Chemoselective Coupling Reactions Research Articles

Development of Novel Hypervalent Iodine Compounds Bearing Intramolecular Halogen Bonding

In recent years, halogen bonding (XB) interaction has attracted much attention in organic synthesis, especially for the activation of substrates. On the other hand, the use of XB interaction for the “stabilization” of molecules has been less explored. In this manuscript, the authors described our recent work on the development of new class of N-acyliminoiodinanes and iodonium ylides, which can be used as nitrene and carbene equivalents, respectively. The intramolecular XB interactions were confirmed by X-ray structure and natural bond orbital (NBO) analyses. The synthesized N-acyliminoiodinanes were found to be activated by photo-irradiation to react with silyl enol ethers, glycals, alkynes, and(hetero)aromatic compounds to afford the corresponding aminated adducts. In addition, the iodonium ylides baring intramolecular XB interaction underwent additive-free chemoselective coupling reaction of thioamides, even in protic polar solvents. The intramolecular XB could also control the coordination mode of the nucleophile via σ-holes, suppressing undesired side reactions. These findings would pave new avenues chemoselective coupling reactions using hypervalent iodine compounds.

Recent advances in the application of ligands in palladium-catalyzed chemoselective coupling reactions at C–Br, C–OTf, and C–Cl sites

This article presents a comprehensive analysis of the progress in palladium-catalyzed coupling reactions, with an emphasis on how ligand characteristics affect the chemoselectivity of aryl (pseudo)halides.

Synthesis of GO and rGO@Fe3O4@Ni as remarkable nanocatalyst systems for solvent‐free and chemoselective coupling reactions of dimedone with aromatic aldehydes

In this work, we synthesized modified GO and rGO@Fe3O4@Ni nanocomposite. The synthesized nanomaterials were characterized using Fourier‐transform infrared spectroscopy (FT‐IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy‐dispersive X‐ray spectroscopy (EDX), X‐ray powder diffraction (XRD), vibrating sample magnetometer (VSM), Brunauer‐Emmett‐Teller (BET), and inductively coupled plasma optical emission spectroscopy (ICP‐OES). Furthermore, GO and rGO@Fe3O4@Ni were applied as catalysts in multicomponent coupling reactions (MCRs) of dimedone with structurally diverse aromatic aldehydes. All reactions were fulfilled rapidly and efficiently in solvent‐free conditions at 90°C. The results showed that GO and rGO@Fe3O4@Ni expedited the coupling reactions chemoselectively in such a way that GO directed the MCRs to the production of bisdimedones while rGO@Fe3O4@Ni drove the reactions one more step forward and afforded xanthenediones as the cyclization products. In addition, reusability of the examined nanocatalyst systems was carried out for four consecutive cycles without the significant loss of catalytic activity.

Divergent and Chemoselective Transformations of Thioamides with Designed Carbene Equivalents.

The reactions of thioamides with ortho-nitro-substituted iodonium ylides proceeded under mild conditions to give enaminones or thiazoles, depending on the iodonium ylide used. This protocol allowed the use of protic solvents, including aqueous solutions, and therefore coupling reactions with complex molecules such as peptides or steroids were possible. A mild and efficient method for the synthesis of various iodonium ylides was established. DFT calculations suggested that the halogen bonding between a thioamide and iodonium ylide was important in this chemoselective coupling reaction. The potential use of enaminones conjugated with pharmaceuticals as prodrugs was also demonstrated.

Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure-activity relationship studies.

Extremely potent, new hepatitis C virus (HCV) nonstructural 5A (NS5A) featuring substituted biaryl sulfate core structures was designed and synthesized. Based on the previously reported novel HCV NS5A inhibitors featuring biaryl sulfate core structures which exhibit two-digit picomolar half-maximal effective concentration (EC50) values against HCV genotype 1b and 2a, the new inhibitors equipped with the sulfate core structures containing diversely substituted aryl groups were explored. In this study, highly efficient, chemoselective coupling reactions between an arylsulfonyl fluoride and an aryl silyl ether, known as the sulfur(vi) fluoride exchange (SuFEx) reaction, were utilized. Among the inhibitors prepared based on the SuFEx chemistry, compounds 14, 15 and 29 exhibited two-digit picomolar EC50 values against GT-1b and single digit or sub nanomolar activities against the HCV GT-2a strain. Nonsymmetrical inhibitors containing an imidazole and amide moieties on each side of the sulfate core structures were also synthesized. In addition, a biotinylated probe targeting NS5A protein was prepared for labeling using the same synthetic methodology.

ChemInform Abstract: Chemo‐Controlled Cross‐Coupling of Di(hetero)aryl Disulfides with Grignard Reagents: C—C vs.C—S Bond Formation.

AbstractThe protocol for the chemoselective coupling reaction affords either a C—S bond in presence of ferrocene catalyst or the formation of a C—C bond in presence of palladium acetate catalyst.

Divergent and convergent synthesis of polymannosylated dibranched antigenic peptide of the immunodominant epitope MBP(83–99)

Multiple antigenic peptide (MAP) systems are dendrimeric structures bearing multiple copies of identical or different peptide epitopes, and they have been demonstrated to show enhanced immunogenicity. Herein, we report the direct (divergent) and indirect (convergent) synthesis, using contemporary synthetic approaches, of a di-branched antigenic peptide (di-BAP) containing the immunodominant epitope MBP(83–99), which is implicated in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The direct synthesis (di-BAP 1) was performed using microwave irradiation. The indirect synthesis (di-BAP 2) was carried out performing an efficient chemoselective coupling reaction through the formation of a thioether bond. Both di-BAPs were conjugated to polysaccharide mannan since mannosylation is a promising technique to achieve modulation in immune response. The conjugation was achieved through free amino groups of both di-BAPs via the formation of Schiff bases. The mannan-conjugated di-BAPs were further evaluated in vivo in a prophylactic vaccination protocol, prior to EAE induction in Lewis rats.

Smart Design of Stable Extracellular Matrix Mimetic Hydrogel: Synthesis, Characterization, and In Vitro and In Vivo Evaluation for Tissue Engineering

AbstractThe simplicity and versatility of hydrazone crosslinking has made it a strategy of choice for the conjugation of bioactive molecules. However, the labile nature of hydrazone linkages and reversibility of this coupling reaction restricts its full potential. Based on the fundamental understanding of hydrazone stability, this problem is circumvented by resonance‐stabilization of a developing N2 positive charge in a hydrazone bond. A novel chemistry is presented to develop a resilient hydrazone bond that is stable and non‐ reversible under physiological conditions. A carbodihydrazide (CDH) type hydrazide derivative of the biomolecule forms intrinsically stabilized hydrazone‐linkages that are nearly 15‐fold more stable at pH 5 than conventional hydrazone. This chemoselective coupling reaction is catalyst‐free, instantaneous, and virtually non‐cleavable under physiological conditions, therefore can serve as a catalyst‐free alternative to click chemistry. This novel crosslinking reaction is used to tailor a hyaluronan hydrogel, which delivered exceptional hydrolytic stability, mechanical properties, low swelling, and controlled enzymatic degradation. These desired characteristics are achieved without increasing the chemical crosslinking. The in vivo evaluation of this hydrogel revealed neo‐bone with highly ordered collagen matrix mimicking natural bone regeneration. The proximity ligation assay or PLA is used to detect blood vessels, which highlighted the quality of engineered tissue.

Efficient 18F-Labeling of Large 37-Amino-Acid pHLIP Peptide Analogues and Their Biological Evaluation

Solid tumors often develop an acidic microenvironment, which plays a critical role in tumor progression and is associated with increased level of invasion and metastasis. The 37-residue pH (low) insertion peptide (pHLIP) is under study as an imaging platform because of its unique ability to insert into cell membranes at a low extracellular pH (pH(e) < 7). Labeling of peptides with [(18)F]-fluorine is usually performed via prosthetic groups using chemoselective coupling reactions. One of the most successful procedures involves the alkyne-azide copper(I) catalyzed cycloaddition (CuAAC). However, none of the known "click" methods have been applied to peptides as large as pHLIP. We designed a novel prosthetic group and extended the use of the CuAAC "click chemistry" for the simple and efficient (18)F-labeling of large peptides. For the evaluation of this labeling approach, a D-amino acid analogue of WT-pHLIP and an L-amino acid control peptide K-pHLIP, both functionalized at the N-terminus with 6-azidohexanoic acid, were used. The novel 6-[(18)F]fluoro-2-ethynylpyridine prosthetic group, was obtained via nucleophilic substitution on the corresponding bromo-precursor after 10 min at 130 °C with a radiochemical yield of 27.5 ± 6.6% (decay corrected) with high radiochemical purity ≥98%. The subsequent Cu(I)-catalyzed "click" reaction with the azido functionalized pHLIP peptides was quantitative within 5 min at 70 °C in a mixture of water and ethanol using Cu-acetate and sodium L-ascorbate. [(18)F]-D-WT-pHLIP and [(18)F]-L-K-pHLIP were obtained with total radiochemical yields of 5-20% after HPLC purification. The total reaction time was 85 min including formulation. In vitro stability tests revealed high stability of the [(18)F]-D-WT-pHLIP in human and mouse plasma after 120 min, with the parent tracer remaining intact at 65% and 85%, respectively. PET imaging and biodistribution studies in LNCaP and PC-3 xenografted mice with the [(18)F]-D-WT-pHLIP and the negative control [(18)F]-L-K-pHLIP revealed pH-dependent tumor retention. This reliable and efficient protocol promises to be useful for the (18)F-labeling of large peptides such as pHLIP and will accelerate the evaluation of numerous [(18)F]-pHLIP analogues as potential PET tracers.

ChemInform Abstract: Chemoselective Coupling Reactions of 5,7‐Dimethoxyphthalide with the Remotely Functionalized Alkyl Iodides: Facile Racemic Synthesis of Helicobacter pylori Antibiotics.

AbstractThe synthesis includes various CJ molecules and sporotricale methyl ether (IV).

Chemoselective and Regiospecific Suzuki Coupling on a Multisubstituted sp3-Carbon in 1,1-Diborylalkanes at Room Temperature

The palladium-catalyzed Suzuki-Miyaura cross-coupling on a multisubstituted sp(3)-carbon in 1,1-diborylalkanes was achieved at room temperature. The generation of a monoborate intermediate by virtue of the adjacent B atom could result in the chemoselective coupling reaction under ambient conditions.

Chemoselective Coupling Reactions of 5,7-Dimethoxyphthalide with the Remotely Functionalized Alkyl Iodides: Facile Racemic Synthesis of Helicobacter pylori Antibiotics

Highly chemoselective coupling reactions of 5,7-dimethoxyphthalide carbanion with the remotely functionalized long chain alkyl iodides have been demonstrated to accomplish the concise and efficient synthesis of Helicobacter pylori antibiotics, the CJ-molecules, and sporotricale methyl ether.

Total Synthesis of (+)-Azinothricin and (+)-Kettapeptin

Asymmetric total syntheses of (+)-azinothricin and (+)-kettapeptin have been completed through a common new pathway that exploits a highly chemoselective coupling reaction between the fully elaborated cyclodepsipeptide 5 and the glycal activated esters 3 and 4 at the final stages of both respective syntheses.

ChemInform Abstract: Highly Chemoselective Coupling Reactions of Organovanadium Compounds.

AbstractIn der ersten Arbeit wird gezeigt, daß Grignard‐Verbindungen (I) mit VCl3 (II) über intermediäre Organo‐Vanadiumverbindungen (III) mit zahlreichen Säurechloriden (IV) die Ketone (V) liefern.

Highly chemoselective coupling reactions of organovanadium compounds

Organovanadium compounds generated in dichloromethane from equimolar amounts of vanadium trichloride and Grignard reagents underwent the chemoselective cross-coupling reaction with acid chlorides leading to the corresponding ketones. Treatment with allyl halides resulted in allylation of organovanadium compounds. In the case of propargyl bromide, regioselective displacement occurred to produce allene derivatives.