Two types of reactions with organometallic reagents are described. The first is a radical reaction derived from homolytic cleavage of organometallic species such as triethylborane. Generation of ethyl radical from triethylborane and its synthetic use were developed. The new method was applied to the radical reactions in water. The second is a reaction based on heterolytic cleavage of ate complexes such as R3MnMgX and R3MgLi. The reactions were initiated by halogen-metal exchange reaction or single electron transfer from ate complexes to the substrate. Cobalt catalyzed new reactions are also disclosed.
The selective construction of carbon-fluorine bonds is of great interest to medicinal chemists because the replacement of hydrogen and oxygen atoms with fluorine atom in biologically active molecules can confer molecules with improved physicochemical properties and biological activities. Since the first discovery of enantioselective fluorination using N-fluorocamphorsultam, our synthetic interests have been focused on the development of chiral N-fluorosulfonamide derivatives capable of enantioselective fluorination. However, these initial efforts revealed several limitations in both chemical yields and enantioselectivities of the fluorinated products. We present here the background of our recent development of the enantioselective fluorination reaction and some successful applications of the methods to the design and synthesis of fluoroisosteres of biologically active natural products. Two novel approaches using the cinchona alkaloids/Selectfluor® combination and bis (oxazoline) -metal complex have been pursued, respectively. Cinchona alkaloid/ Selectfluor® combination, i.e., N-fluoroammonium salts of cinchona alkaloids, was found to be an effective enantioselective fluorinating reagent for a wide range of substrates such as silyl enol ethers, β-keto esters, arylcyano esters, and oxindoles without any additives. The bis (oxazoline) s were found to be efficient and unique catalysts for enantioselective fluorination in the presence of a catalytic amount of metal salts. An interesting phenomenon, “elective” enantioselectivity, has been observed in the fluorination of β-keto esters. Switching the metal center from copper to nickel in the presence of the same bis (oxazoline) ligands gave a complete reversal of enantioselectivity.
In 1979, Ito and Saegusa etal. discovered that the corresponding silyl enol ethers of the alkenyl ketones produce the cyclic β, γ-unsaturated ketones in the presence of palladium acetate. In addition, Kende etal. and Shibasaki etal. have individually investigated the reaction mechanism of cycloalkenylation process and the application to bioactive natural product syntheses, e.g. quadrone, phyllocladene, and capnellene derivatives. During the course of our investigations toward total syntheses of terpenoids, such as hirsutene and stemodin, we also reported synthetic routes to the bicyclo [3.3.0] octane ring system and decalin unit using Pd (II) -promoted cycloalkenylations. However, the process employing stoichiometric amounts of Pd (OAc) 2 suffers from low yields on large scale due probably to tarry Pd (0) species produced by reductive elimination. This is a serious limitation in the application of cycloalkenylation involving Pd (II). To solve this problem, we developed a novel palladium-catalyzed cycloalkenylation by applying Larock's conditions. On top of that, the methodology was successfully adapted for the synthesis of the bicyclo [3.2.1] octanes, bicyclo [3.3.0] octanes, benzo-fused bicyclo [3.3.0] octanes, and the tandem cycloalkenylation process. In this review, we would like to give a comprehensive coverage of the above-described aspects of palladium-catalyzed cycloalkenylations.
A trans-glycosylation method was developed to study the role of the oligosaccharide component of bioactive glycoconjugates. In order to reveal the hepatoprotective function of the oligosaccharide moieties attaching soyasaponins, the fabatriose was cut by endo-glucuronidase from soyasaponin I. The fabatriose was converted to trichloroacetimidate derivative and pasted to a steroidal aglycone to give neosaponin. In addition, to pursue the function of sugar chains against anti-proliferation of tumor cells, three kinds of oligosaccharides (the mimosatetraose, the chacotriose, and the lycotetraose, which were prepared from cytotoxic natural glycosides) were derived to glycosyl donors and transformed to appropriate aglycones to achieve neosaponins. When the hepatoprotective activity and cytotoxicity of the obtained neosaponins were tested, these activities depended on the kind of the oligosaccharide moiety corresponding to the natural glycosides, while the efficacy was influenced by these aglycone parts. The trans-glycosylation method developed here could be applied to synthesize novel bioactive glycosides.
This article describes the synthesis of poison frog alkaloids using the highly stereoselective conjugate addition reaction as the key step. First total synthesis of the alkaloid 223A has been achieved. The proposed structure for natural 223A was revised and the relative stereostructure was determined by this total synthesis. First total syntheses of tricyclic alkaloid 205B and quinolizididne 207I have been achieved, and the absolute stereochemistry of both natural products was determined by these total syntheses. Investigations of the inhibitory effects of synthetic poison frog alkaloids on neuronal nicotinic acetylcholine receptors have also been conducted, and we found the 5, 8-disubstituted indolizidine 235B'is a promising lead compound for the drug design to treat autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).
Organic compounds, whose structure and absorption spectrum are changed by photoirradiation with a particular wavelength and vise versa by the other light irradiation, are called photochromic. The metal-ion complexing abilities and selectivities of several crown ether derivatives bearing photochromic moiety have been so far investigated under photoirradiation conditions, and remarkable changes in their properties were often realized. Several compounds, such as crowned photochromic compounds, are isomerized and their absorption spectra are simultaneously changed by metal ion complexation even under dark conditions. In this paper, quantitative evaluation of metal-ion complexing abilities of crowned photochromic compounds caused by photoirradiation with electrospray ionization mass spectrometry (ESI-MS) was described. Liquid-liquid extraction and liquid membrane transport using photochromic crown compounds with photoirradiation were also shown as metal-ion separation methods. Absorption spectral changes with metal ion complexation of photochromic crown compounds were applied to metal ion determination using liquid-liquid extraction and micelles containing them.