Stereoselectivity of Conformationally Restricted Glucosazide Donors

Glycosylations of 4,6-tethered glucosazide donors with a panel of model acceptors revealed the effect of acceptor nucleophilicity on the stereoselectivity of these donors. The differences in reactivity among the donors were evaluated in competitive glycosylation reactions, and their relative reactivities were found to be reflected in the stereoselectivity in glycosylations with a set of fluorinated alcohols as well as carbohydrate acceptors. We found that the 2-azido-2-deoxy moiety is more β-directing than its C-2-<i>O</i>-benzyl counterpart, as a consequence of increased destabilization of anomeric charge development by the electron-withdrawing azide. Additional disarming groups further decreased the α-selectivity of the studied donors, whereas substitution of the 4,6-benzylidene acetal with a 4,6-di-<i>tert</i>-butyl silylidene led to a slight increase in α-selectivity. The C-2-dinitropyridone group was also explored as an alternative for the nonparticipating azide group, but this protecting group significantly increased β-selectivity. All studied donors exhibited the same acceptor-dependent selectivity trend, and good α-selectivity could be obtained with the weakest acceptors and most reactive donors

Reagent Controlled Stereoselective Synthesis of α‑Glucans

The development of a general glycosylation method that allows for the stereoselective construction of glycosidic linkages is a tremendous challenge. Because of the differences in steric and electronic properties of the building blocks used, the outcome of a glycosylation reaction can vary greatly when switching form one glycosyl donor–acceptor pair to another. We here report a strategy to install <i>cis</i>-glucosidic linkages in a fully stereoselective fashion that is under direct control of the reagents used to activate a single type of donor building block. The activating reagents are tuned to the intrinsic reactivity of the acceptor alcohol to match the reactivity of the glycosylating agent with the reactivity of the incoming nucleophile. A protecting group strategy is introduced that is based on the sole use of benzyl-ether type protecting groups to circumvent changes in reactivity as a result of the protecting groups. For the stereoselective construction of the α-glucosyl linkages to a secondary alcohol, a per-benzylated glusosyl imidate donor is activated with a combination of trimethylsilyltriflate and DMF, while activation of the same imidate donor with trimethylsilyl iodide in the presence of triphenylphosphine oxide allows for the stereoselective <i>cis</i>-glucosylation of primary alcohols. The effectiveness of the strategy is illustrated in the modular synthesis of a <i>Mycobacterium tuberculosis</i> nonasaccharide, composed of an α-(1–4)-oligoglucose backbone bearing different α-glucosyl branches

Branching of poly(ADP-ribose): Synthesis of the Core Motif

The synthesis of the core motif of branched poly­(adenosine diphosphate ribose) (poly­(ADPr)) is described, and structural analysis reasserted the proposed stereochemistry for branching. For the synthesis, a ribose trisaccharide was first constructed with only α-<i>O</i>-glycosidic linkages. Finally, the adenine nucleobase was introduced via a Vorbrüggen-type glycosylation reaction. The orthogonality of the selected protecting groups was demonstrated, allowing for the construction of branched poly­(ADPr) oligomers in the near future

2,2-Dimethyl-4-(4-methoxy-phenoxy) butanoate and 2,2-Dimethyl-4-azido Butanoate: Two New Pivaloate-ester-like Protecting Groups

The title compounds were developed to extend the available orthogonalities within the class of protecting groups removed by assisted cleavage. The mild, complementary (oxidative vs reductive) reaction conditions for the removal, together with their pivaloate-like character, were exploited, in combination with a levulinoyl-ester functioning as a third orthogonal protecting group, in the assembly of a <i>Streptococcus mutans</i> hexasaccharide built up from a oligorhamnose backbone featuring β-glucosyl appendages

Reagent Controlled Stereoselective Synthesis of α‑Glucans

The development of a general glycosylation method that allows for the stereoselective construction of glycosidic linkages is a tremendous challenge. Because of the differences in steric and electronic properties of the building blocks used, the outcome of a glycosylation reaction can vary greatly when switching form one glycosyl donor–acceptor pair to another. We here report a strategy to install <i>cis</i>-glucosidic linkages in a fully stereoselective fashion that is under direct control of the reagents used to activate a single type of donor building block. The activating reagents are tuned to the intrinsic reactivity of the acceptor alcohol to match the reactivity of the glycosylating agent with the reactivity of the incoming nucleophile. A protecting group strategy is introduced that is based on the sole use of benzyl-ether type protecting groups to circumvent changes in reactivity as a result of the protecting groups. For the stereoselective construction of the α-glucosyl linkages to a secondary alcohol, a per-benzylated glusosyl imidate donor is activated with a combination of trimethylsilyltriflate and DMF, while activation of the same imidate donor with trimethylsilyl iodide in the presence of triphenylphosphine oxide allows for the stereoselective <i>cis</i>-glucosylation of primary alcohols. The effectiveness of the strategy is illustrated in the modular synthesis of a <i>Mycobacterium tuberculosis</i> nonasaccharide, composed of an α-(1–4)-oligoglucose backbone bearing different α-glucosyl branches

Mapping the Reactivity and Selectivity of 2‑Azidofucosyl Donors for the Assembly of <i>N</i>‑Acetylfucosamine-Containing Bacterial Oligosaccharides

The synthesis of complex oligosaccharides is often hindered by a lack of knowledge on the reactivity and selectivity of their constituent building blocks. We investigated the reactivity and selectivity of 2-azidofucosyl (FucN₃) donors, valuable synthons in the synthesis of 2-acetamido-2-deoxyfucose (FucNAc) containing oligosaccharides. Six FucN₃ donors, bearing benzyl, benzoyl, or <i>tert</i>-butyldimethylsilyl protecting groups at the C3-<i>O</i> and C4-<i>O</i> positions, were synthesized, and their reactivity was assessed in a series of glycosylations using acceptors of varying nucleophilicity and size. It was found that more reactive nucleophiles and electron-withdrawing benzoyl groups on the donor favor the formation of β-glycosides, while poorly reactive nucleophiles and electron-donating protecting groups on the donor favor α-glycosidic bond formation. Low-temperature NMR activation studies of Bn- and Bz-protected donors revealed the formation of covalent FucN₃ triflates and oxosulfonium triflates. From these results, a mechanistic explanation is offered in which more reactive acceptors preferentially react via an S_N2-like pathway, while less reactive acceptors react via an S_N1-like pathway. The knowledge obtained in this reactivity study was then applied in the construction of α-FucN₃ linkages relevant to bacterial saccharides. Finally, a modular synthesis of the <i>Staphylococcus aureus</i> type 5 capsular polysaccharide repeating unit, a trisaccharide consisting of two FucNAc units, is described

Stereoselective Ribosylation of Amino Acids

The glycosylation properties of ribofuranosyl <i>N</i>-phenyltrifluoroacetimidates toward carboxamide side chains of asparagine and glutamine were investigated. Conditions were found that promote nearly exclusive formation of the α-anomerically configured <i>N</i>-glycosides. The strategy allows for the synthesis of Fmoc-amino acids suitably modified for the preparation of ADP-ribosylated peptides. Furthermore, ribosylation of serine with these donors proved to be completely α-selective, and for the first time, α-ribosylated glutamic and aspartic acid, the naturally occurring sites for poly-ADP-ribosylation, were synthesized

Cyanopivaloyl Ester in the Automated Solid-Phase Synthesis of Oligorhamnans

The development of effective protecting group chemistry is an important driving force behind the progress in the synthesis of complex oligosaccharides. Automated solid-phase synthesis is an attractive technique for the rapid assembly of oligosaccharides, built up of repetitive elements. The fact that (harsh) reagents are used in excess in multiple reaction cycles makes this technique extra demanding on the protecting groups used. Here, the synthesis of a set of oligorhamnan fragments is reported using the cyanopivaloyl (PivCN) ester to ensure effective neighboring group participation during the glycosylation events. The PivCN group combines the favorable characteristics of the parent pivaloyl (Piv) ester, stability, minimal migratory aptitude, minimal orthoester formation, while it can be cleaved under mild conditions. We show that the remote CN group in the PivCN renders the PivCN carbonyl more electropositive and thus susceptible to nucleophilic cleavage. This feature is built upon in the automated solid-phase assembly of the oligorhamnan fragments. Where the use of a Piv-protected building block failed because of incomplete cleavage, PivCN-protected synthons performed well and allowed the generation of oligorhamnans, up to 16 monosaccharides in length

Synthetic α- and β‑Ser-ADP-ribosylated Peptides Reveal α‑Ser-ADPr as the Native Epimer

A solid-phase methodology to synthesize oligopeptides, specifically incorporating serine residues linked to ADP-ribose (ADPr), is presented. Through the synthesis of both α- and β-anomers of the phosphoribosylated Fmoc-Ser building block and their usage in our modified solid-phase peptide synthesis protocol, both α- and β-ADPr peptides from a naturally Ser-ADPr containing H2B sequence were obtained. With these, and by digestion studies using the human glycohydrolase, ARH3 (hARH3), compelling evidence is obtained that the α-Ser-ADPr linkage comprises the naturally occurring configuration

Chemoselective Cleavage of <i>p</i>‑Methoxybenzyl and 2‑Naphthylmethyl Ethers Using a Catalytic Amount of HCl in Hexafluoro-2-propanol

A new, fast, mild and chemoselective deprotection method to cleave <i>p</i>-methoxybenzyl and 2-naphthylmethyl ethers using catalytic amounts of hydrochloric acid in a 1:1 mixture of hexafluoro-2-propanol (HFIP) and methylene chloride (DCM) is described. The scope of the methodology becomes apparent from 14 examples of orthogonally protected monosaccharides that are subjected to HCl/HFIP treatment. The applicability of the HCl/HFIP method is illustrated by the synthesis of a sulfated β-mannuronic acid disaccharide