Doctor of Philosophy

dissertationDesign of synthetic strategies that allow facile access to a stereocenter in a catalytic fashion is highly desirable. This dissertation details the development of a palladium-catalyzed process that enables strategic coupling of alkenyl groups with multisubstituted alkenes in a highly enantioselective fashion to generate tertiary or quaternary allylic stereocenters. Chapter 1 focuses on the existing modern methods that allow incorporation of an alkenyl moiety in a catalytic and enantioselective manner. In Chapter 2, a palladium-catalyzed intermolecular enantioselective coupling of alkenyl triflates with acyclic primary or racemic secondary alkenols is described. Applying this strategy, a wide array of functionalized alkenyl groups can be installed at positions β, γ, or δ to a carbonyl group in high enantioselectivity. It is necessary to use electron deficient alkenyl triflates to direct selective β-hydride elimination and prevent catalyst arrest. To demonstrate the synthetic potential of this process, a two-step derivatization of the resulting Heck product led to the formation of a tricyclic core structure, present in various natural products. The application of the redox-relay Heck strategy to trisubstituted alkenes afforded the construction of quaternary stereocenters and is described in Chapter 3. Specifically, the reaction of terminal (E)-alkenyl triflates, in the presence of a Pd(0) catalyst and a chiral ligand leads to the formation of allylic quaternary stereocenters in high enantioselectivity. iv To further illustrate the synthetic applicability of this transformation, the alkene introduced in a chiral Heck product was readily processed via simple organic transformations to access remotely functionalized chiral tertiary alcohol, acid, and amine products. Finally, Chapter 4 explores the applicability of highly polarized alkenes as potential substrates in the redox-relay Heck reaction. A number of electron-deficient alkenyl triflates underwent selective coupling with acyclic aryl enol ethers in the presence of a chiral palladium catalyst to provide chiral allylic ether products in high yields and excellent enantiomeric ratio. Furthermore, the significance of this process was demonstrated through the formation of chiral allylic alcohol achieved via a simple cleavage of the p-methoxyphenyl moiety

Enantioselective Palladium-Catalyzed Alkenylation of Trisubstituted Alkenols To Form Allylic Quaternary Centers

In this report, we describe the generation of remote allylic quaternary stereocenters β, γ, and δ relative to a carbonyl in high enantioselectivity. We utilize a redox-relay Heck reaction between alkenyl triflates and acyclic trisubstituted alkenols of varying chain-lengths. A wide array of terminal (<i>E</i>)-alkenyl triflates are suitable for this process. The utility of this functionalization is validated further by conversion of the products, via simple organic processes to access remotely functionalized chiral tertiary acid, amine, and alcohol products

Palladium-Catalyzed Enantio­selective Heck Alkenylation of Acyclic Alkenols Using a Redox-Relay Strategy

We report a highly enantio­selective intermolecular Heck reaction of alkenyl triflates and acyclic primary or racemic secondary alkenols. The mild reaction conditions permit installation of a wide range of alkenyl groups at positions β, γ, or δ to a carbonyl group in high enantio­selectivity. The success of this reaction is attributed to the use of electron-withdrawing alkenyl triflates, which offer selective β-hydride elimination followed by migration of the catalyst through the alkyl chain to give the alkenylated carbonyl products. The synthetic utility of the process is demonstrated by a two-step modification of a reaction product to yield a tricyclic core structure, present in various natural products

Formation of Chiral Allylic Ethers via an Enantioselective Palladium-Catalyzed Alkenylation of Acyclic Enol Ethers

This report details a palladium-catalyzed process to access highly functionalized, optically active allylic aryl ethers. A number of electron-deficient alkenyl triflates underwent enantio­selective and site-selective coupling with acyclic aryl enol ethers in the presence of a chiral palladium catalyst. This transform provides chiral allylic ether products in high yields and excellent enantiomeric ratios, furnishing a unique disconnection to incorporate hetero­atoms at a stereo­center. Finally, the applicability of the products to target synthesis was demonstrated through the formation of a chiral allylic alcohol and the generation of a flavone-inspired product