As an intermediate in the synthesis of dihydrokainic acid, diethyl 2-oxo-5-isopropyl-4-piperidinemalonate (VIII-i, -ii) was prepared by the process shown in Chart 2. Ethyl 2-cyano-3-methylbutyrate (I) was hydrolyzed to the carboxylic acid compound (II), then to its chloride (III), and condensed with diethyl malonate in the presence of magnesium ethoxide to the butyroylmalonate compound (IV). Decarboxylation of (IV) by heating gave butyroylacetate compound (V) which was reduced to two kinds of hydroxy-piperidones (VI-i and -ii). Each of these was boiled with acetic anhydride and both afforded the same dihydropyridone compound (VII) which was submitted to the Michael condensation with diethyl malonate to give two kinds of piperidone compound (VIII-i and -ii). (VIII-i) was derived to its half ester (IX-i), ethoxycarbonylmethyl compound (XI-i). (VIII-ii) was also derived through its dicarboxylic acid compound (X-ii) to the carboxymethyl compound (XII-ii), thereby confirming the structure of (VIII-i) and (VIII-ii), and proved that these compounds are stereoisomers with regard to the C4-C5 position. It was assumed that the configuration of the side chain in C4-C5 is in trans in the product (VIII-i) with overwhelmingly large yield and cis in the other product (VIII-ii).
