Combinatorial synthesis of an oligosaccharide library by using beta-bromoglycoside-mediated iterative glycosylation of selenoglycosides: rapid expansion of molecular diversity with simple building blocks

A new method for constructing an oligosaccharide library composed of structurally defined oligosaccharides is presented based on an iterative glycosylation of selenoglycosides. Treatment of 2-acyl-protected selenoglycosides with bromine selectively generates beta-bromoglycosides, which serve as glycosyl cation equivalents in the oligosaccharide synthesis. Thus, the coupling of the bromoglycosides with another selenoglycoside affords the corresponding glycosylated selenoglycosides, which can be directly used to next glycosylation. The iteration of this sequence allows the synthesis of a variety of oligosaccharides including an elicitor active heptasaccharide. A characteristic feature of the iterative glycosylation is that glycosyl donors and acceptors with the same anomeric reactivity can be selectively coupled by activation of the glycosyl donor prior to coupling with the glycosyl acceptor. Therefore, same selenoglycosides can be used for both the glycosyl donors and the acceptors. This feature has been exemplified by a construction of an oligosaccharide library directed to elicitor-active oligosaccharides. The library composed of stereochemically defined oligoglucosides with considerable structural diversity can be constructed starting from simple selenoglycosides.     

Allyl protecting group mediated intramolecular aglycon delivery (IAD): synthesis of α-glucofuranosides and β-rhamnopyranosides

The use of allyl protecting group mediated intramolecular aglycon delivery (IAD) as a strategy for intramolecular glycosylation has been extended to allow the stereoselective synthesis of α-glucofuranosides and β-rhamnopyranosides, in a totally stereoselective fashion. The efficiency of intramolecular glycosylation is dependent on the protecting group pattern of the glycosyl donor, and on the steric bulk of the glycosyl acceptor.     

Hydroxynorleucine as a glycosyl acceptor is an efficient means for introducing amino acid functionality into complex carbohydrates

A new approach to the synthesis of biologically relevant glycosyl amino acids using a non-natural amino acid as the glycosyl acceptor is described. The procedure involves a glycosylation reaction of a suitable carbohydrate donor with Fmoc-l-hydroxynorleucine benzyl ester. This reaction results in the direct incorporation of the amino acid moiety. The acceptor can be used for the preparation of α- or β-O-linked glycosides depending upon the nature of the glycosyl donor. This method has been applied in the synthesis of six different tumor-associated carbohydrate antigens.     

Synthesis of a pentasaccharide repeating unit of the O-antigen of enteroadherent Escherichia coli O154 strain

A straightforward linear synthetic strategy has been developed for the synthesis of the pentasaccharide repeating unit of the cell wall O-antigenic polysaccharide of enteroadherent Escherichia coli O154 strain. Newly developed glycosylation conditions using glycosyl trichloroacetimidate derivatives as glycosyl donors and nitrosyl tetrafluoroborate as the glycosylation activator have been used in all of the glycosylation reactions throughout the synthetic scheme. The stereochemical outcomes of the glycosylations were excellent and the yields were very good.     

Oligosaccharide synthesis with glycosyl phosphate and dithiophosphate triesters as glycosylating agents

Described is an efficient one-pot synthesis of alpha- and beta-glycosyl phosphate and dithiophosphate triesters from glycals via 1,2-anhydrosugars. Glycosyl phosphates function as versatile glycosylating agents for the synthesis of beta-glucosidic, beta-galactosidic, alpha-fucosidic, alpha-mannosidic, beta-glucuronic acid, and beta-glucosamine linkages upon activation with trimethylsilyl trifluoromethanesulfonate (TMSOTf). In addition to serving as efficient donors for O-glycosylations, glycosyl phosphates are effective in the preparation of S-glycosides and C-glycosides. Furthermore, the acid-catalyzed coupling of glycosyl phosphates with silylated acceptors is also discussed. Glycosyl dithiophosphates are synthesized and are also used as glycosyl donors. This alternate method offers compatibility with acceptors containing glycals to form beta-glycosides. To minimize protecting group manipulations, orthogonal and regioselective glycosylation strategies with glycosyl phosphates are reported. An orthogonal glycosylation method involving the activation of a glycosyl phosphate donor in the presence of a thioglycoside acceptor is described, as is an acceptor-mediated regioselective glycosylation strategy. Additionally, a unique glycosylation strategy exploiting the difference in reactivity of alpha- and beta-glycosyl phosphates is disclosed. The procedures outlined here provide the basis for the assembly of complex oligosaccharides in solution and by automated solid-phase synthesis with glycosyl phosphate building blocks exclusively or in concert with other donors.     

Synthesis of di-branched heptasaccharide by one-pot glycosylation using seven independent building blocks

[reaction: see text] We describe an efficient synthesis of di-branched heptasaccharide 1 having phytoalexin elicitor activity in soybeans by one-pot glycosylation. The synthesis involves chemo- and regioselective sequential six-step glycosylations using seven independent building blocks and sequential removal of acyl- and benzyl ether-type protecting groups. The coupling of seven building blocks requires only four chemoselective activitable leaving groups of glycosyl donors. Both the glycosylation and deprotection reactions can be achieved utilizing a parallel manual synthesizer.     

Towards the preparation of 2″-deoxy-2″-fluoro-adenophostin A. Study of the glycosylation reaction

The synthesis of 2″-deoxy-2″-fluoro-adenophostin A framework starting from tri-O-acetylglucal and adenosine is described. The key steps are the formation of the 2-deoxy-2-fluoroglycosyl donor by electrophilic fluorination of tri-O-acetylglucal and the stereoselective glycosylation of a suitable adenosine derivative. The glycosylation reaction was optimized affording the desired 2″-deoxy-2″-fluoroglycoside with excellent α-stereoselectivity and in good yields, taking into account that glycosylations using nucleosides as glycosyl acceptors do not usually give excellent results. In that sense, an improvement of the glycosylation step with respect to that of the reported adenophostin synthesis, using adenosine derivatives as glycosyl donors, has been made.     

Acceptor-dependent stereoselective glycosylation: 2'-CB glycoside-mediated direct beta-D-arabinofuranosylation and efficient synthesis of the octaarabinofuranoside in mycobacterial cell wall

[reaction: see text]. A reliable and generally applicable direct method for the stereoselective beta-arabinofuranosylation employing a 2'-carboxybenzyl arabinofuranoside as the glycosyl donor has been established. The acyl-protective group on glycosyl acceptors is essential for the beta-stereoselectivity. The power of the present acceptor-dependent glycosylation method was demonstrated by the efficient synthesis of the octaarabinofuranoside in arabinogalactan and lipoarabinomannan found in mycobacterial cell wall.     

Stereoselective 1,2-cis glycosylation of 2-O-allyl protected thioglycosides

The technique of intramolecular aglycon delivery (IAD), whereby a glycosyl acceptor is temporarily appended to a hydroxyl group of a glycosyl donor is an attractive method that can allow the synthesis of 1,2-cis glycosides in an entirely stereoselective fashion. 2-O-Allyl protected thioglycoside donors are excellent substrates for IAD, and may be glycosylated stereoselectively through a three-step reaction sequence. This sequence consists of quantitative yielding allyl bond isomerisation, to produce vinyl ethers that can then undergo N-iodosuccinimide mediated tethering of the desired glycosyl acceptor, and subsequent intramolecular glycosylation, to yield either alpha-glucosides or beta-mannosides accordingly. Although attempted one-pot tethering and glycosylation is hampered by competitive intermolecular reaction with excess glycosyl acceptor, this problem can be simply overcome by the use of excess glycosyl donor. Allyl mediated IAD is a widely applicable practical alternative to other IAD approaches for the synthesis of beta-mannosides, that is equally applicable for alpha-gluco linkages. It is advantageous in terms of both simplicity of application and yield, and in addition has no requirement for cyclic 4,6-protection of the glycosyl donor.     

Toward the total synthesis of vineomycin B2: application of an efficient glycosylation methodology using 2,3-unsaturated sugars

The application of an efficient glycosylation methodology using 2,3-unsaturated sugars to synthesize critical precursors required for the total synthesis of an antibiotic, vineomycin B₂ (1), was demonstrated. The required disaccharide, the acurosyl rhodinose derivative of 1, was prepared by chemoselective glycosylation using a 2,3-saturated glycosyl acetate corresponding to the rhodinose moiety and a 2,3-unsaturated glycosyl acetate corresponding to the acurose portion. Further, the right-hand side chain of 1, consisting of β-oxo-tert-alcohol and rhodinose, was constructed by a powerful glycosylation approach using a 2,3-unsaturated glycosyl acetate in an ionic liquid under reduced pressure.     

Total synthesis of the heptasaccharide repeating unit of the iron-binding exopolysaccharide secreted by Klebsiella oxytoca BAS-10

The first total synthesis of a heptasaccharide found in the iron-binding exopolysaccharide produced by Klebsiella oxytoca BAS-10 has been achieved in excellent yield using a block synthetic strategy. A trisaccharide glycosyl donor was stereoselectively coupled with a tetrasaccharide glycosyl acceptor using the trichloroacetimidate activation procedure. The yields and stereo outcome were excellent in each step of glycosylation. A late stage oxidation protocol was adopted for the oxidation of the primary hydroxyl group to the carboxylic functionality while keeping a secondary hydroxyl group unaffected.     

Sequential one-pot glycosylation with glycosyl N-trichloroacetylcarbamate and trichloroacetate including dehydrative approach using 1-hydroxy sugars

An efficient sequential one-pot glycosylation has been developed with glycosyl trichlorocarbamate and trichloroacetate activated by the same Lewis acid and enabled by a change in reaction temperature. The αα-selective glycosylation was achieved using glucose, galactose, and mannose substrates after investigation into the reactivities of the two types of glycosyl donors. Sequential one-pot dehydrative glycosylation, including in situ preparation of glycosyl donors followed by generation of two glycosyl bonds, provided three types of trisaccharide.     

Glycosyl thioimidates as versatile building blocks for organic synthesis

This review discusses the synthesis and application of glycosyl thioimidates in chemical glycosylation and oligosaccharide assembly. Although glycosyl thioimidates include a broad range of compounds, the discussion herein centers on S-benzothiazolyl (SBaz), S-benzoxazolyl (SBox), S-thiazolinyl (STaz), and S-benzimidazolyl (SBiz) glycosides. These heterocyclic moieties have recently emerged as excellent anomeric leaving groups that express unique characteristics for highly diastereoselective glycosylation and help to provide a streamlined access to oligosaccharides.     

Synthesis of pennogenyl saponin analogs using three methods

The synthesis of pennogenyl saponins and related compounds using three popular methods of glycosylation has been reported for the first time. Glycosyl halides, glycosyl trichloroacetimidates, and thioglycosides were used as glycosyl donors in the reactions with pennogenin as the glycosyl acceptor. The reactions occur selectively with the C(3)OH group due to the difference in steric accessibility of the hydroxyl groups at the C(3) and C(17) atoms of pennogenin. This makes it possible to synthesize a series of pennogenyl saponins without C(17)OH group protection. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1789–1792, October, 2006.     

Construction of Interglycosidic N-O Linkage via Direct Glycosylation of Sugar Oximes

Direct glycosylation of sugar oximes and HONHFmoc has been realized for the first time by using glycosyl ortho-hexynylbenzoates as donors under the catalysis of PPh(3)AuOTf, providing an effective approach to the synthesis of N-O linked saccharides, which are of great biological interest.     

Sonochemistry: a powerful way of enhancing the efficiency of carbohydrate synthesis

Using sonication as a means of facilitating organic reactions in carbohydrate chemistry was explored under the conditions used for traditional organic synthesis. An array of representative reactions, including hydroxy group manipulation (acylation, protection/deprotection, acyl group migration), thioglycoside synthesis, azidoglycoside synthesis, 1,3-dipolar cycloaddition and reductive cleavage of benzylidene, commonly used in the synthesis of carbohydrate derivatives was examined. A series of glycosylation reactions that employ thioglycosides, glycosyl trichloroacetimidate, glycosyl bromide and glycosyl acetate as the glycosyl donors was also examined. Our results demonstrate that sonication can significantly shorten the reaction time, enhance the reactivity of reactant and lead to superior yield and excellent stereoselectivity. More importantly, a general protocol of glycosylation may finally be developed. Sonication is compatible to the conditions used for traditional organic synthesis. We believe that sonication can also be applied to other areas of synthetic processes.     

An orthogonal and reactivity-based one-pot glycosylation strategy for both glycan and nucleoside synthesis: access to TMG-chitotriomycin,lipochitooligosaccharides and capuramycin

Both glycans (O-glycosides) and nucleosides (N-glycosides) play important roles in numerous biological processes. Chemical synthesis is a reliable and effective means to solve the attainability issues of these essential biomolecules. However, due to the stereo- and regiochemical issues during glycan assembly, together with problems including the poor solubility and nucleophilicity of nucleobases in nucleoside synthesis, the development of one-pot glycosylation strategies toward efficient synthesis of both glycans and nucleosides remains poor and challenging. Here, we report the first orthogonal and reactivity-based one-pot glycosylation strategy suitable for both glycan and nucleoside synthesis on the basis of glycosyl ortho-(1-phenylvinyl)benzoates. This one-pot glycosylation strategy not only inherits the advantages including no aglycon transfers, no undesired interference of departing species, and no unpleasant odors associated with the previously developed orthogonal one-pot glycosylation strategy based on glycosyl ortho-alkynylbenzoates, but also highly expands the scope (glycans and nucleosides) and increases the number of leaving groups that could be employed for the multistep one-pot synthesis (up to the formation of four different glycosidic bonds). In particular, the current one-pot glycosylation strategy is successfully applied to the total synthesis of a promising tuberculosis drug lead capuramycin and the divergent and formal synthesis of TMG-chitotriomycin with potent and specific inhibition activities toward β-N-acetylglucosaminidases and important endosymbiotic lipochitooligosaccharides including the Nod factor and the Myc factor, which represents one of the most efficient and straightforward synthetic routes toward these biologically salient molecules.

The first one-pot glycosylation strategy for both glycan and nucleoside synthesis based on glycosyl ortho-(1-phenylvinyl)benzoates has been developed, which is applied to the synthesis of TMG-chitotriomycin, lipochitooligosaccharides and capuramycin.     

Lactonization-mediated glycosylations and their application to oligosaccharide synthesis

The concept of lactonization-mediated and related glycosylations led us to develop new methods of glycosylation such as the 2'-carboxybenzyl (CB) glycoside method, the glycosyl pentenoate/phenylselenyl trifluoromethanesulfonate (PhSeOTf) method, and the glycosyl aryl phthalate method. Highly stereoselective beta-mannopyranosylations were achieved by employing the CB glycoside and the glycosyl pentenoate/PhSeOTf methods. The CB glycoside method was also utilized for stereoselective 2-deoxyglycosylation, beta-arabinofuranosylation, and alpha-galactofuranosylation. In addition, these lactonization-mediated methods of glycosylation were employed for the synthesis of complex oligosaccharides. In particular, the CB glycoside method was successfully applied to the synthesis of repeating oligosaccharide subunits of the O-polysaccharide of the lipopolysaccharide from Danish Helicobacter pylori strains and Escherichia coli 077, the synthesis of oligoarabinofuranosides in mycobacterial cell walls, and the total synthesis of antineoplastic agelagalastatin.     

Oligosaccharide Synthesis via Electrophile-Induced Activation of Glycosyl-N-Allylcarbamates 1

Abstract

Glycosyl-N-allyl carbamates, obtained by reaction of anomerically unprotected saccharides with allyl isocyanate, can be activated by an electrophile-induced cyclisation and reacted with glycosyl acceptors to form the corresponding oligosaccharides By this method the mucin core 2 trisaccharide² has successfully been synthesized. Due to the mild glycosylation conditions even 1-O-acetyl protected glycosyl acceptors can be used. This was demonstrated in the synthesis of a 1,6-linked glucosyl trisaccharide whereby a reptitious glycosylation strategy could be applied.

     

Endohexosaminidase-catalysed glycosylation with oxazoline donors: fine tuning of catalytic efficiency and reversibility

A complete series of oxazoline di-, tri-, tetra-, and hexasaccharides, corresponding to the core sections of N-linked glycoprotein high mannose glycans, together with the corresponding oligosaccharides containing a central glucose unit, were synthesised and tested as glycosyl donors for glycosylation of a GlcNAcAsn glycosyl amino acid catalysed by the endohexosaminidases M (Endo M), A (Endo A) and H (Endo H). Whilst Endo H did not catalyse any glycosylation reactions, both Endo M and Endo A efficiently catalysed glycosylations that were not limited to donors containing the Manbeta(1-->4)GlcNAc linkage. Precise structure activity relationships and time course studies have revealed fine-tuning of the efficiency of the synthetic processes which correlated both with the enzyme used and the precise oxazoline structure. Efficient irreversible glycosylation was achievable with both Endo M and Endo A, further demonstrating the use of structurally modified oxazoline donors as transition state mimics in order to promote enzyme-catalysed synthesis, whilst precluding product hydrolysis; enzymes in these cases display "glycoligase" activity.