Shigeru Yamago

In vivo biological behavior of a water-miscible fullerene: 14C labeling, absorption, distribution, excretion and acute toxicity

BACKGROUND Water-soluble fullerenes have recently been shown to exhibit considerable in vitro biological activity including cytotoxicity, site-selective DNA cleavage and inhibition of HIV protease. To assess the potential of these compounds as drugs, studies on the in vivo behavior of fullerenes are needed. We therefore set out to synthesize a radiolabeled, water-soluble fullerene, in order to obtain data on the oral absorption, distribution and excretion of this class of compounds. RESULTS We synthesized a 14C-labeled water-soluble [60]fullerene using dipolar trimethylenemethane, which undergoes cycloaddition to [60]fullerene. When administered orally to rats, this compound was not efficiently absorbed and was excreted primarily in the feces. When injected intravenously, however, it was distributed rapidly to various tissues, and most of the material was retained in the body after one week. The compound was also able to penetrate the blood-brain barrier. Acute toxicity of the water-miscible fullerene was found to be quite low. CONCLUSIONS Although the water-soluble fullerenes (and possibly their simple metabolites) are not acutely toxic, they are retained in the body for long periods, raising concerns about chronic toxic effects. The fact that fullerenes distribute rapidly to many tissues suggests that they may eventually be useful to deliver highly polar drugs through membranes to a target tissue, however, and they may even have applications in the delivery of drugs to the brain. Recent advances in fullerene synthetic chemistry may also make it possible to control fullerene absorption/excretion profiles in the future.

Synthesis of [8]cycloparaphenylene from a square-shaped tetranuclear platinum complex.

Hoop-shaped p-conjugated molecules have attracted the attention of theoretical, synthetic, and supramolecular chemists for more than a half century because of their unique structures which have a distorted p system. Among these types of compounds, cycloparaphenylenes have gained much interest recently because of their potential applications in material science; they are the simplest structural unit of armchair carbon nanotubes. Although they have a simple structure, their synthesis has been a significant challenge. Whereas the parent paraphenylenes adopt an extended linear structure, the induced strain resulting from the cyclic and curved structure of cycloparaphenylenes is the major synthetic drawback. Recently, Bertozzi and co-workers have reported the first, and elegant, synthesis of [9]-, [12]-, and [18]cycloparaphenylenes. More recently, Itami and coworkers have reported a selective synthesis of [12]cycloparaphenylene. Both groups utilize the sp-hybridized carbon atom in either cyclohexa-2,5-diene-1,4-diol or cyclohexane-1,4-diol derivatives to induce the curvature, and the diol units are aromatized in the final step. We report herein the synthesis of [8]cycloparaphenylene, which is the smallest cycloparaphenylene synthesized thus far, based on a new synthetic strategy. We envisioned that cis-coordinated, square-shaped tetra(para-substituted oligoaryl)platinum complex 1 could be used as a universal precursor for [4n]cycloparaphenylenes 2 (Scheme 1). Since the bond angles of the cis substituents in platinum complexes are about 908, formation of 1 should not induce significant strain. Indeed, structurally related coordination complexes of palladium and platinum macrocycles containing a 4,4’-bipyridyl unit have been already reported, and their analogues have been widely used in supramolecular chemistry. However, to the best of our knowledge, there is no report involving the synthesis of 1 with only covalent platinum–carbon bonds. If multiple reductive eliminations of platinum from 1 occur, 2 could be formed despite of the increase of molecular strain. We report herein the synthesis of [8]cycloparaphenylene (n = 2) from the corresponding precursor as a proof of principle for this strategy. We calculated the strain energies of several cycloparaphenylenes before attempting the synthesis. On the basis of density functional theory calculations at the B3LYP/6-31G* level of theory, the strain energy of [8]cycloparaphenylene was 74 kcal mol , whereas those of [9]-, [12]-, and [18]cycloparaphenylenes were 69, 50, and 33 kcal mol , respectively. To synthesize [8]cycloparaphenylene (5), 4,4’-bis(trimethylstannyl)biphenyl 3 was first treated with one equivalent of [PtCl2(cod)] (cod = 1,5-cyclooctadiene) in refluxing THF for 35 hours (Scheme 2). The reaction gave the squareshaped platinum complex 4 a in 57% yield, which was treated with 1,1’-bis(diphenylphosphino)ferrocene (dppf) to give 4b in 91% yield. Bromine-induced reductive elimination from 4b at 95 8C for 17 hours in toluene afforded 5 in 49 % yield upon isolation. Addition of iodine or triphenylphosphine, instead of bromide, did not improve the efficiency of the reductive elimination. In the H NMR spectrum of 5, a single peak was observed at d = 7.48 ppm, and in the C NMR spectrum, peaks were observed at d = 137.8 and 127.6 ppm. These spectra are Scheme 1. Synthetic strategy for [4n]cycloparaphenylene.

Precision Polymer Synthesis by Degenerative Transfer Controlled/Living Radical Polymerization Using Organotellurium, Organostibine, and Organobismuthine Chain-Transfer Agents

Structurally well-defined macromolecules are ubiquitous in nature, with enzymes as prime examples. They are admired not only for the beauty of their structures but also for their ability to catalyze a variety of chemical transformations under mild conditions. For example, nitrogenase catalyzes nitrogen fixation under physiological conditions,1,2 whereas the same reaction in a chemical reactor by the Haber-Bosch process requires ultrahigh pressures and temperatures. The key to the functions of enzymes is the monodispersity and completely controlled amino acid (monomer) sequences of the polymer chain in the biomacromolecule, leading to highly ordered three-dimensional structures. This control combined with the existence of polar functional groups on the amino acid residues precisely located near the active center orchestrates the activity of enzymes. By extrapolating from the structural and functional features of enzymes, one should be able to create new polymers with new properties and/or functions based on precise control of macromolecular structures, namely, molecular weight, molecular weight distribution (MWD), monomer sequence, topology, functional groups, and stereochemistry (tacticity). Controlling all of these factors is a formidable challenge, but significant advances have been made toward this goal since the advent of controlled/living radical polymerization (LRP). Living anionic,3,4 cationic,5 and coordination polymerization6-8 have already been used to control molecular weights and MWDs of the resulting polymers and monomer sequences through block copolymer synthesis. However, these * To whom correspondence should be addressed. E-mail: yamago@ scl.kyoto-u.ac.jp. Shigeru Yamago received his B.S. and Ph.D in chemistry from Tokyo Institute of Technology in 1986 and 1991, respectively, under the supervision of Professor Eiichi Nakamura. During that time, he joined Professor Peter Vollhardt’s group at U.C. Berkeley as a summer student (1988). He became an assistant professor at Tokyo Institute of Technology in 1991 in the group of Professor Eiichi Nakamura and then moved to Kyoto University in 1995 in the group of Professor Jun-ichi Yoshida. He was a Visiting Scientist in Dr. Chryssostomos Chatgilialoglu’s group at Consiglio Nazionale delle Ricerche in Bologna (2000). In 2003, he was appointed Professor of Osaka City University. He had been a Research Fellow of PRESTO program in the Japan Science and Technology Agency from 2002 to 2006. In 2006, he joined Institute for Chemical Research at Kyoto University where he holds Professorship. He received the Incentive Award in Synthetic Organic Chemistry from the Society of Synthetic Organic Chemistry, Japan, in 2001. His research interests include synthetic organic and polymer chemistry, radical chemistry, and element chemistry. Chem. Rev. 2009, 109, 5051–5068 5051

Organotellurium-Mediated Controlled/Living Radical Polymerization Initiated by Direct C−Te Bond Photolysis

UV-vis irradiation of an organotellurium chain transfer agent in the presence of vinyl monomers leads to the formation of highly controlled living polymers with predetermined number average molecular weights and narrow molecular weight distributions.

Organoplatinum‐Mediated Synthesis of Cyclic π‐Conjugated Molecules: Towards a New Era of Three‐Dimensional Aromatic Compounds

This article describes the most recent developments in the synthesis of three-dimensional π-conjugated molecules and the elucidation of their properties made by our research group. Various cycloparaphenylenes (CPPs) of different sizes and a cage-like 3D molecule were synthesized based on the platinum-mediated assembly of π-units and subsequent reductive elimination of platinum. The assembly of π-units by this method mimics the self-assembly process for the formation of supramolecular ligand-metal complexes with 3D cages and polyhedral structures. Furthermore, reductive elimination of platinum successfully took place with high efficiency, despite the high strain energy of the target molecule. Several size-dependent physical properties of CPPs, namely the photophysical, redox, and host-guest chemistries, were also clarified. These results are of use for a molecular-level understanding of CNT physical properties as well as fullerene peapods. Theoretical and electrochemical studies suggest that small CPPs and their derivatives should be excellent lead compounds for molecular electronics.

Synthesis and Characterization of [5]Cycloparaphenylene

The synthesis of highly strained [5]cycloparaphenylene ([5]CPP), a structural unit of the periphery of C60 and the shortest possible structural constituent of the sidewall of a (5,5) carbon nanotube, was achieved in nine steps in 17% overall yield. The synthesis relied on metal-mediated ring closure of a triethylsilyl (TES)-protected masked precursor 1c followed by removal of the TES groups and subsequent reductive aromatization. UV-vis and electrochemical studies revealed that the HOMO-LUMO gap of [5]CPP is narrow and is comparable to that of C60, as predicted by theoretical calculations. The results suggest that [5]CPP should be an excellent lead compound for molecular electronics.

Synthesis, Characterization, and Properties of [4]Cyclo‐2,7‐pyrenylene: Effects of Cyclic Structure on the Electronic Properties of Pyrene Oligomers

A cyclic tetramer of pyrene, [4]cyclo-2,7-pyrenylene ([4]CPY), was synthesized from pyrene in six steps and 18% overall yield by the platinum-mediated assembly of pyrene units and subsequent reductive elimination of platinum. The structures of the two key intermediates were unambiguously determined by X-ray crystallographic analysis. DFT calculations showed that the topology of the frontier orbitals in [4]CPY was essentially the same as those in [8]cycloparaphenylene ([8]CPP), and that all the pyrene units were fully conjugated. The electrochemical analyses proved the electronic properties of [4]CPY to be similar to those of [8]CPP. The results are in sharp contrast to those obtained for the corresponding linear oligomers of pyrene in which each pyrene unit was electronically isolated. The results clearly show a novel effect of the cyclic structure on cyclic π-conjugated molecules.

Partial Charge Transfer in the Shortest Possible Metallofullerene Peapod, La@C82⊂[11]Cycloparaphenylene

[11]Cycloparaphenylene ([11]CPP) selectively encapsulates La@C82 to form the shortest possible metallofullerene-carbon nanotube (CNT) peapod, La@C82 ⊂[11]CPP, in solution and in the solid state. Complexation in solution was affected by the polarity of the solvent and was 16 times stronger in the polar solvent nitrobenzene than in the nonpolar solvent 1,2-dichlorobenzene. Electrochemical analysis revealed that the redox potentials of La@C82 were negatively shifted upon complexation from free La@C82 . Furthermore, the shifts in the redox potentials increased with polarity of the solvent. These results are consistent with formation of a polar complex, (La@C82 )(δ-) ⊂[11]CPP(δ+) , by partial electron transfer from [11]CPP to La@C82 . This is the first observation of such an electronic interaction between a fullerene pea and CPP pod. Theoretical calculations also supported partial charge transfer (0.07) from [11]CPP to La@C82 . The structure of the complex was unambiguously determined by X-ray crystallographic analysis, which showed the La atom inside the C82 near the periphery of the [11]CPP. The dipole moment of La@C82 was projected toward the CPP pea, nearly perpendicular to the CPP axis. The position of the La atom and the direction of the dipole moment in La@C82 ⊂[11]CPP were significantly different from those observed in La@C82 ⊂CNT, thus indicating a difference in orientation of the fullerene peas between fullerene-CPP and fullerene-CNT peapods. These results highlight the importance of pea-pea interactions in determining the orientation of the metallofullerene in metallofullerene-CNT peapods.

Photoinduced Switching from Living Radical Polymerization to a Radical Coupling Reaction Mediated by Organotellurium Compounds

An efficient and simple method for the synthesis of symmetric macromolecules by photoinduced switching from radical polymerization to a radical coupling reaction is reported. Structurally well-defined telechelic polyisoprenes and ABA-triblock copolymers were prepared by successive organotellurium-mediated living radical polymerization (TERP) under thermal conditions, followed by a polymer-end radical coupling reaction under photoirradiation.

Isolation and Characterization of the Cycloparaphenylene Radical Cation and Dication

Charged nanobelts: The radical cation and the dication of [8]cycloparaphenylene ([8]CPP) were prepared and isolated as hexahaloantimonate salts by the one- or two-electron chemical oxidation of [8]CPP with NOSbF6 or SbCl5 . ESR spectroscopy of CPP(.+) and single-crystal X-ray analysis of CPP(2+) demonstrated that the spin and charge were equally and fully delocalized over the para-phenylene rings.