Synthesis of deoxybenzoins from ß-alkoxy styrenes and arylboronic acids via palladium-catalyzed regioselective Heck-arylation reactions.

Palladium-catalyzed synthesis of deoxybenzoin derivatives from styryl ethers and arylboronic acids is reported. The reaction proceeds under mild conditions in the presence of TEMPO and provides the desired products in good to excellent yields. Simple operation, broad substrate scope, and functional group tolerance are the salient features of the developed methodology.

Copper(I)-Catalyzed Sandmeyer-Type S-Arylation of 1-Thiosugars with Aryldiazonium Salts under Mild Conditions.

Preparation of S-aryl thioglycosides from 1-thiosugars via S-arylation was demonstrated under mild reaction conditions. A wide range of protected and unprotected 1-thiosugars derived from glucose, glucosamine, galactose, mannose, ribose, maltose, and lactose underwent cross-coupling reactions with functionalized aryldiazonium salts in the presence of copper(I) chloride and DBU. The desired products were obtained in 55-88% yields within 5 min. Various functional groups, including halogens, were tolerated under standard reaction conditions. Synthesis of the biologically relevant antidiabetic dapagliflozin S-analogue and arbutin S-analogues (tyrosinase inhibitors) was demonstrated.

Multicomponent Synthesis of S-Benzyl Dithiocarbamates from para-Quinone Methides and Their Biological Evaluation for the Treatment of Alzheimer's Disease.

Multicomponent synthesis of biologically relevant S-benzyl dithiocarbamates from para-quinone methides, amines, and carbon disulfide are described under catalyst and additive-free conditions. The reactions proceeded at room temperature in a short span of time with excellent yields. One of the synthesized compounds, 3e showed considerable acetylcholinesterase (AChE) inhibitory (51.70 + 5.63% at 20 µm) and antioxidant (63.52 ± 1.15 at 20 µm) activities.

Controlled reduction of activated primary and secondary amides into aldehydes with diisobutylaluminum hydride.

A practical method is disclosed for the reduction of activated primary and secondary amides into aldehydes using diisobutylaluminum hydride (DIBAL-H) in toluene. A wide range of aryl and alkyl N-Boc, N,N-diBoc and N-tosyl amides were converted into the corresponding aldehydes in good to excellent yields. Reduction susceptible functional groups such as nitro, cyano, alkene and alkyne groups were found to be stable. Broad substrate scope, functional group compatibility and quick conversions are the salient features of this methodology.

Synthesis of functionalized S-benzyl dithiocarbamates from diazo-compounds via multi-component reactions with carbon disulfide and secondary amines.

Triflic acid promoted multi-component synthesis of functionalized S-benzyl dithiocarbamates from diazo compounds, carbon disulfide and secondary amines is reported. The reactions proceeded at room temperature and gave the desired dithiocarbamates in good yields. Wide-substrate scope and easy operation are the important features of this methodology.

Microbe-focused glycan array screening platform.

Interactions between glycans and glycan binding proteins are essential for numerous processes in all kingdoms of life. Glycan microarrays are an excellent tool to examine protein-glycan interactions. Here, we present a microbe-focused glycan microarray platform based on oligosaccharides obtained by chemical synthesis. Glycans were generated by combining different carbohydrate synthesis approaches including automated glycan assembly, solution-phase synthesis, and chemoenzymatic methods. The current library of more than 300 glycans is as diverse as the mammalian glycan array from the Consortium for Functional Glycomics and, due to its microbial focus, highly complementary. This glycan platform is essential for the characterization of various classes of glycan binding proteins. Applications of this glycan array platform are highlighted by the characterization of innate immune receptors and bacterial virulence factors as well as the analysis of human humoral immunity to pathogenic glycans.

Diversification of α-ketoamides via transamidation reactions with alkyl and benzyl amines at room temperature.

A wide range of N-tosyl α-ketoamides underwent transamidation with various alkyl amines in the absence of a catalyst, base, or additive. On the other hand, transamidation in N-Boc α-ketoamides was achieved in the presence of Cs2CO3. The reactions proceeded at room temperature and provided good to excellent yields of transamidation products under the optimized conditions. Broad substrate scope, functional group tolerance and quick conversions are the important features of the developed methodology.

Palladium-catalyzed synthesis of α-aryl acetophenones from styryl ethers and aryl diazonium salts via regioselective Heck arylation at room temperature.

Preparation of α-aryl acetophenones from styryl ethers and aryldiazonium salts is described. The reaction is catalyzed by palladium acetate at room temperature in the absence of ligand and base. The developed method is highly attractive in terms of reaction conditions, substrate scope, functional group tolerance and yields. Synthetic applications of the present method are demonstrated by preparing α-aryl indoles and 3-aryl isocoumarin from styryl ethers.

Chemoselective Synthesis of Aryl Ketones from Amides and Grignard Reagents via C(O)-N Bond Cleavage under Catalyst-Free Conditions.

Conversion of a wide range of N-Boc amides to aryl ketones was achieved with Grignard reagents via chemoselective C(O)-N bond cleavage. The reactions proceeded under catalyst-free conditions with different aryl, alkyl, and alkynyl Grignard reagents. α-Ketoamide was successfully converted to aryl diketones, while α,ß-unsaturated amide underwent 1,4-addition followed by C(O)-N bond cleavage to provide diaryl propiophenones. N-Boc amides displayed higher reactivity than Weinreb amides with Grignard reagents. A broad substrate scope, excellent yields, and quick conversion are important features of this methodology.

Regioselective Nitration of N-Alkyl Anilines using tert-Butyl Nitrite under Mild Condition.

Regioselective ring nitration of N-alkyl anilines is reported using tert-butyl nitrite. The reactions proceed efficiently with a wide range of substrates providing synthetically useful N-nitroso N-alkyl nitroanilines in excellent yields which can be easily converted into N-alkyl phenylenediamines and N-alkyl nitroanilines using Zn-AcOH and HCl/MeOH, respectively.

tert-Butyl nitrite promoted transamidation of secondary amides under metal and catalyst free conditions.

A mild and efficient method is demonstrated for the transamidation of secondary amides with various amines including primary, secondary, cyclic and acyclic amines in the presence of tert-butyl nitrite. The reaction proceeds through the N-nitrosamide intermediate and provides the transamidation products in good to excellent yields at room temperature. Moreover, the developed methodology does not require any catalyst or additives.

Tris(pentafluorophenyl)borane-Promoted Stereoselective Glycosylation with Glycosyl Trichloroacetimidates under Mild Conditions.

Tris(pentafluorophenyl)borane-promoted stereoselective glycosylation with trichloroacetimidate glycosyl donors is described. The reactions proceed efficiently with a wide range of acceptors, from sugar to nonsugar, under mild conditions in the presence of a catalytic amount of B(C6F5)3. The perbenzylated glucosyl α-imidate provides ß-selective glycosides in 70-92% yields.

Palladium catalyzed stereocontrolled synthesis of C-aryl glycosides using glycals and arenediazonium salts at room temperature.

A stereocontrolled synthesis of aryl-C-glycosides was achieved using glycals and aryldiazonium salts in the presence of palladium acetate. A wide range of glycals including d-glucal, d-galactal, l-rhamnal, d-xylal and d-ribal underwent C-arylation at the anomeric carbon in the presence of different aryldiazonium tetrafluoroborates and gave synthetically useful 2,3-deoxy-3-keto-α-aryl-C-glycosides in good to excellent yields. Broad substrate scope, simple operation and room temperature reactions make this protocol very attractive in organic synthesis.

tert-Butyl nitrite mediated nitrogen transfer reactions: synthesis of benzotriazoles and azides at room temperature.

A conversion of o-phenylenediamines into benzotriazoles was achieved at room temperature using tert-butyl nitrite. The optimized conditions are also well suited for the transformation of sulfonyl and acyl hydrazines into corresponding azides. This protocol does not require any catalyst or acidic medium. The desired products were obtained in excellent yields in a short span of time.

Copper promoted N-alkylation of sulfoximines with alkylboronic acid under mild conditions.

The copper meditated N-methylation of sulfoximines using methylboronic acid is reported. The reactions provide excellent yields in a short span of time under mild conditions. The optimized conditions were also found to be suitable for the N-alkylation of sulfoximine with different alkylboronic acids. In addition, N-methylation and cyclopropylation of the bioactive l-methionine sulfoximine derivative was demonstrated under standard reaction conditions.

Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites.

Identification of carbohydrate sequences that determine affinity to specific chemokines is a critical step for strategies to interfere with chemokine-mediated leukocyte trafficking. Here, we first characterized the development of allergic asthma in Tie2-dependent and inducible Ext1-knockout (Tie2-Ext1(iKO)) mice. We showed that heparan sulfate is essential for leukocyte recruitment in the peribronchial region and bronchoalveolar lavage fluid (BALF), and is crucial for induction of airway hyperresponsiveness. Our glycan microarray showed a unique affinity profile of chemokine CCL20 to substructures of heparin and heparin-like oligo/di/monosaccharides. Among them, we identified a synthetic and not naturally occurring monosaccharide, 2,4-O-di-sulfated iduronic acid (Di-S-IdoA), as a potential inhibitor for CCL20-heparan sulfate interaction. Mice injected with Di-S-IdoA via tail vain or nasal inhalation showed attenuated leukocyte recruitment into inflammatory sites and BALF. These results demonstrate a critical role of chemokine-heparan sulfate interaction in the asthma development and Di-S-IdoA as a potential drug for asthma treatment.

Urea-hydrogen peroxide prompted the selective and controlled oxidation of thioglycosides into sulfoxides and sulfones.

A practical method for the selective and controlled oxidation of thioglycosides to corresponding glycosyl sulfoxides and sulfones is reported using urea-hydrogen peroxide (UHP). A wide range of glycosyl sulfoxides are selectively achieved using 1.5 equiv of UHP at 60 °C while corresponding sulfones are achieved using 2.5 equiv of UHP at 80 °C in acetic acid. Remarkably, oxidation susceptible olefin functional groups were found to be stable during the oxidation of sulfide.

Long-term nonsense suppression therapy moderates MPS I-H disease progression.

Nonsense suppression therapy is a therapeutic approach aimed at treating genetic diseases caused by in-frame premature termination codons (PTCs; also commonly known as nonsense mutations). This approach utilizes compounds that suppress translation termination at PTCs, which allows translation to continue and partial levels of deficient protein function to be restored. We hypothesize that suppression therapy can attenuate the lysosomal storage disease mucopolysaccharidosis type I-Hurler (MPS I-H), the severe form of α-L-iduronidase deficiency. α-L-iduronidase participates in glycosaminoglycan (GAG) catabolism and its insufficiency causes progressive GAG accumulation and onset of the MPS I-H phenotype, which consists of multiple somatic and neurological defects. 60-80% of MPS I-H patients carry a nonsense mutation in the IDUA gene. We previously showed that 2-week treatment with the designer aminoglycoside NB84 restored enough α-L-iduronidase function via PTC suppression to reduce tissue GAG accumulation in the Idua(tm1Kmke) MPS I-H mouse model, which carries a PTC homologous to the human IDUA-W402X nonsense mutation. Here we report that long-term NB84 administration maintains α-L-iduronidase activity and GAG reduction in Idua(tm1Kmke) mice throughout a 28-week treatment period. An examination of more complex MPS I-H phenotypes in Idua(tm1Kmke) mice following 28-week NB84 treatment revealed significant moderation of the disease in multiple tissues, including the brain, heart and bone, that are resistant to current MPS I-H therapies. This study represents the first demonstration that long-term nonsense suppression therapy can moderate progression of a genetic disease.

Synthesis of phenylethanoid glycosides from acrylic esters of glucose and aryldiazonium salts via palladium-catalyzed cross-coupling reactions and evaluation of their anti-Alzheimer activity.

Cinnamic acid-containing sugar compounds such as phenylethanoid glycosides are widely present in nature and display various biological activities. In this work, the synthesis of trans-cinnamic acid containing phenylethanoid glycosides was achieved via palladium-catalyzed cross-coupling reactions between glycosyl acrylic esters and aryldiazonium salts. A wide range of functionalized aryldiazonium salts were successfully coupled with 6-O- and 4-O-acrylic esters of glucose under optimized conditions. The reactions proceeded at room temperature in the absence of additives and base. The desired products were obtained in good to excellent yields. Selected compounds from the library were screened for anti-Alzheimer activity, while compound 16 displayed significant inhibitory activities against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes.

The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse.

Suppression therapy utilizes compounds that suppress translation termination at in-frame premature termination codons (PTCs) to restore full-length, functional protein. This approach may provide a treatment for diseases caused by nonsense mutations such as mucopolysaccharidosis type I-Hurler (MPS I-H). MPS I-H is a lysosomal storage disease caused by severe α-L-iduronidase deficiency and subsequent lysosomal glycosaminoglycan (GAG) accumulation. MPS I-H represents a good target for suppression therapy because the majority of MPS I-H patients carry nonsense mutations, and restoration of even a small amount of functional α-L-iduronidase may attenuate the MPS I-H phenotype. In this study, we investigated the efficiency of suppression therapy agents to suppress the Idua-W392X nonsense mutation in an MPS I-H mouse model. The drugs tested included the conventional aminoglycosides gentamicin, G418, amikacin, and paromomycin. In addition, the designer aminoglycosides NB54 and NB84, two compounds previously designed to mediate efficient PTC suppression with reduced toxicity, were also examined. Overall, NB84 suppressed the Idua-W392X nonsense mutation much more efficiently than any of the other compounds tested. NB84 treatment restored enough functional α-L-iduronidase activity to partially reverse abnormal GAG accumulation and lysosomal abundance in mouse embryonic fibroblasts derived from the Idua-W392X mouse. Finally, in vivo administration of NB84 to Idua-W392X mice significantly reduced urine GAG excretion and tissue GAG storage. Together, these results suggest that NB84-mediated suppression therapy has the potential to attenuate the MPS I-H disease phenotype.