Manganese-Catalyzed Chemoselective Coupling of Secondary Alcohols, Primary Alcohols and Methanol.

Herein, we report a manganese-catalyzed three-component coupling of secondary alcohols, primary alcohols and methanol for the synthesis of ß,ß-methylated/alkylated secondary alcohols. Using our method, a series of 1-arylethanol, benzyl alcohol derivatives, and methanol undergo sequential coupling efficiently to construct assembled alcohols with high chemoselectivity in moderate to good yields. Mechanistic studies suggest that the reaction proceeds via methylation of a benzylated secondary alcohol intermediate to generate the final product.

Multifunctional Glyco-Nanosheets to Eradicate Drug-Resistant Bacteria on Wounds.

Bacterial infection is becoming increasingly lethal with the emergence of antimicrobial resistance, and wounds plagued by such infection are notoriously difficult to heal. Here, the first use of galactose-black phosphorus nanosheets, (Gal-BP NSs) as a delivery platform for synergistic antibiotic (kanamycin, Kana) and photothermal treatments against the Gram-negative microbial strain, Pseudomonas aeruginosa PAO1 (PAO1) is reported. Gal-BP NSs@Kana can actively target PAO1 and release kanamycin into the bacterial cytoplasm upon near-infrared laser irradiation. This strategy kills most of the PAO1 through a simultaneous burst of intracellular kanamycin release and photothermal treatment. Comparable antibacterial activities of Gal-BP NSs@Kana are observed within in vivo mouse models at their wound sites. In addition, this platform accelerates wound healing from PAO1 infection via promotion of neoangiogenesis and collagen production at the wound sites. This work demonstrates the material properties of Gal-BP NS in fighting bacterial infections and in the treatment of wound healing.

Synthetic biohybrid peptidoglycan oligomers enable pan-bacteria-specific labeling and imaging: in vitro and in vivo.

Peptidoglycan is the core component of the bacterial cell wall, which makes it an attractive target for the development of bacterial targeting agents. Intercepting its enzymatic assembly with synthetic substrates allows for labeling and engineering of live bacterial cells. Over the past two decades, small-molecule-based labeling agents, such as antibiotics, d-amino acids or monosaccharides have been developed for probing biological processes in bacteria. Herein, peptidoglycan oligomers, substrates for transglycosylation, are prepared for the first time using a top-down approach, which starts from chitosan as a cheap feedstock. A high efficiency of labeling has been observed in all bacterial strains tested using micromolar substrates. In contrast, uptake into mammalian cells was barely observable. Additional mechanistic studies support a hypothesis of bacteria-specific metabolic labeling rather than non-specific binding to the bacterial surface. Eventually, its practicality in bacterial targeting capability is demonstrated in resistant strain detection and in vivo infection models.

One-Pot Cascade Transformation of Glucal into Structurally Diverse Drug-Like Scaffolds.

A diversity-oriented synthesis strategy to produce three types of structurally drug-like N-heterocyclic-fused rings has been developed from abundant biomass-derived d-glucal, aniline and water in a stereoselective manner. The overall transformation which entails a cascade of Ferrier reaction and 4π conrotatory imino-Nazarov cyclization was performed in one-pot allowing convenient preparation of scaffolds of high molecular complexity from relatively simple starting materials. While indoline-fused products were readily accessible using ortho-unsubstituted secondary anilines as substrates, reactions with ortho-hydroxyl-anilines furnished fused 1,4-benzoxazines instead. In both cases, InBr3 acted as the Lewis acid catalyst. By altering InBr3 to Ln(OTf)3 , the indoline-fused products could be further converted into tetrahydroquinoline-fused cyclopentenones via ensuing retro-ene rearrangement.

Stereo- and regioselective glycosylation with protection-less sugar derivatives: an alluring strategy to access glycans and natural products.

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.

Venturing beyond Donor-Controlled Glycosylation: New Perspectives toward Anomeric Selectivity.

Glycans are complex compounds consisting of sugars linked glycosidically, existing either as pure polysaccharides or as part of glycoconjugates. They are prevalent in nature and possess important functions in regulating biological pathways. However, their diversity coupled with physiochemical similarities makes it challenging to isolate them in large quantities for biochemical studies, hence hampering progress in glycobiology and glycomedicine. Glycochemistry presents an alternative strategy to obtain pure glycan compounds through artificial synthetic methods. Efforts in glycochemistry have been centered on glycosylation, the key reaction in glycochemistry, especially with regards to anomeric stereoselectivity in polysaccharides and glycoconjugates. In particular, the stereoelectronic and steric properties of glycosyl donors are commonly used to direct the stereoselectivity in glycosylation reactions. Classic glycosylation strategies typically involve saturated glycosyl donors, proceeding either directly using hydrogen bonds and conformational constraints or indirectly by installing moieties covalently through neighboring group participation and intramolecular aglycon delivery. Over the past years, new glycosylation strategies, tapping on the foundations of transition metal catalysis, have emerged. To leverage the power of coordination chemistry, unsaturated glycosyl donors were introduced. Not only are the number of protection/deprotection steps reduced, the resultant unsaturated glycoside provides opportunities for downstream functionalizations, allowing quick access to a variety of sugars, including rare sugars. Alongside the glycosyl donor, an equally important but neglected aspect for targeting stereoselective glycosylation is the glycosyl acceptor. In the case of dual-directing donors, glycosyl acceptors have proved themselves capable of becoming the dominating factor for stereocontrol. Interestingly, rational manipulation or selection of glycosyl acceptors with particular nucleophilicity and p Ka values can lead to different stereoselectivities, thereby proving the tunability of such acceptors to favor the formation of one anomer over the other stereoselectively. By further venturing beyond substrate controlled stereoselectivity, we are presented with the opportunity to effect stereoselective glycosylation through glycosylating reagents. Of the key reagents, stereoselective catalyst stands out as a greener and efficient alternative to direct stereoselective control with stoichiometric substrates. Recently, investigations into this approach of stereocontrol presented an intriguing range of stereoselectivities, achieved by merely varying the nature of catalysts used. Another crucial effort in glycochemistry is enhancing the efficiencies of glycosylations, by reducing the number of preparative steps before or during glycosylation. Through using transient masking groups or one-pot synthetic strategies, these streamlined approaches provide enormous convenience and practicability for oligosaccharide syntheses. This Account presents mainly our advancements beyond the conventional donor-controlled strategies over the past decade, with emphasis placed on mechanistic explanations of anomeric selectivities, thereby providing perspectives to inspire further progress toward a generalized unified strategy for preparing every type of glycan.

Asymmetric syntheses of 8-oxabicyclo[3,2,1]octane and 11-oxatricyclo[5.3.1.0]undecane from glycals.

Herein, we describe an efficient method to prepare enantiomerically pure 8-oxabicyclo[3.2.1]octanes via gold(i)-catalyzed tandem 1,3-acyloxy migration/Ferrier rearrangement of glycal derived 1,6-enyne bearing propargylic carboxylates. The resultant compounds could then undergo interrupted Nazarov cyclization to afford diastereomerically pure 11-oxatricyclo[5.3.1.0]undecanes.

A minimalist approach to stereoselective glycosylation with unprotected donors.

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.

Reversing the stereoselectivity of a palladium-catalyzed O-glycosylation through an inner-sphere or outer-sphere pathway.

An efficient and concise method for the construction of various O-glycosidic bonds by a palladium-catalyzed reaction with a 3-O-picoloyl glucal has been developed. The stereochemistry of the anomeric center derives from either an inner-sphere or outer-sphere pathway. Harder nucleophiles, such as aliphatic alcohols and sodium phenoxides give ß-products, and α products result from using softer nucleophiles, such as phenol.

Stereocontrolled O-glycosylation with palladium-catalyzed decarboxylative allylation.

The Pd-π-allyl intermediate in an electron-rich glycal system with poor reactivity is employed as an efficient glycosyl donor. Starting from glucal derived carbonate, various O-glycosides were formed via a palladium-catalyzed reaction through a tandem decarboxylation, proton abstraction, and nucleophilic addition, in good yields with excellent selectivity. Iterative glycosylation with the same strategy may provide an access to complex oligosaccharides.

One-pot synthesis of ß-N-glycosyl imidazole analogues via a palladium-catalysed decarboxylative allylation.

A concise and highly efficient strategy for the synthesis of N-glycosyl imidazole analogues is reported. This reaction is based on a palladium catalysed decarboxylative allylation and three steps, namely, carbamation, decarboxylation and allylation are involved. All the substrates can afford the desired products with excellent yields and selectivities.

ß-Type glycosidic bond formation by palladium-catalyzed decarboxylative allylation.

Decarboxylative allylation of glycals: A ß-type glycosidic bond has been constructed in high regio- and stereoselectivity by means of a palladium-catalyzed decarboxylative O-glycosylation. Various kinds of glycals with different protecting groups have been examined for this reaction to afford a diverse set of glycosylated products, including phenolic O-glycosides, thiophenolic S-glycoside, aliphatic O-glycosides, and disaccharides with excellent ß-selectivity and reasonable to excellent yields.