Degree Date

2024

Degree

Doctor of Philosophy (PhD)

Department

Chemistry

Abstract

The Birch reduction-alkylation coupled to the desymmetrizing Mizoroki-Heck reaction is a novel synthetic tool to form potentially bioactive phenanthridinone analogs from inexpensive and easily available starting materials. This work describes a rare example of the direct replacement of palladium for nickel in our previously reported enantioselective intramolecular Heck reaction. A Ni-catalyzed enantioselective intramolecular Mizoroki-Heck reaction has been developed to transform symmetrical 1,4- cyclohexadienes with attached aryl halides to phenanthridinone analogs containing quaternary stereocenters. Moreover, this approach provides direct access to six-member ring heterocyclic systems bearing all-carbon quaternary stereocenters, which have been much more challenging to form enantioselectively with nickel-catalyzed Heck reactions. The first part of this project describes important advances in reaction optimization enabling control of unwanted proto-dehalogenation and alkene reduction side products. The second section focuses on the development of enantioselective strategy with a newly synthesized chiral iQuinox-type bidentate ligand. In the third section, we describe efforts to explore the substrate scope and to subsequently transform the 1,3-diene Heck products into molecules with potentially greater therapeutic relevance. In the last project chapter, mechanistic investigations and a computational study of the key 1,2-migratory insertion step shed light on the catalytic cycle and the basis for the enantioselectivity. Altogether, this work presents a very attractive alternative to the palladium-catalyzed process and should facilitate the application of Ni catalysis to traditional Heck transformations.

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