Koji Miki

A new ruthenium-catalyzed cyclopropanation of alkenes using propargylic acetates as a precursor of vinylcarbenoids

Abstract [RuCl 2 (CO) 3 ] 2 catalyzes intermolecular cyclopropanation of various alkenes with propargylic acetates to give vinylcycloropanes in good yields. The key intermediate of this reaction is a vinylcarbene complex generated by nucleophilic attack of the carbonyl oxygen of the acetate to an internal carbon of alkyne activated by the ruthenium complex.

Tetradehydrodinaphtho[10]annulene: A Hitherto Unknown Dehydroannulene and a Viable Precursor to Stable Zethrene Derivatives

The synthesis and structural characterization of hitherto unknown tetradehydrodinaphtho[10]annulene, a hydrocarbon whose synthesis had been attempted four decades ago, was achieved for the first time. Moreover, the dinaphtho[10]annulene was transformed smoothly into stable zethrene derivatives substituted at its 7,14-positions, showing that it serves as a good reservoir of zethrene derivatives. Optical and electrochemical properties of a disubstituted zethrene derivative are also presented.

Ring-opening metathesis polymerization-based synthesis of polymeric nanoparticles for enhanced tumor imaging in vivo: Synergistic effect of folate-receptor targeting and PEGylation.

We have synthesized amphiphilic copolymers using ring-opening metathesis polymerization (ROMP), a copper-catalyzed dipolar click reaction, and osmium-catalyzed dihydroxylation. The resulting copolymers were easily conjugated with folate and dye (indocyanine green) moieties, using a transamidation method. The copolymers exhibited high water solubility and formed nanometer-sized self-assemblies in aqueous medium. The amphiphilic copolymers modified by dihydroxylation of the polymer backbone exhibited much lower cmc values than the non dihydroxylated copolymer. Copolymers conjugated with folate moieties reduced the fluorescence intensity of aqueous polymer solutions both in vitro and in vivo, but their self-assemblies efficiently accumulated at tumor sites because of folate-receptor recognition at tumor tissue. The PEGylation of copolymers improved the stability of the self-assemblies in aqueous medium as well as the tumor site selectivity in vivo. Furthermore, the fluorescent nanoparticles consisting of PEG- and folate-conjugated ROMP-based copolymers accumulated in tumor tissue selectively and efficiently, whereas accumulation in all other normal organs was reduced. The PEGylation and folate conjugation can synergistically improve the in vivo tumor site selectivity of ROMP-based copolymers.

Synthesis of 2-pyranylidene or (2-furyl)carbene–chromium complexes from conjugated enyne carbonyl compounds with Cr(CO)5(THF)

Abstract The reaction of β-ethynyl α,β-unsaturated esters or amides with Cr(CO) 5 (L) (L=Et 2 O, THF), derived from chromium hexacarbonyl, gives 2-pyranylidene–chromium complexes in good yields. The conjugated ene-carbonyl-vinylidene complex is a key intermediate to these Fischer-type oxacarbene complexes. In contrast, β-ethynyl α,β-unsaturated ketones react with Cr(CO) 5 (THF) to give (2-furyl)carbene complexes via nucleophilic attack of the carbonyl oxygen atom to the intermediate π-alkyne–chromium complexes. Some chemical transformation, such as [4+2] type cyclization of 2-pyranylidene complexes with alkynes and aldehyde formation from (2-furyl)carbene complexes, has also been described.

High‐Contrast Fluorescence Imaging of Tumors In Vivo Using Nanoparticles of Amphiphilic Brush‐Like Copolymers Produced by ROMP

Optical imaging techniques used to detect malignant tumors by endoscopy or at surgery require near-infrared fluorescence (NIRF) probes containing dyes with high signal-to-noise (S/ N) ratios. Along with a high S/N ratio in the near-infrared spectral region, these probes must accumulate specifically in the targeted tumor tissues. Spherical amphiphilic assemblies with diameters of 50–200 nm, such as liposomes, liposomelike assemblies, and micelles or vesicles of polymer conjugates, have been investigated with the expectation that they accumulate in solid tumors because of their enhanced permeability and retention (EPR) effect. Optical tumor imaging faces two problems. The first problem is the stability of the self-assembled amphiphilic copolymers. The disassembly of amphiphiles under diluted conditions, especially in blood vessels, reduces both their S/N ratio and specificity as probes for tumors. The second problem concerns the fluorescence intensities. Hydrophobic dyes attached to copolymers are prone to aggregate in aqueous solution, and self-quenching therefore reduces the quantum yields. To address the first problem, we focused our attention on the cross-linked assemblies of copolymers with hydrophobic and hydrophilic polymeric side chains (Figure 1). Because the polymer backbone bearing hydro-

Ring-opening metathesis polymerization-based synthesis of ICG-containing amphiphilic triblock copolymers for in vivo tumor imaging.

Water-soluble triblock copolymers consisting of hydrophobic-hydrophilic-dye segments were synthesized by ring-opening metathesis polymerization (ROMP) of norbornadiene monomers, copper-catalyzed click reaction, osmium-catalyzed dihydroxylation, and the following transformations. These polymers in aqueous conditions could form spherical assemblies, whose diameters were 50-60 nm by TEM measurement. From in vivo optical imaging experiments, the spherical assemblies of these copolymers could be efficiently accumulated in tumor cells. In addition, the spherical assemblies of water-soluble polymers accumulated in a tumor cell over two weeks.

Synthesis of Strained Pyridine-Containing Cyclyne via Reductive Aromatization

The Sonogashira-Hagihara coupling reactions of 2,6-diiodopyridine and cis-3,6-diethynyl-3,6-dimethoxycyclohexa-1,4-diene or cis-9,10-diethynyl-9,10-dimethoxy-9,10-dihydroanthracene gave macrocyclic compounds having alternating 2,6-diethynylpyridine and 3,6-dimethoxycyclohexa-1,4-diene segments. Transformation of the C(3)-symmetric 2,6-diethynylpyridine-based cyclotrimer was efficiently achieved using tin-mediated reductive aromatization under mild conditions.

A new route to 3-acyl-2-aminobenzofurans: palladium-catalysed cycloisomerisation of 2-(cyanomethyl)phenyl esters.

Treatment of 2-(cyanomethyl)phenyl esters with a catalytic amount of Pd(OAc)(2), PCy(3), and Zn afforded 3-acyl-2-aminobenzofuran derivatives in good to excellent yields, which can be used as building blocks for the synthesis of benzofuran fused heterocycles.

Near-Infrared Dye-Conjugated Amphiphilic Hyaluronic Acid Derivatives as a Dual Contrast Agent for In Vivo Optical and Photoacoustic Tumor Imaging

Amphiphilic hyaluronic acid (HA) derivatives bearing hydrophobic indocyanine green dye derivatives and hydrophilic poly(ethylene glycol) were synthesized through the use of condensation and copper-catalyzed click cyclization reactions. The amphiphilic HA derivatives dissolved in water and formed self-assemblies in which the near-infrared dyes were tightly packed and arranged to form dimers or H-aggregates. By irradiating an aqueous solution of HA derivatives with near-infrared light, photoacoustic signals were detected along with fluorescence emission. Self-assemblies consisting of HA derivatives could smoothly accumulate in tumor tissues by passive tumor targeting. By utilizing HA derivatives as a contrast agent, tumor sites were clearly visualized by optical imaging as well as by photoacoustic tomography.

Influence of side chain length on fluorescence intensity of ROMP-based polymeric nanoparticles and their tumor specificity in in-vivo tumor imaging.

In this study, amphiphilic brush-like copolymers conjugated with short alkyl or long polymeric chains of various lengths are synthesized using ring-opening metathesis polymerization (ROMP) of substituted norbornadiene monomers followed by chemical transformations. These amphiphilic copolymers form spherical self-assemblies in aqueous media with diameters of 132-244 nm. The low critical aggregation concentration of these assemblies (2.5 × 10(-3) -1.4 × 10(-5) g/L) indicates that they are quite stable in dilute conditions. An appropriate length of polymer side chain that conjugates the polymer backbone with a hydrophobic ICG (indocyanine green) moiety enhanced the fluorescence intensities of these self-assemblies in aqueous solution as well as in tumor-bearing mice. A longer side chain conjugated with tumor targeting agents could significantly affect the tumor specificity of self-assemblies to a greater extent. The self-assemblies bearing hydrophilic tumor targeting agents, such as a glucosamine molecule and a cyclic RGD (arginine-glycine-asparatic acid) peptide, accumulated in tumor tissues with high selectivity, while those having a hydrophobic targeting agent, such as folate moieties, accumulated in tumor sites with low selectivity. The results demonstrated here unambiguously indicate that the fluorescence intensity and tumor specificity of self-assemblies are strongly affected by the length of side chains that conjugate with dyes and targeting agents.