Itsumaro Kumadaki

Trifluoromethylation of aliphatic halides with trifluoromethyl copper

Abstract A solution of trifluoromethyl copper complex in hexamethylphosphoric triamide was found to be useful for trifluoromethylation of aliphatic halides.

Induction of cytotoxicity in human lung adenocarcinoma cells by 6-O-carboxypropyl-α-tocotrienol, a redox-silent derivative of α-tocotrienol

Tocotrienols are one of the most potent anticancer agents of all natural compounds and the anticancer property may be related to the inactivation of Ras family molecules. The anticancer potential of tocotrienols, however, is weakened due to its short elimination half life in vivo. To overcome the disadvantage and reinforce the anticancer activity in tocotrienols, we synthesized a redox‐silent analogue of α‐tocotrienol (T3), 6‐O‐carboxypropyl‐α‐tocotrienol (T3E). We estimated the possibility of T3E as a new anticancer agent against lung adenocarcinoma showing poor prognosis based on the mutation of ras gene. T3E showed cytotoxicity against A549 cells, a human lung adenocarcinoma cell line with a ras gene mutation, in a dose‐dependent manner (0–40 μM), whereas T3 and a redox‐silent analogue of α‐tocopherol (T), 6‐O‐carboxypropyl‐α‐tocopherol (TE), showed much less cytotoxicity in cells within 40 μM. T3E cytotoxicity was based on the accumulation of cells in the G1‐phase of the cell‐cycle and the subsequent induction of apoptosis. Similar to this event, 24‐hr treatment of A549 cells with 40 μM T3E caused the inhibition of Ras farnesylation, and a marked decrease in the levels of cyclin D required for G1/S progression in the cell‐cycle and Bcl‐xL, a key anti‐apoptotic molecule. Moreover, the T3E‐dependent inhibition of RhoA geranyl‐geranylation is an inducing factor for the occurrence of apoptosis in A549 cells. Our results suggest that T3E suppresses Ras and RhoA prenylation, leading to negative growth control against A549 cells. In conclusion, a redox‐silent analogue of T3, T3E may be a new candidate as an anticancer agent against lung adenocarcinoma showing poor prognosis based on the mutation of ras genes.

Studies on organic fluorine compounds. Part 35. Trifluoromethylation of pyrimidine- and purine-nucleosides with trifluoromethyl–copper complex

Halogenated nucleoside derivatives were trifluoromethylated using a solution of a trifluoromethyl–copper complex, which was prepared by shaking trifluoromethyl iodide and copper powder in hexamethylphosphoric triamide and filtering off the excess of copper powder. The following trifluoromethylated nucleosides were obtained in moderate to good yields: 5-trifluoromethyl-uridine, -deoxyuridine, -cytidine, -deoxycytidine, and -arabinosylcytosine; 8-trifluoromethyl-adenosine, -deoxyadenosine, and -inosine; and 6-trifluoromethylribofuranosylpurine. This procedure offers simple synthesis of many trifluoromethyl compounds.

Location and dynamics of α-tocopherol in model phospholipid membranes with different charges

Abstract Studies were made on the position and dynamics of the OH-group of α-tocopherol in phospholipid membranes. There was no difference in the spin-lattice (T1) relaxation times at the 5a-position of α-tocopherol labeled with 13C- or C19F3-determined from the nuclear magnetic resonance (NMR) spectra of liposomes positively charged with stearylamine (SA) and negatively charged with dicetylphosphate (DCP). The zeta-potentials of egg yolk phosphatidylcholine (EYPC) liposomes with and without SA or DCP were not affected by incorporation of 20 mol% α-tocopherol, though incorporation of 10 mol% ascorbylpalmitate decreased the zeta-potentials of EYPC and EYPC-SA liposomes. The PO stretching band (1235 cm−1) of the phosphate group and CO stretching band (1734 cm−1) of the acyl ester linkage in dimyristoylphosphatidylcholine (DMPC) liposomes, measured by Fourier transform-infrared (FT-IR) spectroscopy, were not changed by incorporation of α-tocopherol. These results suggest that no specific interaction occurred between the OH-group of α-tocopherol and the polar interfacial region of the bilayer. The dynamic quenching effects of n-(N-oxy-4,4′-dimethyloxazolidine-2-yl)stearic acids (n-NSs) on the intrinsic fluorescence of α-tocopherol were in the order 5-NS > 7-NS = 12-NS > 16-NS. Acrylamide, a water-soluble fluorescence quencher with a very low capacity to penetrate through phospholipid bilayers, had very low quenching efficiency. These results indicate that the bulk of the chromanol moiety of α-tocopherol is located in a position close to that occupied by the nitroxide group of 5-NS in the membranes and is poorly exposed at the membrane surface. No difference was found in the oxidation rates of α-tocopherol induced by water-soluble 2,2′-azobis(2-amidinopropane)dihydrochloride (AAPH) in gel state dipalmitoylphosphatidylcholine (DPPC) liposomes and liquid crystalline state DMPC liposomes, indicating that the OH-group is not located deep in the hydrophobic region.

Reactions of trifluoromethyl ketones. IX. Investigation of the steric effect of a trifluoromethyl group based on the stereochemistry on the dehydration of trifluoromethyl homoallyl alcohols

Abstract In a previous paper we reported that a trifluoromethyl group behaves as a larger substituent than a butyl or a phenyl group and slightly larger than a sec-butyl group in ene reactions of trifluoromethyl carbonyl compounds. Dehydration of trifluoromethyl homoallyl alcohols, which are obtained by the ene reaction of trifluoromethyl ketones, has now been extensively investigated to compare further the steric effect of a trifluoromethyl group with those of other substituents. A trifluoromethyl group behaves as a substituent as large as a cyclohexyl group and a little smaller than a sec-butyl group. Differences between steric effects in the ene reaction and in the dehydration are discussed.

Mechanistic Studies on α-Trifluoromethylation of Ketones via Silyl Enol Ethers and Its Application to Other Carbonyl Compounds

Synthesis of alpha-CF(3) carbonyl compounds has been recognized to be difficult up to now because the polarization of CF(3)(delta-)-I(delta+) is opposite to that of CH(3)(delta+)-I(delta-), and this makes it difficult to introduce CF(3)(+) unit to enolates. We recently reported an effective alpha-trifluoromethylation of ketones by using Et(2)Zn with Rh catalyst, but the mechanism has not fully been cleared. Now, we carried out the detailed mechanistic studies and found the involvement of a highly reactive alkylrhodium complex which derived from Et(2)Zn and RhCl(PPh(3))(3) in this alpha-trifluoromethylation. Furthermore, this alpha-trifluoromethylation was applied to other types of carbonyl compounds in good yields.

Synthesis of aryltrifluoromethylacetylenes

Abstract Aryltrifluoromethylacetylenes were synthesized by an intramolecular Wittig reaction of trifluoroacetylarylidenephosphoranes, which were synthesized from arylmethyl halides.

Direct Synthesis of 1,3-Diketones by Rh-Catalyzed Reductive α-Acylation of Enones

1,3-Diketones were synthesized from alpha,beta-unsaturated ketones by treatment with acid chlorides and Et(2)Zn in the presence of RhCl(PPh(3))3. This is a very simple and extremely chemoselective reaction to give the adduct at the alpha-position of alpha,beta-unsaturated ketones.

Progress on the syntheses of fluorine analogs of natural porphyrins potentially useful for the diagnosis and therapy of certain cancers

Abstract Hematoporphyrin derivative (HpD) or photofrin II is used as a photosensitizer of photodynamic therapy (PDT) of cancer. However, these are complex mixtures of porphyrin derivatives. We have synthesized fluorine analogs of naturally important porphyrin derivatives, such as protoporphyrin (PP) and hematoporphyrin (HP) for application for the diagnosis and therapy of cancer. Some of these fluorine analogs were found to localize to tumor tissues and/or be taken up selectively by tumor cells. In this review, our former results are outlined briefly, then our recent studies on synthesis of chiral fluorine analogs of HP and synthesis of fluorine analogs of PP using our new zinc reagents will be discussed.

Trifluoromethyl trifluoromethanesulfonate (CF3SO2OCF3)

Trifluoromethyl trifluoromethanesulfonate (1) was synthesized by the reaction of silver trifluoromethanesulfonate with trifluoromethyl iodide in a benzene solution. Reaction of 1 with an enamine gave trifluoromethanesulfonyl compound. This is the first example of SO2-O bond fission of alkyl trifluoromethanesulfonate.