Synthesis of 8-Methoxycarbonyloctylβ-Glycosides of Tri-and Tetrasaccharides Related to Schizophyllan and Neoglycoproteins Therefrom

Abstract

The 8-methoxycarbonyloctyl β-glycosides of the trisaccharides O-β-d-Glcp-(1 → 6)- O-β-d-Glcp-(1 → 3)-d-Glcp and O-β-d-Glcp-(1 → 3)-O-[β-d -Glcp-(1 → 6)]-d-Glcp and of the tetrasaccharide O-β-d-Glcp-(1 → 3)-O-[β-d-Glcp-(1 → 6)]-O-β-d-Glcp-(1 → 3)-d-Glcp, corresponding to the fragments of schizophyllan, have been synthesized by using mono- to tetrasaccharide 1-thioglycosides as glycosyl donors, each bearing a participating benzoyl group in the 2-position, and N-iodosuccinimide and silver triflate as promoter. Saponification of the tri- and tetrasaccharide β-glycosides, followed by attachment to bovine serum albumin of the resulting sugar derivatives having a carboxyl group at the aglycon terminal, provided neoglycoproteins for immunological studies of the polysaccharide.     

Synthesis of Oligosaccharide Structures from the Lipopolysaccharide of Moraxella catarrhalis

The synthesis of the octasaccharide [p-(trifluoroacetamido)phenyl]ethyl 4-O-[2-O-(2-acetamido-2-deoxy-alpha-D-glucopyranosyl)-beta-D-glucopyranosyl]-6-O-[2-O-[4-O-(4-O-alpha-D-galactopyranosyl-beta-D-galactopyranosyl)-alpha-D-glucopyranosyl]-beta-D-glucopyranosyl]-3-O-beta-D-glucopyranosyl-alpha-D-glucopyranoside, representing the outer part of the lipooligosaccharide from Moraxella catarrhalis serotype A, is described, together with a hepta-, a hexa-, and a pentasaccaride, composing parts thereof with shorter oligosaccharide chains substituted in the 6-position of the central 3,4,6-branched glucose moiety. The versatility of the use of thioglycosides in oligosaccharide synthesis is shown, since throughout the synthesis thioglycosides are used as glycosyl donor precursors, either directly in dimethyl(methylthio)sulfonium triflate (DMTST)-promoted coupling reactions or after conversion to the corresponding glycosyl bromide in silver triflate-promoted couplings. The effects of different protecting groups, anomeric leaving groups, and solvents used in the various coupling reactions are often substantial, which necessitates the use of easily convertible intermediates.     

Synthetic Studies on Sialoglycoconjugates 50: Total Synthesis of Ganglioside GD2

Abstract

As more and more biological functions^1-10 of gangliosides are being revealed, their facile, stereocontrolled synthesis is strongly required. We have developed^11-l4 an α-stereoselective glycosylation of sialic acids, α-sialyl-(2→8)-sialic acid and α-sialyl-(2→8)-α-sialyl-(2→8)-sialic acid, by using their 2-thioglycosides as the glycosyl donor and suitably protected acceptors, and dimethyl(methy1thio)sulfonium triflate (DMTST) or N-iodosuccinimide (NIS)-trifluoromethanesufonic acid (or TMS triflate) as the glycosyl promoter in acetonitrile. In this way, we have synthesized a variety of gangliosides¹⁵ and their analogs.¹⁶ Previously,¹³ we synthesized Ganglioside GD3 containing α-sialyl-(2-8)-sialic acid residue in the molecule, in connection with a novel approach for systematic synthesis of polysialo-glycoconjugates. As a part of our continuing studies on the synthesis and elucidation of the functions of gangliosides, we describe here a facile, stereocontrolled, total synthesis of ganglioside GD2. Ganglioside GD2, which was first isolated from human brain by R. Kuhn et al.,¹⁷ is well known as a human melanoma associated antigen.¹⁸     

Lithium Triflate as a New Promoter of Glycosylation Under Neutral Conditions 1

Abstract

The glycosyl donors 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl trichloroacetimidate and 3,4,6-tri-O-benzyl-α-D-fucopyranosyl trichloroacetimidate were activated under neutral conditions with a catalytic amount (0.05 equiv) of lithium triflate and reacted with a series of alcohols including an acid sensitive sugar to give the corresponding glycosides in high yields. The stereoselectivity of the glycosylation was improved by introducing a participating group next to the anomeric position.

     

α-Glucosylation Reactions with 2,3,4,6-Tetra-O-Benzyl-β-D-Glucopyranosyl Fluoride and Triflic Anhydride as Promoter

ABSTRACT

Triflic anhydride is a suitable promoter for the glucosylation of glycosyl aceptors of medium or low reactivity using 2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl fluoride as donor. In the glucosylation of reactive hydroxyl groups competing triflate formation was observed. The use of molecular sieves as acid scavenger allows the formation of triflates of reactive alcohols under non-basic conditions.     

Silver Triflate. A Mild Alternative Catalyst for Glycosylation Conditions Using Trichloroacetimidates as Glycosyl Donors

Although trimethylsilyl triflate (TMSOTf) has been widely used to promote glycosyl trichloroacetimidates in oligosaccharide synthesis, silver triflate (AgOTf) was proved to be a mild and in some cases more efficient catalyst in TMSOTf‐sensitive glycosylations. Migration and degradation in some specific coupling reactions can be reduced significantly under this alternative glycosylation condition.     

Donor‐Bound Glycosylation for Various Glycosyl Acceptors: Bidirectional Solid‐Phase Semisynthesis of Vancomycin and Its Derivatives

The glycosidation of a polymer‐supported glycosyl donor, N‐phenyltrifluoroacetimidate, with various glycosyl acceptors is reported. The application of the polymer‐supported N‐phenyltrifluoroacetimidate is demonstrated in the synthesis of vancomycin derivatives. 2‐O‐[2‐(azidomethyl)benzoyl]glycosyl imidate was attached to a polymer support at the 6‐position by a phenylsulfonate linked with a C13 alkyl spacer. Solid‐phase glycosidation with a vancomycin aglycon, selective deprotection of the 2‐(azidomethyl)benzoyl group, and glycosylation of the resulting 2‐hydroxy group with a vancosamine unit were performed. Nucleophilic cleavage from the polymer support with acetate, chloride, azido, and thioacetate ions provided vancomycin derivatives in pure form after simple purification. The semisynthesis of vancomycin was achieved by deprotection of the acetate derivative.     

Alternative Syntheses of (l→3)-β-D-Galacto-Oligosaccharides

ABSTRACT

Galactosyl halides bearing different substituents at O-3 [i.e. acetyl (15), benzoyl (14), benzyl (3), bromoacetyl (12), and the 2, 3, 4, 6-tetra-O-benzoyl-β-D-galactopyranosyl group (17)] have been prepared, and used to study the stereoselectivity of the coupling reaction to position O-3 of different galactose derivatives [i.e. methyl 2, 4, 6-tri-O-acetyl-(9) and 2, 4, 6-tri-O-benzoyl-β-D-galactopyranoside (7), l, 2, 4, 6-tetra-O-benzoyl-β-D-galactose (6) and O-(2, 4, 6-tri-O-benzoyl-β-D-galactopyranosyl)-(1→3)-β-D-galactose (33)], as well as to benzoic acid. In more polar solvents, using silver trifluoro-methanesulfonate as the promoter, a higher proportion of β-linked products was formed, whereas with silver perchlorate as the promoter the α-linked product predominated. Under basic conditions, applied to prevent anomerisation of 1-O-benzoylated nucleophiles 6 and 33, no orthoesters were found as end products. Under those conditions, a better overall yield of the β-(l→3)-linked galactotriose 31 was obtained by condensation of die disaccharide glycosyl donor 17 and the monosaccharide glycosyl acceptor 6 than by condensation of 14 and 33. The disaccharide glycosyl chloride 17 was obtained in 75% yield by the cleavage of the corresponding methyl glycoside with dichloromethyl methyl ether.     

Synthetic Studies on Sialoglycoconjugates 16: α-Predominant Glycoside Synthesis of N-Acetylneuraminic Acid With the Primary Hydroxyl Group in Carbohydrates Using Dimethyl(Methylthio)Sulfonium Triflate as a Glycosyl Promoter

ABSTRACT

Coupling of the primary hydroxyl group in the suitably protected 2-(trimethylsilyl)ethyl glycosides of D-glucopyranose (3), N-acetyl-D-glucosamine (7), N-acetyl-D-galactosamine (9), D-lactose (10), and N-acetylneuraminic acid (11), with methyl (methyl 5-acetamido-4, 7,8, 9-tetra-O-acetyl-3, 5-dideoxy-2-thio-D-glycero-α-D-galacto-2-nonulopyranosid)onate (12) as the glycosyl donor in acetonitrile in the presence of dimethyl(methylthio)sulfonium triflate (DMTST) as a glycosyl promoter and molecular sieves 3A, gave predominantly the corresponding α-glycosides 13, 15, 17, 25, and 29 of N-acetylneuraminic acid in 43-71% yields, respectively, together with the ß-glycosides (13-24%).     

Chemical Synthesis of an Octasaccharide Derivative Related to Group B Streptococcus Cell-Wall Polysaccharide

Group B Streptococcus (GBS) is the major pathogen that causes invasive infectious diseases in neonates and infants. The development of preventive and therapeutic strategies against GBS infection has been becoming the most pressing subject worldwide. Group B carbohydrate (GBC), the group B-specific polysaccharide that distinguishes GBS with other streptococci species, has been identified as an attractive antigen for diagnosis and vaccine development because of its highly conservative tetra-antennary structure. In this paper, a highly convergent [3 + 5] glycosylation strategy for efficient synthesis of an octasaccharide derivative related to GBC oligosaccharide unit II has been developed. In this synthesis, each glycosylation reaction was efficiently constructed with glycosyl imidates, especially trifluoroacetimidate, as donors, and each glycosidic bond was stereoselectively controlled via the neighboring group participation effect of acyl group on the 2-O-position of imidate donors or the solvent effect of Et₂O. Furthermore, the aminoethylphosphate group was smoothly installed on the 6-O-position of d -glucitol residue using the phosphoramidite method. After global deprotection, the target octasaccharide was successfully obtained from d -glucitol in 29 steps with an overall yield of 1.37%. The free amino group installed on the aminoethylphosphate spacer of the target molecule enables its modification with functionalized biomolecules for further biological studies.      

The Synthesis of the 2′′- and 2′′′-Monodeoxygenated Analogues of β-Maltosyl-(1→4)-Trehalose

Abstract

Two derivatives of β-maltosyl-(1→4)-trehalose monodeoxygenated at C-2′′ or C-2′′′ have been synthesized in [2+2] block syntheses. O-(2,3,4,6-Tetra-O-benzyl-α-D-glucopyranosyl)-(1→4)-3,6-di-O-benzyl-1,2-di-O-acetyl-β-D-glucopyranose (6), prepared from the respective orthoester, was coupled to the glycosyl acceptor 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranosyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside. In the resulting tetrasaccharide 8, the only ester group was removed and replaced by a xanthate which was reduced in a Barton-McCombie reaction to afford the 2′′-deoxygenated tetrasaccharide 12. For the synthesis of a 2′′′-deoxygenated derivative, a maltose building block was assembled from two monosaccharides. The key building block was ethyl 2,3,6-tri-O-benzyl-1-thio-β-D-glucopyranoside (14) which was used i) as a glycosyl acceptor in a phenylselenyl chloride mediated coupling reaction with tri-O-benzyl-glucal and ii) after the first coupling as a glycosyl donor to react with glycosyl acceptor 7 to give tetrasaccharide 18. The phenylselenyl group was reduced with tributyltin hydride on the disaccharide level. Deprotection of 18 furnished the 2′′′-deoxy-maltosyl-(1→4)-trehalose 20.     

Communication: Synthetic Studies on Sialoglycoconjugates 25: Reactivity of Glycosyl Promoters in α-Glycosylation of N-Acetyl-Neuraminic Acid with the Primary and Secondary Hydroxyl Groups in the Suitably Protected Galactose and Lactose Derivatives

Development of an efficient α-glycoside synthesis of sialic acids is critically significant for the syntheses of sialoglycoconjugates, especially gangliosides which carry important biological functions¹ in biological systems. Previously, we demonstrated² a new α-glycosylation of sialic acids by use of dimethyl(methylthio)sulfonium triflate (DMTST)³ as the glycosyl promoter, the suitably protected glycosyl acceptors and the methyl 2-thioglycoside 1 of N-acetylneuraminic acid (Neu5Ac) as the donor in acetonitrile under kinetically controlled conditions, and accomplished⁴ the syntheses of a variety of gangliosides and their analogs.     

β‐Selective Glycosylation by Using O‐Aryl‐Protected Glycosyl Donors

New glycosyl donors have been developed that contained several para‐substituted O‐aryl protecting groups and their stereoselectivity for the glycosylation reaction was evaluated. A highly β‐selective glycosylation reaction was achieved by using thioglycosides that were protected by 4‐nitrophenyl (NP) groups, which were introduced by using the corresponding diaryliodonium triflate. Analysis of the stereoselectivities of several glycosyl donors indicated that the β‐glycosides were obtained through an S_N2‐type displacement from the corresponding α‐glycosyl triflate. The NP group could be removed by reduction of the nitro group and acylation, followed by oxidation with ceric ammonium nitrate (CAN).     

Synthesis of Disaccharide Nucleosides by the O‐Glycosylation of Natural Nucleosides with Thioglycoside Donors

Disaccharide nucleosides constitute an important group of naturally‐occurring sugar derivatives. In this study, we report on the synthesis of disaccharide nucleosides by the direct O‐glycosylation of nucleoside acceptors, such as adenosine, guanosine, thymidine, and cytidine, with glycosyl donors. Among the glycosyl donors tested, thioglycosides were found to give the corresponding disaccharide nucleosides in moderate to high chemical yields with the above nucleoside acceptors using p‐toluenesulfenyl chloride (TolSCl) and silver triflate (AgOTf) as promoters. The interaction of these promoters with nucleoside acceptors was examined by ¹H NMR spectroscopic experiments.     

Glycosylation Using a Thioglycoside and Methyl Trifluoro-Methanesulfonate. A New and Efficient Method for CIS and Trans Glycoside Formation

Abstract

For the synthesis of large oligosaccharides and biologically active oligosaccharide derivatives it is often desirable to use a block synthesis, that is to link an oligosaccharide residue to another or to a non-carbohydrate aglycon. It is sometimes difficult to prepare glycosyl halide derivatives of the oligosaccharides in good yields, and there is a need for glycosylating agents which can be prepared under mild conditions and in good yields.     

An Economical Synthesis of Lewis X,Sialyl Lewis X and Their α-Galactosyl Analogues

Abstract

Economical syntheses of the Lewis X trisaccharide 8 and sialyl Lewis X tetrasaccharide 18 epitopes and the syntheses of the α-galactosyl epimers 9 and 20 of these structures are described. Thioglycosides 2, 5, 11 and 15 were used as glycosyl donors to construct the desired compounds in a stepwise manner in dimethyl(methylthio)sulphonium triflate promoted couplings. Benzyl 3-O-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)-2-acetamido-6-O-benzyl-2-deoxy-α-D-glucopyranoside (4) was a key structure in these syntheses, and was synthesised in multi-gram scale.     

Synthesis of 4H-furo[3,2-b]indoles. II. Bromination,acylation and nitration of 4H- and 4-benzoylfuro[3,2-b]indoles

Monobromination and monoacylation at the 2-position of 4H-furo[3,2-b]indole ring (III) were facilitated by the benzoyl group in the 4-position; subsequent nitration attempts were unsuccessful.     

O,O-dimethylthiophosphonosulfenyl bromide-silver triflate: a new powerful promoter system for the preactivation of thioglycosides

O,O-Dimethylthiophosphonosulfenyl bromide (DMTPSB) in combination with silver triflate provides a powerful thiophilic promoter system. Both "armed" and "disarmed" thioglycoside glycosyl donors can be activated to form glycosidic linkages efficiently by the pre-activation protocol. The usefulness of this new promoter is illustrated by a successful iterative one-pot oligosaccharide assembly.     

Linear synthesis of a protected H-type II pentasaccharide using glycosyl phosphate building blocks.

A linear synthesis of a fully protected H-type II blood group determinant pentasaccharide utilizing glycosyl phosphate and glycosyl trichloroacetimidate building blocks is reported. Envisioning an automated solid-phase synthesis of blood group determinants, the utility of glycosyl phosphates in the stepwise construction of complex oligosaccharides, such as the H-type II antigen, is demonstrated. Installation of the central glucosamine building block required the screening of a variety of nitrogen protecting groups to ensure good glucosamine donor reactivity and protecting group compatibility. The challenge to differentiate C2 of the terminal galactose in the presence of other hydroxyl and amine protecting groups prompted us to introduce the 2-(azidomethyl)benzoyl group as a novel mode of protection for carbohydrate synthesis. The compatibility of this group with traditionally employed protecting groups was examined, as well as its use as a C2 stereodirecting group in glycosylations. The application of the 2-(azidomethyl)benzoyl group along with a systematic evaluation of glycosyl donors allowed for the completion of the pentasaccharide and provides a synthetic strategy that is expected to be generally amenable to the solid support synthesis of blood group determinants.     

The Synthesis of Four Dideoxygenated Analogues of β-Maltosyl-(1→4)-Trehalose

Abstract

Four derivatives of β-maltosyl-(1→4)-trehalose were prepared, each with two deoxy functions in one of the constitutive disaccharide building blocks. 2,3-Di-O-acetyl-4,6-dideoxy-4,6-diiodo-α-D-galactopyranosyl- (1→4) ?1,2,3,6-tetra-O-acetyl-D-glucopyranose (3) was employed as a precursor for the 4?,6?-dideoxygenated tetrasaccharide 9: coupling of 3 with 2,3,6-tri-O-benzyl-α-D-glucopyranosyl 2,3,6-tri-O-benzylidene-α-D-glucopyranoside (4) furnished the tetrasaccharide 5 which was deiodinated and deprotected to yield the target tetrasaccharide 9. Secondly, the dideoxygenated maltose derivative 3-deoxy-4,6-O-isopropylidene-2-O-pivaloyl-β-D-glucopyranosyl- (1→4) ?1,6-anhydro-3-deoxy-2-O-pivaloyl-β-D-glucopyranose (10) was ring-opened to the anomeric acetate 11. A [2+2] block synthesis with 4 in TMS triflate mediated glycosylation gave a tetrasaccharide which was deprotected to the 3″,3?-dideoxygenated analogue of β-maltosyl-(1→4)-trehalose. For the third tetrasaccharide, 2,3,2″,3′-tetra-O-benzyl-α,α-trehalose was iodinated at the primary positions and deiodinated in the presence of palladium-on-carbon, then this acceptor was selectively glycosylated with hepta-O-acetyl-maltosyl bromide (20). Removal of protective groups furnished the maltosyl trehalose tetrasaccharide deoxygenated at positions C-6 and C-6′. to prepare a 3,3′-dideoxygenated trehalose, the free hydroxyl groups of 2-O-benzyl-4,6-O-(R)-benzylidene-α-D-glucopyranosyl 2-O-benzyl-4,6-O-(R)-benzylidene-α-D-glucopyranoside (25) were reduced by Barton-McCombie deoxygenation. One of the benzylidene groups was opened reductively with sodium cyanoborohydride. The resulting free hydroxyl group at the 4′-position was glycosylated in a Koenigs-Knorr reaction with 20 to yield the 3,3′-dideoxygenated tetrasaccharide 32, the fourth target oligosaccharide, after deprotection.