Cyclophellitol aziridines have found wide application as mechanism-based, covalent, and irreversible inhibitors of retaining glycosidases. These compounds, like their parent compound,... Show moreCyclophellitol aziridines have found wide application as mechanism-based, covalent, and irreversible inhibitors of retaining glycosidases. These compounds, like their parent compound, cyclophellitol (a natural product retaining beta-glucosidase inactivator), make use of the mechanism of action of retaining glycosidases, which process their substrate through the formation of a transient covalent intermediate. In contrast, inverting glycosidases, the other main family of glycosyl hydrolases, do not employ such a covalent intermediate, and, as a consequence, useful scaffolds for mechanism-based inhibitor design have yet to be discovered. In this work, we explore chemistries that allow for the construction of cyclitol aziridines with the aziridine electrophile attached in an exocyclic fashion, more distal from the anomeric carbon - thus putatively closer to an inverting glycosidase active site nucleophile. The developed chemistries have allowed for the synthesis of a focused library of differently N-substituted, alpha-and beta-glucopyranose configured cyclitol aziridines for future evaluation as inhibitors or inactivators of alpha-and beta-glucosidases alike. Show less
Cyclic peptides represent a popular class of macrocyclic drug candidates and therefore their solid phase synthesis has attracted much attention. In this contribution we present an efficient method... Show moreCyclic peptides represent a popular class of macrocyclic drug candidates and therefore their solid phase synthesis has attracted much attention. In this contribution we present an efficient method of side-chain anchoring for ornithine and lysine residues to be used in the standard Fmoc-based synthesis of cyclic peptides via on-resin cyclization. We demonstrate that the side chain of ornithine and lysine protected with N-Bocgroup can efficiently be converted to the isocyanate which is then immobilized on Wang-type resin in almost quantitative yield. We further show the synthesis of four biologically active cyclic peptides employing the side chain ornithine anchoring. Our method is at least on a par with the previously reported methodologies in terms of yield and the purity of the final products and is arguably operationally more straightforward. Show less
Ham, A. van der; Overkleeft, H.S.; Filippov, D.V.; Schneider, G.F. 2021
4H-Cyclopenta[def]phenanthrene (CPP) is a valuable building block in the production of photoactive polymers, which find use in a wide range of organic electronic applications. Of particular... Show more4H-Cyclopenta[def]phenanthrene (CPP) is a valuable building block in the production of photoactive polymers, which find use in a wide range of organic electronic applications. Of particular importance is their use in the development of blue-colored, organic light-emitting diodes (OLEDs), which remains a challenge in the field. Unfortunately, commercial sources and synthetic procedures known in the literature are unable to provide enough CPP for large scale implementation. Herein, we report on the development of a novel, gram-scale synthesis of CPP in three steps, starting from pyrene. The key steps in our methodology are the ring contraction of pyrene-4,5-dione to oxoCPP in a single step, as well as the direct reduction of oxoCPP to CPP. Apart from the small number of synthetic steps, our methodology benefits from the use of relatively non-hazardous reagents, together with optimized purification procedures, making CPP accessible in useful quantities. Show less
The palladium-catalyzed oxidation of glucopyranosides has been investigated using relativistic density functional theory (DFT) at ZORA-BLYP-D3(BJ)/TZ2P. The complete Gibbs free energy profiles for... Show moreThe palladium-catalyzed oxidation of glucopyranosides has been investigated using relativistic density functional theory (DFT) at ZORA-BLYP-D3(BJ)/TZ2P. The complete Gibbs free energy profiles for the oxidation of secondary hydroxy groups at C2, C3, and C4 were computed for methyl beta-glucoside and methyl carba-beta-glucoside. Both computations and oxidation experiments on carba-glucosides demonstrate the crucial role of the ring oxygen in the C3 regioselectivity observed during the oxidation of glucosides. Analysis of the model systems for oxidized methyl beta-glucoside shows that the C3 oxidation product is intrinsically favored in the presence of the ring oxygen. Subsequent energy decomposition analysis (EDA) and Hirschfeld charge analysis reveal the role of the ring oxygen: it positively polarizes C1/C5 by inductive effects and disfavors any subsequent buildup of positive charge at neighboring carbon atoms, rendering C3 the most favored site for the beta-hydride elimination. Show less
FiveC-glycosyl functionalized lysine building blocks, featuringC-glycosidic derivatives of alpha-rhamnose, alpha-mannose, alpha-galactose, beta-galactose, and beta-N-acetyl glucosamine have been... Show moreFiveC-glycosyl functionalized lysine building blocks, featuringC-glycosidic derivatives of alpha-rhamnose, alpha-mannose, alpha-galactose, beta-galactose, and beta-N-acetyl glucosamine have been designed and synthesized. These derivatives, equipped with acid-labile protecting groups, are eminently suitable for solid-phase synthesis of multivalent glycopeptides. The lysine building blocks were prepared fromC-allyl glycosides that underwent a Grubbs cross-metathesis with an acrylate, followed by a reduction of the C=C double bond in the resulting alpha,beta-unsaturated esters, and liberation of the carboxylate to allow condensation with a lysine side chain. The thus obtainedC-glycosides, five in total, were applied in the solid-phase peptide synthesis (SPPS) of three glycopeptides, showing the potential of the described building blocks in the assembly of well-defined mimics of homo- and heteromultivalent glycopeptides and glycoclusters. Show less
Reintjens N.R.M., Koemans T.S., Zilverschoon N., Castelli R., Cordfunke R.A., Drijfhout J.W., Meeuwenoord N.J., Overkleeft H.S., Filippov D.V., Marel G.A. van der, Codée J.D.C. 2020
Five C-glycosyl functionalized lysine building blocks, featuring C-glycosidic derivatives of alpha-rhamnose, alpha-mannose, alpha-galactose, beta-galactose, and beta-N-acetyl glucosamine have been... Show moreFive C-glycosyl functionalized lysine building blocks, featuring C-glycosidic derivatives of alpha-rhamnose, alpha-mannose, alpha-galactose, beta-galactose, and beta-N-acetyl glucosamine have been designed and synthesized. These derivatives, equipped with acid-labile protecting groups, are eminently suitable for solid-phase synthesis of multivalent glycopeptides. The lysine building blocks were prepared fromC-allyl glycosides that underwent a Grubbs cross-metathesis with an acrylate, followed by a reduction of the C=C double bond in the resulting alpha,beta-unsaturated esters, and liberation of the carboxylate to allow condensation with a lysine side chain. The thus obtainedC-glycosides, five in total, were applied in the solid-phase peptide synthesis (SPPS) of three glycopeptides, showing the potential of the described building blocks in the assembly of well-defined mimics of homo- and heteromultivalent glycopeptides and glycoclusters. Show less
We have quantum chemically analyzed the ring-opening reaction of the model non-symmetrical epoxide 2,2-dimethyloxirane under basic and acidic conditions using density functional theory at OLYP/TZ2P... Show moreWe have quantum chemically analyzed the ring-opening reaction of the model non-symmetrical epoxide 2,2-dimethyloxirane under basic and acidic conditions using density functional theory at OLYP/TZ2P. For the first time, our combined activation strain and Kohn-Sham molecular orbital analysis approach have revealed the interplay of physical factors that control the regioselectivity of these chemical reactions. Ring-opening under basic conditions occurs in a regime of strong interaction between the nucleophile (OH-) and the epoxide and the interaction is governed by the steric (Pauli) repulsion. The latter steers the attack preferentially towards the sterically less encumbered C-beta. Under acidic conditions, the interaction between the nucleophile (H2O) and the epoxide is weak and, now, the regioselectivity is governed by the activation strain. Protonation of the epoxide induces elongation of the weaker (CH3)(2)C-alpha-O bond, and effectively predistorts the substrate for the attack at the sterically more hindered side, which goes with a less destabilizing overall strain energy. Our quantitative analysis significantly builds on the widely accepted rationales behind the regioselectivity of these ring-opening reactions and provide a concrete framework for understanding these indispensable textbook reactions. Show less
Wang, L.; Overkleeft, H.S.; Marel, G.A. van der; Codee, J.D.C. 2019
Pre‐activation based glycosylations have become a very powerful tool in the assembly of oligosaccharides and the use of nucleophilic additives allows for the in situ generation of reactive... Show morePre‐activation based glycosylations have become a very powerful tool in the assembly of oligosaccharides and the use of nucleophilic additives allows for the in situ generation of reactive intermediates with tailored reactivity. We here use a glycosylation strategy that is based on the use of per‐benzylated imidate building blocks for the fully stereoselective construction of a spacer equipped Aspergillus fumigatus α‐1,3‐octaglucan. We have used the trimethylsilyl iodide (TMSI)‐triphenylphosphine oxide (Ph3P=O) for the stereoselective installation of an azidopropanol spacer and triflic acid (TfOH)‐dimethyl formamide (DMF) enabled glycosylations for the coupling reactions with the secondary glucosyl C‐3‐alcohols. An operationally simple in situ activation coupling procedure is introduced and used for the final glycosylation events towards the octasaccharide. Show less
Iminosugars are an important class of natural products and have been subject to extensive studies in organic synthesis, bioorganic chemistry and medicinal chemistry, yet only a limited number of... Show moreIminosugars are an important class of natural products and have been subject to extensive studies in organic synthesis, bioorganic chemistry and medicinal chemistry, yet only a limited number of these studies are on glycosylated iminosugars. Here, a general route of synthesis is presented towards glycosylated 1‐deoxynojirimycin derivatives based on the oxidation–reductive amination protocol that in the past has also been shown to be a versatile route towards 1‐deoxynojirimycin. The strategy can be applied on commercial disaccharides, as shown in four examples, as well as on disaccharides that are not commercially available and are synthesized for this purpose, as shown by a fifth example. Show less
Beenakker, T.J.M.; Wander, D.P.A.; Codée, J.D.C.; Aerts, J.M.F.G.; Marel, G.A. van der; Overkleeft, H.S. 2017
Cyclophellitol and cyclophellitol aziridine are potent and irreversible inhibitors of retaining β‐glucosidases. They preferentially adopt a 4H3 half‐chair conformation, thereby mimicking the... Show moreCyclophellitol and cyclophellitol aziridine are potent and irreversible inhibitors of retaining β‐glucosidases. They preferentially adopt a 4H3 half‐chair conformation, thereby mimicking the substrate‐transition‐state conformation characteristic of retaining β‐glucosidases. As a consequence, both compounds bind tightly to the enzyme active site, and attack of the catalytic nucleophile onto the epoxide/aziridine results in enzyme deactivation. Replacement of the epoxide oxygen in cyclophellitol by a (substituted) carbon yielded carba‐cyclophellitols, a conceptually new class of inhibitors of retaining β‐glucosidases, as we demonstrated in a recent communication. In this paper, in‐depth synthetic studies of this class of compounds are described, and the preparation of a comprehensive set of structurally and configurationally new carba‐cyclophellitols is presented. Show less
