An approach to the synthesis of Lycopodium alkaloids.
Creators: name: Hess, Friedrich K.
Publisher: name: Université d'Ottawa / University of Ottawa
Year: 1963
Subjects: subject: Chemistry, Inorganic.

description: The syntheses of a number of new [3.3.1]bicyclononane derivatives are described. Representative compounds include 1-cyano-3-methyl-4-hydroxybicyclo[3.3.1]nonan-9-one, 1-amino-3-methyl-4,9-dihydroxybicyclo[3.3.1]nonane, ethyl-7-methylbicyclo[3.3.1]non-3-en-9-one-1-carboxylate, as well as the following derivatives of ethyl-bicyclo[3.3.1]non-3-en-9-one-1-carboxylate: 1-aminobicyclo[3.3.1]non-3-en-9-one, ethyl-3-hydroxy-4-bromobicyclo[3.3.1]nonan-1-carboxylate, ethyl-4-bromobicyclo[3.3.1]nonan-3,9-dione-1-carboxylate and ethyl-bicyclo[3.3.1]nonan-3,9-dione-1-carboxylate. A Michael condensation of 2-cyanocyclohexanone with alpha-methyl acrolein afforded 1-cyano-3-methyl-4-hydroxybicyclo[3.3.1]nonan-9-one as a 1:1 complex. Acetylation furnished a mixture of the epimeric acetates, which were separated by fractional crystallization. Oxidation of 1-cyano-3-methyl-4-hydroxybicyclo[3.3.1]nonan-9-one converted it into 1-cyano-3-methylbicyclo[3.3.1]nonan-4,9-dione. Reduction of 1-cyano-3-methyl-4-hydroxybicyclo[3.3.1]nonan-9-one, then saponification of the nitrile group, followed by a Hofmann rearrangement of the amide gave 1-amino-3-methyl-4,9-dihydroxybicyclo[3.3.1]nonane. Several attempts were made to effect cyclization between alpha-methyl acrolein and 2-carbomethoxy-4-ethylenedioxycyclohexanone. However, the desired bicyclononane compound was not obtained. An alternative approach was also studied; alkylation using 1-chloro-2-methyl-3-bromopropane and 2-carboethoxycyclohexanone or 2-carbomethoxy-4-ethylenedioxy-cyclohexanone gave in both cases the C-alkylated product. Attempts to cyclize these compounds using a variety of methods gave predominantly 0-alkylated products. The base-catalyzed reaction between 2-carboethoxy-4-methylcyclohexanone and acrolein yielded beta-(1-ethoxycarbonyl-2-keto-5-methylcyclohexyl) propionaldehyde. Treatment of the latter with acid effected cyclization yielding ethyl-7-methylbicyclo[3.3.1]non-3-en-9-one-1-carboxylate. Ethyl-bicyclo[3.3.1]non-3-en-9-one-1-carboxylate was converted by the following steps: saponification of the ester, conversion of the acid into the acid azide, followed by rearrangement of the latter to the amine hydrochloride; addition of base liberated 1-aminobicyclo[3.3.1]non-3-en-9-one. Treatment of ethyl-bicyclo[3.3.1]non-3-en-9-one-1-carboxylate with N-bromosuccinimide in acid solution gave ethyl-3-hydroxy-4-bromobicyclo[3.3.1]nonan-1-carboxylate, which on oxidation furnished ethyl-4-bromobicyclo[3.3.1]nonan-3,9-dione-1-carboxylate. Reductive removal of the bromine with zinc-acetic acid gave ethyl-bicyclo[3.3.1]nonan-3,9-dione-1-carboxylate. Hydrolysis of the ester in the last compound gave the corresponding acid. Attempts to prepare 1-aminobicyclo[3.3.1]nonan-3,9-dione failed. Infrared and n.m.r. spectra were used extensively in the structure determination of these compounds as well as their by-products. The identity of all key-compounds was further corroborated by analytical data and ultraviolet spectra.