Direct,stereoselective thioglycosylation enabled by an organophotoredox radical strategy

While strategies involving a 2e⁻ transfer pathway have dictated glycosylation development, the direct glycosylation of readily accessible glycosyl donors as radical precursors is particularly appealing because of high radical anomeric selectivity and atom- and step-economy. However, the development of the radical process has been challenging owing to notorious competing reduction, elimination and/or S_N side reactions of commonly used, labile glycosyl donors. Here we introduce an organophotocatalytic strategy through which glycosyl bromides can be efficiently converted into corresponding anomeric radicals by photoredox mediated HAT catalysis without a transition metal or a directing group and achieve highly anomeric selectivity. The power of this platform has been demonstrated by the mild reaction conditions enabling the synthesis of challenging α-1,2-cis-thioglycosides, the tolerance of various functional groups and the broad substrate scope for both common pentoses and hexoses. Furthermore, this general approach is compatible with both sp² and sp³ sulfur electrophiles and late-stage glycodiversification for a total of 50 substrates probed.

Organophotoredox mediated HAT catalysis is developed for achieving high anomerically selective thioglycosylation of glycosyl bromides.     

Stereoretentive Reactions at the Anomeric Position: Synthesis of Selenoglycosides

Reported is the stereospecific cross‐coupling of anomeric stannanes with symmetrical diselenides, resulting in the synthesis of selenoglycosides with exclusive anomeric control. The reaction proceeds without the need for directing groups and is compatible with free hydroxy groups as demonstrated in the preparation of glycoconjugates derived from mono‐, di‐, and trisaccharides and peptides (35 examples). Given its generality and broad substrate scope, the glycosyl cross‐coupling method presented herein can find use in the synthesis of selenium‐containing glycomimetics and glycoconjugates.     

Glycosyl thioimidates as versatile building blocks for organic synthesis

This review discusses the synthesis and application of glycosyl thioimidates in chemical glycosylation and oligosaccharide assembly. Although glycosyl thioimidates include a broad range of compounds, the discussion herein centers on S-benzothiazolyl (SBaz), S-benzoxazolyl (SBox), S-thiazolinyl (STaz), and S-benzimidazolyl (SBiz) glycosides. These heterocyclic moieties have recently emerged as excellent anomeric leaving groups that express unique characteristics for highly diastereoselective glycosylation and help to provide a streamlined access to oligosaccharides.     

Studies on the Selectivity Between Nickel-Catalyzed 1,2-cis-2-Amino Glycosylation of Hydroxyl Groups of Thioglycoside Acceptors with C(2)-Substituted Benzylidene N-Phenyl Trifluoroacetimidates and Intermolecular Aglycon Transfer of the Sulfide Group

The stereoselective synthesis of saccharide thioglycosides containing 1,2-cis-2-amino glycosidic linkages is challenging. In addition to the difficulties associated with achieving high α-selectivity in the formation of 1,2-cis-2-amino glycosidic bonds, the glycosylation reaction is hampered by undesired transfer of the anomeric sulfide group from the glycosyl acceptor to the glycosyl donor. Overcoming these obstacles will pave the way for the preparation of oligosaccharides and glycoconjugates bearing the 1,2-cis-2-amino glycosidic linkages because the saccharide thioglycosides obtained can serve as donors for another coupling iteration. This approach streamlines selective deprotection and anomeric derivatization steps prior to the subsequent coupling event. We have developed an efficient approach for the synthesis of highly yielding and α-selective saccharide thioglycosides containing 1,2-cis-2-amino glycosidic bonds, via cationic nickel-catalyzed glycosylation of thioglycoside acceptors bearing the 2-trifluoromethylphenyl aglycon with N-phenyl trifluoroacetimidate donors. The 2-trifluoromethylphenyl group effectively blocks transfer of the anomeric sulfide group from the glycosyl acceptor to the C(2)-benzylidene donor and can be easily installed and activated. The current method also highlights the efficacy of the nickel catalyst selectively activating the C(2)-benzylidene imidate group in the presence of the anomeric sulfide group on the glycosyl acceptors.     

Synthesis of DTPA-conjugated (1,4)-linked 2-aminoglycosides varying in the anomeric configuration and their MRI contrast effect

We describe the efficient synthesis of DTPA-conjugated oligosaccharides composed of alpha- and/or beta-linked tri to monoglucosamines. Gd(iii) complex with DTPA-conjugated chitotriitol has been reported to be an effective MRI contrast agent. In order to elucidate the structure-property relationships, we planned to synthesize the DTPA-conjugated 2-amino-tri-, di-, and monosaccharides varying in configuration at the anomeric positions and the C2 position on the reducing end. Our strategy for the synthesis of the DTPA-conjugated oligosaccharides involves O-perbenzyl protected 2-amino-tri-, di-, and monosaccharides as key intermediates. The 2-aminoglycosides were prepared by non-selective glycosidation of 2-azido-2-deoxyglycosyl donors, followed by separation of two anomeric isomers. Although the synthesis involves separation of the stereoisomers, it circumvents not only the careful tuning of reaction conditions, but also the time-consuming preparation of glycosyl donors attached to different protecting groups. The protected 2-aminoglycosides were converted to the fully deprotected DTPA-conjugated tri- to monosaccharides by the same operation. MRI phantom study using the Gd(III) complexes of DTPA-conjugated oligosaccharides indicates that the number of the monosaccharide units was critical for enhancing the relative signal intensity of water protons per Gd, and various stereoisomers would be candidate scaffolds for MRI contrast agents.     

Toward Libraries of Biotinylated Chondroitin Sulfate Analogues: From Synthesis to In Vivo Studies

Chondroitin sulfate‐E (CS‐E) oligosaccharidic analogues (di to hexa) were prepared from lactose. In these compounds, the 2‐acetamido group was replaced by a hydroxyl group. This modification speeded up the synthesis, and large oligosaccharides were constructed in a few steps from a lactose‐originated block. The protecting groups used were as follows; Fmoc for hydroxyl groups to be glycosylated, allyl group for anomeric position protection, and trichoroacetimidate leaving groups were used to prepare up to octasaccharides. We took advantage of the presence of allyl group to develop a click biotinylation, through its transformation into a 3‐azido‐2‐hydroxyl propyl group in two steps (epoxidation and sodium azide epoxide opening). The biotinylating agent was a water‐soluble propargylated and biotinylated triethylene glycol (PEG). By using surface plasmon resonance (SPR), it was shown that the di‐, tetra‐, and hexasaccharides display a binding affinity and selectivity toward HSF/GSF and CXCL12 similar to that of CS‐E. A parallel study confirmed their mimicry of natural compounds, based on the hexasaccharide interaction with Otx2, a homeodomain protein involved in brain maturation, thus validating our simplification approach to synthesize bioactive GAG.     

Synthesis of Carbohydrates with an Anomeric Thiol Moiety for Elaboration into Metabolically Stable Thioglycosides

ABSTRACT

The synthesis of thioglycosides for use as metabolically stable biological probes is an area of continued interest. This paper describes the synthesis of functionalised carbohydrates which contain an anomeric thio group. During the course of this work we have examined the most viable route into compounds such as the specifically functionalised carbohydrates 36 and 37, and have also investigated the usefulness of disulfides as protecting groups for anomeric thiols.     

Highly regioselective synthesis of amino-functionalized dendritic polyglycerols by a one-pot hydroformylation/reductive amination sequence

[reaction: see text] Dendritic architectures with neutral core structures and amines groups in the shell are a synthetic challenge, and there is a need for an efficient access. In this paper, highly selective Rh-catalysts are used for sequential hydroformylation/reductive amination of dendritic perallylated polyglycerols 1 with various amines in a one-pot procedure to give dendritic polyamines 3a-e in high yields (73-99%). In all cases, complete conversion of the allyl ether and aldehyde intermediate has been observed. Furthermore, the use of protected amines provides reactive core-shell-type architectures after deprotection. These soluble but membrane filterable multifunctional dendritic polyamines are of high interest as reagents in synthesis or as supports in homogeneous catalysis as well as nonviral vectors for DNA-transfection.     

de novo asymmetric synthesis of daumone via a palladium-catalyzed glycosylation

The enantioselective syntheses of daumone and two analogues have been achieved in seven to eight steps. This route relies upon a diasteroselective palladium-catalyzed glycosylation reaction for the formation of the anomeric bond. The asymmetry of the sugar and aglycone portion of daumone were introduced by Noyori reduction of an acylfuran and a propargyl ketone. A highly diastereoselective epoxidation and reductive ring opening established the desired C-2 and C-4 stereochemistry of daumone. [reaction: see text]     

Readily Removable Directing Group Assisted Chemo‐ and Regioselective C(sp3)H Activation by Palladium Catalysis

Currently used directing groups for selective aliphatic β‐functionalization of carbonyl compounds show excellent reactivity and selectivity with an amide as a linker. Described herein is 2‐piconimide, used for the first time with commercially available 2‐picolinamide/2‐picolic acid as precursors, to direct C? H arylation/alkenylation by palladium catalysis. The directing group is essential for promoting the sequnetial primary and secondary C(sp³)? H arylation with different aryl iodides in one substrate. The directing group was easily removed under simple reaction conditions at room temperature.     

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. These highly stereoretentive processes are ideally suited for the preparation of carbohydrate-based therapeutics and were demonstrated in the synthesis of antidiabetic drugs. Next, the application of the glycosyl cross-coupling method to the preparation of Se-glycosides and to glycodiversification of small molecules and peptides are highlighted. These reactions proceed with exclusive anomeric control for a broad range of substrates and tolerate carbohydrates with free hydroxyl groups. Taken together, anomeric nucleophiles have emerged as powerful tools for the synthesis of oligosaccharides and glycoconjugates and their future applications will open new possibilities to incorporate saccharides into small molecules and biologics.     

Entschuldigung: Readily Removable Directing Group Assisted Chemo‐ and Regioselective C(sp3)?H Activation by Palladium Catalysis

Currently used directing groups for selective aliphatic β‐functionalization of carbonyl compounds show excellent reactivity and selectivity with an amide as a linker. Described herein is 2‐piconimide, used for the first time with commercially available 2‐picolinamide/2‐picolic acid as precursors, to direct C H arylation/alkenylation by palladium catalysis. The directing group is essential for promoting the sequnetial primary and secondary C(sp³) H arylation with different aryl iodides in one substrate. The directing group was easily removed under simple reaction conditions at room temperature.     

C-C, C-O and C-N bond formation via rhodium(III)-catalyzed oxidative C-H activation

Rhodium(III)-catalyzed direct functionalization of C-H bonds under oxidative conditions leading to C-C, C-N, and C-O bond formation is reviewed. Various arene substrates bearing nitrogen and oxygen directing groups are covered in their coupling with unsaturated partners such as alkenes and alkynes. The facile construction of C-E (E = C, N, S, or O) bonds makes Rh(III) catalysis an attractive step-economic approach to value-added molecules from readily available starting materials. Comparisons and contrasts between rhodium(III) and palladium(II)-catalyzed oxidative coupling are made. The remarkable diversity of structures accessible is demonstrated with various recent examples, with a proposed mechanism for each transformation being briefly summarized (critical review, 138 references).     

Preparation of nucleosides derived from 2-nitroimidazole and D-arabinose, D-ribose, and D-galactose by the Vorbrüggen method and their conversion to potential precursors for tracers to image hypoxia

2-Nitroimidazole was silylated using hexaethyldisilazane and then reacted with 1-O-acetyl derivatives of D-arabinose, D-ribose, and D-galactose in acetonitrile at mild temperatures (-20 °C to rt), catalyzed by triethylsilyl triflate (Vorbrüggen conditions). The α-anomer was formed in the former case and the β-anomers in the latter two cases (highly) selectively. When D-arabinose and D-ribose were silylated with tert-butyldiphenylsilyl chloride in pyridine at the hydroxyl groups at C-5 and acetylated at the other ones in a one-pot reaction, mixtures of anomeric 1-O-acetyl derivatives were obtained. These were coupled by the Vorbrüggen method and then deblocked at C-5 and tosylated to give precursors for tracers to image hypoxia in four steps without using Hg(CN)(2) necessary for other methods. The Vorbrüggen conditions enable a shorter route to azomycin nucleoside analogues than the previous coupling procedures.     

MALDI linear-field reflectron TOF post-source decay analysis of underivatized oligosaccharides: Determination of glycosidic linkages and anomeric configurations using anion attachment

Six different anionic species (fluoride, chloride, bromide, iodide, nitrate, and acetate) are tested for their abilities to form anionic adducts with neutral oligosaccharides that are detectable by MALDI-TOF mass spectrometry. Fluoride and acetate cannot form anionic adducts with the oligosaccharides in significant yields. However, bromide, iodide, and nitrate anionic adducts consistently appear in higher abundances relative to [M - H](-), just like the highly stable chloride adducts. Post-source decay (PSD) decompositions of Br(-), I(-), and NO(3)(-) adducts of oligosaccharides provide no structural information, i.e., they yield the respective anions as the main product ions. However, determination of linkage types is achieved by analysis of structurally-informative diagnostic peaks offered by negative ion PSD spectra of chloride adducts of oligosaccharides, whereas the relative peak intensities of pairs of diagnostic fragment ions allow differentiation of anomeric configurations of glycosidic bonds. Thus, simultaneous identification of the linkage types and anomeric configurations of glycosidic bonds is achieved. Our data indicate that negative ion PSD fragmentation patterns of chloride adducts of oligosaccharides are mainly determined by the linkage types. Correlation may exist between the linkage positions and fragmentation mechanisms and/or steric requirements for both cross-ring and glycosidic bond fragmentations. PSD of the chloride adducts of saccharides containing a terminal Glcalpha1-2Fru linkage also yields chlorine-containing fragment ions which appear to be specifically diagnostic for a fructose linked at the 2-position on the reducing end. This also allows differentiation from saccharides with a 1-1 linked pyranose on the same position.     

Activation of Carboxylic Acids in Asymmetric Organocatalysis

Organocatalysis, catalysis using small organic molecules, has recently evolved into a general approach for asymmetric synthesis, complementing both metal catalysis and biocatalysis. 1 Its success relies to a large extent upon the introduction of novel and generic activation modes. 2 Remarkably though, while carboxylic acids have been used as catalyst directing groups in supramolecular transition‐metal catalysis, 3 a general and well‐defined activation mode for this useful and abundant substance class is still lacking. Herein we propose the heterodimeric association of carboxylic acids with chiral phosphoric acid catalysts as a new activation principle for organocatalysis. This self‐assembly increases both the acidity of the phosphoric acid catalyst and the reactivity of the carboxylic acid. To illustrate this principle, we apply our concept in a general and highly enantioselective catalytic aziridine‐opening reaction with carboxylic acids as nucleophiles.     

Rhodium(III)‐Catalyzed ortho CH Heteroarylation of (Hetero)aromatic Carboxylic Acids: A Rapid and Concise Access to π‐Conjugated Poly‐heterocycles

Rh^III‐catalyzed oxidative C? H/C? H cross‐coupling between (hetero)aromatic carboxylic acids and various heteroarenes has been accomplished to construct highly functionalized ortho‐carboxy‐substituted bi(hetero)aryls. The use of a carboxy group as the directing group obviates tedious steps for installation and removal of extra directing groups, and enables a facile one‐step synthesis of ortho‐carboxy bi(hetero)aryls. The method provides opportunities for rapid assembly of a library of important fluorene and coumarin‐type poly‐heterocycles through intramolecular electrophilic substitution or oxidative lactonization. As illustrative examples, the strategy developed herein greatly streamlines accesses to a variety of appealing polyheterocycles such as DTPO (5H‐dithieno[3,2‐b:2′,3′‐d]pyran‐5‐one), CPDTO (cyclopentadithiophen‐4‐one), and indenothiophenes.     

Saccharide display on microtiter plates

New insight into the importance of carbohydrates in biological systems underscores the need for rapid synthetic and screening procedures for them. Development of an organic synthesis-compatible linker that would attach saccharides to microtiter plates was therefore undertaken to facilitate research in glycobiology. Galactosyllipids containing small, hydrophobic groups at the anomeric position were screened for noncovalent binding to microtiter plates. When the lipid component was a saturated hydrocarbon between 13 and 15 carbons in length, the monosaccharide showed complete retention after aqueous washing and could be utilized in biological assays. This alkyl chain was also successfully employed with more complex oligosaccharides in biological assays. In light of these findings, this method of attachment of oligosaccharides to microtiter plates should be highly efficacious to high-throughput synthesis and analyses of carbohydrates in biological assays.     

Rhodium(III)‐Catalyzed ortho C?H Heteroarylation of (Hetero)aromatic Carboxylic Acids: A Rapid and Concise Access to π‐Conjugated Poly‐heterocycles

Rh^III‐catalyzed oxidative C H/C H cross‐coupling between (hetero)aromatic carboxylic acids and various heteroarenes has been accomplished to construct highly functionalized ortho‐carboxy‐substituted bi(hetero)aryls. The use of a carboxy group as the directing group obviates tedious steps for installation and removal of extra directing groups, and enables a facile one‐step synthesis of ortho‐carboxy bi(hetero)aryls. The method provides opportunities for rapid assembly of a library of important fluorene and coumarin‐type poly‐heterocycles through intramolecular electrophilic substitution or oxidative lactonization. As illustrative examples, the strategy developed herein greatly streamlines accesses to a variety of appealing polyheterocycles such as DTPO (5H‐dithieno[3,2‐b:2′,3′‐d]pyran‐5‐one), CPDTO (cyclopentadithiophen‐4‐one), and indenothiophenes.     

Synthesis of Reversed C‐Acyl Glycosides through Ni/Photoredox Dual Catalysis

The incorporation of C‐glycosides in drug design has become a routine practice for medicinal chemists. These naturally occurring building blocks exhibit attractive pharmaceutical profiles, and have become an important target of synthetic efforts in recent decades. 1 Described herein is a practical, scalable, and versatile route for the synthesis of non‐anomeric and unexploited C‐acyl glycosides through a Ni/photoredox dual catalytic system. By utilizing an organic photocatalyst, a range of glycosyl‐based radicals are generated and efficiently coupled with highly functionalized carboxylic acids at room temperature. Distinctive features of this transformation include its mild conditions, impressive compatibility with a wide array of functional groups, and most significantly, preservation of the anomeric carbon: a handle for further, late‐stage derivatization.