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The ene reactions of trifluoromethyl carbonyl compounds give products which may be dehydrated to trifluoromethyl dienes; the Diels Alder reaction of these have been investigated. The dienes from trifluoromethyl ketones hardly reacted, probably because the steric effect of the trifluoromethyl group prevents the diene from taking up a cisoid form. Dienes obtained from the ene reaction of trifluoroacetaldehyde have one substituent at a terminal position and react with dienophiles to give trifluoromethylated cyclohexene derivatives.

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.

The ene reactions of trifluoromethyl carbonyl compounds give products which may be dehydrated to trifluoromethyl dienes; the Diels Alder reaction of these have been investigated. The dienes from trifluoromethyl ketones hardly reacted, probably because the steric effect of the trifluoromethyl group prevents the diene from taking up a cisoid form. Dienes obtained from the ene reaction of trifluoroacetaldehyde have one substituent at a terminal position and react with dienophiles to give trifluoromethylated cyclohexene derivatives.

In the course of our study on the ene reaction of trifluoromethyl ketones, a trifluoromethyl group has been observed to behave as a larger substituent than commonly believed in the biomedicinal field. To estimate the steric effect of a trifluoromethyl group, we synthesized several trifluoromethyl ketones (RCOCF)3 and examined in detail their ene reaction with cyclohexene, a 1, 2-disubstituted ene having the least steric requirement. In this reaction, a trifluoromethyl group was found to behave as if it were a much larger substituent than a phynyl or isobutyl group and as large as a sec-butyl group.

As an extension of our studies on the ene reaction of trifluoromethyl ketones, the ene reaction of trifluoroacetaldehyde was examined. The aldehyde reacted with various ene compounds as a good enophile in the presence of Lewis acids, among which methylaluminum dichloride workded best, though polymerization of the aldehyde caused by the Lewis acid among which methylaluminum dichloride worked best, though polymerization of the aldehyde caused by the Lewis acid often lowered the isolation yields of the ene reaction. The ene reaction products were successfully oxidized to trifluoromethyl β, γ-unsaturated ketones with Dess Martin reagent. Reduction of the ene reaction products followed by oxidation with Jones reagent gave saturated trifluoromethyl ketones. The β, γ-unsaturated ketone rearranged on thermolysis to an α, β-unsaturated ketone. These ketones obtained were converted to otehr types of trifluoromethyl compounds. Thus, the ene reaction of trifluoroacetaldehyde provides a versatile method for synthesis of many types of trifluoromethyl compounds. During this derivatization, a trifluoromethyl group was found to behave as a much larger substituent than a decyl group.

With the aim of obtaining a porphyrin derivative useful for diagnosis and therapy of cancer, fluorine analogues of protoporphyrin, in which the vinyl group(s) were replaced by difluorovinyl group(s), were synthesized by the reaction of the formylporphyrins with sodium chlorodifluoroacetate in the presence of triphenylphosphine. Some improvements in the reported procedures for the synthesis of formylporphyrins are also described. Preliminary results of biological tests of the products showed that 8(2),8(2)-difluoroprotoporphyrin accumulates to gastric cancer more selectively than other fluorine analogues and that 3(2),3(2),8(2),8(2)-tetrafluoroprotoporphyrin is taken up by rat hepatoma cells more readily than the others.

The reaction of 2-bromo-2-chloro-1,1,1-trifluoroethane (1) with 2-octanone (3a)in the presence of magnesium did not give 2-chloro-1,1,1-trifluoro-3-nonanol(4a)but 2-bromo-2chloro-1,1,1-trifluoro-3-methyl-3-nonanol (5a) and 2-chloro-1,1-difluoro-3-methyl-1-nonen-3-ol (6a). This suggested that the primary Grignard reagent, 1-chloro-2,2,2-trifluoroethymagnesium bromide (2), reacted with excess 1 rather than with the ketone 3a to give 1-bromo-1chloro-2,2,2-trifluoroethylmagnesium bromide (8), which added to the ketone to give 5a

In the study of ene reaction of trifluoromethyl ketones, a trifluoromethyl group was found to behave as a much larger substituent than commonly believed. Similar results were obtained in the dehydration of trifluoromethyl homoallyl alcohols.

Flavin-containing monooxygenase (FMO) was partially purified from rat brain microsomes through two successive chromatographies on columns of DEAE Sepharose and 2',5'-ADP Sepharose. The specific activity, benzydamine N-oxidation of partially purified brain FMO, was 122-fold higher than that of microsomes. A single band of 60 kDa was recognized by Western blotting analysis with anti-rat liver FMO. The Km value of brain FMO for thiourea was 4-fold lower, but that for cysteamine was 10-fold higher than that of liver FMO. The enzymatic activity for n-octylamine was detected in neither brain nor liver FMO. Kinetic analysis for neurotoxins also revealed that Km values of brain FMO for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1,2,3,4-tetrahydroisoquinoline (TIQ) and N-methyl TIQ (NMTIQ) were lower than those of liver FMO. These results indicate that rat brain FMO catalyzes several substrates of liver FMO involving neurotoxins, but it seems likely that the kinetic properties of brain FMO are somewhat different from those of liver FMO.

With the aim of obtaining a porphyrin derivative useful for diagnosis and therapy of cancer, fluorine analogs of hematoporphyrin, which had trifluorohydroxyethyl group(s) in the place of hydroxyethyl groups, were synthesized by the reaction of deuteroporphyrin dimethyl ester with trifluoroacetaldehyde in the presence of aluminum chloride. Preliminary results of biological tests of the products showed that the hexafluoro analog of hematoporphyrin accumulates to Human liver cancer cells more selectively than other fluorine analogs

The reaction of 2-bromo-2-chloro-1,1,1-trifluoroethane (1) with 2-octanone (3a) in the presence of magnesium did not give 2-chloro-1,1,1-trifluoro-3- methyl-3-nonanol (4a) but 2-bromo-2-chloro-1,1,1-trifluoro-3-methyl-3- nonanol (5a) and 2-chloro-1,1-difluoro-3-methyl-1-nonen-3-ol (6a). This suggested that the primary Grignart reagent, 1-chloro-2,2,2-trifluoroethylmagnesium bromide (2), reacted with excess 1 rather than with the ketone 3a to give 1-bromo-1-chloro-2,2,2-trifluoroethylmagnesium bromide (8), which added to the ketone to give 5a. Detection of 1,1,1-trifluoro-2-chloroethane supported this mechanism. Compound 5a was formed preferentially at −53 °C, and on warming to 0 °C, the amount of 5a decreased while that of 6a increased. Therefore, compound 6A must be formed by reduction of 5a with excess magnesium. Treatment of 6a with hydrogen fluoride gave 2-chloro-1,1,1-trifluoro-3-methyl- 2-nonene (9a). Cyclohexanone (3b) and acetophenone (3c) reacted similarly to give corresponding products.

3-(5-Substituted-1, 3, 4-thiadiazol-2-yl) ceph-3-em derivatives were prepared by oxidative ring closure with 2, 3-dichloro-5, 6-dicyanobenzoquinone directly or after acetylation of 3-thiocarbonylhydrazones, which were obtained from the reaction of 3-formylceph-3-ems and thiocarbonylhydrazines. The antibacterial activity of 7-thienylacetamido-3-(5-substituted-1, 3, 4-thiadiazol-2-yl) ceph-3-em derivatives (4) against gram-positive organisms was similar to that of cephalothin (CET), while the activity against gram-negative organisms was superior to that of CET. A similar oxidative ring closure reaction with other thiocarbonylhydrazones is also discussed.

The ene reaction of 1, 1, 1-trifluoroacetone with various olefinic compounds proceeded in the presence of aluminum chloride at low temperature to give allylmethyl (trifluoromethyl)carbinols. Olefinic compounds with a terminal vinyl group reacted smoothyl, but some olefins with an inner double bond did not react at all. Trifluoroacetone was also found to undergo a Friedel-Crafts type reaction with aromatic compounds.

Starting from cephalosporin thiolactones (1), a sequence of reactions (bromination, hydrolysis, oxidation and opening of the dioxo thiophene ring) yielded 3-carboxyceph-3-ems (10). Several reactions of thiolactone derivatives are also described.

1- (Trifluoromethyl) homoallyl alcohols, which were obtained by the ene reaction of trifluoromethyl ketones with olefins, were cyclized to 2-(trifluoromethyl) tetrahydrofurans in the presence of p-toluenesulfonic acid, a typical Brensted acid. The ease of this cyclization depends on the substituents on the homoallyl system. The stereochemistry of the cyclization products was established by analysis of the two dimensional nuclear Overhauser effects. The stable conformations of the tetrahydrofuran compounds were estimated by means of molecular mechanics calculations of the steric energy. The observed ratio of the products was consistent with that estimated from the steric energy calculations.

Four epimeric 17-hydroxy-16-ethylestr-4-en-3-ones (11) having potent antiandrogenic activity were prepared stereoselectively starting from 16α-ethyl-16β, 17β-diol monoacetate (2). The nuclear magnetic resonance spectra of the four epimers and other 16-substituted estranes and androstanes were investigated in order to elucidate the possibility for the assignment of the unknown configurations at the positions of 16 and 17. The data of the coupling constants (J16, 17) and the chemical shifts (13-methyl protons and 17-proton) can be used for the determination of the configuration at the positions of 16 and 17.

γ- and δ-Tocopherol were converted to iodo compounds, which were trifluoromethylated with trifluoromethyl iodide and copper powder in HMPA.

Etude des reactions des 2 cetones du titre avec le phenyl-3 propene, l'hexene-1 et l'octene-1. Obtention d'alcools homoallyliques α-trifluoromethyles

The mechanism of anti-androgenic action of a steroidal compound, TSAA-291, was summarized and discussed in reference to its drug-designing and structure-activity relationship. The target of the drug-design was to obtain a substance which is inactive in androgenic activity and is capable of antagonistically competing with androgen for the receptor. With this intention, the androgen molecule was rendered with a steric hindrance influencing upon the functional 17β-hydroxy group. Introduction of a bulky group at the steroidal position-13 or -16 led to anti-androgenic properties. Intense steric hindrance by introducing an enormously bulky group or complete elimination of the 17β-hydroxy group rather decreased the anti-androgenic activity. Of these anti-androgens thus synthesized, TSAA-291 proved to be the most active in the anti-androgen assay and also antagonistic against the uptake of [3H]testosterone by the rat ventral prostate.

With intention of obtaining a porphyrin derivative useful for diagnosis and therapy of cancer, fluorine analogues of protoporphyrin, in which the vinyl group(s) were replaced by difluorovinyl group(s), were synthesized by the reaction of the formylporphyrins with sodium chlorodifluoroacetate in the presence of triphenylphosphine.

A series of N-hydroxyamino acids and their esters (9a, b, d-k) coupled with N-hydroxyglycinamide (9c) were synthesized through facile preparations of N-furfurylidenealkoxy (and hydroxy) carbonylalkylamine N-oxides (7a, b, d-g) and N-furfurylidenecarbamoylmethylamine N-oxide (7c) followed by hydrolysis. The method was applied to the syntheses of emimycin (1) and hadacidin monosodium salt (2b).

金沢大学大学院医学系研究科, The mixture of enol acetates (II and III) of 16-acetyl-estrone-3-methyl ether underwent hydrogenolysis under high pressure (100kg/cm^2) of hydrogen in the presence of Raney Ni to form the 16β-ethyl-17β-ol compound (X) in high yield. The mechanism of hydrogenolysis was discussed. This facile and stereoselective introduction of 16β-ethyl and 17β-hydroxy groups was applied to the synthesis of 16β-ethyl-19-nortestosterone (TSAA-291,XIX), which shows strong antiandrogenic activity.

The ene reaction product of trifluoroacetone with cyclohexene, 3-(2, 2, 2-trifluoro-1-hydroxy-1-methylethyl)-cyclohexene (1), was converted to trifluorinated analogues of p- and m-menthane derivatives. For introduction of a functional group at suitable positions of the cyclohexene ring, oxidation of 1 was carried out to give 1-(2, 2, 2-trifluoro-1-hydroxy-1-methylethyl)-2-cyclohexen-1-ol (2), 4-(2, 2, 2-trifluoro-1-hydroxy-1-methylethyl)-2-cyclohexen-1-one (3) and 3-(2, 2, 2-trifluoro-1-hydroxy-1-methylethyl)-2-cyclohexen-1-one (4). Selenium dioxide gave only a small amount of 2. The best oxidizing reagent among those examined was tert-butyl hydroperoxide with chromium trioxide or chromium hexacarbonyl as a catalyst. In the presence of basic compounds such as pyridine or dimethylpyrazole, chromium trioxide gave a larger amount of 4 than 3, while in the presence of acetic acid, 3 was formed preferentially though the total yield was very low. Oxidation of 1 with tert-butyl hydroperoxide catalyzed by chromium hexacarbonyl gave 3 in excess over 4 in satisfactory yields. Treatment of the carbonyl compounds (3 or 4) with methylmagnesium iodide gave a p- or m-menthane skeleton with fluorine substituents, and these products were converted to some fluorine analogues of monoterpenes.

The Diels-Alder reaction of 5-ethoxy-4-ethoxycarbonylmethyloxazole (I) with dienophiles was investigated. The stereochemistry of the addition products that had an exocyclic double bond was confirmed by the spectroscopic data. The reaction of I with maleic anhydride gave endo-(II) and exo-adduct (III), and the isomerization of II to 1II proceeded easily. The reaction of I with eight symmetrical dienophiles afforded the isomeric adducts. Similar treatment of asymmetrical dienophiles afforded the corresponding adducts, respectively. The stereochemistry of these adducts was discussed.

17α-Hydroxy-3-methoxy-8, 14-secoestra-1, 3, 5 (10), 9-tetraen-14-one (IIa) which is an intermediate for the total synthesis of estrogens has been optically resolved. The isomer which has unnatural configuration at C-13 has been converted to estrapentaene 3-methyl ether (IVa) via the 9, 14-epoxy intermediates (XI, XII, XIII, XV).

The improved method for synthesizing gonanes having the allyl group at C-13 was examined. Potassium salt of 2-ethoxycarbonylmethylcyclopentane-1, 3-dione (I) was choosen as a starting material and the ethoxycarbonylmethyl group was converted into the allyl group after the steroid skeleton was formed.

5α-Pregnane-3β, 5, 16β, 20α-tetrol (VIa) and 5α-pregnane-3β, 5, 16β, 20β-pentol (VIII) were synthesized according to the scheme shown in the Figure.

Chlorination of diosgenin acetate followed by treatment with performic acid, dechlorination, and hydrolysis has given pregn-5-ene-3β, 16β, 20α-triol in 60∼70% overall yield. When the chlorination was conducted in a dimethylformamide solution, the main product was 3β-acetoxy-5-chloro-6β-formyloxy-5α, 25D-spirostan. Validity of this novel reaction was confirmed by expriments in the cholesterol series. Synthesis of 9α-chloro-11β-formyloxysteroids from l9(11)-steroids has also been facilitated.

5α-Pregnane-3β, 5, 6β, 20α-tetrol (IIIa), 5α-pregnane-3β, 5, 6β, 20β-tetrol (IV), 5α-pregnane-3β, 6β, 16β, 20α-tetrol (VIIIa), 5α-pregnane-3β, 6α, 16β, 20α-tetrol (XIa), and 5α-pregnane-3β, 6α, 16β, 20β-tetrol (XIII) were synthesized according to the schemes shown in Chart 1 and Chart 2.