Studies on Antibiotics and Related Substances. XVIII. The Synthesis of 5-Methyl-2-methylenecyclopentanone-3-carboxylic Acid, an Antitumor Substance, and Related Mannich Bases

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1) The Mannich reaction of 5-methylcyclopentanone-3-carboxylic acid with formaldehyde and dimethylamine hydrochloride gave a mixture of 2-(dimethylaminomethyl)-5-methylcyclopentanone-3-carboxylic acid (VI) and two kinds of geometrical isomers of 5-(dimethylaminomethyl)-5-methylcyclopentanone-3-carboxylic acid (IIa and IIb), from which IIa, an unstable methiodide (VII) of methyl ester of VI, and IIb were isolated. 2) Methyl 2-(dimethylaminomethyl)-5-methylcyclopentanone-3-carboxylate methiodide (VIII) was degraded to give methyl 5-methyl-2-methylencylopentanone-3-carboxylate (IX), which was then hydrolyzed to 5-methyl-2-methyleneclycopentanone-3-carboxylic acid (X), a homolog of sarkomycin. 3) The steric relation between IIa and IIb has been discussed. 4) The destructive distillation of methyl 2-(dimethylaminomethyl)-5-methylcyclopentan-one-3-carboxylate (VII), followed by hydrolysis, afforded 2,5-dimethylcyclopenten-1-one-3-carboxylic acid (XII), an isomer of X. It was found that the product was obtained also by the thermal decomposition of the methyl ester hydrochloride of IIa. This funding may be accounted for on the assumption that a rearrangement of the dimethylaminomethyl group occurred through a kind of retrograde Mannich reaction. 5) Some derivatives of the above-mentioned Mannich bases were described. 6) Both X and its methyl ester were found to possess antitumor and antibacterial activities.
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