Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Ellman, Jonathan
Abstract
Both transition-metal catalysis and photocatalysis are useful and versatile platforms for developing novel synthetic methodologies. The first two chapters of this dissertation will discuss the development of cobalt(III)-catalyzed C–H bond additions with dienes and carbonyls to access homoallylic alcohols. The third and fourth chapters describe the light-mediated, highly diastereoselective epimerization of saturated nitrogen heterocycles via reversible hydrogen atom transfer (HAT).Chapter 1 describes an efficient CoIII-catalyzed three-component strategy to prepare homoallylic alcohols containing acyclic quaternary centers is disclosed. This transformation enables the introduction of two C–C σ bonds through C–H bond activation and sequential addition to internally substituted dienes and a wide range of aldehydes and activated ketones. Isoprene and other internally monosubstituted dienes are effective inputs, with the reaction proceeding with high diastereoselectivity for those substrate combinations that result in more than one stereogenic center. Moreover, the opposite relative stereochemistry can be achieved by employing 1,2-disubstituted dienes. A mechanism for the transformation is proposed based upon the relative stereochemistry of the products and studies with isotopically labeled starting materials. Chapter 2 describes a highly diastereoselective three-component C–H bond addition across butadiene and ketones is described. This transformation provides homoallylic tertiary alcohols through the formation of two C–C σ bonds and with complete selectivity for an E-alkene isomer. The reaction exhibits good scope with respect to activated ketone inputs, including highly strained cyclic and electron-deficient cyclic and acyclic ketones. Additionally, high diastereoselectivities were achieved for alcohols prepared from unsymmetrical ketones. Chapter 3 describes a combined photocatalytic and HAT approach for the light- mediated epimerization of readily accessible piperidines to provide the more stable diastereomer with high selectivity. The generality of the transformation was explored for a large variety of di- to tetrasubstituted piperidines with aryl, alkyl, and carboxylic acid derivatives at multiple different sites. Piperidines without substitution on nitrogen as well as N-alkyl and aryl derivatives were effective epimerization substrates. The observed diastereoselectivities correlate with the calculated relative stabilities of the isomers. Demonstration of reaction reversibility, luminescence quenching, deuterium labeling studies, and quantum yield measurements provide information about the mechanism. Chapter 4 describes the first photocatalyzed epimerization of morpholines and piperazines. This method proceeds by reversible HAT and provides an efficient strategy for editing the stereochemical configurations of these saturated nitrogen heterocycles, which are prevalent in drugs. More stable morpholine and piperazine isomers are obtained from synthetically accessible but less stable stereoisomers, and a broad scope is demonstrated in terms of substitution patterns and functional group compatibility. The observed distributions of diastereomers correlate well with the calculated relative energies of the diastereomer pairs. Mechanistic studies, including luminescence quenching, deuterium labeling reactions, and determination of reversibility support a thiyl radical mediated HAT pathway for epimerization. Investigation of piperazine epimerization led to the development of new thiol free conditions for the highly stereoselective epimerization of N,N’-dialkyl piperazines.
Recommended Citation
shen, zican, "Co(III)-Catalyzed Synthesis of Homoallylic Alcohols and Light-Mediated, Highly Diastereoselective Epimerization of Saturated N-Heterocycles" (2022). Yale Graduate School of Arts and Sciences Dissertations. 699.
https://elischolar.library.yale.edu/gsas_dissertations/699