We have been interested in the reactions of α-diazocarbonyl compounds which produce reactive intermediates such as ketenes and ketocarbenes under thermal and photochemical conditions. The first part of this report describes the synthesis and reaction of bis(diazoketone)s. The thermal reaction of bis(diazoketone)s produced unpreceedented trans-hydroindenones in a quite good yield. Trans-hydroindenones are sensitive to acid and base to produce well-known cis-hydroindenones. Therefore, it is conceivable that the absolutely neutral conditions for the thermal reactions, which suppress the enolization and isomerization pathway, were indispensable for the formation of trans-hydroindenones. In the second part we focused our attention on molecular design of photoinduced DNA-cleaving agents, which may be useful in molecular biology and cancer photodynamic therapy. The first compound we developed has an a-diazoketone group conjugated with the ene-yne system and was expected to mimic the function of neocarzinostatin chromophore, which cleaves DNA by the hydrogen abstraction of a benzenoid diradical. The second compound we investigated has the dibenzoyldiazomethane (DBDM) system. The Wolff rearrangement of DBDM produces the highly electrophilic benzoylketene, which seemed to react with nucleobase resulting in modification of DNA. These α-diazocarbonyl compounds showed very efficient DNA cleavage under photoirradiation conditions and the latter compound may be used as an artificial DNA photonuclase.
A novel series of N-acylamino acid analogues of 2 (1H) -quinolinone was synthesized and evaluated for antiulcer activity against acetic acid-induced gastric ulcer in rats. Out of this investigation, 2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinon-4-yl] propionic acid (rebamipide, OPC-12759) was identified The structureactivity relationships are discussed. Rebamipide did not only increase the healing rate of a chronic gastric ulcer model, acetic acid-induced gastric ulcer in rats, but also prevented recurrence and/or relapse of the ulcer in long term observation Rebamipide inhibited the formation of gastric mucosal lesions induced by various conditions. Rebamipide did not inhibit gastric acid secretion, although it potentiated gastric mucosal defensive factors such as mucus secretion, alkaline secretion, gastric mucosal blood flow and mucosal barrier. Rebamipide inhibited ethanol-induced gastric mucosal necrosis, which was completely abolished by pretreatment with indomethacin, suggesting the mucosal protective effect is associated with endogenous prostaglandins. Rebamipide inhibited production of superoxide from polymorphonuclear leukocytes and scavenged hydroxyl radical in vitro. Rebamipide showed useful efficacy on Helicobacter pylori-induced cell damage associated with activated neutrophils. The enantiomers of rebamipide were synthesized by using three efficient methods. Both enantiomers showed anti-ulcer activity against acetic acid-induced gastric ulcer and EtOH-induced gastric ulcer. The pair of enantiomers showed a small difference in activity.
Our recent works concerning asymmetric synthesis via chiral π-allyl transition metal complexes are reviewed; focussed on inter- and intramolecular asymmetric palladium-catalyzed allylations of chiral enamines, imines, and hydrazones bearing allyl esters or phosphine groups, and intramolecular asymmetric metallo-ene reactions. A novel and excellent method for asymmetric α-allylation of carbonyl compounds via their chiral enamines and imines bearing allyl esters has been developed. Readily available chiral allyl esters, (S) -proline and (S) -valine allyl ester, have been found to serve as good asymmetric allylating reagents in the palladium-catalyzed reactions of the chiral enamines and imines derived from them.
Alkylorganozinc reagents, non-functionalized and functionalized with electrophilic functional groups, e.g., ester, ketone, nitrile, etc., display unique reactivity toward, π-allylpalladium complexes : They do not undergo usual coupling reaction, providing allylalkanes, instead, they form rather stable (reductive elimination resistant) alkylallylpalladium complexes, which either undergo a reductive carbonylative coupling reaction to provide alkyl allyl ketones under carbon monoxide (1 atm ; unsymmetrical ketone synthesis via palladium catalyzed three-component coupling reaction of allylic benzoates, carbon monoxide, and alkylorganozincs) or react further with another mole of organozinc reagents to furnish an equilibrium mixture with dialkylpalladium and allylzinc species (umpolung of π-allylpalladium via transmetallation with organozincs). Stereo-defined allylzincs, generated by this umpolung technique with inversion of configuration at the allylic center of allylic benozoates, react with aldehydes with high regio- and stereoselectivities. Mechanistic details of these unique reactions are discussed.
This article summarizes our free-radical approach to the general synthesis of fluorine-substituted cyclic compounds. Radical cyclization reactions of substrates containing the fluorine substituent on the initial radical site (CF3-C·, -CF2-C·) or the radical acceptor (Fn-C=C, CF3-C=C) proceeded effectively to give fluorine-substituted cyclopentane, cyclohexane, tetrahydrofuran and tetrahydropyran derivatives. In many cases, fluorine substituents exert no effect on the reactivity and the regioselectivity of the radical cyclization. In particular, an intermediary β-fluorine-substituted carbon radical is synthetically useful since ordinary carbanion chemistry is ineffective in forming C-C bond at the carbon β to the fluorine substituent.
The first synthesis of the antifungal antibiotic tautomycin, a potent protein phosphatase inhibitor, has been achieved via aldol coupling of two large subunits, a right-hand C1-C21 ketone and a left-hand aldehyde (left from C22). The C1-C10 segment was synthesized through a remote stereochemical control process using a spiroketal template After joining with the C11-C18 segment, the spiroketal moiety was selectively constructed. Then the right-hand C1-C21 ketone was synthesized via Roush asymmetric crotylboration. The left-hand aldehyde was prepared by esterification of a C21-C26 segment and a dialkylmaleic anhydride segment. The C21-C26 segment was synthesized through a regioselective opening of an epoxy alcohol and the dialkylmaleic anhydride segment was through a diastereoselective olefination. Completely stereoselective assemblage of the two subunits, the right-hand and the left-hand, was achieved employing the Mukaiyama aldol reaction. Further functional group manipulations including desilylation, oxidation at C2, and deprotection of tert-butyl ester with concomitant anhydride formation provided tautomycin which was identical with the natural product. As a preliminary study, derivatizations and degradation of the natural product were also examined to support the total synthesis.