SYNTHESIS OF ANTITUMOR AGENTS

点击翻译按钮获取中文摘要

The chief objective this proposal is to investigate the scope and applicability of several reactions of transition metal carbene complexes in organic synthesis and to employ them in the synthesis of members of two families of antitumor agents. A tandem Diel-Alder/cyclohexadienone annulation sequence is proposed for development of a synthetic approach to the norditerpene dilactones wentilactone A, nagilactone F, nagilactone D, and podolide. This would be the first general synthetic approach to this family of compounds and should be flexible enough to allow for the preparation of members with a diversity of functionality. A synthetic route to the pseudoquaianolides is proposed that involve as the key step a cyclopropanation reaction of carbene complexes and the synthetic target in this class of compounds is the antitumor agent helenalin. Among some of the other objectives are the development of a synthetic route to the prostaglandins which will be illustrated by the synthesis of PGE2 and involves the cyclopropanation reactions of carbene complexes. The prostaglandin family has a remarkably broad range of physiological effects and special interests have been focused on inflammation, reproduction, and allergic responses. The chemistry that makes this approach possible was an outcome of the work directed to the synthesis of the antitumor agent helenalin. The efforts on the synthesis of helenalin also has lead to a new approach to the synthesis of pyridoxine which in pyridoxal phosphate, its active form, serves as cofactor for the great majority of enzymes catalyzing chemical changes in alpha- amino acids. Finally, new approaches to asymmetric aldol, Diels- Alder and Claisen reactions mediated by transition metal carbene complexes will be investigated. The latter will be a general study that is warranted by the important position that these reactions hold in traditional synthetic organic methodology.