Synthesis of Optically Pure Norcantharidin Analogue NCA‐01, a Highly Selective Protein Phosphatase 2B Inhibitor,and its Derivatives

An efficient synthetic route to optically pure norcantharidin analogue NCA‐01, a highly selective inhibitor of protein phosphatase 2B (PP2B; calcineurin), has been developed. The absolute stereochemistry of the enantiomers was determined by X‐ray crystallographic analysis. Optically pure NCA derivatives that had various substituents at the C1 position were synthesized in a similar manner. The PP2B‐inhibitory activities of NCA‐01 and its derivatives were independent of the enantiomeric form. NCA‐01 dimethyl ester potently inhibited IL‐2 production in Jurkat cells.     

Crystallization during polymerization with special reference to synthetic polypeptides

In order to pursue the possibilities of the extended chain crystals formed in the course of polymerization, kinetics of the heterogeneous polymerization of L-and DL-alanine NCA in acetonitrile and the morphologies of the resultant polymers were studied. Electron microscopy revealed that the fibers formed in the beginning of polymerization thickened as the polymerization proceeded and that the growth mechanism of the polypeptide crystals is quite similar to that of polyoxymethylene crystals during the polymerization of trioxane in cyclo-hexane. X-ray diffraction patterns and IR spectroscopy revealed that the growing chain molecules, when they attained a certain degree of polymerization (DP = -3 to 4) beyond which they lost solubility in the system, crystallized into the form of ribbon-like fibers in which molecules, with the β-conformation, were aligned perpendicularly to the fiber axis. As the growing chains attained a critical length by further polymerization, they began to take the α-helical conformation which seemed to be more stable than the β-conformation in the later stages. The crystals grew successively thereafter, taking the α-helical conformation through addition of the monomer molecules onto the reactive chain ends.

The grown polypeptide chains were loosely packed but extended α-helices in the crystals throughout the polymerization. Possible mechanisms are proposed for the nucleation and the subsequent growth of the crystals in the course of polymerization.

The polymerization of N-carboxy anhydrides of glycine and β-alanine has also been studied in acetonitrile with n-butylamine as initiator. As was expected from the similarity of the backbone chain structure to nylons, the polymer precipitated in the form of a spherulite consisting of ribbon-like crystalline units just as in the case of nylons previously reported. The molecules in the ribbon-like crystals were arranged antiparallel, forming a hydrogen-bond sheet.     

Direct alkylation of aromatics using alcohols in the presence of NaHSO4/SiO2

Simple and efficient procedure for alkylation of aromatics from alcohols in the presence of NaHSO₄/SiO₂ was developed. Various triaryl methanes were obtained in good yields in short reaction time. For instance the reaction of mesitylene with benzhydrol in the presence of NaHSO₄/SiO₂ gave the corresponding triaryl methane in a quantitative yield. NaHSO₄/SiO₂ was regenerated by simple treatment and could be recycled eight times without activity loss.     

The Last Step of Kanamycin Biosynthesis: Unique Deamination Reaction Catalyzed by the α-Ketoglutarate-Dependent Nonheme Iron Dioxygenase KanJ and the NADPH-Dependent Reductase KanK

Mystery solved: Using heterologous expression, the activities of two enzymes exclusively belonging to the kanamycin biosynthetic pathway have been identified in vitro. A distinctive reaction mechanism to produce kanamycin is proposed and the previously unknown catalytic deamination activity of KanJ dioxygenase is uncovered.     

Synthesis and electrochemical properties of bipyrimidine bridged triruthenium complexes

A new μ(4)-bpym-bridged dimer of an oxoacetao-triruthenium complex with carbonyl, [{Ru(3)O(CH(3)COO)(5)(CO)(py)}(2)(μ(4)-bpym)], was synthesized. The complex possesses two stable mixed-valence states associated with Ru(3)(III,III,II)/Ru(3)(III,II,II) and Ru(3)(III,III,III)/Ru(3)(III,III,II). The IR-spectroelectrochemistry reveals ν(CO) spectra in five oxidation states, Ru(3)(III,III,III)-Ru(3)(III,III,III) to Ru(3)(III,II,II)-Ru(3)(III,II,II) and both the mixed-valence states show a spectrum indicating medium interaction between the Ru(3) units.     

Axial chirality of donor-donor, donor-acceptor, and tethered 1,1'-binaphthyls: a theoretical revisit with dynamics trajectories

The circular dichroism (CD) spectra of (R)-2,2'-dimethoxy-1,1'-binaphthyl (DD) and its untethered and tethered donor-acceptor analogues (DA and DA7-DA9) were investigated experimentally and theoretically. The experimental CD spectra of DD and DA resembled each other in several aspects, displaying a positive-positive-negative Cotton effect pattern in the (1)L(b)-(1)L(a) region and a strong negative couplet at the (1)B(b) band, but significantly differed in transition energy and rotatory strength. The couplet amplitude (A) of the main band was 1.6 times larger in DA than in DD, despite the comparable extinction coefficients and seemingly analogous conformations. An additional positive Cotton effect was observed at the CT (CT) band for donor-acceptor binaphthyl DA. Our theoretical prediction of the CD spectra of binaphthyls involves three sequential first principle quantum mechanics (QM) calculations. Thus, the geometry optimizations of a series of conformers with varying dihedral angles were performed by the dispersion-corrected DFT-D method using the B97-D functional and the TZV2P basis set. The potential curve as a function of the dihedral angle (θ) was obtained by using the SCS-MP2/TZVPP single-point energy calculations with and without application of the solvent correction. The CD spectrum of each conformer was independently calculated by the second-order approximate coupled cluster calculation (CC2 method) using the TZVPP basis sets and the resolution of the identity (RI-J) approximation. The (net) theoretical CD spectrum was obtained by averaging over all possible conformers, where the dynamics trajectories based on the relative SCS-MP2 energies were taken into account. By using 17 possible conformers at θ varying from 50 to 130° by 5° intervals, the experimental CD spectra were successfully reproduced in a quantitative manner, enabling us to characterize properly almost all of the important spectral features and chiroptical properties. The two-state model, reported previously, turned out to have led to the right answer with wrong reasons. The couplet sign and amplitude A are critical functions of θ and can be used not only for (qualitatively) determining the absolute configuration but also for quantitatively analyzing the binaphthyl conformations. The angle dependence of A was already argued in the classical coupled oscillator and exciton chirality theories to provide reasonable structure elucidations but only in a qualitative or semiquantitative manner. Our method is able to predict the A value quantitatively as a function of θ. For tethered binaphthyls DA7-DA9, particular care should be exercised in the conformational assessment based on the classical treatment because the amplitude A was shown to be significantly affected by the existence of the tether itself. In the present method, the couplet amplitude A was nicely related to the dihedral angle θ of DA and DD by the state-of-the-art ab initio calculations, enabling us to gain the quantitative information about the conformation of axially chiral binaphthyls. The Cotton effect at the CT band also serves as a complementary clue for elucidating the conformation of donor-acceptor binaphthyls.     

Computational analysis of the proton translocation from Asp96 to schiff base in bacteriorhodopsin

The potential energy change during the M --> N process in bacteriorhodopsin has been evaluated by ab initio quantum chemical and advanced quantum chemical calculations following molecular dynamics (MD) simulations. Many previous experimental studies have suggested that the proton transfer from Asp96 to the Schiff base occurs under the following two conditions: (1) the hydrogen bond between Thr46 and Asp96 breaks and Thr46 is detached from Asp96 and (2) a stable chain of four water molecules spans an area from Asp96 --> Schiff base. In this work, we successfully reproduced the proton-transfer process occurring under these two conditions by molecular dynamics and quantum chemical calculations. The quantum chemical computation revealed that the proton transfer from Asp96 to Shiff base occurs in two-step reactions via an intermediate in which an H(3)O(+) appears around Ala215. The activation energy for the proton transfer in the first reaction was calculated to be 9.7 kcal/mol, which enables fast and efficient proton pump action. Further QM/MM (quantum mechanical/molecular mechanical) and FMO (fragment molecular orbital) calculations revealed that the potential energy change during the proton transfer is tightly regulated by the composition and the geometry of the surrounding amino acid residues of bacteriorhodopsin. Here, we report in detail the Asp96 --> Schiff base proton translocation mechanism of bacteriorhodopsin. Additionally, we discuss the effectiveness of combining quantum chemical calculations with truncated cluster models followed by advanced quantum chemical calculations applied to a whole protein to elucidate its reaction mechanism.     

A bifunctional catalyst for carbon dioxide fixation: cooperative double activation of epoxides for the synthesis of cyclic carbonates

We have developed a very active bifunctional porphyrin catalyst showing a high turnover number (TON = 103,000) for the synthesis of cyclic carbonates from CO(2) and epoxides under solvent-free conditions.     

Orientational anisotropy for Rouse eigenmodes during creep and recovery process

The Rouse model is a well established model for nonentangled polymer chains and its dynamic behavior under step strain has been fully analyzed in the literature. However, to the knowledge of the authors, no analysis has been made for the orientational anisotropy for the Rouse eigenmodes during the creep and creep recovery processes. For completeness of the analysis of the Rouse model, this anisotropy is calculated from the Rouse equation of motion. The calculation is simple and straightforward, but the result is intriguing in a sense that respective Rouse eigenmodes do not exhibit the single Voigt-type retardation. Instead, each Rouse eigenmode has a distribution in the retardation time. This behavior, reflecting the interplay among the Rouse eigenmodes of different orders under the constant stress condition, is quite different from the behavior under rate-controlled flow (where each eigenmode exhibits retardation/relaxation associated with a single characteristic time).List of abbreviations and symbols a Average segment size at equilibrium - A_p(t) Normalized orientational anisotropy for the p-th Rouse eigenmode defined by Eq. (14) - p-th Fourier component of the Brownian force (=x, y) - F_B(n,t) Brownian force acting on n-th segment at time t - G(t) Relaxation modulus - J(t) Creep compliance - J_R(t) Recoverable creep compliance - k_B Boltzmann constant - N Segment number per Rouse chain - Q_j(t) Orientational anisotropy of chain sections defined by Eq. (21) - r(n,t) Position of n-th segment of the chain at time t - S(n,t) Shear orientation function (S(n,t)=a^–2<u_x(n,t)u_y(n,t)>) - T Absolute temperature - u(n,t) Tangential vector of n-th segment at time t (u = r/n) - V(r(n,t)) Flow velocity of the frictional medium at the position r(n,t) - X_p(t), Y_p(t), and Z_p(t) x-, y-, and z-components of the amplitudes of p-th Rouse eigenmode at time t - Strain rate being uniform throughout the system - Segmental friction coefficient - ₀ Zero-shear viscosity - _p Numerical coefficients determined from Eq. (25) - Gaussian spring constant ( = 3k_BT/a²) - Number of Rouse chains per unit volume - (t) Shear stress of the system at time t - _steady Shear stress in the steadily flowing state - _R Longest viscoelastic relaxation time of the Rouse chain     

A combined experimental and theoretical study on the conformation of multiarmed chiral aryl ethers

Four series of multiarmed chiral aryl ethers carrying two, three, five, or eight side-chains on a variety of aromatic core molecules (2-5) were prepared. The structure and conformation of 2 and 3 (in the solid state) were determined by the X-ray crystallographic analyses. While a pair of alternated (anti) conformers (i.e, up-down and down-up) were found in the crystal of 2, three side-arms in 3 were aligned in the same direction to give a C(3)-symmetric syn-conformation. Examinations by dispersion-corrected density functional (DFT-D) calculations revealed that two out of six anti- and two out of four syn-conformers of 2 are energetically most important. Two calculated structures of anti-conformers are in good agreement with those found in the solid state by X-ray analysis. Similarly, relevant conformations of syn-3, fully alternated 4, and C(5)-symmetric 5 were optimized at the DFT-D-B-LYP/TZVP level. The structure and conformation of the side-arms in 2-5 in solution were further studied by temperature dependent (1)H NMR and UV-vis spectroscopy. In addition, comparative experimental and theoretical CD spectral studies were carried out in order to elucidate the contribution of the thermodynamically less-stable minor isomers in solution. The CD spectral changes observed for 2 and 3 at varying temperatures were quite different, while the parent chiral arene 1, as well as 4 and 5, only showed an increased intensity of the negative Cotton effect for the (1)L(b) band. The latter behavior is readily accounted for in terms of the conformational freezing of the chiral groups at low temperatures. The unusual CD spectral behavior observed for 2 and 3 was rationalized by the conformational alteration of the side-arms. Because of attractive van der Waals interactions between the aromatic units of the arms in nonpolar solvents, the syn-conformations become gradually more important for 2 at low temperatures, which eventually results in a weak positive Cotton effect for the (1)L(b) band. This was also supported by the SCS-MP2/TZVPP single-point energy calculations for the relevant conformers of 2. For 3, the contribution of the C(3)-symmetrical conformer becomes more important than the less-symmetrical isomers at low temperatures. The conformations of 2 and 3 in their excited states as well as in the oxidized states were also examined.