Dimethyl Sulfoxide → 6-Methoxytetrahydropyran-3-carboxylic acid

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Reaction Steps

Dimethyl 4,4-dimethoxybutane-1,1-dicarboxylate was prepared by the Michael addition of dimethyl malonate to acrolein followed by acetalization. Subsequent hydroxymethylation with formaldehyde in the presence of potassium hydrogen carbonate gave nearly quantitatively dimethyl 1-hydroxy-5,5-dimethoxypentane-2,2-dicarboxylate. This compound rapidly underwent acid-catalyzed intramolecular cyclization in a dilute solution in benzene, aided by the favored six-membered ring formation, to yield dimethyl 6-methoxytetrahydropyran-3,3-dicarboxylate. The tetrahydropyran derivative was saponified to the free dicarboxylic acid, which was then decarboxylated in diglyme or dimethyl sulfoxide at 120°-140° C. to give 6-methoxytetrahydropyran-3-carboxylic acid as a stereoisomeric mixture in a quantitative yield. The carboxylic acid was then heated in a dilute solution in toluene in the presence of a catalytic amount of p-toluenesulfonic acid to give the desired bicyclic lactone (I). The overall yield based on acrolein was approximately 20%.

Provenance & Evidence