Development of a Ni-Catalyzed Enantioselective Intramolecular Mizoroki- Heck Reaction for the Synthesis of Phenanthridinone Derivatives

<p>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. </p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Open Access

Discipline thesis:degree_discipline

Chemistry

Year

2024

Author dc:creator

• Rachii, Diana

Repository record dc:identifier

https://repository.brynmawr.edu/dissertations/260

OAI identifier oai:identifier

oai:repository.brynmawr.edu:dissertations-1263