The 2-naphthylmethyl (NAP) group in carbohydrate synthesis: first total synthesis of the GlyCAM-1 oligosaccharide structures

Total syntheses of the GlyCAM-1 (glycosylation-dependent cell adhesion molecule-1) oligosaccharide structures: [alpha-NeuAc-(2 --> 3)-beta-Gal-(1 --> 4)-[alpha-Fuc-(1 --> 3)]-beta-(6-O-SO3Na)-GlcNAc-(1 --> 6)]-[alpha-NeuAc-(2 --> 3)-beta-Gal-(1 --> 3)]-alpha-GalNAc-OMe (1) and [alpha-NeuAc-(2 --> 3)-beta-Gal-(1 --> 4)-[alpha-Fuc-(1 --> 3)]-beta-GlcNAc-(1 --> 6)]-[alpha-NeuAc-(2 3)-beta-Gal-(1 --> 3)]-alpha-GalNAc-OMe (2) through a novel sialyl LewisX tetrasaccharide donor are described. Employing sequential glycosylation strategy, the starting trisaccharide was regio- and stereoselectively constructed through coupling of a disaccharide imidate with the monosaccharide acceptor phenyl-6-O-naphthylmethyl-2-deoxy-2-phthalimido-1-thio-beta-D-glucopyranoside with TMSOTf as a catalyst without affecting the SPh group. The novel sialyl Lewisx tetrasaccharide donor 3 was then obtained by alpha-L-fucosylation of trisaccharide acceptor with the 2,3,4-tri-O-benzyl-1-thio-beta-L-fucoside donor. The structure of the novel sialyl Lewisx tetrasaccharide was established by a combination of 2D DQF-COSY and 2D ROESY experiments. Target oligosaccharides 1 and 2 were eventually constructed through heptasaccharide which was obtained by regioselective assembly of advanced sialyl Lewisx tetrasaccharide donor 3 and a sialylated trisaccharide acceptor in a predictable and controlled manner. Finally, target heptasaccharides 1 and 2 were fully characterized by 2D DQF-COSY, 2D ROESY, HSQC, HMBC experiments and FAB mass spectroscopy.     

N-连接的糖蛋白核心甘露五糖及其异构体的合成研究

以1,2-O-亚乙基-4,6-O-亚苄基-β-D-甘露糖(2)和2,3,4,6-四-O-苯甲酰基-α-D-甘露吡喃糖基三氯乙酰亚胺酯(3)为基本原料，经一些简单的化学转换和选择性的糖基化反应，得到了甘露核心五糖及其异构体。     

Synthesis of sulfonic acid analogues of the non-reducing end trisaccharide of the antithrombin binding domain of heparin

Three sulfonic acid trisaccharides related to the antithrombin-binding DEFGH domain of heparin were synthesised. Trisaccharides carrying the sulfonatomethyl moiety at position 2 or 6 were prepared in high yields by [DE+F] couplings using the same disaccharide uronate donor and the appropriate sulfonic acid acceptor, respectively. The trisaccharide with a 3-deoxy-3-sulfonatomethyl function could be obtained with high efficacy by a [D+EF] coupling where the carboxylic function of the EF uronate acceptor was created at a disaccharide level.     

The amide group in N-acetylglucosamine glycosyl acceptors affects glycosylation outcome

Glycosylation of a disaccharide containing N-acetylglucosamine with rhamnosyl and mannosyl trichloracetimidates under triethysilyl triflate catalysis led to the competitive formation of glycosyl imidates. While the rhamnosyl imidate could be rearranged to the thermodynamically favored trisaccharide, the mannosyl analogue was resistant to rearrangement. Glycosylation with perbenzylated thiorhamnosides activated with methyl triflate (MeOTf) gave the trisaccharide as well as the methyl imidate trisaccharide. The less reactive alpha-thioethyl donor led to a higher relative amount of methyl imidate trisaccharide to trisaccharide than the more reactive beta-thioglycoside. When using a more reactive thioethyl fucoside only the trisaccharide was obtained. Interestingly, the acceptor treated with MeOTf gave the N-methyl imidate that could be easily rhamnosylated and subsequently converted to the N-acetamido trisaccharide. This strategy to glycosylate O-4 of N-acetylglucosamine is under further investigation. Alternatively, bis-N-acetylation of the glucosamine prevented the formation of imidates and allowed the efficient synthesis of two Lewis A trisaccharide analogues.     

Convergent synthesis of a common pentasaccharide-repeating unit corresponding to the O-specific polysaccharide of Escherichia coli O4:K3, O4:K6, and O4:K12

A convergent chemical synthesis of a pentasaccharide found in the O-specific polysaccharide of Escherichia coli O4:K3, O4:K6, and O4:K12 has been achieved in excellent yield. A [3+2] block synthetic strategy has been adopted to couple a disaccharide donor 11 with a trisaccharide acceptor 10 for the construction of the pentasaccharide derivative 12 which on deprotection furnished target pentasaccharide 1 as its 4-methoxyphenyl glycoside. Disaccharide thioglycoside donor 11 and trisaccharide acceptor 10 were prepared from suitably protected monosaccharide intermediates. Yields were excellent in all steps.     

Synthesis of the Trisaccharide Repeating Unit of the K-Antigen from Klebsiella Type-63

Abstract

The benzyl substituted ethyl thioglycoside of L-fucose was found to be a more reactive donor compared to 2-O-benzyl substituted p-tolyl thioglycoside of D-galactose. Using the benzyl substituted ethyl thioglycoside of L-fucose (8), as a donor and the suitably substituted p-tolyl thioglycoside of D-galactose (7) as acceptor, the p-tolyl thioglycoside of the disaccharide, 9, was prepared. This disaccharide donor was allowed to react with a suitably protected galactopyranosyluronic acid acceptor, 16, to give the trisaccharide repeating unit of the K-antigen from Klebsiella type 63.     

A double regio- and stereoselective glycosylation strategy for the synthesis of N-glycans

A building block approach for biantennary N-linked oligosaccharides from glycoproteins (N-glycans) has been developed. Starting from a core trisaccharide (beta-mannosyl chitobiose) containing a benzylidene-protected beta-mannoside, the attachment of the disaccharide building blocks for the antennae can be performed in a double regio- and stereoselective manner. A short synthesis of a GlcNPhtbeta1,2Man donor was developed. The benzylidene acetal moiety, as a minimal protection of the beta-mannoside, allows selective alpha-glycosylation at OH-3 of the 2,3-diol with GlcNbeta1,2Man trichloroacetimidate donors. Subsequent debenzylidenation leads to a 4,6-diol, which can be selectively extended at OH-6. Overreaction at OH-4 was generally low when phthalimido-protected donors were used. This general strategy represents a modular synthesis of N-glycans and their glycoconjugates.     

Study of carbohydrate-carbohydrate interactions: total synthesis of 6d-deoxy Lewis pentaosyl glycosphingolipid

This article describes total synthesis of 6d-deoxy Lewis^x pentaosyl glycosphingolipid, a useful tool for study of the Lewis^x-Lewis^x interaction. A 6-deoxy galactose donor was condensed with a diol of glucosamine to provide regioselectively a β 1→4 linked disaccharide, which was further fucosylated to a protected deoxy Lewis^x trisaccharide. Glycosylation of a lactoside diol with the 6d-deoxy Lewis^x trisaccharide gave regio- and stereoselectively a pentasaccharide in excellent yield. After chemical modification, this pentasaccharide reacted with the 3-O-benzoylated azidosphingosine to form a glycosphingolipid, which, after azide reduction followed by condensation with stearic acid and deprotection, afforded the target compound.     

一种木葡聚糖类寡糖的化学合成及生物活性

天然木葡聚糖类寡糖是一类对植物生长具有调节作用的寡糖, 本文以3个单糖组分为原料, 经5步合成了一种木葡聚糖三糖(1)(总产率15%), 以及该三糖的糖苷缀合物1a及其异构体1b. 利用糖基化立体选择性原则, 一步偶联反应同时得到所需的α,β连接产物, 整个合成路线高效简捷. 活性测试结果表明, 3种目标寡糖在1 mg/L浓度下, 对烟草的生长均显示出一定的促进作用, 表明所合成的3种寡糖有望发展成为植物生长促进剂.     

Synthesis of 3″- and 4″-deoxy-Lewisx trisaccharides: A useful tool for study of carbohydrate-carbohydrate interaction

Synthesis of 3″-deoxy and 4″-deoxy Lewis^x trisaccharides is described. Phenyl 2,3,6-tri-O-benzoyl-4-deoxy-1-thio-β-d-xylo-hexopyranoside was condensed with a diol of glucosamine to give regio- and stereo-selectively a disaccharide. Stereoselective fucosylation of this disaccharide provided a protected deoxy Lewis^x trisaccharide which was deprotected to give the 4″-deoxy Lewis^x trisaccharide. Application of the similar synthetic sequence provided the 3″-deoxy Lewis^x trisaccharide.     

Complex oligosaccharide investigations: synthesis of an octasaccharide incorporating the dimeric Le(x) structure of PSGL-1

The synthesis of an octasaccharide containing the dimeric Le(x) oligosaccharide structure found in PSGL-1 carbohydrate chains is reported. Several approaches were investigated employing regioselective and stereoselective glycosylation procedures, and a novel Lewis(x) trisaccharide donor, 7, was prepared and utilized as a key intermediate building block in the scheme developed for the construction of octasaccharide 3. Toward the preparation of 7, investigations into the influence of different protecting groups upon the relative reactivities of disaccharide acceptor moieties, 25 or 26, and the fucosyl donors, 10 and 11, were conducted using similar glycosylating conditions. Dramatic differences were noted between the effects of electron-donating and electron-withdrawing groups upon the reactivity of the acceptor hydroxyl. A similar effect upon the glycosylating capability of the donor molecule was, likewise, observed. The repeat use of donor 7 was instrumental in the synthesis of the desired dimeric octasaccharide structure 3. The structure and purity of 3 and important intermediates were fully characterized by DQF-COSY, TOCSY, ROESY, and ESI mass spectroscopy.     

Synthesis of the non-reducing end trisaccharide of the antithrombin-binding domain of heparin and its bioisosteric sulfonic acid analogues

A glucoronic acid-containing trisaccharide related to the antithrombin-binding DEFGH domain of heparin and its methanesulfonic acid analogues were synthesized. Trisaccharides without sulfonic acid content or possessing a sulfonatomethyl moiety at position 2 or 6 of unit F were prepared in high yields by [DE+F] couplings using the same disaccharide uronate donor, respectively. Synthesis of the trisaccharide with a 3-deoxy-3-sulfonatomethyl function was accomplished in three different pathways, from which a [D+EF] coupling and applying a non-oxidized precursor of the glucuronic acid afforded the trisaccharide in the highest yield.     

An Efficient Synthesis of the Lewis A (Lea) Antigen Pentasaccharide Moiety

Abstract

Starting material for the synthesis of Lewis A pentasaccharide (1) was azidoglucose derivative 2 which was readily transformed into the 3,4-O-unprotected derivative 3 or the 3-O-unprotected derivative 5, respectively. Reaction of 3 and O-galactosyltrichloroacetimidate 6 led preferentially to the desired β(1-3)-connected disaccharide 8 which could be selectively obtained from donor 6 and acceptor 5 via disaccharide 9. 4a-O-Fucosylation of 8 with fucosyl donor 10 furnished trisaccharide 11 which was transformed into triosyl donor 13; glycosylation of lactose derivative 14 as acceptor furnished the desired pentasaccharide in high yield. Azide reduction and N-acetylation and O-deprotection afforded the title compound 1 in high overall yield.     

Stereoselective Synthesis of the Hexasaccharide Repeating Unit of the Cell Wall Polysaccharide from Kineosporia aurantiaca VKM Ac-720T Employing the Direct Glycosylation with Anomeric Hydroxy Sugars Involving Glycosyl Phthalate Intermediates

Synthesis of a suitably protected form of the hexasaccharide repeating unit of the cell wall polymer from Kineosporia aurantiaca VKM Ac-720 ^T has been achieved by the stereoselective direct glycosylation of a trisaccharide acceptor with a trisaccharide donor having an anomeric hydroxy group involving a glycosyl phthalate intermediate. Both the trisaccharide acceptor and the trisaccharide donor were obtained from a common trisaccharide, of which two β-mannopyranosyl linkages were constructed stereoselectively by employing the direct glycosylation method with the anomeric hydroxy sugar involving a glycosyl phthalate intermediate and the 2′-carboxybenzyl glycoside method, respectively.     

Anomeric reactivity-based one-pot oligosaccharide synthesis: a rapid route to oligosaccharide libraries

The assembly of an oligosaccharide library has been achieved in a practical and efficient manner employing a' one-pot sequential approach. With the help of the anomeric reactivity values of thioglycosides, using a thioglycoside (mono- or disaccharide) with one free hydroxyl group as acceptor and donor coupled with another fully protected thioglycoside, a di- or trisaccharide is selectively formed without self-condensation and subsequently reacted in situ with an anomerically inactive glycoside (mono- or disaccharide) to form a tri- or tetrasaccharide in high overall yield. The approach enables the rapid assembly of 33 linear or branched fully protected oligosaccharides using designed building blocks. These fully protected oligosaccharides have been partially or completely deprotected to create 29 more structures to further increase the diversity of the library.     

New synthesis of idraparinux,the non-glycosaminoglycan analogue of the antithrombin-binding domain of heparin

Idraparinux, the fully O-sulfated, O-methylated, heparin-related pentasaccharide possessing selective factor Xa inhibitory activity, was prepared by a new synthetic pathway. This route was based on a [2+3] block synthesis utilizing a 6-O-silyl-protected l-idose-containing trisaccharide acceptor, which was glycosylated with a disaccharide donor containing a non-oxidized precursor of the glucuronic acid. The unique strategy of multiple functionalizations at pentasaccharide levels, involving triple methylation followed by oxidation of the glucose and the idose precursors into d-glucuronic and l-iduronic acids in one step, proved to be highly efficient, providing the target pentasaccharide through a 39-step synthesis starting from d-glucose and methyl α-d-glucopyranoside.     

Synthesis and anticoagulant activity of bioisosteric sulfonic-Acid analogues of the antithrombin-binding pentasaccharide domain of heparin

Two pentasaccharide sulfonic acids that were related to the antithrombin-binding domain of heparin were prepared, in which two or three primary sulfate esters were replaced by sodium-sulfonatomethyl moieties. The sulfonic-acid groups were formed on a monosaccharide level and the obtained carbohydrate sulfonic-acid esters were found to be excellent donors and acceptors in the glycosylation reactions. Throughout the synthesis, the hydroxy groups to be methylated were masked in the form of acetates and the hydroxy groups to be sulfated were masked with benzyl groups. The disulfonic-acid analogue was prepared in a [2+3] block synthesis by using a trisaccharide disulfonic acid as an acceptor and a glucuronide disaccharide as a donor. For the synthesis of the pentasaccharide trisulfonic acid, a more-efficient approach, which involved elongation of the trisaccharide acceptor with a non-oxidized precursor of the glucuronic acid followed by post-glycosidation oxidation at the tetrasaccharide level and a subsequent [1+4] coupling reaction, was elaborated. In vitro evaluation of the anticoagulant activity of these new sulfonic-acid derivatives revealed that the disulfonate analogue inhibited the blood-coagulation-proteinase factor?Xa with outstanding efficacy; however, the introduction of the third sulfonic-acid moiety resulted in a notable decrease in the anti-Xa activity. The difference in the biological activity of the disulfonic- and trisulfonic-acid counterparts could be explained by the different conformation of their L-iduronic-acid residues.     

Synthesis of biantennary complex-type nonasaccharyl asn building blocks for solid-phase glycopeptide synthesis

The biantennary complex-type N-glycans bearing LacNAc and LacdiNAc as the nonreducing end motif were synthesized in a protected form suitable to use in the Fmoc solid-phase peptide synthesis studies. Two approaches for the nonasaccharide synthesis were examined by taking advantage of the highly β-selective glycosylation with GlcNTCA (N-phenyl)trifluoroacetimidate. An earlier approach, which involved the reaction of the trisaccharide donor (Gal-GlcNTCA-Man) and trisaccharide acceptor (Man-GlcNPhth(2)-N(3)), produced a mixture of nonasaccharide isomers. On the other hand, mannosylation of the trisaccharide acceptor (Man-GlcNPhth(2)-N(3)) stereoselectively afforded the known pentasaccharide (Man(3)-GlcNPhth(2)-N(3)), which was reacted with the disaccharyl glycosyl donor (Gal-GlcNTCA or GalNTCA-GlcNTCA) to produce the desired nonasaccharide as a single stereoisomer. Selective dephthaloylation followed by N-acetylation furnished the GlcNAc(2) functionality. The resulting nonasaccharyl azides were condensed with Fmoc-Asp(OPfp)-OBu(t) or Fmoc-Asp(OPfp)-OPac in the presence of Ph(CH(3))(2)P and HOOBt. Finally, the Zn reduction and cleavage of the tert-butyl ester or Zn reduction alone produced the targeted nonasaccharyl Asn building blocks.     

Regio- and stereoselective glycosylation of 2-(o-dihydroxyborylbenzyl) thioglucoside and unprotected methyl glycosides

A highly regio- and stereoselective glycosylation of a boronic acid-containing thioglucoside and unprotected methyl glycosides is described. A boronic acid moiety was installed at the ortho-position of the 2-O-benzyl group of a thioglucosyl donor. This provides transient partial protection for the unprotected glycosyl acceptor upon condensation and concomitantly prearranged the acceptor with respect to the donor for the ensuing intramolecular glycosylation.     

The first total synthesis of telephiose A

The first total synthesis of telephiose A (1), a novel trisaccharide ester having two acetyl groups and two benzoyl groups, was achieved by using glucosyl donor 6 and disaccharide acceptor 12. The crucial key step was the stereoselective construction of the β-d-glucosidic linkage featuring the neighboring group participation of the 2-O-N-phenylcarbamoyl group (of donor 6), which can be selectively deprotected in the presence of acetyl and benzoyl groups. Donor 6 was prepared from d-glucose in eight steps (33% yield), whereas acceptor 12 was prepared from sucrose in six steps (35% yield). Precursors 6 and 12 were reacted in subsequent reactions (five steps) to afford 1 in 22% yield.