Linkage-Editing of Melibiosamine: Synthesis and Biological Evaluation of CH- and CHF-Linked Analogs.

Melibiosamine (Gal-α(1,6)-GlcNH), consisting of galactose and glucosamine linked by an α(1,6)-glycosidic bond, is an artificial disaccharide derivative that selectively inhibits the proliferation of K562 tumor cells relative to HUC-F2 normal cells. In this study, we employed a linkage-editing strategy to synthesize CH- and CHF-linked melibiosamine analogs through chemo- and stereoselective hydrogenation of fluorovinyl--glycoside. ()-CHF-Melibiosamine exhibited more potent antiproliferative activity than -linked melibiosamine, while ()-CHF-melibiosamine was less potent.

Structure-activity relationship study of nitrogen signaling factors.

We have synthesized 10 analogs of oxylipins, which are nitrogen signaling factors (NSFs) that mediate cell-to-cell communication in the fission yeast Schizosaccharomyces pombe, and evaluated their structure-activity relationships with the aim of developing molecular probes for NSFs. We found that the OH or OAc group at C10 could be replaced with a compact amide (17) or carbamate (19). Introducing an alkyne as a detection tag at C10 led to decreased, though still sufficient, activity.

Linkage-Editing Pseudo-Glycans: A Reductive α-Fluorovinyl--Glycosylation Strategy to Create Glycan Analogs with Altered Biological Activities.

The acetal (-glycoside) bonds of glycans and glycoconjugates are chemically and biologically vulnerable, and therefore -glycosides are of interest as more stable analogs. We hypothesized that, if the -glycoside linkage plays a vital role in glycan function, the biological activities of -glycoside analogs would vary depending on their substituents. Based on this idea, we adopted a "linkage-editing strategy" for the creation of glycan analogs (pseudo-glycans).

Iridium-Catalyzed, Site-Selective Silylation of Secondary C(sp)-H Bonds in Secondary Alcohols and Ketones.

We report the iridium-catalyzed, stereoselective conversion of secondary alcohols or ketones to -1,3-diols by the silylation of secondary C-H bonds γ to oxygen and oxidation of the resulting oxasilolane. The silylation of secondary C-H bonds in secondary silyl ethers derived from alcohols or ketones is enabled by a catalyst formed from a simple bisamidine ligand. The silylation occurs with high selectivity at a secondary C-H bond γ to oxygen over distal primary or proximal secondary C-H bonds.

Photoredox-catalyzed protecting-group-free -glycosylation with glycosyl sulfinate the Giese reaction.

-Glycoside analogs of naturally occurring glycoconjugates are useful tools for chemical biology studies, but their synthesis usually requires protection of the hydroxyl groups of the glycosyl donors. Here we report protecting-group-free and photoredox-catalyzed -glycosylation with glycosyl sulfinates and Michael acceptors the Giese radical addition.

Ligand-Controlled Stereoselective Synthesis and Biological Activity of 2-Exomethylene Pseudo-glycoconjugates: Discovery of Mincle-Selective Ligands.

Glycoconjugate analogues in which the sp -hybridized C2 position of the carbohydrate structure (normally bearing a hydroxy group) is converted into a compact sp -hybridized exomethylene group are expected to have unique biological activities. We established ligand-controlled Tsuji-Trost-type glycosylation methodology to directly prepare a variety of these 2-exomethylene pseudo-glycoconjugates, including glucosylceramide analogues, in an α- or β-selective manner. Glucocerebrosidase GBA1 cleaves these synthetic pseudo-β-glucosylceramides similarly to native glucosylceramides.

Synthesis and biological activity of ganglioside GM3 analogues with a (S)-CHF-Sialoside linkage and an alkyne tag.

The alkyne tag, consisting of only two carbons, is widely used as a bioorthogonal functional group due to its compactness and nonpolar structure, and various probes consisting of lipids bearing an alkyne tag have been developed. Here, we designed and synthesized analogues of ganglioside GM3 bearing an alkyne tag in the fatty acid moiety and evaluated the effect of the alkyne tag on the biological activity. To eliminate the influence of other factors such as degradation of the glycan chain when evaluating biological activity in a cellular environment, we introduced the tag into sialidase-resistant (S)-CHF-linked GM3 analogues developed by our group.

Harringtonine Ester Derivatives with Enhanced Antiproliferative Activities against HL-60 and HeLa Cells.

Harringtonine (HT), produced from species, is known to exhibit potent antiproliferative activity against myeloid leukemia cells by inhibiting protein synthesis. A previous study using acute promyelocytic leukemia (HL-60) cells raised the possibility that the C-5' methyl group of HT plays an important role in regulating leukemia cell line antiproliferative activity. In order to investigate the effect of hydrocarbon chains at C-5' on the resultant activity, the C-5' methyl group was replaced with various straight- and branched-chain hydrocarbons using the corresponding alcohols, and their antiproliferative activity against HL-60 and HeLa cells was investigated.

Effect of Alkynyl Group on Reactivity in Photoaffinity Labeling with 2-Thienyl-Substituted α-Ketoamide.

Minimalist photo-reactive probes, which consist of a photo-reactive group and a tag for detection of target proteins, are useful tools in chemical biology. Although several diazirine-based and aryl azide-based minimalist probes are available, no keto-based minimalist probe has yet been reported. Here we describe minimalist probes based on a 2-thienyl-substituted α-ketoamide bearing an alkyne group on the thiophene ring.

Preparation of Oxysterols by C-H Oxidation of Dibromocholestane with Ru(Bpga) Catalyst.

Seven mono- and dihydroxycholesterols were prepared by direct C-H oxidation of the cholestane skeleton with a recently developed Ru(Bpga) catalyst (Ru(Bpga) = [RuCl (bpga) (PPh)] Cl; bpga = 2-(bis(pyridin-2-ylmethyl)amino)--(2,6-dimethylphenyl)acetamide)). Due to the high selectivity of the Ru(Bpga) complex for tertiary C-H, the reaction afforded a mixture of 25-, 20-, 17-, and 14-oxygenated cholesterols that could be easily separated by high-performance liquid chromatography. These results suggest that late-stage C-H oxidation could be a viable strategy for preparing candidate metabolites of biologically important molecules.

β-Glycosyl Trifluoroborates as Precursors for Direct α-C-Glycosylation: Synthesis of 2-Deoxy-α--glycosides.

-Glycosides are metabolically stable mimics of natural -glycosides and are expected to be useful tools for investigation of the biological functions of glycans. Here, we describe the synthesis of a series of aryl and vinyl -glycosides by stereoinvertive sp-sp cross-coupling reactions of 2-deoxyglycosyl boronic acid derivatives with aryl or vinyl halide, mediated by a photoredox/nickel dual catalytic system. Hydrogenation of the vinyl -glycosides afforded C-linked 2'-deoxydisaccharide analogues.

Synthesis of DFGH-Ring Derivatives of Physalins via One-Pot Construction of GH-Ring and Evaluation of Their NF-κB-Inhibitory Activity.

We designed and synthesized a series of derivatives containing the right-side DFGH-ring structure of physalin-type natural products, decorated with a hydrophobic substituent. The synthetic scheme utilizes a highly efficient, one-pot protocol for simultaneous construction of the GH-ring system, promoted by HF/pyridine. Among the compounds synthesized, inhibited TNF-α-stimulated NF-κB activation with similar potency to physalin B.

Unified Total Synthesis of Pentacyclic Stemoamide-type Alkaloids.

The collective synthesis of pentacyclic stemoamide-type alkaloids is recognized as a daunting task despite high demand for a comprehensive biological profiling of these natural products. In this Letter, we report a unified synthesis of seven pentacyclic alkaloids and two unnatural derivatives. The keys to success are (1) the chemoselective assembly of four five-membered building blocks, (2) the direct oxidation of pyrrolidine natural products to pyrrole derivatives, and (3) the stereodivergent construction of totally E- or Z-substituted butenolides.

Synthesis of CH-linked α-galactosylceramide and its glucose analogues through glycosyl radical-mediated direct C-glycosylation.

We describe a new synthetic approach for C-linked glycolipid analogues, in which the cleavable O-glycosidic linkage is replaced by a carbon unit. Direct C-glycosylation of a conformationally constrained and stable C1-sp hybridized xanthate carbohydrate with carefully designed sphingosine units afforded the CH-linked analogue of antitumor-active KRN7000 and its glucose congener.

Sequential Xanthalation and -Trifluoromethylation of Phenols: A Procedure for the Synthesis of Aryl Trifluoromethyl Ethers.

Molecules containing trifluoromethoxyaryl groups are of interest in pharmaceutical, agrochemical, and materials science research, due to their unique physical and electronic properties. Many of the known methods to synthesize aryl trifluoromethyl ethers require harsh reagents and highly controlled reaction conditions and rarely occur when heteroaromatic units are present. The two-step -trifluoromethylation of phenols via aryl xanthates is one such method that suffers from these drawbacks.

Stereospecific Overman Rearrangement of Substituted Cyclic Vinyl Bromides: Access to Fully Substituted α-Amino Ketones.

A versatile thermal Overman rearrangement of enantioenriched, cyclic allylic alcohols providing tertiary allylic amines has been developed. The vinyl bromide used to control enantioselectivity in a preceding CBS reduction is utilized as a synthetic handle for the preparation of tertiary α-amino ketones and related derivatives in an asymmetric fashion.

Crystal structure of (-)-(5,7,8,9,10)-8-methyl-7-[(5)-3-methyl-2-oxooxolan-3-en-5-yl]-1-aza-6-oxatri-cyclo-[8.3.0.0]tridecan-13-one monohydrate.

The title compound, CHNO·HO, is an epimer of the natural tetra-cyclic alkaloid isosaxorumamide which consists of a fused 5-7-5 tricyclic core and a di-hydro-furan-one substituent. The terminal di-hydro-furan ring is essentially planar with a maximum deviation of 0.0273 (14) Å from the mean plane and oxolane, azepane and pyrrolidine rings in the tricyclic ring system adopt twist, twist-chair and envelope forms, respectively.

Unified Total Synthesis of Stemoamide-Type Alkaloids by Chemoselective Assembly of Five-Membered Building Blocks.

A unified total synthesis of stemoamide-type alkaloids is reported. Our synthetic approach features the chemoselective convergent assembly of five-membered building blocks via stemoamide as the common precursor to tetracyclic natural products. The synthesis consists of two successive coupling reactions of the three five-membered building blocks.

(5R*)-5-[(2S*,5S*)-1-Meth-oxy-5-phenyl-pyrrolidin-2-yl]-3-methyl-furan-2(5H)-one.

In the title compound, C16H19NO3, the pyrrolidine ring is in a twist conformation. The dihedral angle between the di-hydro-furan ring [maximum deviation = 0.0016 (11) Å] and the phenyl ring is 47.

Two-step synthesis of multi-substituted amines by using an N-methoxy group as a reactivity control element.

The development of a two-step synthesis of multi-substituted N-methoxyamines from N-methoxyamides is reported. Utilization of the N-methoxy group as a reactivity control element was the key to success in this two-step synthesis. The first reaction involves a N-methoxyamide/aldehyde coupling reaction.

Total synthesis of (±)-gephyrotoxin by amide-selective reductive nucleophilic addition.

A chemoselective approach for the total synthesis of (±)-gephyrotoxin has been developed. The key to success was the utilization of N-methoxyamides, which enabled the direct coupling of the amide with an aldehyde and selective reductive nucleophilic addition to the amide in the presence of a variety of sensitive and electrophilic functional groups, such as a methyl ester. This chemoselective approach minimized the use of protecting-group manipulations and redox reactions, which resulted in the most concise and efficient total synthesis of (±)-gephyrotoxin described to date.