Chemistry and Chemical Biology ETDs

Publication Date

Summer 7-15-2019

Abstract

Alkenes serve as one of the most important feedstocks for organic synthesis, having two vicinal sites for bond formation. In alkenes, both vicinal sites can be functionalized with two reagents in a process commonly known as alkene difunctionalization, which results in the formation of two new bonds. A number of alkenes difunctionalization reactions, such as diamination, dioxygenation, carboamination and carbooxygenation, are known. However, difunctionalization of alkenes with two carbon-based entities, termed alkene dicarbofunctionalization, is relatively less common. Development of such a process could provide a powerful method to introduce two different carbon fragments across an alkene in a regioselective manner, enabling a modular, convergent and expedient synthesis of complex structural cores prevalent in pharmaceutical and natural products. In this dissertation, we describe the discovery and development of two novel Ni-catalyzed alkene dicarbofunctionalization reactions.

The first part of my dissertation focuses on the development of three-component Ni-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arylzinc reagents. This reaction enables the successful addition of primary, secondary and tertiary alkyl halides, and arylzinc reagents across the alkenes in vinylarenes in a highly regioselective manner. The reaction also shows a high degree of functional group tolerance. Detailed mechanistic investigations by quantitative kinetics, competition studies, and radical probes indicate that this reaction proceeds by a single electron transfer (SET) process with the direct halogen atom abstraction from alkyl halides by a Ni-catalyst being the rate limiting step. We have also demonstrated the application of this novel reaction in the synthesis of a precursor of Zoloft (an antidepression drug) and in the late-state synthesis of a potential FLAP inhibitor and its analogs.

The second part of my dissertation describes a Ni/terpyridine-catalyzed two-component cyclization/coupling reaction of alkene tethered to alkyl halides with arylzinc reagents. This reaction enabled us to synthesize a large number of complex carbo- and N and O-based heterocycles, which are prevalent in bioactive natural products and pharmaceutically relevant molecules. We further applied this new cyclization/coupling method to the concise synthesis of six bioactive lignan natural products containing three different structural frameworks. The synthesis of these natural products can also be performed in gram-scale quantities. We also conducted mechanistic investigations through competition studies and radical probes, which indicated that the current reaction proceeds via Ni(I)/Ni(III) catalytic cycle in an analogous manner to the well-known Ni/terpyridine-catalyzed Negishi cross-coupling reaction.

Project Sponsors

University of New Mexico

Language

English

Keywords

Alkene Dicarbofunctionalization, Organic Chemistry, Synthesis, Nickel chemistry, Natural Products

Document Type

Dissertation

Degree Name

Chemistry

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Ramesh Giri

Second Committee Member

Yang Qin

Third Committee Member

Mark Chalfant Walker

Fourth Committee Member

Rodolfo Tello-Aburto

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