Birch reduction conditions led to the reduction of the N-chloroacetates to N-acetates, rather than to their transamidation leading to free amines that would require re-acetylation.…”

“…Because we aimed at preparing both GlcLe x Le x analogues 2 and 3 and dimLe x derivatives 4 and 5 in a convergent synthesis, we prepared trisaccharide 17 as the common intermediate for all four final targets. Trisaccharide 17 was prepared stepwise from monosaccharide building blocks 9, [7] 12, and 15 [8] (Schemes 1 and 2). We report an improved synthesis of donor 9 from known [9] thioglycoside 6.…”

Synthesis of Tumor-Associated LeaLex Hexasaccharides: Instability of a Thiol-Containing Oligosaccharide in Mass Spectrometry and Hypermetalation Detected by ESI FAIMS

“…Similarly, the structure of aminohexyl glycoside 3 was confirmed by HRMS and by the presence of a triplet at 2.97 ppm corresponding to the terminal CH 2 Figure 2) that we have reported. 9 We observed that this triplet at 2.89 ppm matched that of a minor compound formed when preparing the Le x analogue and that we assumed to be the corresponding hexyl thiol glycoside. We thus concluded that hexasaccharide 4 was likely a thiol rather than a disulfide dimer.…”

“…Deprotection of the 6-azidohexyl glycoside 21 in the same conditions gave the 6-aminohexyl glycoside hexasaccharide 3 as the ammonium acetate salt in 61% yield after purification on a Biogel® P2 column eluted with 0.05 M ammonium acetate and repeated freeze-drying. We have shown 9 that under dissolving metal condition an S-acetyl hexyl chain underwent desulfurization to give the corresponding hexyl glycoside. Thus hexasaccharide 22 first underwent Zemplèn deacetylation and the crude reaction product was then submitted to dissolving metal conditions to give the 6-thiohexyl hexasaccharide High resolution mass spectrometry along with 1 H NMR spectroscopy that showed a triplet at 0.85 ppm corresponding to the hexyl methyl group, confirmed the structure of the hexyl glycoside 2.…”