Potential antitumor agents. Synthesis, reactivity, and cytoxicity of alpha-methylene carbonyl compounds

The alpha-methylene lactones 9, 12, 21, and 24 were prepared by a mild, convenient alpha-methylenation process using the alpha-ethyloxalyl derivatives in nonoptimized yields ranging from 23 to 90%. The rates of reaction of these and several other lactones with cysteine at pH 7.4 and their KB toxicities were measured. These studies showed that neither the strained trans-fused alpha-methylene lactone 12 nor the hydroxy-alpha-methylene lactones 5 and 6 reacted with cysteine with rates comparable to elephantopin. Based on these limited studies, the rate of cysteine addition appears to be relatively insensitive to changes in strain energy and neighboring groups. In addition, the rate constant for reaction with cysteine did not correlate with cytotoxicity.