Synthesis of nitrogen-containing heterocycles. 8. Preparation and ring-opening of spiro[cycloalkane-[1′,2′,4′]triazolo[1′,5′-c]pyrimidine] derivatives

Diaminomethylene- and aminomethylthiomethylenehydrazones [2] of cyclic ketones 1–8 readily reacted with ethoxymethylenemalononitrile to give spiro[cycloalkane-1,2′-[1,2′,4′]triazolo[1,5′-c]pyrimidine-8′-carbonitrile] derivatives 12–19 through the electrocyclic reaction of the initially formed condensation products 26 in moderate to high yields. The spiro[cyclopentanetriazolopyrimidine] derivatives underwent ring-opening at the cycloalkane moiety upon heating in solution to give 2-alkyl-5-substituted-[1,2,4]triazolo[1,5-c]pyrimidine-8′-carbonitriles 20–23 . When an alkyl substituent was introduced into the cyclopentane ring, cleavage of the spiro compounds occurred preferentially at the cyclopentane moiety between the spiro carbon and the more branched one. In contrast, the cyclohexane ring, especially of spiro-5-amino-triazolopyrimidines 17 and 18 strongly resisted to ring-opening under similar conditions, but those of 5-methylthiotriazolopyrimidines 14 gave up to 17 percent of cleavage after prolonged heating in hot ethanol. 2-t-Butyl-5-methylthio-2,3-dihydro[1,2,4]triazolo[1,5-c]pyrimidine-8-carbonitrile 25 [R³ = C(CH₃)₃] was highly susceptible to the cleavage even at room temperature and produced the corresponding 2-unsubstituted triazolopyrimidine 24 with loss of the t-butyl group.     

Synthesis of 1-(5,6-dihydro-2H-thiopyran-2-yl)uracil by a Pummerer-type thioglycosylation reaction: the regioselectivity of allylic substitution

1-(5,6-Dihydro-2H-thiopyran-2-yl)uracil derivatives, a new 4′-thio-D4-nucleoside analogue, were synthesized by reacting 5,6-dihydro-2H-thiopyran sulfoxide and persilylated uracil in a Pummerer-type thioglycosylation reaction. The reaction of 5-alkyl substituted dihydrothiopyran sulfoxide 7 only gave 1-(dihydrothiopyran-2-yl)uracil 9. On the other hand, the reaction with a 5-siloxy substituted derivative of 7 resulted in a mixture of products with the uracil moiety at either the α- or the γ-position. The use of a prolonged reaction time resulted in the exclusive formation of the 4-substituted dihydrothiopyran derivative 10. The result suggests that an equilibrium is operative in the formation of the α- and γ-adducts and that the latter should be more thermodynamically stable than the former. This conclusion was also supported by theoretical calculations.     

Regioselective hydrosilylations of propiolate esters with tris(trimethylsilyl)silane

Lewis acid and substituent dependency on the regioselectivity of hydrosilylation of propiolate esters 1a-c with tris(trimethylsilyl)silane (2a) was found. The reaction of methyl and ethyl propiolate esters and 2a without Lewis acid and in the presence of EtAlCl2 and Et2AlCl gave beta-silicon-substituted Z-alkenes 3 selectively. On the other hand, reaction in the presence of AlCl3 in dichloromethane gave alpha-silicon-substituted alkenes 4. In the case of trifluoroethyl propiolate ester 1c, reaction with aluminum chloride-based Lewis acids gave alpha-silicon-substituted alkenes 4 exclusively. Two competitive mechanisms, free-radical and ionic, are proposed as the source of the complementary regioselectivity displayed in these reactions. A transition state of the radical-forming step was obtained computationally. The reaction of various reactive acetylene substrates and 2a without Lewis acid and without solvent at room temperature gave beta-silicon-substituted Z-alkenes 3 selectively.     

Control of Chromophore Symmetry by Positional Isomerism of Peripheral Substituents

The first example of the control of porphyrinoid chromophore symmetry based on the positional isomerism of peripheral substituents has been achieved by preparing tetraazaporphyrins (TAPs) with C_4h, D_2h, C_2v, and C_s symmetry due to the relative arrangement of peripheral tert‐butylamino and cyano groups as push and pull substituents, respectively. The four structural isomers were successfully isolated and characterized by ¹H NMR spectroscopy and X‐ray crystallography. The band morphology in the Q‐band region varies depending on the molecular symmetry due to the significant perturbation introduced into the chromophore by the push and pull substituents. The C_4h and C_2v isomers exhibit a single Q band, whereas the Q bands of the D_2h and C_s isomers show a marked splitting. The magnetic circular dichroism spectra indicate that the push–pull TAPs retain the properties of the 16‐membered 18π‐electron perimeter generally observed for porphyrinoids. Theoretical calculations have demonstrated that the perturbation introduced by the substituents lowers the D_4h symmetry of the parent TAP π‐conjugated system, and this results in significant spectral changes. A novel approach to the fine‐tuning of the spectral properties of porphyrinoids based on changes in the chromophore symmetry is described.     

A synthesis of 2-substituted 2-aminoethanol derivatives having inhibitory activity against protein kinase C.

A series of 2-aminoethanol derivatives was synthesized and their inhibitory activities against protein kinase C were investigated. Among these compounds, 2-endo-hexadecylamino-5-norbornene-2- exo-methanol (4h) and 2-endo-hexadecylamino-5-norbornene-2,3-exo-dimethanol (4i) inhibited protein kinase C at the IC50 values of 2 x 10(-5) and 1 x 10(-5) M, respectively, but not protein kinase A at a concentration of 1 x 10(-3) M. The structure-activity relationships are discussed.     

Synthesis,structure, and dynamic behavior of cyclopentadienyl-lithium, -sodium,and -potassium annelated with bicyclo[2.2.2]octene units: a systematic study on site exchange of alkali metals on a cyclopentadienyl ring in tetrahydrofuran

Novel cyclopentadienyl (Cp)-alkali metal complexes 1-M and 2-M (M = Li, Na, K), in which the Cp ring is annelated with two bicyclo[2.2.2]octene units and substituted with a phenyl group for 1 and a tert-butyl group for 2, were synthesized, and their structures and dynamic behaviors were investigated by means of X-ray crystallography, dynamic (13)C NMR, and DFT calculations. The X-ray crystallography results indicated that 1-Li, 1-Na, and 2-Na form monomeric contact ion pairs (CIP) with three THF molecules coordinated to the metal atom. Also, in THF-d(8), all of the 1-M and 2-M form monomeric CIP in the ground state. However, variable-temperature (13)C NMR measurements of 1-M and 2-M in THF-d(8) demonstrated dynamic behavior in which the metal ion exchanges positions between the upper and lower faces of the Cp ring. From a study of the concentration dependence of the dynamic behavior, the exchange was found to proceed principally as an intramolecular process at concentration ranges lower than 0.2 M. The experimentally observed deltaG values for the intramolecular exchange process for all the 1-M and 2-M (except for 2-Li, whose intramolecular process was too slow to observe) were found to be quite similar in THF-d(8) solution and to fall within the range of 12-14 kcal mol(-)(1). Within this range, a tendency was observed for the deltaG values to increase as the size of the metal decreased. Theoretical calculations (B3LYP/6-31G(d)) afforded considerably large values as the gas-phase dissociation energy for 1-M (162.7 kcal mol(-)(1) for M = Li; 131.6 kcal mol(-)(1) for M = Na; 110.9 kcal mol(-)(1) for M = K) and for 2-M (170.0 kcal mol(-)(1) for M = Li; 137.5 kcal mol(-)(1) for M = Na; 115.4 kcal mol(-)(1) for M = K). These values should be compensated for by a decrease in the solvation energies for the metal ions with increasing size, as exemplified by the calculated solvation energy for M(+)(Me(2)O)(4), which serves as a model for metal ions solvated with four molecules of THF (-122.9 kcal mol(-)(1) for M = Li; -94.7 kcal mol(-)(1) for M = Na; -67.7 kcal mol(-)(1) for M = K). This compensation results in a small difference in the overall energy for dissociation of 1-M or 2-M in ethereal solutions, thus supporting the similar deltaG values observed for the intramolecular metal exchange.     

TUMOR IMAGING WITH [111niIn]MONO-DTPA-ETHYLENEGLYCOL-Ga-DEUTEROPORPHYRIN

Abstract Mono-DPTA-ethyleneglycol-Ga-deuteroporphyrin (MDEGD) was synthesized, by coordinating non-radioactive Ga in the porphyrin ring and connecting DTPA (diethylene-triamine-N,N,N,N,N,-pentaacetic acid) to its side chain. By labeling with 111_In, chemicals for scintigraphy were developed. They were applied to Syrian golden hamsters with implanted pancreatic gland cancers and C57-black mice with Lewis lung cancer to enable tumor imaging and biodistribution examination. A comparative study was also conducted with [⁶⁷Ga]citrate. In the resultant data, [¹¹¹In]MDEGD showed larger tumor/lung, tumor/kidney and tumor/blood ratio with [⁶⁷Ga]citrate. The affinity of [ⁿIn]MDEGD in inflammatory tissue was much lower than that of ⁶⁷Ga citrate. [¹¹¹In]MDEGD lost its photosensitivity.     

Mass spectra of π-cyclopentadienyl-diene cobalt complexes

Many reports on the mass spectra of organotransition-metal complexes have appeared in recent years,¹ whilst there have only been a few reports on the mass spectra of transition metal olefin complexes, some metal carbonyl olefin complexes²³⁴ and π-cyclooctenyl-π-cyclooctadienyl cobalt.⁵ Recently fragmentation paths of π-cyclopentadienyl-cyclooctadiene rhodium were elucidated by King.⁶ The present authors found metastable ions in the mass spectra of π-cyclopentadienyl-diene cobalt complexes as well as in the mass spectra of π-cyclopentadienyl-diene rhodium complexes.⁷. In the present paper the authors wish to report the mass spectra of several π-cyclopentadienyl diene cobalt complexes.     

Geographical distribution of plutonium derived from the atomic bomb in the eastern area of Nagasaki

In order to know the distribution of plutonium derived from the Nagasaki atomic bomb, soil samples were measured to determine the ²⁴⁰Pu/²³⁹Pu isotope ratio of and concentrations of ^239+240Pu and ¹³⁷Cs. The ^239+240Pu concentrations in soils, except for Nishiyama area, were close to the average concentration of soil collected in Japan. In soils collected at the Nishiyama area and at the eastern area of Nagasaki Prefecture and at part of northern area in Kumamoto Prefecture, the ²⁴⁰Pu/²³⁹Pu ratios were lower than the global fallout values. This suggests that plutonium from the atomic bomb was deposited in the eastern area from the hypocenter reaching up to 100 km eastwards.     

Quinolone Analogs 14: Synthesis of Antimalarial 1‐Aryl‐3‐(4‐quinolon‐2‐yl)ureas and Related Compounds

The 4‐quinolone‐2‐carbohydrazide 6a was converted into 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas 5a , 5b , 5c , 5d , 5e , 1‐aryl‐3‐(4‐quinolon‐2‐yl)imidazolidine‐2,4‐diones 9a , 9b , and N‐(4‐quinolon‐2‐yl)carbamates 10a , 10b via 4‐quinolone‐2‐carbonylazide 7a . The 4‐methoxyquinoline‐2‐carbohydrazide 6b was also transformed into 1‐aryl‐3‐(4‐methoxyquinolin‐2‐yl)ureas 11a , 11b , 11c , 11d , 1‐aryl‐3‐(4‐methoxyquinolin‐2‐yl)imidazolidine‐2,4‐diones 12a , 12b , and N‐(4‐methoxyquinolin‐2‐yl)carbamates 13a , 13b via 4‐methoxyquinoline‐2‐carbonylazide 7b . Some of the 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas 5a , 5b , 5c , 5d , 5e showed the in vitro antimalarial activity to chloroquine‐resistant Plasmodium falciparum, wherein IC₅₀ was 0.93 to 4.00 μM.