Total syntheses of nobilamides B and D: application of traceless Staudinger ligation

Nobilamide B is a long-acting antagonist of transient receptor potential vanilloid-1 (TRPV1), and is expected to show therapeutic potential for treatment of pain. This linear heptapeptide possesses a Z-didehydroaminobutanoic acid moiety at the C-terminus. Stereoselective construction of the didehydroamino acid moiety was successfully achieved by application of the traceless Staudinger ligation. The combination of solid-phase peptide synthesis and the Staudinger ligation allowed rapid access to not only nobilamide B, but also its macrocyclic analogue nobilamide D.     

Synthesis of fused-tricyclic indole derivatives through an acid-promoted skeletal rearrangement

We developed a novel method for synthesizing fused-tricyclic indole derivatives with a 3-aminomethyl indole motif through a reaction cascade involving ipso-Friedel–Crafts alkylation of phenols, rearomatization of the spirocyclohexadienone unit, and iso-Pictet–Spengler reaction. Using TFA as an acid promoter, six-, seven-, and eight-membered ring-fused indoles were obtained in 31–99% yield.     

Binding of Scandium Ions to Metalloporphyrin–Flavin Complexes for Long‐Lived Charge Separation

A porphyrin–flavin‐linked dyad and its zinc and palladium complexes (MPor?Fl: 2 ?M, M=2 H, Zn, and Pd) were newly synthesized and the X‐ray crystal structure of 2 ?Pd was determined. The photodynamics of 2 ?M were examined by femto‐ and nanosecond laser flash photolysis measurements. Photoinduced electron transfer (ET) in 2 ?H₂ occurred from the singlet excited state of the porphyrin moiety (H₂Por) to the flavin (Fl) moiety to produce the singlet charge‐separated (CS) state ¹(H₂Por^.+?Fl^.?), which decayed through back ET (BET) to form ³[H₂Por]*?Fl with rate constants of 1.2×10¹⁰ and 1.2×10⁹ s^?1, respectively. Similarly, photoinduced ET in 2 ?Pd afforded the singlet CS state, which decayed through BET to form ³[PdPor]*?Fl with rate constants of 2.1×10¹¹ and 6.0×10¹⁰ s^?1, respectively. The rate constant of photoinduced ET and BET of 2 ?M were related to the ET and BET driving forces by using the Marcus theory of ET. One and two Sc³⁺ ions bind to the flavin moiety to form the Fl?Sc³⁺ and Fl?(Sc³⁺)₂ complexes with binding constants of K₁=2.2×10⁵ M ^?1 and K₂=1.8×10³ M ^?1, respectively. Other metal ions, such as Y³⁺, Zn²⁺, and Mg²⁺, form only 1:1 complexes with flavin. In contrast to 2 ?M and the 1:1 complexes with metal ions, which afforded the short‐lived singlet CS state, photoinduced ET in 2 ?Pd???Sc³⁺ complexes afforded the triplet CS state (³[PdPor^.+?Fl^.??(Sc³⁺)₂]), which exhibited a remarkably long lifetime of τ=110 ms (k_BET=9.1 s^?1).     

UV resistance of encapsulated low molecular weight aromatic compounds in fluoroalkyl end‐capped trimethoxyvinylsilane oligomer/silica nanocomposites

Sol–gel reactions of fluoroalkyl end‐capped trimethoxyvinylsilane oligomer in the presence of low molecular weight aromatic compounds (ArH) such as 1,1′‐bi(2‐naphthol) (BINOL) and 2‐hydroxy‐4‐methoxy benzophenone (HMB) were found to proceed smoothly under alkaline conditions at room temperature to give the corresponding fluorinated oligomeric silica nanocomposites‐encapsulated aromatic compounds (BINOL and HMB) [R_F‐(VM‐SiO₂)_n‐R_F/ArH nanocomposites]. UV light irradiation (λ_max: 254 nm) toward R_F‐(VM‐SiO₂)_n‐R_F/ArH nanocomposites showed that photodegradation of encapsulated ArH was not observed at all in the fluorinated nanocomposites cores, although the parent ArH can exhibit an effective photodegradation behavior under similar conditions. Especially, encapsulated ArH can exhibit no weight loss corresponding to the contents of the aromatic compounds in the fluorinated nanocomposites even after calcination at 800°C. Therefore, fluoroalkyl end‐capped trimethoxyvinylsilane oligomer has high potential for not only the thermal resistance but also the UV resistance fluorinated polymeric materials. Copyright © 2014 John Wiley & Sons, Ltd.     

Hydrazide and hydrazine reagents as reactive matrices for MALDI‐MS to detect gaseous aldehydes

The reagents 19 hydrazide and 14 hydrazine were examined to function as reactive matrices for matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) to detect gaseous aldehydes. Among them, two hydrazide (2‐hydroxybenzohydrazide and 3‐hydroxy‐2‐naphthoic acid hydrazide) and two hydrazine reagents [2‐hydrazinoquinoline and 2,4‐dinitrophenylhydrazine (DNPH)] were found to react efficiently with carbonyl groups of gaseous aldehydes (formaldehyde, acetaldehyde and propionaldehyde); these are the main factors for sick building syndrome and operate as reactive matrices for MALDI‐MS. Results from accurate mass measurements by JMS‐S3000 Spiral‐TOF suggested that protonated ion peaks corresponding to [M + H]⁺ from the resulting derivatives were observed in all cases with the gaseous aldehydes in an incubation, time‐dependent manner. The two hydrazide and two hydrazine reagents all possessed absorbances at 337 nm (wavelength of MALDI nitrogen laser), with, significant electrical conductivity of the matrix crystal and functional groups, such as hydroxy group and amino group, being important for desorption/ionization efficiency in MALDI‐MS. To our knowledge, this is the first report that gaseous molecules could be derivatized and detected directly in a single step by MALDI‐MS using novel reactive matrices that were derivatizing agents with the ability to enhance desorption/ionization efficiency. Copyright © 2014 John Wiley & Sons, Ltd.     

Assessment of macrocyclic triamine ligands as synthons for organometallic 99mTc radiopharmaceuticals

In a search of coordination molecules suitable to the fac-{(99m)Tc(CO)3}(+) core as a synthon for (99m)Tc-radiopharmaceuticals, nonradioactive rhenium complexes of two macrocyclic triamine compounds with different chelate ring structures, 1,4,7-triazacyclononane (9N3) and 1,5,9-triazacyclododecane (12N3), were synthesized and characterized. (99m)Tc-labeled 9N3 and 12N3 compounds were also prepared using [(99m)Tc(OH 2)3(CO)3](+) and were characterized by both in vitro and in vivo studies. 9N3 produced a single rhenium complex, whereas 12N3 generated two major complexes. The crystallographic data and infrared absorption wavenumber assigned to the C-O stretch suggested that the coordination geometry of 9N3 would be more suitable to fac-{Re(CO)3}(+) than that of 12N3. In contrast, both 9N3 and 12N3 provided a single (99m)Tc-labeled compound. However (99m)Tc-labeled 9N3 exhibited higher stability than (99m)Tc-labeled 12N3 in rat plasma and in the presence of histidine at an elevated temperature. In biodistribution studies, both (99m)Tc-labeled compounds did not show any specific accumulation of radioactivity in any organs except for the excretory organs such as the liver and kidney. These findings showed that 9N3 would constitute a macrocyclic chelating molecule of choice to prepare (99m)Tc radiopharmaceuticals using a fac-{(99m)Tc(CO)3}(+) core.     

Ligand-Controlled Regiodivergence in Nickel-Catalyzed Vinylcyclopropane Rearrangement

A ligand-controlled regiodivergence in Ni-catalyzed rearrangement of vinylcyclopropanes to 1,4- or 1,5-disubstituted cyclopentenes is reported. The 1,4- or 1,5-disubstituted cyclopentene is selectively obtained depending on the choice of ligands. Detailed kinetic studies and density functional theory calculations on the catalytic cycle revealed that the product selectivity is determined at the reductive elimination step from the six-membered η₁-allyl intermediate.     

Synthesis of an Octacyclic C60 Fragment

Fragments of buckminsterfullerene (C₆₀) include the monumental three compounds corannulene, sumanene, and truxene. These three have served as leading molecules in ongoing research for curved, fused, and π-extended polyaromatic materials. Achieving more structural variations that join the ranks of these three archetypes remains challenging. Herein we report synthesis of an octacyclic hydrocarbon that is an unexplored C₆₀-fragment, namely, a 4,11-dihydrodiindeno[7,1,2-ghi:7′,1′,2′-pqr]chrysene (C₂₈H₁₆, which we named Metelykene). The key to success was solution-compatible synthesis in which double pentagonal rings flank hexagonal ones. This solution-phase approach, coupled with the resulting non-planar π-conjugation, is so straightforward that it offers an entry to a derivative such as a cardo aromatic monomer.     

Solid-state Chromism of Zwitterionic Triarylmethylium Salts

Zwitterionic triarylmethylium dyes 1 and 2 were synthesized by using a synthetic unit of a tetraarylborate. The zwitterionic structure of 1 and 2 exhibits varied molecular assembly and induces charge transfer transition. These properties gave them specific optical features such as solvatochromism and mechanochromism in the solid state, that is, the green solid of 2 changes to yellow or red solid by dissolution & evaporation or grinding, respectively. The three colors were reproduced independently in different crystal forms, which were prepared from different recrystallization conditions. The diffuse reflectance measurement and powder X-ray diffraction demonstrated the correlation between the colors and the solid-state structures. The single crystal X-ray analysis revealed face-to-face dimeric assembly in each crystal. Among the crystal structures, the intermolecular distances and packing patterns were notable differences. Based on these results, it can be suggested that unique color change of zwitterionic triarylmethylium dyes originates from the alternation of intermolecular interactions.