The overal objectives of this proposal are to develop new synthetic methods for the synthesis of the neolignan antitumor agent, Megaphone, the antileukemic agent, Sergeolide, and a general class of chiral butyrolactones containing thiophenyl and halogen substituents. This last class of compounds can functions as latent alkylating and acylating agents for cancer chemotherapy. The molecule, Sergeolide, is a representative of a new type of quassinoids, a class of natural products that already has one candidate, Bruceantin, in clinical trials at NCI. Sergeolide contains the new feature of an enol butenolide ring which chemically behaves as a bis-alkylating agent. This proposal will provide direct and efficient methodology to prepare this new functionality in order to probe its effectiveness in the chemotherapy of cancer. All of our simple lactones and many of the synthetic intermediates will be tested for activity at NCI and/or Warner-Lambert Research Laboratories in Ann Arbor.