Iwao Ojima

Catalytic asymmetric synthesis

Preface. Preface to the Second Edition. Preface to the First Edition. Contributors. 1 Catalytic Asymmetric Synthesis in Non-ConventionalMedia/Conditions (Chikako Ogawa and Shu Kobayashi). 2 Asymmetric Organocatalysis. 2A Enantioselective Organocatalysis Involving Iminium, Enamine,SOMO and Photoredox Activation (Allan J. B. Watson and David W.C. MacMillan). 2B Asymmetric Acid-Base Bifunctional Catalysis with OrganicMolecules (Yi Wang and Li Deng). 2C Asymmetric Phase-Transfer and Ion Pair Catalysis (SeijiShirakawa and Keiji Maruoka). 3 Chiral Lewis Acids and Bronsted Acids in AsymmetricSynthesis (Hisashi Yamamoto and Cheol Hong Cheon). 4 Asymmetric Synthesis through C?H Activation (Huw M.L. Davies and Jorn Hansen). 5 Asymmetric Carbon-Heteroatom Bond-Forming Reactions(Yoshiji Takemoto and Hideto Miyabe). 6 Enzyme-Catalyzed Asymmetric Synthesis (HaraldGroger). 7 Transition Metal-Catalyzed Homogeneous AsymmetricHydrogenation (Gao Shang, Wei Li and Xumu Zhang). 8 Asymmetric Carbon-Carbon Bond Forming Reactions. 8A Catalytic Asymmetric Conjugate Addition (Jian-Xin Ji andAlbert S. C. Chan). 8B Enantioselective Allylic Substitutions withCarbon-Nucleophiles (Gunter Helmchen,Uli Kazmaier andSebastian Forster). 8C Asymmetric Carbometallation and Carbocyclizations (IwaoOjima, Joseph J. Kaloko, Stephen J. Chaterpaul, Yu-Han Gary Tengand Chi-Feng Lin). 8D Asymmetric Ene Reactions and Cycloadditions (Koichi Mikamiand Kohsuke Aikawa). 8E Catalytic Enantioselective Olefin Metathesis Reactions(Amir H. Hoveyda, Steven J. Malcolmson, Simon J. Meek and AdilR. Zhugralin). 9 Asymmetric Hydrosilation of Carbon-Carbon Double Bonds andRelated Reactions (Jin Wook Han and Tamio Hayashi). 10 Asymmetric Carbonylations (Cyril Godard, AuroraRuiz, Montserrat Dieguez, Oscar Pamies and CarmenClaver). 11 Asymmetric Oxidations and Related Reactions(Kazuhiro Matsumoto and Tsutomu Katsuki). 12 Asymmetric Amplification and Autocatalysis (KensoSoai, Tsuneomi Kawasaki, and Takanori Shibata). 13 Asymmetric Polymerization (Shingo Ito and KyokoNozaki). Index.

New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of β-lactam synthon method

Abstract Highly efficient chiral ester enolate-imine condensation giving 3-hydroxy-4-aryl-β-lactams with excellent enantiomeric purity is successfully applied to the asymmetric synthesis of the enantiomerically pure taxol C-13 side chain, N-benzoyl-(2R,3S)-3-phenyl-isoserine and its analogs. (3R,4S)-N-benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone readily derived from the 3-hydroxy-4-phenyl-β-lactam is coupled with protected baccatin IIIs, followed by deprotection to give optically pure taxol and 10-deacetyl-7,10-bis(Troc)-taxol in good yields. Fully assigned 1H, 13C, and 2D (COSY and HETCOR) NMR spectra of taxol thus synthesized are shown and discussed.

Asymmetric synthesis of building-blocks for peptides and peptidomimetics by means of the β-lactam synthon method

Recent advances in the syntheses of enantiopure synthetic building blocks useful for non-protein amino acids, dipeptides, oligopeptides using solid state peptide synthesis, isoserines (norstatines), dipeptide isosteres [hydroxy(keto)ethylene, hydroxyethylamine, hydroxyethylene and dihydroxyethylene isosteres], taxoids, polyamines, poly(amino alcohol)s and poly(amino ether)s, and other biologically active compounds through applications of the β-lactam Synthon method is reviewed.

Recent advances in catalytic asymmetric reactions promoted by transition metal complexes

Revue sur les reactions asymetriques utilisant des complexes des metaux de transition comme catalyseurs

Mechanism-Based Tumor-Targeting Drug Delivery System. Validation of Efficient Vitamin Receptor-Mediated Endocytosis and Drug Release

An efficient mechanism-based tumor-targeting drug delivery system, based on tumor-specific vitamin-receptor mediated endocytosis, has been developed. The tumor-targeting drug delivery system is a conjugate of a tumor-targeting molecule (biotin: vitamin H or vitamin B-7), a mechanism-based self-immolative linker and a second-generation taxoid (SB-T-1214) as the cytotoxic agent. This conjugate (1) is designed to be (i) specific to the vitamin receptors overexpressed on tumor cell surface and (ii) internalized efficiently through receptor-mediated endocytosis, followed by smooth drug release via glutathione-triggered self-immolation of the linker. In order to monitor and validate the sequence of events hypothesized, i.e., receptor-mediated endocytosis of the conjugate, drug release, and drug-binding to the target protein (microtubules), three fluorescent/fluorogenic molecular probes (2, 3, and 4) were designed and synthesized. The actual occurrence of these processes was unambiguously confirmed by means of confocal fluorescence microscopy (CFM) and flow cytometry using L1210FR leukemia cells, overexpressing biotin receptors. The molecular probe 4, bearing the taxoid linked to fluorescein, was also used to examine the cell specificity (i.e., efficacy of receptor-based cell targeting) for three cell lines, L1210FR (biotin receptors overexpressed), L1210 (biotin receptors not overexpressed), and WI38 (normal human lung fibroblast, biotin receptor negative). As anticipated, the molecular probe 4 exhibited high specificity only to L1210FR. To confirm the direct correlation between the cell-specific drug delivery and anticancer activity of the probe 4, its cytotoxicity against these three cell lines was also examined. The results clearly showed a good correlation between the two methods. In the same manner, excellent cell-specific cytotoxicity of the conjugate 1 (without fluorescein attachment to the taxoid) against the same three cell lines was confirmed. This mechanism-based tumor-targeting drug delivery system will find a range of applications.

Characterization of the Taxol Binding Site on the Microtubule IDENTIFICATION OF Arg282 IN β-TUBULIN AS THE SITE OF PHOTOINCORPORATION OF A 7-BENZOPHENONE ANALOGUE OF TAXOL

Photoaffinity labeling methods have allowed a definition of the sites of interaction between Taxol and its cellular target, the microtubule, specifically β-tubulin. Our previous studies have indicated that [3H]3′-(p-azidobenzamido)Taxol photolabels the N-terminal 31 amino acids of β-tubulin (Rao, S., Krauss, N. E., Heerding, J. M., Swindell, C. S., Ringel, I., Orr, G. A., and Horwitz, S. B. (1994) J. Biol. Chem. 269, 3132–3134) and [3H]2-(m-azidobenzoyl)Taxol photolabels a peptide containing amino acid residues 217–233 of β-tubulin (Rao, S., Orr, G. A., Chaudhary, A. G., Kingston, D. G. I., and Horwitz, S. B. (1995) J. Biol. Chem. 270, 20235–20238). The site of photoincorporation of a third photoaffinity analogue of Taxol, [3H]7-(benzoyldihydrocinnamoyl) Taxol, has been determined. This analogue stabilizes microtubules polymerized in the presence of GTP, but in contrast to Taxol, does not by itself enhance the polymerization of tubulin to its polymer form. CNBr digestion of [3H]7-(benzoyldihydrocinnamoyl)Taxol-labeled tubulin, with further arginine-specific cleavage by clostripain resulted in the isolation of a peptide containing amino acid residues 277–293. Amino acid sequence analysis indicated that the photoaffinity analogue cross-links to Arg282 in β-tubulin. Advances made by electron crystallography in understanding the structure of the tubulin dimer have allowed us to visualize the three sites of photoincorporation by molecular modeling. There is good agreement between the binding site of Taxol in β-tubulin as determined by photoaffinity labeling and electron crystallography.

Reduction of carbonyl compounds via hydrosilylation : II. Asymmetric reduction of ketones via hydrosilylation catalyzed by a rhodium(I) complex with chiral phosphine ligands

Abstract Effective asymmetric reduction of alkyl phenyl, dialkyl and alkyl cyclohexyl ketones has been achieved via hydrosilylation, catalyzed by a rhodium(I) complex with optically active phosphine ligands using various hydrosilanes. A mechanism of the induction of asymmetry is proposed in view of the stereochemical course of the reaction.

Antithrombotic agents: From RGD to peptide mimetics

This review covers the recent advances in the development of highly potent inhibitors of platelet aggregation as potential therapeutic drugs for thrombosis related to cardiovascular and cerebrovascular diseases. The discovery of RGD sequence-directed cell surface receptors (the integrins) has led to extensive research in the development of small RGD containing peptides and their mimetics as antithrombotic agents. These agents work by inhibiting platelet aggregation through competitive blocking of fibrinogen to the platelet surface receptor, GPIIb/IIIa. The pharmacophoric nature of the aspartic acid and arginine side chains of the RGD unit has allowed the development of strategies for rational design, largely based on assumed bioactive RGD conformations and lead optimization. Applications of such strategies, from RGD peptides to peptide hybrids and then to non-peptide mimetics, are described. Also discussed is the important issue of specificity toward GPIIb/IIIa, keeping in view that the RGD unit is a key recognition signal for a variety of cell surface receptors.

Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, As A New Class of Antitubercular Agents

Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5-6 μg/mL (2-15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds did not show appreciable cytotoxicity (IC(50) > 200 μM) against Vero cells, which inhibited Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly, leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation.

A highly efficient route to taxotere by the β-Lactam Synthon Method

Taxotere, a highly promising anticancer drug, is synthesized through an efficient coupling of 7,10-diTroc-10-deacetylbaccatin III with enantiomerically pure (3R,4S)-1-tBOC-3-EEO- 4-phenylazetidin-2-one which is obtained via chiral ester enolate - imine cyclocondensation.