Total synthesis of dissectol A, using an enediolate-based Tsuji-Trost reaction.

Dissectol A is a rearranged terpene glycoside isolated from several flowering plants. Starting from glucose, the densely functionalized bicyclic structure has been prepared via site-selective oxidation and an intramolecular allylic alkylation reaction with an enediolate as the nucleophile. Despite earlier reports, dissectol A is not effective at inhibiting DevRS signaling in whole-cell Mycobacterium tuberculosis and does not inhibit growth of the bacterium.

The synthesis of fructose-based surfactants.

This study describes the synthesis of a new class of surfactants that is based on the bioderived building blocks fructose, fatty acid methyl esters (FAME), and hydroxy propionitrile (cyanoethanol, 3-HP). The synthesis is scalable, is carried out at ambient conditions, and does not require chromatography. The produced surfactants have excellent surfactant properties with critical micelle concentrations and Krafft points comparable to current glucose-based surfactants.

Regioselective palladium-catalysed aerobic oxidation of dextran and its use as a bio-based binder in paperboard coatings.

The coatings industry is aiming to replace petrochemical-based binders in products such as paints and lacquers with bio-based alternatives. Native polysaccharide additives are already used, especially as adhesives, and here we show the use of oxidised dextran as a bio-based binder additive. Linear dextran with a molecular weight of 6 kDa was aerobically oxidised in water at the C3-position of its glucose units, catalysed by [(neocuproine)PdOAc]2(OTf)2. The resulting keto-dextran with different oxidation degrees was studied using adipic dihydrazide as a crosslinker in combination with the commercial petrochemical-based binder Joncryl®. Coating experiments show that part of the Joncryl® can be replaced by keto-dextran while maintaining the desired performance.

Asymmetric Total Synthesis and Structural Revision of DAT2, an Antigenic Glycolipid from Mycobacterium tuberculosis.

DAT2 is a member of the diacyl trehalose family (DAT) of antigenic glycolipids located in the mycomembrane of Mycobacterium tuberculosis (Mtb). Recently it was shown that the molecular structure of DAT2 had been incorrectly assigned, but the correct structure remained elusive. Herein, the correct molecular structure of DAT2 and its methyl-branched acyl substituent mycolipanolic acid is determined. For this, four different stereoisomers of mycolipanolic acid were prepared in a stereoselective and unified manner, and incorporated into DAT2. A rigorous comparison of the four isomers to the DAT isolated from Mtb H37Rv by NMR, HPLC, GC, and mass spectrometry allowed a structural revision of mycolipanolic acid and DAT2. Activation of the macrophage inducible Ca2+-dependent lectin receptor (Mincle) with all four stereoisomers shows that the natural stereochemistry of mycolipanolic acid / DAT2 provides the strongest activation, which indicates its high antigenicity and potential application in serodiagnostics and vaccine adjuvants.

Site-Selective Palladium-catalyzed Oxidation of Unprotected Aminoglycosides and Sugar Phosphates.

The site-selective modification of complex biomolecules by transition metal-catalysis is highly warranted, but often thwarted by the presence of Lewis basic functional groups. This study demonstrates that protonation of amines and phosphates in carbohydrates circumvents catalyst inhibition in palladium-catalyzed site-selective oxidation. Both aminoglycosides and sugar phosphates, compound classes that up till now largely escaped direct modification, are oxidized with good efficiency. Site-selective oxidation of kanamycin and amikacin was used to prepare a set of 3'-modified aminoglycoside derivatives of which two showed promising activity against antibiotic-resistant E. coli strains.

Correction: π-Facial selectivity in the Diels-Alder reaction of glucosamine-based chiral furans and maleimides.

Correction for 'π-Facial selectivity in the Diels-Alder reaction of glucosamine-based chiral furans and maleimides' by Cornelis H. M. van der Loo et al., Org. Biomol. Chem., 2023, 21, 1888-1894, https://doi.org/10.1039/D2OB02221D.

Substituted anilides from chitin-based 3-acetamido-furfural.

The synthesis of aromatic compounds from biomass-derived furans is a key strategy in the pursuit of a sustainable economy. Within this field, a Diels-Alder/aromatization cascade reaction with chitin-based furans is emerging as a powerful tool for the synthesis of nitrogen-containing aromatics. In this study we present the conversion of chitin-based 3-acetamido-furfural (3A5F) into an array of di- and tri-substituted anilides in good to high yields (62-90%) via a hydrazone mediated Diels-Alder/aromatization sequence. The addition of acetic anhydride expands the dienophile scope and improves yields. Moreover, replacing the typically used dimethyl hydrazone with its pyrrolidine analogue, shortens reaction times and further increases yields. The hydrazone auxiliary is readily converted into either an aldehyde or a nitrile group, thereby providing a plethora of functionalized anilides. The developed procedure was also applied to 3-acetamido-5-acetylfuran (3A5AF) to successfully prepare a phthalimide.

CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms.

The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells.

PGL-III, a Rare Intermediate of Mycobacterium leprae Phenolic Glycolipid Biosynthesis, Is a Potent Mincle Ligand.

Although leprosy (Hansen's disease) is one of the oldest known diseases, the pathogenicity of Mycobacterium leprae (M. leprae) remains enigmatic. Indeed, the cell wall components responsible for the immune response against M. leprae are as yet largely unidentified. We reveal here phenolic glycolipid-III (PGL-III) as an M. leprae-specific ligand for the immune receptor Mincle. PGL-III is a scarcely present trisaccharide intermediate in the biosynthetic pathway to PGL-I, an abundant and characteristic M. leprae glycolipid. Using activity-based purification, we identified PGL-III as a Mincle ligand that is more potent than the well-known M. tuberculosis trehalose dimycolate. The cocrystal structure of Mincle and a synthetic PGL-III analogue revealed a unique recognition mode, implying that it can engage multiple Mincle molecules. In Mincle-deficient mice infected with M. leprae, increased bacterial burden with gross pathologies were observed. These results show that PGL-III is a noncanonical ligand recognized by Mincle, triggering protective immunity.

Site-selective introduction of thiols in unprotected glycosides.

Thioglycosides or S-linked-glycosides are important glycomimetics. These thioglycosides are often prepared by glycosylating deoxythio sugar acceptors, which are synthesized via elaborate protecting group manipulations. We discovered that a carbonyl group, formed by site-selective oxidation of unprotected saccharides, can be converted into a thiol moiety. The transformation involves SN1-substitution of a chloro-azo intermediate, formed by oxidation of the corresponding trityl hydrazone, with a thiol. The prepared deoxythio sugars provide, in combination with the recently developed protecting group-free glycosylation of glycosyl fluorides, a protecting group-free synthesis of thioglycosides.

A Predictive Model for the Pd-Catalyzed Site-Selective Oxidation of Diols.

A predictive model, shaped as a set of rules, is presented that predicts site-selectivity in the mono-oxidation of diols by palladium-neocuproine catalysis. For this, the factors that govern this site-selectivity within diols and between different diols have been studied both experimentally and with computation. It is shown that an electronegative substituent antiperiplanar to the C-H bond retards hydride abstraction, resulting in a lower reactivity. This explains the selective oxidation of axial hydroxy groups in vicinal cis-diols. Furthermore, DFT calculations and competition experiments show how the reaction rate of different diols is determined by their configuration and conformational freedom. The model has been validated by the oxidation of several complex natural products, including two steroids. From a synthesis perspective, the model predicts whether a natural product comprising multiple hydroxy groups is a suitable substrate for site-selective palladium-catalyzed oxidation.

Aggregation pheromones have a non-linear effect on oviposition behavior in Drosophila melanogaster.

Female fruit flies (Drosophila melanogaster) oviposit at communal sites where the larvae may cooperate or compete for resources depending on group size. This offers a model system to determine how females assess quantitative social information. We show that the concentration of pheromones found on a substrate increases linearly with the number of adult flies that have visited that site. Females prefer oviposition sites with pheromone concentrations corresponding to an intermediate number of previous visitors, whereas sites with low or high concentrations are unattractive. This dose-dependent decision is based on a blend of 11-cis-Vaccenyl Acetate (cVA) indicating the number of previous visitors and heptanal (a novel pheromone deriving from the oxidation of 7-Tricosene), which acts as a dose-independent co-factor. This response is mediated by detection of cVA by odorant receptor neurons Or67d and Or65a, and at least five different odorant receptor neurons for heptanal. Our results identify a mechanism allowing individuals to transform a linear increase of pheromones into a non-linear behavioral response.

Site-Selective Electrochemical Oxidation of Glycosides.

Quinuclidine-mediated electrochemical oxidation of glycopyranosides provides C3-ketosaccharides with high selectivity and good yields. The method is a versatile alternative to Pd-catalyzed or photochemical oxidation and is complementary to the 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-mediated C6-selective oxidation. Contrary to the electrochemical oxidation of methylene and methine groups, the reaction proceeds without oxygen.

A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages.

Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside-producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd-induced lipid substrates that define Gaucher's disease, Wolman's disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis-induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.

π-Facial selectivity in the Diels-Alder reaction of glucosamine-based chiral furans and maleimides.

Furans derived from carbohydrate feedstocks are a versatile class of bio-renewable building blocks and have been used extensively to access 7-oxanorbornenes via Diels-Alder reactions. Due to their substitution patterns these furans typically have two different π-faces and therefore furnish racemates in [4 + 2]-cycloadditions. We report the use of an enantiopure glucosamine derived furan that under kinetic conditions predominantly affords the exo-product with a high π-face selectivity of 6.5 : 1. The structure of the product has been resolved unequivocally by X-ray crystallography, and a multi-gram synthesis (2.8 g, 58% yield) confirms the facile accessibility of this multifunctional enantiopure building block.

Racemic Total Synthesis of Elmonin and Pratenone A, from Streptomyces, Using a Common Intermediate Prepared by peri-Directed C-H Functionalization.

The first total synthesis of elmonin and pratenone A, two complex rearranged angucyclinones from Streptomyces, is reported. Using peri-directed C-H functionalization, the key naphthalene fragment present in both synthetic targets was efficiently prepared. Coupling to two anisole-derived fragments gave access to the natural products, in which elmonin was prepared using a biomimetic spiro-ketalization.

Site-Selective Modification of (Oligo)Saccharides.

Oligosaccharides, either as such or as part of glycolipids, glycopeptides, or glycoproteins, are ubiquitous in nature and fulfill important roles in the living cell. Also in medicine and to some extent in materials, oligosaccharides play an important role. In order to study their function, modifying naturally occurring oligosaccharides, and building in reactive groups and reporter groups in oligosaccharides, are key strategies. The development of oligosaccharides as drugs, or vaccines, requires the introduction of subtle modifications in the structure of oligosaccharides to optimize efficacy and, in the case of antibiotics, circumvent bacterial resistance. Provided the natural oligosaccharide is available, site-selective modification is an attractive approach as total synthesis of the target is often very laborious. Researchers in catalysis areas, such as transition-metal catalysis, enzyme catalysis, organocatalysis, and photoredox catalysis, have made considerable progress in the development of site-selective and late-stage modification methods for mono- and oligosaccharides. It is foreseen that the fields of enzymatic modification of glycans and the chemical modification of (oligo)saccharides will approach and potentially meet each other, but there is a lot to learn and discover before this will be the case.

Site-Selective Dehydroxy-Chlorination of Secondary Alcohols in Unprotected Glycosides.

To circumvent protecting groups, the site-selective modification of unprotected glycosides is intensively studied. We show that site-selective oxidation, followed by treatment of the corresponding trityl hydrazone with tert-butyl hypochlorite and a H atom donor provides an effective way to introduce a chloride substituent in a variety of mono- and disaccharides. The stereoselectivity can be steered, and a new geminal dichlorination reaction is described as well. This strategy challenges existing methods that lead to overchlorination.

Late-Stage Modification of Aminoglycoside Antibiotics Overcomes Bacterial Resistance Mediated by APH(3') Kinases.

The continuous emergence of antimicrobial resistance is causing a threat to patients infected by multidrug-resistant pathogens. In particular, the clinical use of aminoglycoside antibiotics, broad-spectrum antibacterials of last resort, is limited due to rising bacterial resistance. One of the major resistance mechanisms in Gram-positive and Gram-negative bacteria is phosphorylation of these amino sugars at the 3'-position by O-phosphotransferases [APH(3')s]. Structural alteration of these antibiotics at the 3'-position would be an obvious strategy to tackle this resistance mechanism. However, the access to such derivatives requires cumbersome multi-step synthesis, which is not appealing for pharma industry in this low-return-on-investment market. To overcome this obstacle and combat bacterial resistance mediated by APH(3')s, we introduce a novel regioselective modification of aminoglycosides in the 3'-position via palladium-catalyzed oxidation. To underline the effectiveness of our method for structural modification of aminoglycosides, we have developed two novel antibiotic candidates overcoming APH(3')s-mediated resistance employing only four synthetic steps.

Synthesis of phosphatidic acids via cobalt(salen) catalyzed epoxide ring-opening with dibenzyl phosphate.

With a CoIII(salen)OTs catalyst, dibenzyl phosphate ring-opens a variety of terminal epoxides with excellent regio-selectively and yields up to 85%. The reaction is used in a highly efficient synthesis of enantiopure mixed-diacyl phosphatidic acids, including a photoswitchable phosphatidic acid mimic.