Free-radical hydrothiolation of the endocyclic double bond of enoses is reported. Reaction between 2-acetoxy-D-glucal and a range of thiols including amino acid, peptide, glycosyl thiols, and sugars with primary or secondary thiol functions gave S-linked α-glucoconjugates and S-disaccharides with full regio- and stereoselectivity. Addition of glycosyl thiols to a 2,3-unsaturated glycoside also proceeded with good selectivity and afforded a series of 3-deoxy-S-disaccharides.

Sugar-modified nucleosides are prime synthetic targets in anticancer and antiviral drug development. Radical mediated thiol-ene coupling was applied for the first time on nucleoside enofuranoside derivatives to produce a broad range of thio-substituted d-ribo, -arabino, -xylo and l-lyxo configured pyrimidine nucleosides. In contrast to the analogous reactions of simple sugar exomethylenes, surprisingly, hydrothiolation of nucleoside alkenes under the standard conditions of various initiation methods showed low to moderate yields and very low stereoselectivity. Optimizing the reaction conditions, we have found that cooling the reaction mixture has a significant beneficial effect on both the conversion and the stereoselectivity, and UV-light initiated hydrothiolation of C2'-, C3'- and C4'-exomethylene derivatives of nucleosides at -80 °C proceeded in good to high yields, and, in most cases, in excellent diastereoselectivity. Beyond the temperature, the solvent, the protecting groups on nucleosides and, in some cases, the configuration of the thiols also affected the stereochemical outcome of the additions. The anomalous l-lyxo diastereoselectivity observed upon the addition of 1-thio-β-d-gluco- and galactopyranose derivatives onto C4',5'-unsaturated uridines is attributed to steric mismatch between the d-ribo C4'-radical intermediates and the β-configured 1-thiosugars.

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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.

Computational description of conformational and dynamic properties of anticoagulant heparin analogue pentasaccharides is of crucial importance in understanding their biological activities. We designed and synthesized idraparinux derivatives modified with sulfonatomethyl moieties at the D, F, and H glucose units that display varied potencies depending on the exact nature of the substitution. In this report we examined the capability of molecular dynamics (MD) simulations to describe the conformational behavior of these novel idraparinux derivatives. We used Gaussian accelerated MD (GAMD) simulations on the parent compound, idraparinux, to choose the most suitable carbohydrate force field for these type of compounds. GAMD provided significant acceleration of conformational transitions compared to classical MD. We compared descriptors obtained from GAMD with NMR spectroscopic parameters related to geometrical descriptors such as scalar couplings and nuclear Overhauser effects (NOE) measured on idraparinux. We found that the experimental data of idraparinux is best reproduced by the CHARMM carbohydrate force field. Furthermore, we propose a torsion angle parameter for the sulfonatomethyl group, which was developed for the chosen CHARMM force field using quantum chemical calculations and validated by comparison with NMR data. The work lays down the foundation of using MD simulations to gain insight into the conformational properties of sulfonato-methyl group modified idraparinux derivatives and to understand their structure−activity relationship thus enabling rational design of further modifications.

A new methodology for the synthesis of the most challenging heparin building block has been developed. Orthogonally protected l‐idosyl glycosyl donors were prepared by C5 epimerization of the corresponding thioglucosides using the hydroboration/oxidation method followed by a 4,6‐acetal formation. The α‐anomeric configuration was crucial, and the bulky C4 substituent was advantageous for the high l‐ido diastereoselectivity. The 4,6‐arylmethylene group proved to be a directing element in glycosylation, whereby stereoselective α‐idosylation could be achieved by using idosyl donors without a C‐2 participating group.

A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.0]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H-H distances obtained from a new ROESY NMR method. The synthesis was compatible with silyl, trityl and dimethoxytrityl protecting groups. A new reagent mixture containing ZnCl, EtSiH and hexafluoroisopropanol was developed for detritylation of the acid-sensitive tricyclano nucleosides.

D-glucuronate and l-iduronate containing disaccharides related to the antithrombin-binding pentasaccharide of heparin, in which one of the sulfate esters is systematically replaced by a sodium sulfonatomethyl moiety, were synthesized. The sulfonic acid group was introduced by stereoselective radical addition onto the exomethylene moiety of the appropriate glycoside derivatives, and the resulting sulfonatomethyl glucosides were used as acceptors.