Glycosyl Sulfones Research Articles

Emerging Advances of the Radical Pathway Glycosylation Enabled by Bench‐Stable Glycosyl Donors: Glycosyl Sulfoxides, Glycosyl Sulfones, and Glycosyl Sulfinates

AbstractIn synthetic carbohydrate chemistry, the modification of glycosyl radicals pathway stands as a central area of focus. The radical‐based reactions often demonstrate remarkable compatibility with various functional groups owing to the mild initiation conditions. In particular, the identification of novel glycosyl radical precursors, combined with advanced reaction techniques, has substantially broadened the scope of glycosyl compound synthesis. Despite the presence of versatile donors, the synthesis of noble donors is still addressed as a synthetic need and challenges associated with sugar chemistry. Currently, a new class of glycosyl radical precursors has been developed which enables the production of C‐, S‐, O‐, and N‐glycosides efficiently. In this light, we highlight strategies towards bench‐stable glycosyl sulfoxides, sulphone, and sulfite donors that can enable the site‐, regio‐ and stereoselective transformation of protected or naked sugar synthons in synthetic carbohydrate chemistry. Here, this review article covers the recent developments in the selective glycosyl radical diversification such as glycosyl alkylation, arylation, alkenylation, sulfuration, C−H activation, and DNA conjugation via the bench‐stable donors along with mechanistic aspects, challenges, and future directions.

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.

Base‐Promoted Glycosylation Allows Protecting Group‐Free and Stereoselective O‐Glycosylation of Carboxylic Acids**

AbstractHere 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.

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.

Radical Pathway Glycosylation Empowered by Bench-Stable Glycosyl Donors.

ConspectusThe study of carbohydrates has emerged as a crucial research area in various disciplines due to their pivotal roles in cellular processes. To facilitate in-depth exploration of their biological functions, chemical glycosylation reactions that allow facile access of glycoconjugates to a broad research community are highly needed. In classical glycosylation reactions, a glycosyl donor is activated by an acid to generate a reactive electrophilic intermediate, which subsequently forms a glycosidic bond upon reaction with a nucleophilic acceptor. Such an ionic pathway glycosylation has been the mainstay technique for glycoconjugate synthesis and allowed the synthesis of numerous intricate structures. Nevertheless, limitations still exist. For instance, when labile glycosyl donors or harsh activating conditions are required, these methods show limited tolerance to hydroxyl groups that are abundant on sugar rings. In addition, achieving good stereocontrol represents another longstanding obstacle. In recent years, new modes of donor activation have been sought to tackle the above challenges.We noted that glycosylation methods passing through the intermediacy of glycosyl radicals via a cascade of single-electron transfer steps possess significant but underexplored potential. Progress in this area has been slow due in large part to a dearth of handy methods to generate and maneuver glycosyl radicals. Most existing methods call for either forcing conditions or unstable/inconvenient starting materials. In order to better exploit the power of the radical pathway glycosylation, we have developed a range of glycosyl donors─namely, glycosyl sulfoxides, glycosyl sulfones, and glycosyl sulfinates─that are bench stable and can be readily prepared from simple starting materials. These donors can be activated to form glycosyl radicals under mild conditions. Enabled by the use of these donors, we have developed a series of glycosylation methods that could be used for making O-, S-, or C-glycosides, some of which were previously difficult to access. In many cases, no protecting group on glycosyl donors is required. As an illustration of their potential utility, our methods have been adopted in the preparation of sugar-drug conjugates, sugar-DNA conjugates, glycopeptides, and even glycoproteins. While in most cases the intrinsic reactivity of glycosyl radical intermediates can be explored to access axially configured products, some of the methods also allow the utilization of external, delicate reagents, or catalysts to override such innate preference and achieve catalyst-controlled stereoselectivity.We believe that radical pathway glycosylation has enormous potential and can inspire the development of novel methods for glycoside synthesis. In this Account, we highlight the design principles for the development of our glycosyl donors, summarize our recent advancements in radical pathway glycosylation enabled by their use, and provide an outlook on the future directions of this field.

Stereoselective Arylation of Glycosyl Sulfones: Access to α- and β-Isomers

Stereoselective Arylation of Glycosyl Sulfones: Access to α- and β-Isomers

Stereoselective C-Aryl Glycosylation by Catalytic Cross-Coupling of Heteroaryl Glycosyl Sulfones.

Stereoselective C-glycosylation reactions are increasingly gaining attention in carbohydrate chemistry because they enable glycosyl precursors, easily accessible as anomeric mixtures, to converge to a single diastereomeric product. However, controlling the stereochemical outcome via transition metal catalysis remains challenging, and methods that leverage bench-stable heteroaryl glycosyl sulfone donors to facilitate glycosylation are rare. Here, we show two complementary nonprecious metal catalytic systems, based on iron or nickel, which are capable of promoting efficient C-C coupling between heteroaryl glycosyl sulfones and aromatic nucleophiles or electrophiles via distinct mechanisms and modes of activation. Diverse C-aryl glycosides were secured with excellent selectivity, scope, and functional group compatibility, and reliable access to both α and β isomers could be achieved for key sugar residues.

StereoselectiveC‐Aryl Glycosylation by Catalytic Cross‐Coupling of Heteroaryl Glycosyl Sulfones

AbstractStereoselectiveC‐glycosylation reactions are increasingly gaining attention in carbohydrate chemistry because they enable glycosyl precursors, readily accessible as anomeric mixtures, to converge to a single diastereomeric product. However, controlling the stereochemical outcome through transition‐metal catalysis remains challenging, and methods that leverage bench‐stable heteroaryl glycosyl sulfone donors to facilitate glycosylation are rare. Herein, we show two complementary nonprecious metal catalytic systems, based on iron or nickel, which are capable of promoting efficient C−C coupling between heteroaryl glycosyl sulfones and aromatic nucleophiles or electrophiles through distinct mechanisms and modes of activation. DiverseC‐aryl glycosides were secured with excellent selectivity, scope, and functional‐group compatibility, and reliable access to both α and β isomers was possible for key sugar residues.

A Comparison of the Antibacterial Efficacy of Carbohydrate Lipid-like (Thio)Ether, Sulfone, and Ester Derivatives against Paenibacillus larvae.

Paenibacillus larvae is the causative agent of American foulbrood (AFB), the most serious bacterial disease affecting developing honeybee larvae and pupas. In this study, a library of 24 (thio)glycosides, glycosyl sulfones, 6-O-esters, and ethers derived from d-mannose, d-glucose, and d-galactose having C10 or C12 alkyl chain were evaluated for their antibacterial efficacy against two P. larvae strains. The efficacy of the tested compounds determined as minimal inhibitory concentrations (MICs) varied greatly. Generally, dodecyl derivatives were found to be more potent than their decylated analogs. Thioglycosides were more efficient than glycosides and sulfones. The activity of the 6-O-ether derivatives was higher than that of their ester counterparts. Seven derivatives with dodecyl chain linked (thio)glycosidically or etherically at C-6 showed high efficacy against both P. larvae strains (MICs ranged from 12.5 μM to 50 μM). Their efficacies were similar or much higher than those of selected reference compounds known to be active against P. larvae-lauric acid, monolaurin, and honeybee larval food components, 10-hydroxy-2-decenoic acid, and sebacic acid (MICs ranged from 25 μM to 6400 μM). The high efficacies of these seven derivatives suggest that they could increase the anti-P. larvae activity of larval food and improve the resistance of larvae to AFB disease through their application to honeybee colonies.

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.

Stereoselective Synthesis of 1,2‐cis‐Glycosyl Sulfones and Their Application in One‐Pot Julia Olefination for the Synthesis of exo‐Glycals

AbstractGlycosyl sulfones are important intermediates in the synthesis of various sugar derivatives. However, their 1,2‐cis‐isomers have not been extensively studied because of lower availability. Herein, we report the highly stereoselective synthesis of heteroaryl‐substituted 1,2‐cis‐glycosyl sulfones via glycosylation of heteroarylthiols and subsequent oxidation by magnesium monoperphthalate. One‐pot Julia olefination using these 1,2‐cis‐glycosyl sulfones was also studied. It furnished thermodynamically less stable (E)‐exo‐glycals with E/Z selectivity of up to 91 : 9.

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.

Glycosylation Enabled by Successive Rhodium(II) and Brønsted Acid Catalysis.

Herein, we reported on a highly efficient glycosylation reaction comprising two chronological meticulously designed catalytic cycles: (1) rhodium-catalyzed formation of sulfonium ylide and (2) Brønsted acid-catalyzed formation of sulfonium ion. This protocol highlighted an effective and robust tactic to prepare a glycosyl sulfonium ion from a glycosyl sulfonium ylide precursor amenable for glycosylation.

A Study on Stereoselective Glycosylations via Sulfonium Ion Intermediates

The stereoselective synthesis of 1,2‐cis‐linkages can be achieved by an Sn2‐like displacement of glycosylation intermediates such as glycosyl triflates and sulfonium ions, provided that they display the right combination of stability and reactivity. Herein, we report the use of an achiral auxiliary that can impose neighboring group participation to afford glycosyl sulfonium ions, aided by the Thorpe–Ingold effect. We investigated the glycosylation properties of the sulfonium ions and used variable temperature NMR (VT‐NMR) studies to investigate their role in the glycosylation mechanism. The influence of the structure of the auxiliary, the protecting groups and stereochemistry of the glycosyl donor were investigated and led to the identification of a highly α‐selective galactose donor.

ChemInform Abstract: Synthetic Carbohydrate Research Based on Organic Electrochemistry

AbstractReview: 59 refs.

Do Glycosyl Sulfonium Ions Engage in Neighbouring‐Group Participation? A Study of Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity

Neighbouring-group participation has long been used to control the synthesis of 1,2-trans-glycosides. More recently there has been a growing interest in the development of similar strategies for the synthesis of 1,2-cis-glycosides, in particular the use of auxiliary groups that generate sulfonium ion intermediates. However, there has been some debate over the role of sulfonium ion intermediates in these reactions: do sulfonium ions actually engage in neighbouring-group participation, or are they a resting state of the system prior to reaction through an oxacarbenium ion intermediate? Herein, we describe the reactivities and stereoselectivities of a family of bicyclic thioglycosides in which an oxathiane ring is fused to the sugar to form a trans-decalin-like structure. A methyl sulfonium ion derived from one such glycosyl donor is so stable that it can be crystallised from ethanol, yet it reacts with complete stereoselectivity at high temperature. The importance of a ketal group in the oxathiane ring for maintaining this high stereoselectivity is investigated using a combination of experiment and ab initio calculations. The data are discussed in terms of S(N)1 and S(N)2 type mechanisms. Trends in stereoselectivity across a series of compounds are more consistent with selective addition to oxacarbenium ions rather than a shift between S(N)1 and S(N)2 mechanisms.

Direct Synthesis of Diastereomerically Pure Glycosyl Sulfonium Salts

It is reported that stable glycosyl sulfonium salts can be generated via direct anomeric S-methylation of ethylthioglycosides. Mechanistically, this pathway represents the first step in the activation of thioglycosides for glycosidation; however, it can further allow for the synthesis and isolation of quasi-stable sulfonium ions, representing a new approach for studying these key intermediates.

Glycosyl Sulfonium Ions as Storable Intermediates for Glycosylations

Glycosyl sulfonium ions, which serve as persistent glycosyl cation equivalents, were prepared by the addition of diorganosulfides to an electrochemically generated glycosyl triflate. Low-temperature and variable-temperature NMR studies were performed to reveal the structure, stability, and reactivity of glycosyl sulfonium ions. The glycosyl sulfonium ions could be used as storable intermediates for reactions with various glycosyl acceptors including thioglycosides to give the corresponding disaccharides.