anti-Selective direct catalytic asymmetric Mannich-type reaction of hydroxyketone providing beta-amino alcohols

An anti-selective direct catalytic asymmetric Mannich-type reaction is described. The Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 complex promoted a Mannich-type reaction of 2-hydroxy-2'-methoxyacetophenone (2) and N-diphenylphosphinoyl imines 3. Using as little as 0.25-1 mol % of the catalyst, we obtained Mannich adducts 4 in excellent yield (up to 99%), diastereoselectivity (anti/syn = up to >98/2), and enantiomeric excess (up to >99.5%). The anti-selectivity in the present system is complementary to that observed using previously reported methods, providing a novel efficient method to synthesize anti-beta-amino alcohols in a highly enantioselective manner. Facile deprotection of the N-diphenylphosphinoyl group and commercial availability of both Et(2)Zn solution and (S,S)-linked-BINOL 1 also make the present catalysis practical.     

Development of KiBank, a database supporting structure-based drug design

KiBank is a database of inhibition constant (K_i) values with 3D structures of target proteins and chemicals. K_i values were accumulated from peer-reviewed literature searched via PubMed. The 3D structure files of target proteins were originally from Protein Data Bank (PDB), while the 2D structure files of the chemicals were collected together with the K_i values and then converted into 3D ones. In KiBank, the chemical and protein 3D structures with hydrogen atoms were optimized by energy minimization and stored in MDL MOL and PDB format, respectively.

KiBank is designed to support structure-based drug design. It provides structure files of proteins and chemicals ready for use in virtual screening through automated docking methods, while the K_i values can be applied for tests of docking/scoring combinations, program parameter settings, and calibration of empirical scoring functions. Additionally, the chemical structures and corresponding K_i values in KiBank are useful for lead optimization based on quantitative structure–activity relationship (QSAR) techniques.

KiBank is updated on a daily basis and is freely available at http://kibank.iis.u-tokyo.ac.jp/. As of August 2004, KiBank contains 8000 K_i values, over 6000 chemicals and 166 proteins covering the subtypes of receptors and enzymes.     

A new synthesis of gamma-lactams based on the reaction of vinyl sulfilimines with dichloroketene

The reactions of several aryl-, furanyl-, and vinyl substituted sulfilimines with dichloroketene proceeded at 25 degrees C to yield thioalkyl substituted gamma-lactams which, in turn, were converted to a variety of nitrogen-containing substrates. [reaction: see text]     

Titanium(IV)-promoted Mukaiyama aldol-Prins cyclizations

[reaction: see text] A new version of the Mukaiyama aldol-Prins (MAP) cyclization has been developed. Unsaturated enol ethers such as 3 were found to couple with aldehydes in the presence of TiBr(4) to give 4-bromotetrahydropyran products. This cascade reaction sequence leads to the formation of two new carbon-carbon bonds, a ring, and three new stereogenic centers. We expect this reaction to be a powerful new tool in synthesis.     

15N-, 1H-, and 13C-NMR chemical shifts and electronic properties of aromatic diamines and dianhydrides

We measured the ¹⁵N-, ¹H-, and ¹³C-NMR chemical shifts for a series of aromatic diamines and aromatic tetracarboxylic dianhydrides dissolved in DMSO-d₆, and discuss the relationships between these chemical shifts and the rate constants of acylation (k) as well as such electronic-property-related parameters such as ionization potential (IP), electronic affinity (EA), and the energy ε of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). The ¹⁵N chemical shifts of the amino group of diamines (δ_N) depend monotonically on the logarithm of k (log k) and on IP. We inferred the reactivities of diamines whose acylation rates have not been measured from their δ_N, and we propose an arrangement of diamines in the order of their reactivity. The ¹H chemical shift of amino hydrogens (δ_H) and the ¹³C chemical shift of carbons bonded to nitrogen (δ_C) are roughly proportional to δ_N, but these shifts are not as closely correlated with log k and IP. Although the ¹³C chemical shifts of the carbonyl carbon of dianhydrides (δ_C,) varies much less than the δ_C and δ_N of diamines, δ_C, can be an index of acylation reactivity for dianhydrides because it is closely correlated with ε_LUMO. These facts indicate that the chemical shifts of diamines and dianhydrides are displaced according to their electron-donor and electron-acceptor properties, and that these chemical shifts can be used as indices of the electronic properties of monomers. Changes in reactivity caused by the introduction of trifluoromethyl groups into diamines and dianhydrides are inferred from the displacements of δ_N and δ_C © 1992 John Wiley & Sons, Inc.     

Anomalous dissolution behavior of the diazepam — γ-cyclodextrin complex in polymer solutions

The dissolution process of the diazepam — -cyclodextrin complex in aqueous polymer solutions has been studied. Hydroxypropyl cellulose and polyvinylpyrrolidone stabilize the supersaturated state of the complex, maintaining the higher drug level for a longer period. Polyethyleneglycol and dextran accelerated the dissociation of the complex, and caused a rapid decrease in drug concentration. These anomalous dissolution behaviors are discussed on the basis of viscosity changes of the polymer solutions along with the competitive interaction of polymers for the inclusion complex.     

Recovery of intact yeast chromosomal DNA from agarose gel plugs using coil-globule transition

In the current studies, we designed a new approach for sizing and isolating chromosomal DNA using coil-globule transition, which avoids fragmentation of giant DNA due to mechanical stress. Although coil-globule transition is reversible and globular DNA is tolerant to mechanical stress, globular DNA cannot be manipulated by an electric field because of the loss of its negative charges. In our system, however, DNA is extracted from an agarose gel in a coiled state into a solution of PEG, and coil-globule transition is induced by cations generated at the anode. This method achieves buffer exchange without stirring, which is the main cause of mechanical stress. Real-time analysis of T4dc viral DNA molecules revealed that they change immediately from a coiled to a globular form when the cation concentration is sufficiently high. This method was used to prepare yeast chromosomal DNA in a globular state without fragmentation.     

Effect of interfacial tension on the dynamic behavior of droplet formation during microchannel emulsification

Microchannel (MC) emulsification is a novel technique for producing monodisperse emulsions. In this study, we investigated the effect of interfacial tension on the dynamic behavior of droplet formation with various surfactant concentrations. Interfacial tension did not affect the resultant droplet diameter in lower flow velocity ranges, but it did affect the time-scale parameters. These results were interpreted using the droplet formation mechanism reported in our previous study. At surfactant concentrations below 0.3%, the emulsification behavior was differed from that at higher surfactant concentrations. An analysis of diffusional transfer indicated that dynamic interfacial tension affects the emulsification behavior at lower surfactant concentrations. Dynamic interfacial tension that exceeded the equilibrium value led to a shorter detachment time. This resulted in stable droplet formation of monodispersed emulsions by spontaneous transformation, even at flow velocities above the predicted critical flow velocity. A previous study predicted that the droplet formation would become unstable and polydispersed larger droplets would form over critical flow velocity. Wetting of the MC with the dispersed phase at lower surfactant concentrations induced formation of larger polydispersed droplets at high flow velocities.     

Base oxidation at 5' site of GG sequence in double-stranded DNA induced by UVA in the presence of xanthone analogues: relationship between the DNA-damaging abilities of photosensitizers and their HOMO energies

UVA contributes to skin cancer by solar UV light. Photosensitizers are believed to play an important role in UVA carcinogenesis. We investigated the mechanism of DNA damage induced by photoexcited xanthone (XAN) analogues (XAN, thioxanthone [TXAN] and acridone [ACR]), exogenous photosensitizers, and the relationship between the DNA-damaging abilities and their highest occupied molecular orbital (HOMO) energies. DNA damage by these photosensitizers was examined using 32P-labeled DNA fragments obtained from the p53 tumor suppressor gene. Photoexcited XAN caused DNA cleavage specifically at 5'-G of the GG sequence in the double-stranded DNA only when the DNA fragments were treated with piperidine, suggesting that DNA cleavage is due to base modification with little or no strand breakage. With denatured single-stranded DNA, the extent of XAN-sensitized photodamage was decreased. An oxidative product of G, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo), was formed by photoexcited XAN, and the 8-oxo-dGuo formation was decreased in single-stranded DNA. TXAN and ACR induced DNA photodamage as did XAN, although the order of DNA-damaging ability was XAN > TXAN > ACR. These findings suggest that photoexcited XAN analogues induce nucleobase oxidation at 5'-G of GG sequence in double-stranded DNA through electron transfer. The HOMO energies of these photosensitizers, estimated from ab initio molecular orbital (MO) calculation, decreased in the following order: XAN > TXAN > ACR. Extents of DNA damage increased exponentially with the HOMO energies of XAN analogues. This study suggests that DNA-damaging abilities of photosensitizers can be estimated from their HOMO energies.     

Nanotribology of ethers: effects of molecular asymmetry and fluoroalkyl chains

The tribological properties of the molecularly thin films of asymmetric ether (1,3-dimethylbutyl octyl ether, AE) and fluorinated asymmetric ether (1H,1H,2H,2H-perfluorooctyl-1,3-dimethylbutyl ether, FAE) were investigated. Friction forces and dynamic thicknesses (thicknesses during sliding) were simultaneously measured using the surface forces apparatus, and the effects of molecular asymmetry and fluoroalkyl chains on the friction properties are analyzed. The friction forces (both kinetic and static) and dynamic thicknesses are larger for the AE film than for the FAE film. The two ethers exhibit stick-slip friction at low sliding velocity, but the stick-slip patterns are different. For the AE film, one stick-slip cycle consists of two or more spikes; a large spike is followed by one or more small spike(s) in the cycle. On the other hand, regular stick-slip spikes are observed for the FAE film. The results suggest that the responsible friction mechanisms are completely different between the two ether films. The asymmetric shape of the AE molecule results in a variety of shear-ordered liquid structures in confinement, and the friction (stick-slip) behavior follows the "phase-transition model". In contrast, the FAE molecule is rigid, and the shape of the molecule is rather close to a symmetric cylinder, which leads to a well-ordered two-layer film in confinement. The each molecular layer is strongly adsorbed on adjacent mica substrate and behaves as a fluorinated coating. The friction is governed by the molecular scale "bumpiness" of the fluoroalkyl chains lying on mica surfaces and basically follows the "cobblestone model". The advantage of the thin FAE film as a practical lubricant is also discussed.