This proposal describes the development of new catalytic methods for the enantioselective formation of stereochemically and structurally diverse 1,4-oxygenation patterns. The application of these new methodologies to the asymmetric synthesis of complex natural products is also detailed. Four distinct projects are proposed: (a) development of a method for the enantioselective desymmetrization of symmetrical 1,3-dienes to produce gamma-hydroxyenones, (b) development of an enantioselective addition of organometallic nucleophiles to endoperoxides and 1,2-dioxins for the synthesis of differentially substituted 1,4-oxygenated products, (c) application of these methods to the synthesis of illudin C, a member of a family of cytotoxic natural products, and (d) the utilization of the methods developed for the asymmetric 1,4- dioxygenation of dienes to the synthesis of the actinobolin antitumor antibiotics. In addition to the research training directly associated with the proposed program, the development of an advanced organic chemistry class and the ongoing development of a general chemistry class for undergraduates are planned. In the former, the use of the chemical literature as a means to create a student derived advanced organic "text-book" is presented.
With the support of this CAREER award from the Organic and Macromolecular Chemistry Program, Professor Dean Toste, of the Department of Chemistry at the University of California at Berkeley, is developing novel methods to convert simple molecules into functionally and structurally complex products. In addition, the synthesis of several new catalysts that may prove broadly applicable is targeted. A key component of the project is the application of new reaction methodology to the construction of complex natural products, including antitumor antibiotics, in a highly expeditious manner, allowing for access to these molecules and related analogues in large quantities. The proposed research will not only provide access to these biologically active molecules, but will also provide synthetic chemists with new selective methods for the construction of carbon-oxygen bonds. In addition to the research training directly associated with the proposed program, development of new courses and course materials is targeted, including the use of the chemical literature as a means to create a student derived advanced organic "text-book."