Acid-base catalysis of chiral transition metal complexes having hard anionic ligands such as hydroxo and acetate ligands is described. The Pd, Pt, Cu, and Ni complexes can effectively abstract the α-proton of methylene and methine compounds under non-basic conditions to give chiral enolates. In the case of 1,3-dicarbonyl compounds, the Pd complexes produced such enolates even under acidic conditions, and their cooperative action with protic acid to activate the various electrophiles including enones, imines, and acetals allows unique C-C bond-forming reactions to proceed with excellent enantioselectivity. Additionally, asymmetric protonation in aza-Michael reaction using the Pd hydroxo complex in combination with amine salt is described. For efficient activation of less acidic α-ketoesters, we developed a novel chiral nickel acetate complex, which is particularly effective to promote the asymmetric conjugate addition to nitroolefins. To confirm the utility of the reaction, its application to the asymmetric synthesis of MFPA was successfully demonstrated. Finally, the proposed reaction mechanisms of these reactions are briefly discussed.
Atropisomeric compounds due to rotational restriction around an N-C bond have received much attention recently as novel chiral molecules. However, catalytic enantioselective synthesis of such N-C axially chiral compounds has not so far been reported. We succeeded in the highly enantioselective syntheses of atropisomeric ortho-tert-butyl anilides, lactams and indoles having an N-C chiral axis through chiral palladium-catalyzed N-C bond forming reactions. That is, in the presence of (R)-DTBM-SEGPHOS-Pd(OAc)2 catalyst, N-arylation (Buchwald-Hartwig amination) of achiral ortho-tert-butylanilides with p-iodonitrobenzene proceeded in a highly enantioselective manner (88−96% ee) to give atropisomeric N-(p-nitrophenyl)anilides in good yields. The application of the present catalytic enantioselective N-arylation to an intramolecular version gave atropisomeric lactam derivatives with high optical purity (92−98% ee). The α-alkylation with the lithium enolate prepared from the atropisomeric anilide and lactam products with various alkyl halides proceeded with high diastereoselectivity (diastereomer ratio=31:1-80:1). On the other hand, 5-endo-hydroaminocyclization of achiral ortho-alkynylanilines using (R)-SEGPHOS-PdCl2 catalyst afforded optically active atropisomeric indole derivatives (up to 83% ee) in good yields.
Fluoroacetylene, an interesting haloacetylene, has not received much attention due to its instability and/or explosive nature. In addition, only a few fluoroacetylene derivatives have been reported so far. We have been interested in preparation of easy-handling fluoroacetylene compounds and demonstration of their utilization as a mono-fluorinated versatile building block. This article mainly deals with the following topics. 1) Fluoro(triisopropylsilyl)acetylene was easily prepared from 1,1-difluoroethylene in high yield and its 13C NMR spectrum was recorded for the first time. 2) The spontaneous trimerization of the fluoroacetylene afforded the corresponding fluorinated Dewar benzene instead of fluorinated crowded benzene. 3) Fluoro(silyl or stannyl)acetylenes except for fluoro(triisopropylsilyl)acetylene underwent radical addition reaction with THF to give the β-fluoro-β-(tetrahydrofuran-2'-yl)vinylsilanes. 4) Fluoro(silyl or stannyl)acetylenes were easily transformed into the corresponding 4-fluoropyrazoles regioselectively, which functioned as a versatile 4-fluoropyrazole scaffold.
The naturally occurring marine alkaloid halichlorine, isolated from the black marine sponge Halichondria okadai Kadota, has been claimed to selectively inhibit the induced expression of vascular cell adhesion molecule-1 (VCAM-1) and might therefore be useful in the treatment of allergic inflammatory diseases and cancer. Stimulated by this intriguing biological profile, as well as the challenging architectural features of halichlorine, a significant amount of work related to the synthesis of this compound has been disclosed. Since the first total synthesis of halichlorine by the Danishefsky group, two other syntheses have been reported by Heathcock and more recently by Clive. The remainder of the many publications in this area have dealt very largely with construction of the azaspirocyclic core system and with formal synthesis reliant on the Danishefsky route.
Natural products are a rich source for drug development. However, some biologically relevant natural products possess rather large, complex or labile chemical structures compared to synthetic drugs, which limits chemical modification in a process pursuing a structure-activity relationship. Here we describe the rational simplification of the muraymycins and caprazamycins class of nucleoside natural products to address the issue associated with their molecular complexity. First, the systematic structure-activity relationship (SAR) study of the muraymycins using an Ugi four-component reaction was investigated. Our SAR study of the muraymycins suggests a probable mechanism for inhibition of the MraY. The predicted binding model would provide further direction towards the design of potent MraY inhibitors. Next, function-oriented synthesis (FOS) of caprazamycins was investigated. Based on the conformation-activity relationship study of a series of analogs 36-38, we designed the oxazolidine-containing uridine derivatives 41-44 by restricting the conformation of 36-38. As a result, the tert-butyl ester derivatives 43 were found to be the most active against a range of bacterial strains containing VRE with a similar potency to the parent natural products. These studies provide a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.
Catalytic properties of gold remarkably change by the size of gold particles and the kind of supports. An extremely high catalytic activity for aerobic oxidation of glucose was achieved when the size of gold could be minimized to about 3 nm on Al2O3 and ZrO2. On the other hand, Au/NiO exhibited higher catalytic activity than conventional gold catalysts such as Au/TiO2 for base-free aerobic oxidation of aliphatic alcohol to carboxylic acid with high selectivity (97%) at a full conversion. Gold on NiO also showed high selectivity to alcohol in the presence of amine and promoted the N-formylation of primary amine with methanol. Gold on ZrO2 showed the best catalytic activity and the selectivity for the N-alkylation of primary amine with alcohol to produce secondary amine. The surface hydroxyl groups would participate as acidic and/or basic sites for the adsorption of substrates, deprotonation of alcohol, and hydrogen transfer in the N-alkylation.
Kinetic resolution is an important method for the separation of racemates into their component enantiomers. Recently, development of new artificial catalysts enables to accomplish higher performance of enantiodiscrimination than that by enzymatic catalysts in kinetic resolution.