Synthesis of Epidithiodioxopiperazine Analogues and the Development of a Copper-Catalyzed Stereodivergent 1,3-Dipolar Cycloaddition Reaction
- Author(s): Walton, Mary Catherine
- Advisor(s): Overman, Larry E
- et al.
In Chapter 1, epipolythiodioxopiperazine (ETP) natural products and a short synthesis of novel ETP analogues are introduced. Analogue synthesis and structure-activity relationship studies of their anticancer activity are described.
In Chapter 2, studies toward the development of a catalytic, diastereoselective, and enantioselective 1,3-dipolar cycloaddition (1,3-DC) reaction to improve upon the synthesis of ETP analogues are described. Over 75 different ligands were tested for their effectiveness in accomplishing this goal. A trend between catalyst electronic structure and the reaction diastereoselectivity was discovered where the use of an electron-deficient phosphite ligand resulted in a highly endo adduct-selective reaction. Alternatively, when a bulky electron-rich phosphine was used, the diastereoselectivity reversed to favor the exo cycloadduct.
In Chapter 3, the generality of the diastereodivergent 1,3-DC reactions are explored by investigating aryl imine starting materials with different electronic properties as well as different dipolarophiles. Computational studies performed by our collaborators at UCLA are also described. It was shown that methacrylonitrile is the ideal dipolarophile to exhibit the dramatic changes in diastereoselectivity depending on the ligand used in the catalytic 1,3-DC reaction.