Glutarimide Antibiotics. XI. A Total Synthesis of dl-α-Epiisocycloheximide

A stereoselective synthesis of dl-α-epiisooycloheximide (III) is described. Oxalylation of dl-cis-2,4-dimethylcyclohexanone gave the 6-oxalyl ester which spontaneously decarbonylated on distillation. The product ethyl cis-2,4-dimethylcyclohexanone-6-carboxylate was transformed into the benzyl ester and the latter was then converted to its magnesiobromide salt. Acylation of this salt with 3-glutarimidylacetyl chloride, followed by reductive debenzylation and decarboxylation, afforded dl-dehydroisocycloheximide (V). Catalytic reduction of this compound led to the diol XIII which was selectively chloroacetylated at its side-chain hydroxyl group. Oxidation of the ring hydroxyl of the resulting hydroxy chloroacetate (XIV, Rʹ = COCH₂Cl) yielded the ketone XV (Rʹ = COCH₂CI) and mild saponification of the latter afforded dl-α-epiisocycloheximide (III). The stereochemistry of the intermediates was proved largely by nmr spectroscopy. The relative orientation of the side-chain hydroxyl group of III was deduced by a stereochemical argument involving the facts that diol XIII forms an acetonide, whereas the diol XXIV obtained from III by lithium aluminum tri-t-butoxyhydride reduction does not.