Total Synthesis of Taxol Enabled by Inter- and Intramolecular Radical Coupling Reactions

Taxol is a clinically used drug for the treatment of various types of cancers. Its 6/8/6/4-membered ring (ABCD-ring) system is substituted by eight oxygen functional groups and flanked by four acyl groups, including a β-amino acid side chain. Here we report a 34-step total synthesis of this unusually oxygenated and intricately fused structure. Inter- and intramolecular radical coupling reactions connected the A- and C-ring fragments and cyclized the B-ring, respectively. Functional groups of the A- and C-rings were then efficiently decorated by employing newly developed chemo-, regio-, and stereoselective reactions. Finally, construction of the D-ring and conjugation with the β-amino acid delivered taxol. The powerful coupling reactions and functional group manipulations implemented in the present synthesis provide new valuable information for designing multistep target-oriented syntheses of diverse bioactive natural products.     

Total Synthesis and Biological Evaluation of the Antibiotic Lysocin E and Its Enantiomeric,Epimeric, and N‐Demethylated Analogues

Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid‐phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N‐demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.     

Synthesis of Disaccharide Nucleosides by the O‐Glycosylation of Natural Nucleosides with Thioglycoside Donors

Disaccharide nucleosides constitute an important group of naturally‐occurring sugar derivatives. In this study, we report on the synthesis of disaccharide nucleosides by the direct O‐glycosylation of nucleoside acceptors, such as adenosine, guanosine, thymidine, and cytidine, with glycosyl donors. Among the glycosyl donors tested, thioglycosides were found to give the corresponding disaccharide nucleosides in moderate to high chemical yields with the above nucleoside acceptors using p‐toluenesulfenyl chloride (TolSCl) and silver triflate (AgOTf) as promoters. The interaction of these promoters with nucleoside acceptors was examined by ¹H NMR spectroscopic experiments.     

Antimutagenic activity of ent-kaurane diterpenoids from the aerial parts of Isodon japonicus

From the methanolic extract of the aerial parts of Isodon japonicus, two new ent-kaurane diterpenes, isodonterpenes I and II, were isolated together with 10 known diterpenes. Their chemical structures were elucidated on the basis of chemical and physicochemical evidence. The absolute configuration of isodonterpene I was elucidated by Cu-Kα X-ray crystallographic analysis. Antimutagenic activities of the major diterpenes were evaluated by the Ames test. This study represents the first evaluation of the antimutagenic activities of ent-kaurane diterpenes.     

Calix[4]arene-Based Triple-Stranded Metallohelicate in Water

The title complex is a triple-stranded metallohelicate organized by the self-assembly of 5,17-difunctionalized calix[4]arenes and metal cations with octahedral coordination geometry. Due to hydrophilic triethylene glycol chains on the lower rim of the calix[4]arene, the metallohelicate can encapsulate cationic guests in water. NMR and UV-vis titration experiments reveal that the metallohelicate captures a pyridinium guest with an alanine derivative to form a host-guest complex with a host-guest ratio of 1 : 1. CD spectroscopy confirms the bias of the P- and M-helical sense of the metallohelicate by the captured guest. The metallohelicate captures two molecules of dicationic N,N’-dimethyl-DABCO and monocationic N-methyl quinuclidine, exhibiting a positive allosteric effect. ¹H NMR titration experiments indicate that the bound guests are in close proximately to the aromatic rings of the ligands. Molecular mechanics calculations based on the UV-vis and NMR observations suggest that the first guest preorganizes the conformation of the metallohelicate to facilitate access of the second guest to the cavity.     

Controlling Energy Gaps of π-Conjugated Polymers by Multi-Fluorinated Boron-Fused Azobenzene Acceptors for Highly Efficient Near-Infrared Emission

We demonstrate that multi-fluorinated boron-fused azobenzene (BAz) complexes can work as a strong electron acceptor in electron donor-acceptor (D-A) type π-conjugated polymers. Position-dependent substitution effects were revealed, and the energy level of the lowest unoccupied molecular orbital (LUMO) was critically decreased by fluorination. As a result, the obtained polymers showed near-infrared (NIR) emission (λ_PL=758–847 nm) with high absolute photoluminescence quantum yield (Φ_PL=7–23%) originating from low-lying LUMO energy levels of the BAz moieties (−3.94 to −4.25 eV). Owing to inherent solid-state emissive properties of the BAz units, deeper NIR emission (λ_PL=852980 nm) was detected in film state. Clear solvent effects prove that the NIR emission is from a charge transfer state originating from a strong D-A interaction. The effects of fluorination on the frontier orbitals are well understandable and predictable by theoretical calculation with density functional theory. This study demonstrates the effectiveness of fluorination to the BAz units for producing a strong electron-accepting unit through fine-tuning of energy gaps, which can be the promising strategy for designing NIR absorptive and emissive materials.     

18O/16O-Encoding Strategy for Microscale Stereochemical Determination of Peptidic Natural Products

The demand for more efficient methods of establishing the undetermined stereochemistries of peptidic natural products continues unabated. A new method for microscale stereochemical determination was devised by integrating solid-phase synthesis, split-and-mix randomization, ¹⁸O/¹⁶O-encoding of d /l -configurations, tandem mass spectrometry, and biological evaluation. Here we applied gramicidin A as the molecule for a blind test. Gramicidin A and its 31 diastereomers were randomly prepared in microgram scale with ¹⁸O/¹⁶O-stereochemical encoding and subjected to MS/MS-structural determination and cytotoxicity assay. Only the parent gramicidin A was selected from among the 32 stereoisomers, validating the high reliability of the present strategy.     

Several contributions to soil compactibility induced by cyclic loading test

To investigate the soil compactibility during the cyclic loading, three different kinds of paddy field soils were prepared so as to clarify interrelationships among stress amplitude ratio, bulk density, soil water content and pore water pressure. The presetting values of specimen include the soil water content(percent dry basis) and bulk density of 25% d.b. and 1.1 Mg/m³ respectively. The relation between the number of cyclic loading and axial strain exhibited an asymptotically increasing trend, converging toward a specific value for each experimental condition. Possible effect caused by elastic–plastic characteristics could be recognized, when axial strain for 0.5 Hz excitation becomes greater than the one of 1.0 Hz under same stress amplitude ratio. When the stress amplitude ratio took 0.1, the absolute value of axial strain of 0.5 Hz was greater than the one of 1.0 Hz, whereas its decreasing trend was recognized in the sequence of silt, clay and silty sand. The qualitative relations between pore water pressure and number of cyclic loading were also examined to scrutinize the effect of effective water pressure to the soil compactibility.     

Multi-scale finite element analyses of sheet metals by using SEM-EBSD measured crystallographic RVE models

In this study, two multi-scale analyses codes are newly developed by combining a homogenization algorithm and an elastic/crystalline viscoplastic finite element (FE) method (Nakamachi, E., 1988. A finite element simulation of the sheet metal forming process. Int. J. Numer. Meth. Eng. 25, 283–292; Nakamachi, E., Dong, X., 1996. Elastic/crystalline viscoplastic finite element analysis of dynamic deformation of sheet metal. Int. J. Computer-Aided Eng. Software 13, 308–326; Nakamachi, E., Dong, X., 1997. Study of texture effect on sheet failure in a limit dome height test by using elastic/crystalline viscoplastic finite element analysis. J. Appl. Mech. Trans. ASME(E) 64, 519–524; Nakamachi, E., 1998. Elastic/crystalline viscoplastic finite element modeling based on hardening–softening evaluation equation. In: Proc. of the 6th NUMIFORM, pp. 315–321; Nakamachi, E., Hiraiwa, K., Morimoto, H., Harimoto, M., 2000a. Elastic/crystalline viscoplastic finite element analyses of single- and poly-crystal sheet deformations and their experimental verification. Int. J. Plasticity 16, 1419–1441; Nakamachi, E., Xie, C.L., Harimoto, M., 2000b. Drawability assessment of BCC steel sheet by using elastic/crystalline viscoplastic finite element analyses. Int. J. Mech. Sci. 43, 631–652); (1) a “semi-implicit” finite element (FE) code and (2) a “dynamic explicit” FE code. These were applied to predict the plastic strain induced yield loci and the formability of sheet metal in the macro scale, and simultaneously the crystal texture and hardening evolutions in the micro scale. The isotropic and kinematical hardening laws are employed in the crystalline plasticity constitutive equation. For the multi-scale structure, two-scales are considered. One is a microscopic polycrystal structure and the other a macroscopic elastic plastic continuum. We measure crystal morphologies by using the SEM-EBSD apparatus with a unit of about 3.8 μm voxel, and define a three dimensional (3D) representative volume element (RVE) for the micro polycrystal structure, which satisfy the periodicity condition of crystal orientation distribution. A “micro” finite element modeling technique is newly established to minimize the total number of finite elements in the micro scale. Next, the “semi-implicit” crystallographic homogenization FE code, which employs the SEM-EBSD measured RVE, is applied to the 99.9% pure-iron uni-axial tensile problem to predict the texture evolution and the subsequent yield loci in the various strain paths. These “semi implicit” results reveal that the plastic strain induced anisotropy in the micro and macro levels can be predicted by our FE analyses. The kinematical hardening law leads a distinct plastic strain induced anisotropy. Our “dynamic-explicit” FE code is applied to simulate the limit dome height (LDH) test problem of the mild steel DQSK, the high strength steel HSLA and the aluminum alloy AL6022 sheet metals, which were adopted as the NUMISHEET2005 Benchmark sheet metals (Smith, L.M., Pourboghrat, F., Yoon, J.-W., Stoughton, T.B., 2005. NUMISHEET2005. In: Proc. of 6th Int. Conf. Numerical Simulation of 3D Sheet Metal Forming Processes, PART A and B(Benchmark), pp. 409–451) to estimate formability. The “dynamic explicit” results reveal that the initial crystal orientation distribution has a large affects to a plastic strain induced texture and anisotropic hardening evolutions and sheet formability.