Bischler-Napieralski reaction of the diamide (IX), which was obtained by Schotten-Baumann reaction of 4-hydroxy-3-methoxyphenethylamine (V) with the acid chloride (VII), gave the dihydroisoquinoline derivative (X), which was converted into the dimethiodide (XI). Reduction with sodium borohydride of the above dimethiodide, followed by hydrolysis with an ethanolic sodium hydroxide solution, afforded the stereoisomeric mixture of cuspidaline (I), mp 110° (sinters at 85°), which was also characterized as its O, O-dimethylcuspidaline (XIII), namely, O-methyldauricine. Furthermore, the attempt to obtain the quarternary salt of II and/or III by phenolic oxidative coupling of the dimethiodide (XIV) of I was examined, but resulted in failure.

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Ethoxycarbamido group was shown to be a good substituent for accelerating Bischler-Napieralski reaction of β-phenethylbenzamides as well as alkoxy group and ring-closure occurred selectively at the para position to the ethoxycarbamido group. And an improved synthesis of aminoisoquinoline was achieved by Bischler-Napieralski reaction.

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Dimethylsulfoxonium 3-ethoxycarbonyl-2-phenylallylide derivatives (III-a-f) were prepared from ethyl phenylpropionate derivatives and dimethylsulfoxonium methylide (II) and its addition mechanism were considered. III-a was reacted with dimethyl acetylene-dicarboxylate, ethyl propionate, benzoyl chloride to afford dimethylsulfoxonium 1, 2-dimethoxycarbonyl-5-ethoxycarbonyl-4-phenyl-1, 4-pentadien-3-ylide (VII), dimethyl-sulfoxonium 1, 5-diethoxycarbonyl-4-phenyl-1, 4-pentadien-3-ylide (VIII) and dimethyl-sulfoxonium 1-benzoyl-3-ethoxycarbonyl-2-phenylallylide (IX), respectively. Dimethyl-sulfoxonium 1-phenylcarbamoyl-3-ethoxycarbonyl-2-phenylallylide derivatives (X-a-i) were prepared from III and phenylisocyanate derivatives.

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Ethyl 3-phenyl-1, 3-butadiene-2-carboxylate derivatives (IIa-d) were prepared from dimethylsulfoxonium 3-ethoxycarbonyl-2-phenylallylide by the treatment with triethylamine. These structures were determined by nuclear magnetic resonance spectra, Diels-Alder reaction with tetracyanoethylene and other chemical evidence. The mechanistic assumption for the formation of the butadiene derivatives from sulfoxonium ylides was given. Dimethylsulfoxonium N, 4-diphenyl-3, 4-dehydropiperidino-3, 6-dion-5-ylide derivatives (XIa-c) were obtained from dimethylsulfoxonium 1-phenylcarbamoyl-3-ethoxycarbonyl-2-phenylallylide (Xa-c) by the treatment with sodium ethoxide.

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The reaction of 1-substituted biguanide with phenylenedicarboxylic acid ethyl ester afforded 2-amino-4-(substituted amino)-6-carboxyphenyl-s-triazine (II) along with 2, 2'-phenylenebis [4-amino-6-(substituted amino)-s-triazine] (XIII and XVI). Product II was derived to its guanidinium salt. The related reactions concerned to the above synthetic methods, were also described. Moreover, 2-amino-4-(substituted amino)-6-hydroxyalkyl-s-triazine (IV) was synthesized from the condensation of 1-substituted biguanide with lactone compound.

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2-Hydroxybenzenesulfonamides were prepared in good yield from 2-acetoxyphenyl-sulfonylchlorides via N-acetyl-2-hydroxybenzenesulfonamides, followed by hydrolysis. The preparations of 2-alkyl, aryl, benzyl, or substituted amino-1, 4, 3-benzoxathiazine-4, 4-dioxides were described. Further 2-methyl-, or benzyl-2, 3-dihydro-1, 4, 3-benzoxathiazine-4, 4-dioxide was also prepared.

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The conversion of hecogenin acetate to some C-nor-D-homopregnane derivatives and the synthesis of a nitrogen-free derivative of veratramine from hecogenin are described. These conversions provide final confirmation of the C-9 configuration of vetatramine and correlation with the normal steroids.

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In a series of solubility studies of pyridine derivatives with 8-methoxycaffeine in aqueous solution, an extent of molecular interaction of N, N-dimethylnicotinamide (I) was found to be much less than those of unsubstituted and N-monomethylnicotinamide. Degree of complexation of 3-acetoxypyridine (II) was revealed to be much less than that of methyl nicotinate. Reduced complexing tendencies of I and II were attributed to nonplanar structures of these compounds in solution.

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A new solvent system benzene-n-hexane-diethylamine (25 : 10 : 1), was found to show a good separation of cannabidiol, tetrahydrocannabinol and cannabinol in hemp resin by thin-layer chromatography, in which Rf-values of three constituents were 0.45, 0.35 and 0.25, respectively. Furthermore, the same solvent system was successfully applied to silica gel column chromatography for isolation of three constituents of hemp resin. Using cocaine hydrochloride as an internal standard of gas chromatography, relative retention times of cannabidiol, tetrahydrocannabinol and cannabinol were calculated to be 1.76, 2.34 and 2.88, respectively. Six kinds of hemps grown in India, U.S.A. and Japan, were quantitatively analyzed using gas chromatography, and against a common opinion, Japanese hemps were found to contain considerable amounts of tetrahydrocannabinol, a physiologically active constituent.

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A new sesquiterpenic furano-ketol, curcolone, C₁₅H₁₈O₃, has been isolated from zedoary, Curcuma zedoaria (Zingiberaceae). Physico-chemical studies of curcolone and its derivatives have enabled a decision to be made in favor of I as a representation of the structure and stereochemistry of the ketol.

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A new sesquiterpenic alcohol, kusunol, has been isolated from camphor blue oil, the high boiling fraction of the essential oil of camphor tree, Cinnamomum camphora (Lauraceae). The carbon skeleton and the positions of the double bond and the tertiary hydroxyl group have been deduced from the chemical and physico-chemical studies, which, together with its transformation to α-vetivone and nootkatone, have further permitted the allocation of the absolute stereostructure I to this sesquiterpenoid.

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Reductions of 3-and 8-substituted 4-nitroquinoline 1-oxides with H₂/Pd-C₃ NaBH₄, and phenylhydrazine were examined. These compounds were proved to be easily deoxygenated to produce the corresponding 4-hydroxyaminoquinolines in contrast to the fact that many other substituted 4-nitroquinoline 1-oxides were reduced to 4-hydroxyaminoquinoline 1-oxides under the same reduction conditions. These reductive behaviors were discussed in connection with the polarographic reduction potentials and the carcinogenic activity of these compounds.

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Racemic loliolide (XIII) and its diastereoisomer (XI) were synthesized from 2-bromo-2, 6, 6-trimethylcyclohexanone (II). The syntheses provide unequivocal confirmation for the proposed structure (I).

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Alkyldihydroxy-p-benzoquinone and related compounds were newly prepared and effects of these compounds on a respiration of rat liver intact mitochondria were examined. Structure activity relationship between the benzoquinone derivatives and effects on the mitochondrial respiration was discussed. 1. 2-Methyl-5-octyl-3, 6-dihydroxy-1, 4-benzoquinone and ardisiaquinone B showed specific inhibition of State-3 respiration. But in high concentration they inhibited both State-3 and State-4 respiration. 2. 2-Octyl-3, 5-diydroxy-1, 4-benzoquinone and ardisiaquinone A inhibited both State-3 and State-4 respiration. 3. Rapanone, maesaquinone, polygonaquinone and related compounds having longer alkyl chains did not show any effect. As the result carbon numbers of the side chain have been found to be an important factor to exhibit the activity.

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For the studies on the fate of 3-desoxyestrone in man, estra-1, 3, 5 (10)-trienes having oxygen functions at C-16 and/or C-17, its possible metabolites, have been synthesized as shown in Chart 1.

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Steroidal derivatives having a bicyclo [3. 2. 1] octane bridged ring of the phyllocladene type on the A ring such as compounds (IVa), (IVb), (XXIV) and (VIIIa) were synthesized starting from 5α-cyanocholestan-3-one by three routes. The route consisting of conversion of the cyano group into an acetyl group, and subsequent cyclization was found to be most preferable for the synthesis.

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Some steroidal compounds having a bridged bicyclo [3. 2. 1] octane ring system of the kaurene type were syntheiszed starting from the bridged compound (VIa) of the phyllocladene type by two different routes. The major subject of this work is to convert the bridged system of the phyllocladene type into that of the kaurene tupe. The Wagner-Meerwein type rearrangement was successfully applied for this purpose as exemplified by the coversions XVd-XIV and XXII-XXIII. The allylic alcohol function was also successfully introduced into the bridged five-membered ring.

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Synthesis of the cholestane derivative (V) having a bridged bicyclo [2. 2. 2] octane ring system of the atisine type was attained by various routes starting from 5α-cyanocholestan-3-one (II) as illustrated in Chart 4. The route through the ketal aldehyde (X) and 5α-vinylcholestan-3-one 3-ethylene ketal (XV), the key intermediate for the present synthesis, was found to be most advantageous. However, another route through the bridged acetoxy mesylate (XVI) is also thought to be important, since this intermediate is commonly used for the synthesis of the kaurene-type bridged ring compounds as decribed in the preceding paper. The allylic alcohol function of the atisine type was introduced at the corresponding position with opposite configuration of the hydroxy group giving compound (XXXVIII).

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rac-3-Methoxy-6-oxo-N-methylmorphinan was synthesized from 1-(p-methoxybenzyl)-2-methyl-6-oxo-Δ^{9, 10}-octahydroisoquinoline and also from 1-(p-methoxybenzyl)-2-methyl-6-oxo-Δ^{5, 10}-octahydroisoquinoline by the action of 85% phosphoric acid according to Grewe's cyclization, respectively. 1-(p-Methoxybenzyl)-2-methyl-6, 6-ethylenedioxy-Δ^{9, 10}-octahydroisoquinoline, which was used as a starting material, was prepared from 2-(p-methoxybenzyl)-2-methyl-6, 6-ethylenedioxy-Δ^{9, 10}-octahydroisoquinolinium chloride by means of Stevens'rearrangement.

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Brossi and Teitel have recently reported a synthesis of so-called corpaverine (I), mp 115-117°, whose IR and NMR spectra were identical with those of our sample, but the melting points of both specimens were not identical. Therefore, we have re-examined the synthesis of so-called corpaverine. Cyclization of N-(3-benzyloxy-4, 5-dimethoxy-phenethyl)-4-methoxyphenylacetamide with phosphoryl chloride afforded two isomers, one of which was isolated as its crystals, mp 84-86°, identical with our sample (I) reported previously. Furthermore, the synthesis of 7, 8-dimethoxy-1-(4-methoxybenzyl)-2-methyl-3, 4-dihydroisoquinolin-6-ol (IV) by Grignard reaction was carried out in order to compare our sample with Brossi's sample. At first the cyclization of the formyl derivative (VI) with phosphoryl chloride afforded a mixture of VII and VIII, which was separated by recrystallization of its perchlorates. After reduction with sodium borohydride, 8-benzyloxy-derivative (IX) was obtained as its hydrochloride, mp 188-190°, whose debenzylation gave the anhalamine hydrochloride. Secondly Grignard reaction of the methobromide (XIII) with 4-methoxybenzylmagnesium chloride afforded the benzyl-derivative (XV), whose debenzylation with acid gave a phenolic base, mp 84-86°. The IR (in CHCl₃) and NMR (in CDCl₃) spectra of this sample were not only identical with those of our authentic sample reported by us previously, but also with those of Brossi's sample, mp 115-117°. Accordingly we have concluded to confirm the identity between both specimens and suggesting polymorphism.

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The reaction of sodium alcoholates of prim. α-acetylenic alcohols and carbon disulfide in an aprotic solvent gave new heterocyclic compounds, 4-alkylidene-1, 3-oxathiolane-2-thiones and 4-alkylidene-1, 3-dithiolane-2-thiones.

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Treatment of N^ε-formyllysine with dilute aqueous hydrazine acetate or hydroxylamine hydrochloride in aqueous pyridine regenerated lysine in satisfactory yield. These methods were adopted to convert N^α-acetylseryltyrosylserylmethionylglutamylhistidylphenyl-alanylarginyltryptophylglycyl-N^ε-formyllysylprolylvaline amide to α-melanocyte-stimulating hormone (MSH). The products prepared by two alternate methods behaved quite identically with natural α-MSH on paper and thin-layer chromatographies and their infrared spectra were both identical with that of natural α-MSH. Their in vitro MSH activities were 2.3-5.4×10¹² and 2.4-4.1×10¹² U/g respectively.

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The pentachlorophenyl trichloroacetate and dichloroacetate which were known as a soil sterilizer or a plant growth regulator, were subjected to the ester-exchange reaction with trialkylammonium salts of acylamino acids, and it has been found that they are excellent reagents for the preparation of the pentachlorophenyl active esters of acylamino acids which are known as intermediates in peptide synthesis. Some acylpeptide esters were also synthesized by the direct method utilizing these reagent, thus, the peptide derivatives were obtained in excellent yields and satisfactory purities.

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2-Amino-4-hydroxy-1, 4, 5, 6-tetrahydropyrimidine (I), the cyclic guanidine moiety of tetrodotoxin, and its derivatives were prepared to examine their chemical and physical properties in comparison with the toxin and its derivatives. 1. Oxidation of I with chromium trioxide-pyridine gave β-alacreatinine (III). 2. Etherification of I with alcohols in the presence of acid catalyst afforded the corresponding 4-alkoxy derivatives (IV and V). 3. Acetylation of I under various conditions gave N-acetyl derivative (VI), O-acetyl derivative (VII), and N-acetyl-1, 6-dihydro derivative (VIII) respectively. 4. Interconversion of the acetyl derivatives is also described.

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The Mannich reaction of 3-pyridazinol 1-oxide using benzylamine, gave 6-benzyl-aminomethyl-3-pyridazinol 1-oxide as a major, together with the 6, 6'-(N-benzyl-1, 1'-dimethylamino) bis (3-pyridazinol 1-oxide) as a minor. The Mannich reaction of 5-pyridazinol 1-oxide using benzylamine, ethylamine or methylamine, also gave the corresponding 6-alkylaminomethyl-5-pyridazinol 1-oxides, but, in each case, the 6, 6'-bis compound could not be isolated. The predominance of the enol forms in the structures of 3-pyridazinol 1-oxide and 5-pyridazinol 1-oxide was discussed by comparing the IR spectra of their deuterated compounds with that of 3-pyridinol 1-oxide.

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