Pd-Catalyzed Stereospecific Glycosyl Cross-Coupling of Reversed Anomeric Stannanes for Modular Synthesis of Nonclassical -Glycosides.

Nonclassical -glycosides, distinguished by their unique glycosidic bond connection mode, represent a promising avenue for the development of carbohydrate-based drugs. However, the accessibility of nonclassical -glycosides hinders broader investigations into their structural features and modes of action. Herein, we present the first example of Pd-catalyzed stereospecific glycosylation of nonclassical anomeric stannanes with aryl or vinyl halides.

Si-Linked Glycomimetics through a Stereoselective Silicon Transfer and Anion Addition.

We report a synthesis of silicon-linked glycomimetics, demonstrating unique structural properties and metabolic stability due to the inertness of the C-Si bond. Our method focuses on the stereoselective transfer of silicon and anion addition, revealing that chirality at the silicon atom can be controlled through kinetic resolution. This approach allows for the selective generation of 1,2- and 1,2- isomers via the manipulation of C2-protected silicon ethers and nucleophilic opening of glycal epoxides.

Post-Translational Modifications Control Phase Transitions of Tau.

The self-assembly of Tau(297-391) into filaments, which mirror the structures observed in Alzheimer's disease (AD) brains, raises questions about the role of AD-specific post-translational modifications (PTMs) in the formation of paired helical filaments (PHFs). To investigate this, we developed a synthetic approach to produce Tau(291-391) featuring N-acetyllysine, phosphoserine, phosphotyrosine, and N-glycosylation at positions commonly modified in post-mortem AD brains, thus facilitating the study of their roles in Tau pathology. Using transmission electron microscopy (TEM), cryo-electron microscopy (cryo-EM), and a range of optical microscopy techniques, we discovered that these modifications generally hinder the assembly of Tau into PHFs.

Peptide and Protein Desulfurization with Diboron Reagents.

In this Letter, we report a direct and robust desulfurization method employing water-soluble phosphine, specifically tris(2-carboxyethyl)phosphine hydrochloride (TCEP), and tetrahydroxydiboron (B(OH)), which serves as a radical initiator. This innovative reaction exhibits compatibility with a diverse array of substrates, including cysteine residues in chemically synthesized oligopeptides and cyclic peptides, alkyl thiols in bioactive molecules, disulfides in commercial proteins, and selenocysteine. We optimized the reaction conditions to minimize the formation of undesired oxidized and borylated byproducts.

Desulfurative Borylation of Small Molecules, Peptides, and Proteins.

We introduce a direct conversion of alkyl thiols into boronic acids, facilitated by a water-soluble phosphine, 1,3,5-triaza-7-phosphaadamantane (PTA), in conjunction with tetrahydroxydiboron (B(OH)), acting as both a radical initiator and a boron source. This desulfurative borylation reaction has been successfully applied to various substrates, including cysteine residues in oligopeptides and small proteins, primary alkyl thiols found in pharmaceutical compounds, disulfides, and selenocysteine. Optimization of reaction conditions was undertaken to reduce the formation of unwanted reactions, such as the reduction of alanyl or other primary radicals, and to prevent deleterious reactions between the phosphine and N-terminal amine that lead to methylene adducts by utilizing a buffer containing glycine-glycine (GG) dipeptide.

TMEM106B Fibrils from FTLD Patients and Healthy Controls.

Recent studies involving four research teams have revealed that amyloid fibrils in FTLD-TDP patients and cognitively healthy individuals primarily consist of TMEM106B, a protein previously identified as a risk factor for FTLD-TDP. Through cryogenic electron microscopy, the studies identified various protofilament structures of TMEM106B fibrils from individuals with several neurodegenerative diseases. These findings raise new questions and opportunities for future research, as they suggest that TMEM106B plays a central role in FTLD pathology.

Stereoselective alkyl -glycosylation of glycosyl esters anomeric C-O bond homolysis: efficient access to -glycosyl amino acids and -glycosyl peptides.

-Glycosyl peptides possess excellent metabolic stability and therapeutic properties and thus play critical roles in biological studies as well as drug discoveries. However, the limited accessibility of -glycosyl amino acids has significantly hindered the broader research of their structural features and mode of action. Herein, for the first time we disclose a novel visible-light-driven radical conjugate addition of 1,4-dihydropyridine (DHP)-derived glycosyl esters with dehydroalanine derivatives, generating -glycosyl amino acids and -glycosyl peptides in good yields with excellent stereoselectivities.

Catalytic Amide Activation with Thermally Stable Molybdenum(VI) Dioxide Complexes.

Oxazolines and thiazolines are important constituents of bioactive natural products and pharmaceuticals. Here, we report the development of an effective and practical method of oxazoline and thiazoline formation, which can facilitate the synthesis of natural products, chiral ligands, and pharmaceutical intermediates. This method capitalized on a Mo(VI) dioxide catalyst stabilized by substituted picolinic acid ligands, which is tolerant to many functional groups that would otherwise be sensitive to highly electrophilic alternative reagents.

Umpolung Ala Reagents for the Synthesis of Non-Proteogenic Amino Acids, Peptides and Proteins.

Non-proteogenic amino acids and functionalized peptides are important motifs in modern drug discovery. Here we report that Ala can serve as universal building blocks in the synthesis of a diverse collection of modified amino acids, peptides, and proteins. First, we develop the synthesis of Ala from redox-active esters of aspartic acid resulting in a series of β-boronoalanine derivatives.

Current Landscape of Coccidioidomycosis.

Coccidioidomycosis, also known as Valley fever, is an endemic fungal infection commonly found in the southwestern parts of the United States. However, the disease has seen an increase in both in its area of residency and its prevalence. This review compiles some of the latest information on the epidemiology, current and in-development pharmaceutical approaches to treat the disease, trends and projections, diagnostic concerns, and the overlapping dynamics of coccidioidomycosis and COVID-19, including in special populations.

Organometallic Ala Reagents for Umpolung Peptide Diversification.

Selective modifications of peptides and proteins have emerged as a promising strategy to develop novel mechanistic probes and prepare compounds with translational potentials. Here, we report alanine carbastannatranes Ala as a universal synthon in various C-C and C-heteroatom bond-forming reactions. These reagents are compatible with peptide manipulation techniques and can undergo chemoselective conjugation in minutes when promoted by Pd(0).

Light-Mediated Cross-Coupling of Anomeric Trifluoroborates.

Stereoselective reactions at the anomeric carbon constitute the cornerstone of preparative carbohydrate chemistry. Here, we report stereoselective C-arylation and etherification reactions of anomeric trifluoroborates derived from BMIDA esters. These reactions are characterized by high anomeric selectivities for 2-deoxysugars and broad substrate scope (24 examples), including disaccharides and trifluoroborates with free hydroxyl groups.

Ligand-Free Copper(I)-Mediated Cross-Coupling Reactions of Organostannanes with Sulfur Electrophiles.

The synthesis of aryl thioether through the cross-coupling of C-S bond is a highly attractive area of research due to the prevalence of aryl thioether in bioactive natural products, functional materials, agrochemicals, and pharmaceutically active compounds. Herein, we report a ligand-free Cu(I) mediated electrophilic thiolation of organostannanes with sulfur electrophiles. A selective transfer of alkyl groups was achieved in reactions with alkyl carbastannatranes affording congested thioethers.

Stereochemistry of Transition Metal Complexes Controlled by the Metallo-Anomeric Effect.

The use of stereoelectronic interactions to control reactivity and selectivity has a long history in chemistry. The anomeric effect, one of the fundamental concepts in organic chemistry, describes the preferences of a substituent at the anomeric carbon in glycosides to adopt axial configuration when the anomeric group is an electronegative element such as oxygen or a halogen. The origin of the anomeric effect has been the subject of intense debate.

Catalytic and Photochemical Strategies to Stabilized Radicals Based on Anomeric Nucleophiles.

Carbohydrates, one of the three primary macromolecules of living organisms, play significant roles in various biological processes such as intercellular communication, cell recognition, and immune activity. While the majority of established methods for the installation of carbohydrates through the anomeric carbon rely on nucleophilic displacement, anomeric radicals represent an attractive alternative because of their functional group compatibility and high anomeric selectivities. Herein, we demonstrate that anomeric nucleophiles such as C1 stannanes can be converted into anomeric radicals by merging Cu(I) catalysis with blue light irradiation to achieve highly stereoselective C(sp)-S cross-coupling reactions.

Copper-Catalyzed Oxidative Acetalization of Boronic Esters: An Umpolung Strategy for Cyclic Acetal Synthesis.

A protocol for the acetalization of boronic esters is described. The reaction is catalyzed by copper, and the conditions proved to be mild and were amenable to a variety of functional groups. We expanded the Chan-Lam coupling to include C(sp) nucleophiles and converted them into corresponding acetals.

Total synthesis of micrococcin P1 and thiocillin I enabled by Mo(vi) catalyst.

Thiopeptides are a class of potent antibiotics with promising therapeutic potential. We developed a novel Mo(vi)-oxide/picolinic acid catalyst for the cyclodehydration of cysteine peptides to form thiazoline heterocycles. With this powerful tool in hand, we completed the total syntheses of two representative thiopeptide antibiotics: micrococcin P1 and thiocillin I.

Acyl Glycosides through Stereospecific Glycosyl Cross-Coupling: Rapid Access to C(sp)-Linked Glycomimetics.

Replacement of a glycosidic bond with hydrolytically stable C-C surrogates is an efficient strategy to access glycomimetics with improved physicochemical and pharmacological properties. We describe here a stereoretentive cross-coupling reaction of glycosyl stannanes with C(sp)- and C(sp)-thio(seleno)esters suitable for the preparation -acyl glycosides as synthetic building blocks to obtain C(sp)-linked and fluorinated glycomimetics. First, we identified a set of standardized conditions employing a Pd(0) precatalyst, CuCl additive, and phosphite ligand that provided access to -acyl glycosides without deterioration of anomeric integrity and decarbonylation of the acyl donors (>40 examples).

Stereoselective oxidative glycosylation of anomeric nucleophiles with alcohols and carboxylic acids.

Oligosaccharides, one of the most abundant biopolymers, are involved in numerous biological processes. Although many efforts have been put in preparative carbohydrate chemistry, achieving optimal anomeric and regioselectivities remains challenging. Herein we describe an oxidative glycosylation method between anomeric stannanes and oxygen nucleophiles resulting in the formation of a C-O bond with consistently high anomeric control for glycosyl donors bearing a free C2-hydroxyl group.

Rethinking Carbohydrate Synthesis: Stereoretentive Reactions of Anomeric Stannanes.

In this Concept article, recent advances are highlighted in the synthesis and applications of anomeric nucleophiles, a class of carbohydrates in which the C1 carbon bears a carbon-metal bond. First, the advantages of exploiting the carboanionic reactivity of carbohydrates and the methods for the synthesis of mono- and oligosaccharide stannanes are discussed. Second, recent developments in the glycosyl cross-coupling method resulting in the transfer of anomeric configuration from C1 stannanes to C-aryl glycosides are reviewed.

Asymmetric Synthesis of Chiral 1,2-Amino Alcohols and Morpholin-2-ones from Arylglyoxals.

Chiral 1,2-amino alcohols are privileged scaffolds with important applications as drug candidates and chiral ligands. Although various methods for the preparation of this structural motif have been reported, these methods are limited because of the use of precious metals and ligands. Here, we report a practical and high yielding synthesis of chiral 1,2-amino alcohols using arylglyoxals and pseudoephedrine auxiliary.