Peptidoglycan (PG), an essential exoskeletal polymer in bacteria, is a well-known antibiotic target. PG polymerization requires the action of bacterial transglycosylases (TGases), which couple the incoming glycosyl acceptor to the donor. Interfering with the TGase activity can interrupt the PG assembly. Existing TGase inhibitors like moenomycin and Lipid II analogues always occupy the TGase active sites; other strategies to interfere with proper PG elongation have not been widely exploited. Inspired by the natural 1,6-anhydro-MurNAc termini that mark the ends of PG strands in bacteria, we hypothesized that the incorporation of an anhydromuramyl-containing glycosyl acceptor by TGase into the growing PG may effectively inhibit PG elongation. To explore this possibility, we synthesized 4-O-(N-acetyl-ß-d-glucosaminyl)-1,6-anhydro-N-acetyl-ß-d-muramyl-l-Ala-γ-d-Glu-l-Lys-d-Ala-d-Ala, 1, within 15 steps, and demonstrated that this anhydromuropeptide and its analogue lacking the peptide, 1-deAA, were both utilized by bacterial TGase as noncanonical anhydro glycosyl acceptors in vitro. The incorporation of an anhydromuramyl moiety into PG strands by TGases afforded efficient termination of glycan chain extension. Moreover, the preliminary in vitro studies of 1-deAA against Staphylococcus aureus showed that 1-deAA served as a reasonable antimicrobial adjunct of vancomycin. These insights imply the potential application of such anhydromuropeptides as novel classes of PG-terminating inhibitors, pointing toward novel strategies in antibacterial agent development.
Anti-Bacterial Agents , Peptidoglycan , Peptidoglycan/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/metabolism , Glycosyltransferases/metabolism
In this study, we explore feasibility of the mechanochemical approach in the synthesis of tetrabenzofluorenes (fluoreno[5]helicenes). For this, commercially available phenylated cyclopentadiene precursors are subjected to the Scholl reaction in the solid state using FeCl3 as an oxidant and sodium chloride as the solid reaction medium. This ball milling process gave access to the 5-membered ring containing-helicenes in one synthetic step in high (95-96 %) isolated yields. The solution-phase reactions, however, were found to be moderate to low yielding in this regard (10-40 %).
Corannulene, a curved polycyclic aromatic hydrocarbon, is prepared in a multigram scale through mechanochemical synthesis. Initially, a mixer mill approach is examined and found to be suitable for a gram scale synthesis. For larger scales, planetary mills are used. For instance, 15â g of corannulene could be obtained in a single milling cycle with an isolated yield of 90 %. The yields are lower when the jar rotation rate is lower or higher than 400 revolutions per minute (rpm). Cumulatively, 98â g of corannulene is produced through the ball milling-based grinding techniques. These results indicate the future potential of mechanochemistry in the rational chemical synthesis of highly curved nanocarbons such as fullerenes and carbon nanotubes.
Herein we show that hybridisation of buckybowl corannulene and thiophene-S,S-dioxide motifs is a general approach for the preparation of high electron affinity molecular materials. The devised synthesis is modular and relies on thienannulation of corannnulene-based phenylacetylene scaffolds. The final compounds are highly soluble in common organic solvents. These compounds also exhibit interesting optical properties such as absorption and emission in the blue/green regions of the electromagnetic spectrum. Importantly, a bis-S,S-dioxide derivative exhibits three reversible reductions similar in their strength to the prevalent fullerene-based electron acceptor phenyl-C61 -butyric acid methyl ester (PC61 BM).
The transformation of planar aromatic molecules into π-extended non-planar structures is a challenging task and has not been realized by mechanochemistry before. Here we report that mechanochemical forces can successfully transform a planar polyarene into a curved geometry by creating new C-C bonds along the rim of the molecular structure. In doing so, mechanochemistry does not require inert conditions or organic solvents and provide better yields within shorter reaction times. This is illustrated in a 20-minute synthesis of corannulene, a fragment of fullerene C60, in 66% yield through ball milling of planar tetrabromomethylfluoranthene precursor under ambient conditions. Traditional solution and gas-phase synthetic pathways do not compete with the practicality and efficiency offered by the mechanochemical synthesis, which now opens up a new reaction space for inducing curvature at a molecular level.
It is shown that corannulene-based strained π-surfaces can be obtained through the use of mechanochemical Suzuki and Scholl reactions. Besides being solvent-free, the mechanochemical synthesis is high-yielding, fast, and scalable. Therefore, gram-scale preparation can be carried out in a facile and sustainable manner. The synthesized nanographene structure carries positive (bowl-like) and negative (saddle-like) Gaussian curvatures and adopts an overall quasi-monkey saddle-type of geometry. In terms of properties, the non-planar surface exhibits a high electron affinity that was measured by cyclic voltammetry, with electrolysis and inâ situ UV/vis spectroscopy experiments indicating that the one-electron reduced state displays a long lifetime in solution. Overall, these results indicate the future potential of mechanochemistry in accessing synthetically challenging and functional curved π-systems.
Herein, we devised a method for stereoselective O-glycosylation using an Ir(i)-catalyst which enables both hydroalkoxylation and nucleophilic substitution of glycals with varying substituents at the C3 position. In this transformation, 2-deoxy-α-O-glycosides were acquired when glycals equipped with a notoriously poor leaving group at C3 were used; in contrast 2,3-unsaturated-α-O-glycosides were produced from glycals that bear a good leaving group at C3. Mechanistic studies indicate that both reactions proceed via the directing mechanism, through which the acceptor coordinates to the Ir(i) metal in the α-face-coordinated Ir(i)-glycal π-complex and then attacks the glycal that contains the O-glycosidic bond in a syn-addition manner. This protocol exhibits good functional group tolerance and is exemplified with the preparation of a library of oligosaccharides in moderate to high yields and with excellent stereoselectivities.
In the pursuit of developing potent drug molecules, more efficient and straightforward procedures are in high demand. The evergrowing interest in carbohydrate-based therapeutics and vaccines particularly calls for such reliable and universal approaches that assemble oligosaccharides rapidly and stereoselectively. Hereby, we compiled remarkable efforts made in exploring the possibilities of protection-less glycosylation strategies. Pioneering works using organotin reagents or catalysts were introduced first, followed by the organoboron successors that were deemed less toxic and more versatile alternatives. In the meantime, more species such as copper or caesium were also included and supported by a mechanistic rationale. Lastly, we hope to bring further insights into the synthesis of intricate carbohydrate derivatives, achieved with the aid of glycosylation methods discussed herein.
Biological Products/chemistry , Polysaccharides/chemistry , Sugars/chemistry , Biological Products/chemical synthesis , Glycosylation , Molecular Structure , Polysaccharides/chemical synthesis , Stereoisomerism , Sugars/chemical synthesis
Mechanistic study of carbohydrate interactions in biological systems calls for the chemical synthesis of these complex structures. Owing to the specific stereo-configuration at each anomeric linkage and diversity in branching, significant breakthroughs in recent years have focused on either stereoselective glycosylation methods or facile assembly of glycan chains. Here, we introduce the unification approach that offers both stereoselective glycosidic bond formation and removal of protection/deprotection steps required for further elongation. Using dialkylboryl triflate as an in situ masking reagent, a wide array of glycosyl donors carrying one to three unprotected hydroxyl groups reacts with various glycosyl acceptors to furnish the desired products with good control over regioselectivity and stereoselectivity. This approach demonstrates the feasibility of straightforward access to important structural scaffolds for complex glycoconjugate synthesis.
Glycosylation , Magnetic Resonance Spectroscopy , Catalysis , Chemistry, Organic , Glycoconjugates , Glycosides/chemistry , Oligosaccharides/chemistry , RNA, Transfer/chemistry , Solvents/chemistry , Stereoisomerism
Inherently chiral dinuclear rhodium complexes have been synthesized from the well-known dirhodium(II)-acetate and chiral/achiral amino acids. These complexes have a twisted paddlewheel structure due to axial chirality. Chiral induction could be observed when the ligands were chiral, opposite to the case of achiral ligands, where a racemic mixture was formed. The racemic mixture was separated by chiral HPLC-ECD. The stereochemical properties of these complexes were determined by VCD spectroscopy supported by theoretical calculations at the DFT level. We present a simple route to determine the absolute configuration by an exciton chirality method using VCD spectroscopy.
