Mechanistic Investigations into the Application of Sulfoxides in Carbohydrate Synthesis

The utility of sulfoxides in a diverse range of transformations in the field of carbohydrate chemistry has seen rapid growth since the first introduction of a sulfoxide as a glycosyl donor in 1989. Sulfoxides have since developed into more than just anomeric leaving groups, and today have multiple roles in glycosylation reactions. These include as activators for thioglycosides, hemiacetals, and glycals, and as precursors to glycosyl triflates, which are essential for stereoselective β- mannoside synthesis, and bicyclic sulfonium ions that facilitate the stereoselective synthesis of α-glycosides. In this review we highlight the mechanistic investigations undertaken in this area, often outlining strategies employed to differentiate between multiple proposed reaction pathways, and how the conclusions of these investigations have and continue to inform upon the development of more efficient transformations in sulfoxide based carbohydrate synthesis

Glycal assembly by in situ generation of glycosyl dithiocarbamates and a diversity-oriented approach towards the synthesis of heparin and heparan sulfate oligosaccharides

Glycal assembly was introduced nearly twenty years ago as an alternative strategy for the synthesis of linear and branched carbohydrates, but its adoption has been limited by practical issues of coupling efficiency and yield. This barrier can be lifted by the in situ formation of glycosyl dithiocarbamate (DTC) intermediates in a one-pot coupling of glycal-derived donors and acceptors. α-Epoxyglycals (generated by stereoselective epoxidation) are treated with a mixture of diethylamine and CS 2 to produce β-glycosyl DTCs in quantitative yields, then activated with Cu(I) or Cu(II) triflate at low temperatures for direct coupling with glycal acceptors. The glycosyl coupling is highly β-selective and proceeds in good yields with unencumbered acceptors, despite the presence of a C2 hydroxyl on the donor. The glycosyl DTC intermediates can be further armed by in situ 2-O-benzoylation without resorting to chromatography, to enable the glycosylation of larger or sterically demanding acceptors in high overall yields. The efficiency of the modified glycal assembly method is illustrated with the expedient construction of a branched hexasaccharide comprised of β-1,2- and β-1,3-linkages, performed in 11 synthetic steps and just four chromatographic purifications. Heparan sulfate (HS) and closely related heparin are sulfated polysaccharides belonging to the glycosaminoglycan family. These are the most acidic biopolymer in nature, and can interact with a large number of proteins with diverse biological functions. HS and heparin are comprised of alternating units of D-glucosamine and either D-glucuronic (D-GluA) acid or L-iduronic acid (L-IdoA), and support variable degrees of sulfation. Heparin is already widely used as an antithrombotic agent, and specific sequences within HS or heparin are considered to have potential for treatment of atherosclerosis, inflammation, viral infections, and Alzheimer\u27s disease, but in the most cases the precise molecular structure are unknown. With respect to synthesis, the variable sulfation patterns within HS can be addressed by an orthogonal deprotection/sulfation strategy. HS oligosaccharides can be constructed from readily accessible D-GlcN and D-Glc-A derivatives, but the inclusion of L-IdoA is more difficult. Most methods for preparing L-IdoA are lengthy and laborious, and IdoA has poor reactivity as a glycosyl donor, resulting in low coupling yields. This has encouraged us to develop alternative synthetic strategies for HS-like oligosaccharide that incorporate either D-GlcA or L-IdoA in a synthetically efficient manner. Recently, our laboratory has reported the novel synthetic method for preparing L-hexopyranosides by nucleophilic ring opening of 4-epoxypyranosides, which can be made from readily available D-hexoses in few steps. We use this method to develop a diversity-oriented approach towards the construction of Heparin and Heparan Sulfate Oligosaccharides. A terminal 4-deoxypentenoside can be generated at a late state from β-1,4-linked disaccharides, and can be converted into a terminal D-GlcA unit by stereoselective epoxidation followed by SN 2 ring opening reaction, or a terminal L-IdoA unit by syn additio

Glycal Assembly by the in Situ Generation of Glycosyl Dithiocarbamates

Glycal assembly offers an expedient entry into β-linked oligosaccharides, but epoxyglycal donors can be capricious in their reactivities. Treatment with Et₂NH and CS₂ enables their in situ conversion into glycosyl dithiocarbamates, which can be activated by copper triflate for coupling with complex or sterically congested acceptors. The coupling efficiency can be further enhanced by in situ benzoylation, as illustrated in an 11-step synthesis of a branched hexasaccharide from glucals in 28% isolated yield and just four chromatographic purifications

Synthesis and DNA/RNA Binding Properties of Conformationally Constrained Pyrrolidinyl PNA with a Tetrahydrofuran Backbone Deriving from Deoxyribose

Sugar-derived cyclic β-amino acids are important building blocks for designing of foldamers and other biomimetic structures. We report herein the first synthesis of a C-activated <i>N</i>-Fmoc-protected <i>trans</i>-(2<i>S</i>,3<i>S</i>)-3-aminotetrahydrofuran-2-carboxylic acid as a building block for Fmoc solid phase peptide synthesis. Starting from 2-deoxy-d-ribose, the product is obtained in a 6.7% overall yield following an 11-step reaction sequence. The tetrahydrofuran amino acid is used as a building block for a new peptide nucleic acid (PNA), which exhibits excellent DNA binding affinity with high specificity. It also shows preference for binding to DNA over RNA and specifically in the antiparallel orientation. In addition, the presence of the hydrophilic tetrahydrofuran ring in the PNA structure reduces nonspecific interactions and self-aggregation, which is a common problem in PNA due to its hydrophobic nature

Glycosyl Dithiocarbamates: β‑Selective Couplings without Auxiliary Groups

In this article, we evaluate glycosyl dithiocarbamates (DTCs) with unprotected C2 hydroxyls as donors in β-linked oligosaccharide synthesis. We report a mild, one-pot conversion of glycals into β-glycosyl DTCs via DMDO oxidation with subsequent ring opening by DTC salts, which can be generated in situ from secondary amines and CS₂. Glycosyl DTCs are readily activated with Cu­(I) or Cu­(II) triflate at low temperatures and are amenable to reiterative synthesis strategies, as demonstrated by the efficient construction of a tri-β-1,6-linked tetrasaccharide. Glycosyl DTC couplings are highly β-selective despite the absence of a preexisting C2 auxiliary group. We provide evidence that the directing effect is mediated by the C2 hydroxyl itself via the putative formation of a cis-fused bicyclic intermediate

An α-1,6-and α-1,3-linked glucan produced by Leuconostoc citreum ABK-1 alternansucrase with nanoparticle and film-forming properties.

AbstractAlternansucrase catalyses the sequential transfer of glucose residues from sucrose onto another sucrose molecule to form a long chain polymer, known as “alternan”. The alternansucrase-encoding gene from Leuconostoc citreum ABK-1 (Lcalt) was successfully cloned and expressed in Escherichia coli. Lcalt encoded LcALT of 2,057 amino acid residues; the enzyme possessed an optimum temperature and pH of 40 °C and 5.0, respectively, and its’ activity was stimulated up to 2.4-fold by the presence of Mn2+. Kinetic studies of LcALT showed a high transglycosylation activity, with Km 32.2 ± 3.2 mM and kcat 290 ± 12 s−1. Alternan generated by LcALT (Lc-alternan) harbours partially alternating α-1,6 and α- 1,3 glycosidic linkages confirmed by NMR spectroscopy, methylation analysis, and partial hydrolysis of Lc-alternan products. In contrast to previously reported alternans, Lc-alternan can undergo self-assembly, forming nanoparticles with an average size of 90 nm in solution. At concentrations above 15% (w/v), Lc-alternan nanoparticles disassemble and form a high viscosity solution, while this polymer forms a transparent film once dried.</jats:p

Synthesis and Reactivity of 4′-Deoxypentenosyl Disaccharides

4-Deoxypentenosides (4-DPs) are versatile synthons for rare or higher-order pyranosides, and they provide an entry for structural diversification at the C5 position. Previous studies have shown that 4-DPs undergo stereocontrolled DMDO oxidation; subsequent epoxide ring-openings with various nucleophiles can proceed with both <i>anti</i> or <i>syn</i> selectivity. Here, we report the synthesis of α- and β-linked 4′-deoxypentenosyl (4′-DP) disaccharides, and we investigate their post-glycosylational C5′ additions using the DMDO oxidation/ring-opening sequence. The α-linked 4′-DP disaccharides were synthesized by coupling thiophenyl 4-DP donors with glycosyl acceptors using BSP/Tf₂O activation, whereas β-linked 4′-DP disaccharides were generated by the decarboxylative elimination of glucuronyl disaccharides under microwave conditions. Both α- and β-linked 4′-DP disaccharides could be epoxidized with high stereoselectivity using DMDO. In some cases, the α-epoxypentenosides could be successfully converted into terminal l-iduronic acids via the <i>syn</i> addition of 2-furylzinc bromide. These studies support a novel approach to oligosaccharide synthesis, in which the stereochemical configuration of the terminal 4′-DP unit is established at a post-glycosylative stage