This project is focused on the discovery of new stereoselective radical cyclizations in the context of three alkaloid total syntheses. Synthetic methods that are applicable to substrates adorned with numerous stereocenters and functional groups are extremely valuable to researchers engaged in the synthesis of complex organic molecules. One way to ensure that new methodology is compatible with challenging substrates is to incorporate the reaction development studies into the total synthesis of a natural product. Accordingly, three novel radical cyclizations, each of which creates two stereocenters, will be investigated in the course of synthesizing the alkaloids acutumine, lyconadin A, and hirsutellones A/D. A radical?polar crossover reaction consisting of an intramolecular aryl radical conjugate addition followed by enolate formation and hydroxylation will be explored during the acutumine synthesis. The centerpiece of the lyconadin A synthesis is a tandem process featuring a 7-exo acyl radical cyclization. The synthesis of the hirsutellones will be used as an arena for developing a 12-endo acyl radical macrocyclization. Radical cyclizations have been selected for study because the mild reaction conditions and potential for cascade transformations render them attractive to synthetic chemists.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Steven L. Castle of the Department of Chemistry and Biochemistry at Brigham Young University. Professor Castle's research efforts revolve around the development of new radical cyclizations. This chemistry employs mild reaction conditions, which allow for compatibility with many sensitive functional groups that are present in organic molecules. Successful development of the methodology will positively impact researchers reliant upon chemical synthesis, such as those working in the pharmaceutical, agrochemical, and materials (polymer) industries.
