Design, Synthesis, and Applications of Chiral Spiroketal (SPIROL)-Based Ligands

C2-symmetric axially chiral scaffolds are of significant importance in asymmetric catalysis. Over the past two decades, several chiral spirocyclic scaffolds have demonstrated great promise in both transition metal catalyzed reactions and various organocatalytic transformations. This dissertation describes the development and exploration of two novel diastereomeric C2- symmetric spirocyclic scaffolds termed “SPIROL”s. These studies include the development of convenient, and concise syntheses of both (R,S,S)- and (S,S,S)-diastereomeric series of SPIROLs on decagram scale in a highly enantioselective and diastereoselective fashion. Thus, obtained chiral spiroketal cores are subsequently elaborated into different types of C2-symmetric ligands that are explored in various Ir-, Rh-, Pd-, and Cu-catalyzed asymmetric transformations. In these studies, SPIROLs demonstrated excellent selectivity profiles in all of the explored transformations, and the observed selectivities and yields indicate that SPIROLS hold great promise as the ligands for the asymmetric transition metal catalysis. Chapter 1 is an introduction and overview of recent developments with C2-symmetric spirocyclic ligands in the past five years. A summary of SPINOL-derived ligands and catalysts as well as SPIROL, O-SPINOL, aza-SPINOL and SPSiOL are included. Other interesting miscellaneous spirocyclic scaffolds are also presented in this chapter. Chapter 2 describes the design and development of novel C2-symmetric spirocyclic scaffold SPIROL, which is a major breakthrough for ligands since the discovery of SPINOL. Three steps from commercially available starting material efficiently and selectively assemble the spirocyclic core without need for the chiral resolution. Two structurally distinctive SPIROLs were produced from the same spirocyclic intermediate and independently exploited towards different ligands for future studies. SPIROL-derived ligands demonstrated good yields, excellent enantioselectivities and diastereoselectivities in many kinds of transformations. Chapter 3 describes the development of new SPIROL-based diphosphinite ligands (SPIRAPO) for iridium-catalyzed asymmetric reduction of aromatic heterocycles. A new ligand core with isopropyl substituent on the backbone was also synthesized and studied. Our results suggested that SPIRAPO ligand performed better than other privileged scaffold-derived phosphinites under mild reaction conditions. The ligand is also well tolerated all changes in the heterocycle substitutions and frameworks. Two diastereomeric SPIROL-based phosphinites are compared in this study, and we discovered new properties with SPIROL scaffolds since our last report. Chapter 4 describes the ongoing development of new SPIROL-based oxazoline ligands (SPIROX), and their applications in asymmetric insertion of copper carbenoids. The study showed excellent performance for the insertion into phenols, while unsatisfactory results were observed with silanes and anilines.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/170062/1/siyuans_1.pd