Stable carbocations do not react with non-activated benzenes. The electrophiles, which can react with benzene, are reactive carbenium ions (> C+-X), substituted with a genuine electron-withdrawing group (-X), wherein the substituent X represents carbenium, oxonium, ammonium, O-protonated hydroxylamino, O-protonated N, N-dihydorxylamino, and trifluoromethyl. Experimental evidences, including spectroscopic ones, demonstrated the involvments of these cationic species as discrete reaction intermediates. In this context, a dicationic or tricationic species may participate in various cationic reactions such as the Gatterman-Koch, Pomeranz-Fritsch, Skraup, Bischler-Napieralski and other conventional reactions. Reinvestigations of these reactions should have important implications for the chemistry of Friedel-Crafts and related reactions.
Since fluorine-containing molecules have been recently disclosed their high ability as pharmaceutically active compounds and optical devices, development of new methods are strongly required for the construction of especially, trifluoromethylated molecules in a highly diastereoselective manner. In this article, with pointing out special problems in the field of fluorine chemistry and explaining the reason why the authors reached to the idea to employ building blocks as one of the promising solution to the above problem, our recent results for the stereoselective preparation of chiral materials via organic, enzymatic, and catalytic antibody methodologies, respectively, are discussed in detail.
Construction of hexahydrobenzofuran moiety with both the correct stereochemistry and the C3-C4 double bond is the most important and challenging aspect in the total syntheses of the antiparasitic avermectins and the milbemycins, because this structure, prone to undergo C2-epimerization, double bond-migration, and dehydration, is essential for their biological activity. Successful total syntheses reported thus far have adopted secure strategies introducing the crucial 3, 4-double bond at the final stages after constructing the whole macrolactone structure but they are still less than satisfactory in terms of stereo-and regio-control. We have succeeded for the first time in the straightforward synthesis of the genuine seco-acid possessing the 3, 4-double bond via an oxetane acetal intermediate and have demonstrated that its macrolactonization to milbemycin α1, can be executed without the serious isomerization.
Asymmetric syntheses of FK 506 and (C8, C9-13C2) -FK 506 are reported. The latter compound was designed to facilitate an investigation of the interactions between FK 506 and its receptor, the recently discovered immunophilin, FKBP. The synthesis involved the preparation of intermediates 7-9 in nonracemic forms. The key coupling reactions included a Cram-selective addition of the vinyl Grignard reagent derived from bromide 9 to aldehyde 8 and the addition of the lithioanion of phosphonamide 7 to aldehyde 43, followed by thermal elimination. Dithiane 44 was then hydrolyzed, and glycolic ester 6 (or 6*) was added via an aldol reaction that allowed the introduction of 13C labels at C8 and C9. Elaboration to FK 506 proceeded via a Mukaiyama lactamization reaction and a selective deprotection/oxidation sequence, the efficiency of which was critically dependent upon the order of protecting group removal. 13C labeled FK 506 (2) -FKBP drug protein complex was examined by 13C NMR ; the experiments did not show an enzyme bound tetrahedral intermediate, but revealed a noncovalent, fully reversible interaction of the drug with its receptor. Also delineated are the recent researches aiming at understanding the structural basis for the molecular recognition of immunosuppressants by immunophilins and the biological consequences of their interactions.
Highly active catalysts for the hydrolysis of phosphodiester linkage in RNAs and DNAs, which are applicable to artificial ribonucleases and nucleases, have been reported. Oligoamines such as ethylenediamine and triethylenetetramine (trien), as well as cobalt (III) complexes such as [Co (trien) (H2O) 2] 3+ and [Co (tme) 2 (H2O) 2] 3+ (tme : 1, 1, 2, 2-tetramethylethylenediamine), are so active (105 to 106 fold acceleration) that RNAs are promptly hydrolyzed near neutrality. The large activities are ascribed to intramolecular acid-base cooperation in the catalysts. In addition, pheophorbide, a derivative of chlorophyll, efficiently cleaves DNAs under irradiation of visible light, even in the absence of oxygen. The photocleavage proceeds via a novel mechanism, which involves direct attack of the dye to DNAs (and not attack by singlet oxygen). Simple structures of these catalysts as well as their large activities strongly indicate high potentialities as the catalytic sites in artificial ribonucleases and nucleases.