Molecular design [electronic resource] : part I, synthesis of cyclooctatetraenes as ligands for catalysis; part II, studies on the C1B binding domain of protein kinase C

The concepts of molecular analysis and design bring together structure, mechanism, and synthesis into a useful whole by allowing them to work toward a common goal. This thesis explores these concepts in two major subject areas: New Reactions and Protein/Ligand Interactions. In the first subject area, this work explores a major goal of organic synthesis, the realization of functional value of a molecular target via step economy. Indeed step economy dictates all other economies and costs including time, waste stream, and environmental goals. Improving known reactions is an important part of advancing synthesis. Of even greater consequence is the introduction of new reactions as they change how we think about bond construction. New reactions offer new ways to reduce step count and more effective and environmentally sound process options. This thesis work focuses on new reactions, new scaffolds, novel ligands for catalysis, and computational studies on these to advance this first subject area. In the second subject area, this work investigates protein/ligand interactions in the context of a cooperative project involving protein kinase C ligands. Molecular design and analysis have been fundamental in the development and implementation of this new project. This exciting area of impactful research is expected to provide numerous opportunities for further exploration. In Chapter 1, cyclooctatetraenes (COTs) are introduced as a fascinating class of molecules with great potential utility as building blocks for synthesis, scaffolds for drug discovery, ligands for catalysis, components for molecular detection devices, and novel materials. After discussing the synthesis, properties and applications of COTs, a discussion on metal-bound COTs is presented. This discussion is followed by a comprehensive critical review of the literature involving 1,2,5,6-4 COT ligands in transition metal complexes. This chapter provides background and justification for the further studies on the synthesis and use of COTs explored in Chapters 2-4. Chapter 2 describes the development of the Ni(0)-catalyzed [2+2+2+2] cycloaddition from tethered diynes that has made possible the synthesis of functionalized COTs. The initial design and development work is addressed, including the impact of important reaction variables. This is followed by an exploration of the substrate scope, including the syntheses of highly substituted COTs from non-terminal diynes to give highly substituted COTs. Studies on the physical properties and structure of these molecules are also addressed in the form of NMR experiments and X-ray crystallographic studies. Lastly, an approach toward the COT-containing natural product caulerpin utilizing the methodology is presented. This chapter provides the foundation for the COTs utilized in Chapters 3 and 4. Chapter 3 explores the use of the method developed in Chapter 2 toward metal binding ligands. A rational analysis of the COT scaffold is presented, with an emphasis on the synthesis of C2-symmetric ligands for metals. This is followed by the discussion of the synthesis and evaluation of two different ligand families encompassing 4 ligands in total. Important structural aspects of these ligands are investigated including advanced NMR and crystallographic studies. These ligands represent the first examples of topologically chiral racemic COTs used to coordinate metals through appended functionality. Initial successes and modeling studies in this area of metal-ligand binding led to the inspiration for the COTs and strategy utilized in Chapter 4. Chapter 4 is focused on the development of novel dinaphthocyclooctatetraene (dnCOT) Rh catalysts, and the resulting [5+2] cycloaddition studies. Initial unsuccessful results with COTs from Chapter 2 prompted a detailed analysis of factors involved in COT-metal bonding, including the development of a theoretical method for the prediction of COT geometries. This design-related work in turn guided the efficient synthesis of the dnCOT ligand. In addition, an expedient route to diversified dnCOTs was developed via a common bromide intermediate. The further development of dnCOT as a ligand for Rh included extensive characterization of the ligand and resulting Rh complexes in the form of crystallographic and NMR studies. Following these studies, the use of the Rh/dnCOT complex as a catalyst is examined in the context of the [5+2] cycloaddition. It was found that this species is an excellent catalyst for the reaction featuring superior reactivity in several cases when compared with other catalysts. The behavior of this catalyst was also investigated with respect to regioselectivities. The use of the Rh/dnCOT complex has also been briefly explored as a catalyst for other reactions. Finally, Chapter 5 examines the design and early implementation of a collaborative project involving protein kinase C (PKC) C1b domain ligands and REDOR NMR techniques. An introduction to PKC, bryostatin and REDOR NMR is given, followed by the overall project strategy. The design of NMR-labeled analogs of bryostatin is discussed in detailed, including computational studies used to help guide synthetic efforts. Preliminary work on elucidating the structure of the PKC/bryostatin complex is discussed in the form of docking studies to be integrated with experimental NMR data. The successful synthesis of one of the key labeled analogs designed in the previous sections, labellog 8, is described. Lastly, future directions for this promising project are explored.

Keywords: Chemistry
Advisor: Wender Paul A. primary advisor. Thesis advisor
Du Bois Justin advisor. Thesis advisor
Kool Eric T. advisor. Thesis advisor