The development of general, broadly applicable methods for antitumor quinone synthesis is proposed. Emphasis is placed on the use of organotransition metal chemistry in the development of the synthetic methods, because of the unique ability of transition metal species to facilitate the formation of carbon-carbon bonds under very mild conditions in the presence of sensitive organic functional groups, and because of the ability of transition metal species to stabilize reactive organic intermediates of use in synthetic transformations. A variety of objectives are met by this goal. Simple methods of quinone synthesis that allow flexible variation of the substitutents on the quinone core will facilitate the rapid study of structure-activity relationships of antitumor quinones. The chemistry developed throughout this proposal will also enable the synthesis of complex quinone based natural products to be tackled, and in so doing provide quantities of material needed for detailed biological assay. In a more general sense, the proposed chemistry provides a framework upon which new organic and organometallic reactions can be developed. For the forthcoming grant period, effort will be made in three distinct areas; organometallic development, organic development, and total synthesis. Development of the organometallic aspects of the project will focus on studies of metallacycles as precursors to quinones, phenols, and anilines, and the preparation and reactions of metal pi complexes of quinones quinols, and 6- oxohexadienyls (prepared by O-alkylation of quinone complexes) will be studied. Within the organic realm we will continue to develop very simple synthetic routes to cyclobutenediones and benzocylobutenediones. The cyclobutenedione chemistry has to led to simple thermal route to highly substituted quinones that presumable proceeds through vinylketene intermediates. The use of cyclobutenedione derivatives in the syntheses of phenols, anilines, and pyridones will be explored. Highly functionalized quinones should be useful for the synthesis of other types of complex molecules. Using traditional methods of synthesis, properly substituted quinones as starting materials for the preparation of other important compounds would be too difficult to prepare. However, many appropriately functionalized quinones are easily prepared from alkynes and maleoylcobalt complexes, so quinones synthesized via the chemistry developed in this proposal could become valuable precursors to other classes of compounds such as indoles. The total synthesis goals will center on completing the current approaches to the antitumor antibiotic royleanone and saframycin B. Other total synthesis goals will be chosen to (a) allow the preparation of substances for biological assay and to (b) provide a framework upon which we can continue to probe the development of our various routes to quinone based molecules. New and interesting organic and organometallic compounds will be sent to Dr. Terry Doyle, Director Antitumor Chemistry at Bristol-Myers, for biological assay.
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