Polarity-Matched Initiation of Radical-Polar Crossover Reactions for the Synthesis of C-Allyl Glycosides with gem-Difluoroalkene Groups.

Herein, we disclose a general method for the assembly of C-allyl glycosides containing gem-difluoroalkene groups via a radical-polar crossover strategy. Central to the success of this process is the polarity matching between the benzenesulfinate radical and the glycosyl donor, which facilitates the initiation of the glycosyl radical and the subsequent formation of gem-difluoroalkene sugar derivatives. This method demonstrated good compatibility with various glycosyl donors and functional groups. Furthermore, we showcase the utility of this method in modifying amino acids, potentially paving the way for analogous modifications to peptides.

A Modified Arbuzov-Michalis Reaction for Selective Alkylation of Nucleophiles.

The alkylation of nucleophiles is among the most fundamental and well-developed transformations in chemistry. However, to achieve selective alkylation of complex substrates remains a nontrivial task. We report herein a general and selective alkylation method without using strong acids, bases, or metals. In this method, the readily available phosphinites/phosphites, in combination with ethyl acrylate, function as effective alkylating agents. Various nucleophilic groups, including alcohols, phenols, carboxylic acids, imides, and thiols can be alkylated. This method can be applied in the late-stage alkylation of natural products and pharmaceutical agents, achieving chemo- and site-selective modification of complex substrates. Experimental studies indicate the relative reactivity of a nucleophile depends on its acidity and its steric environment. Mechanistic studies suggest the reaction pathway resembles that of the Arbuzov-Michalis reaction.

Catalytic glycosylation for minimally protected donors and acceptors.

Oligosaccharides have myriad functions throughout biological processes1,2. Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site, stereo- and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose5-8, adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.

Stereoselective synthesis of α-glycosyl azides: allyl glycosyl sulfones as radical precursors.

Despite their critical importance in drug development and biochemistry, efficiently synthesizing α-glycosyl azides has continued to pose significant challenges. In this report, we introduce a universal and practical radical reaction for the stereoselective synthesis of α-glycosyl azides using bench-stable allyl glycosyl sulfones as the donor. This method is characterized by its mild reaction conditions, high stereoselectivity, and extensive scope of glycosyl units. Moreover, the accessibility of several structurally complex drug-sugar conjugates underscores the practicality of our approach.

Preparing glycosyl benzothiazoles from 2-isocyanoaryl thioethers and glycosyl radicals under thermal conditions.

Herein, we report a method for preparing glycosyl benzothiazoles via radical cascade cyclization, in which glycosyl radicals are generated from readily available and bench-stable allyl glycosyl sulfones. This cascade reaction proceeds under simple conditions and tolerates a broad substrate scope in high yield with excellent stereoselectivity. Mechanistic studies support that the reactions proceed via the intermediacy of imidoyl radicals, which attack the appended sulfide unit by a SH2 process to forge the thiazole ring.

Carbohydrate-DNA Conjugation Enabled by Glycosyl Radicals Generated from Glycosyl Sulfinates.

Herein, we report a method that enables the synthesis of carbohydrate-DNA conjugates by radical addition. Key to the success is the use of readily available, bench-stable, and unprotected glycosyl sulfinates as precursors to glycosyl radicals. The redox neutral reaction proceeds under mild and simple conditions and tolerates a broad substrate scope. A small library of carbohydrate-DNA conjugates was prepared.

Palladium catalysis enables cross-coupling-like SN2-glycosylation of phenols.

Despite their importance in life and material sciences, the efficient construction of stereo-defined glycosides remains a challenge. Studies of carbohydrate functions would be advanced if glycosylation methods were as reliable and modular as palladium (Pd)-catalyzed cross-coupling. However, Pd-catalysis excels in forming sp2-hybridized carbon centers whereas glycosylation mostly builds sp3-hybridized C-O linkages. We report a glycosylation platform through Pd-catalyzed SN2 displacement from phenols toward bench-stable, aryl-iodide-containing glycosyl sulfides. The key Pd(II) oxidative addition intermediate diverges from an arylating agent (Csp2 electrophile) to a glycosylating agent (Csp3 electrophile). This method inherits many merits of cross-coupling reactions, including operational simplicity and functional group tolerance. It preserves the SN2 mechanism for various substrates and is amenable to late-stage glycosylation of commercial drugs and natural products.

Base-Promoted Glycosylation Allows Protecting Group-Free and Stereoselective O-Glycosylation of Carboxylic Acids.

Here we report a simple and general method to achieve fully unprotected, stereoselective glycosylation of carboxylic acids, employing bench-stable allyl glycosyl sulfones as donors. Running the glycosylation reaction under basic conditions was crucial for the efficiencies and selectivities. Both the donor activation stage and the glycosidic bond forming stage of the process are compatible with free hydroxyl groups, thereby allowing for the use of fully unprotected glycosyl donors. This transformation is stereoconvergent, occurs under mild and metal-free conditions at ambient temperature with visible light (455 nm) irradiation, and displays remarkable scope with respect to both reaction partners. Many natural products and commercial drugs, including an acid derived from the complex anticancer agent taxol, were efficiently glycosylated. Experimental studies provide insights into the origin of the stereochemical outcome.

The Development of DNA-Compatible S-Glycosyl Transformations.

In this study, we revealed two distinct S-glycosyl transformations in a DNA-encoded library (DEL)-compatible environment. The first approach involves 2-chloro-1,3-dimethylimidazolidinium chloride (DMC)-mediated S-glycosylation, which is facilitated by the coupling of unprotected sugar units with the thiol residue of the DNA-linked compounds. However, this methodology falls short of the requirement for DEL construction due to its limited substrate scope. We further investigated a photoinduced DNA-compatible S-glycosyl transformation through a radical process. In this alternative approach, allyl sugar sulfones serve as sugar donors and are conjugated to DNA-linked compounds upon irradiation with green light. Encouragingly, this on-DNA glycosyl chemistry demonstrated excellent compatibility with functional groups presented in both sugar units and peptides, affording the desired DNA-linked glycosyl derivatives with good to excellent conversions. This pioneering DNA-compatible S-glycosyl transformation represents a valuable tool, facilitating the preparation of glycosyl DELs and offering avenues for the exploration of sugar-incorporated delivery systems.

Generation and Use of Glycosyl Radicals under Acidic Conditions: Glycosyl Sulfinates as Precursors.

We herein report a method that enables the generation of glycosyl radicals under highly acidic conditions. Key to the success is the design and use of glycosyl sulfinates as radical precursors, which are bench-stable solids and can be readily prepared from commercial starting materials. This development allows the installation of glycosyl units onto pyridine rings directly by the Minisci reaction. We further demonstrate the utility of this method in the late-stage modification of complex drug molecules, including the anticancer agent camptothecin. Experimental studies provide insight into the reaction mechanism.

Synthesis of Polydiynes via an Unexpected Dimerization/Polymerization Sequence of C3 Propargylic Electrophiles.

Here, we describe the unexpected discovery of a Cu-catalyzed condensation polymerization reaction of propargylic electrophiles (CPPE) that transforms simple C3 building blocks into polydiynes of C6 repeating units. This reaction was achieved by a simple system composed of a copper acetylide initiator and an electron-rich phosphine ligand. Alkyne polymers (up to 33.8 kg/mol) were produced in good yields and exclusive regioselectivity with high functional group compatibility. Hydrogenation of the product afforded a new polyolefin-type backbone, while base-mediated isomerization led to a new type of dienyne-based electron-deficient conjugated polymer. Mechanistic studies revealed a new α-α selective Cu-catalyzed dimerization pathway of the C3 unit, followed by in situ organocopper-mediated chain-growth propagation. These insights not only provide an important understanding of the Cu-catalyzed CPPE of C3, C4, and C6 monomers in general but also lead to a significantly improved synthesis of polydiynes from simpler starting materials with handles for the incorporation of an α-end functional group.

Alkyl/Glycosyl Sulfoxides as Radical Precursors and Their Use in the Synthesis of Pyridine Derivatives.

We report here the use of simple and readily available alkyl sulfoxides as precursors to radicals and their application in the preparation of pyridine derivatives. We show that alkyl sulfoxides, N-methoxy pyridinium salts and fluoride anions form electron donor-acceptor (EDA) complexes in solution, which, upon visible light irradiation, undergo a radical chain process to afford various pyridine derivatives smoothly. This reaction displays broad scope with respect to both sulfoxides and N-methoxy pyridiniums. The synthetic versatility of sulfoxides as a handle in chemistry adds to their power as radical precursors. Glycosyl sulfoxides are converted to the corresponding pyridyl C-glycosides with high stereoselectivities. Computational and experimental studies provide insights into the reaction mechanism.

Doubly stereoconvergent construction of vicinal all-carbon quaternary and tertiary stereocenters by Cu/Mg-catalyzed propargylic substitution.

The construction of vicinal, congested stereocenters with high selectivities is of general utility in chemistry. To build two such stereocenters in one step from readily available starting materials is very desirable, but remains challenging. We report here a doubly stereoconvergent, Cu/Mg-catalyzed asymmetric propargylic substitution reaction to convert simple starting materials to products with vicinal tertiary and all-carbon quaternary stereocenters in high yields and excellent diastereo- and enantioselectivities. Both the nucleophiles and the electrophiles employed in this transformation are racemic. This reaction uses earth abundant metal catalysts, operates under ambient conditions, and demonstrates broad substrate scope. The products of this reaction are functional group rich and synthetically versatile. Key to the success of this development is the devise of a Cu/Mg dual catalytic system and the identification of a bulky tridentate pyridinebisimidazoline (PyBim) ligand.

Halogen-bond-assisted radical activation of glycosyl donors enables mild and stereoconvergent 1,2-cis-glycosylation.

The chemistry of carbohydrates has a history of over 100 years, but simple, stereoselective and efficient glycosylation methods remain highly needed to facilitate the studies of sugars in various disciplines. Here we report a strategy for 1,2-cis-glycosylation without using metals, strong (Lewis) acids, elaborate catalysts or labile substrates. Our method operates by a unique mechanism: it activates glycosyl donors through a radical cascade rather than the conventional acid-promoted, ionic process. As elucidated by computational and experimental studies, the allyl glycosyl sulfones (as donors) form halogen bond complexes with perfluoroalkyl iodides, which-merely by visible light irradiation-fragment via radical intermediates to give the electrophilic glycosyl iodides. In situ trapping by various nucleophiles affords, in a stereoconvergent manner, the challenging 1,2-cis-glycosides. This metal- and acid-free reaction shows remarkable tolerance to functional groups. The high stereoselectivity holds for a broad array of donors. This study suggests that the simple C2-alkoxy group can serve as an effective directing group for building 1,2-cis-glycosidic bonds.

Selective synthesis of enol ethers via nickel-catalyzed cross coupling of α-oxy-vinylsulfones with alkylzinc reagents.

We describe here a Ni-catalyzed Negishi coupling reaction to prepare 1,2-dialkyl enol ethers in a stereoconvergent fashion. This method employs readily available and bench-stable α-oxy-vinylsulfones as electrophiles. The C-sulfone bond in the α-oxy-vinylsulfone motif is cleaved chemoselectively in these reactions. The mild conditions are tolerant of a variety of functional groups on both partners, thus representing a general strategy for enol ether synthesis. This unique reactivity of α-oxy-vinylsulfones indicates their further application as electrophilic partners in cross-coupling reactions.

Nonenzymatic Stereoselective S-Glycosylation of Polypeptides and Proteins.

Here we report a nonenzymatic glycosylation reaction that builds axial S-glycosidic bonds under biorelevant conditions. This strategy is enabled by the design and use of allyl glycosyl sulfones as precursors to glycosyl radicals and exploits the exceptional functional group tolerance of radical processes. Our method introduces a variety of unprotected glycosyl units to the cysteine residues of peptides in a highly selective fashion. Through developing the second-generation protocol, we applied our method in the direct glycosylation of complex polypeptides and proteins. Computational studies were performed to elucidate the reaction mechanism.

Cobalt-Catalyzed Umpolung Alkylation of Imines To Generate α-Branched Aliphatic Amines.

Here we report a general and mild approach to prepare α-branched aliphatic amines from imines. This method capitalizes on a cobalt-catalyzed umpolung alkylation of imines, employs easily available reaction partners, and demonstrates a broad substrate scope. Mechanistic studies suggest this transformation occurs by a radical pathway.

Generation of Glycosyl Radicals from Glycosyl Sulfoxides and Its Use in the Synthesis of C-linked Glycoconjugates.

We here report glycosyl sulfoxides appended with an aryl iodide moiety as readily available, air and moisture stable precursors to glycosyl radicals. These glycosyl sulfoxides could be converted to glycosyl radicals by way of a rapid and efficient intramolecular radical substitution event. The use of this type of precursors enabled the synthesis of various complex C-linked glycoconjugates under mild conditions. This reaction could be performed in aqueous media and is amenable to the synthesis of glycopeptidomimetics and carbohydrate-DNA conjugates.

A Radical Approach to Making Unnatural Amino Acids: Conversion of C-S Bonds in Cysteine Derivatives into C-C Bonds.

Here we report a general approach to make unnatural amino acids from readily available cysteine derivatives. This method capitalizes on an intramolecular radical substitution process that generates alkyl radicals through C-S cleavage. The resulting alkyl radicals partook in diverse C-C bond forming events. These reactions proceed under mild, photocatalytic conditions at room temperature, and can be performed open to air. The utility of these transformations is further demonstrated in the straightforward synthesis of various unnatural amino acids and peptides that are difficult to access previously.