Date of Award

May 2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John D. Chisholm

Subject Categories

Physical Sciences and Mathematics

Abstract

Herein is disclosed accounts of fundamentally different projects. The focus of this research enveloped the development of synthetic methods to access structurally complex small molecules, especially in the realm of C–C and C–N bond formations. The scope of reactions discussed revolve especially around ruthenium and palladium catalysis, accessing underexplored heterocyclic motifs. The utility of these techniques toward the synthesis of small molecules in drug discovery cannot be understated, as there are few ways to access these elusive moieties. The content is divided into the following four chapters:

The development of methods for the stereoselective synthesis of polysubstituted 1,3-dienes is a challenge to synthetic chemistry. Herein is reported a selective approach for the synthesis of polysubstituted 1,3-dienes using the ruthenium hydride catalyzed intramolecular silylvinylation of alkynes under 80 psi of ethylene gas. This strategy affords a single diene isomer, is applicable to substrates with aryl and alkyl substitution at the propargyl and homopropargyl positions, and has been utilized in the synthesis of 5- and 6-membered oxasilacycles.

N-Substituted-3-amino-4-halopyridines are valuable synthetic intermediates, as they readily provide access to imidazopyridines and similar heterocyclic systems. The direct synthesis of N-substituted-3-amino-4-halopyridines is problematic, as reductive aminations and base promoted alkylations are difficult in these systems. A high yielding deprotection/alkylation protocol mediated by trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate is described, providing access to a wide scope of N-substituted-3-amino-4-halopyridines. This

protocol furnishes many reaction products in high purity without chromatography. Similar reductive amination conditions were also established for deactivated anilines.

An amidation/cyclization approach for the synthesis of chlorinated imidazopyridines from 3-amino-polychloropyridines has been developed. Chlorinated imidazopyridines are often utilized in pharmaceutical settings as scaffolds for the discovery and optimization of biologically active small molecules, as they can be rapidly elaborated to explore chemical space. Regioselective alkylation of the imidazole ring of unsubstituted imidazopyridines is often problematic, however, with poorly selective alkylation conditions providing mixtures which are difficult to separate. This new method allows for regioselective access of chlorinated imidazo[4,5-b]pyridines from inexpensive and readily available 2-chloro-3-aminopyridine precursors.

Bosutinib is a drug developed by Pfizer in 2012 for the treatment of late stage chronic myeloid leukemia (CML). Bosutinib acts as a Src selective non-Receptor Tyrosine Kinase (nRTK) inhibitor, and it has also shown inhibition of breast and prostate cancer cells and suppression of solid tumors. Until recently, Src was originally thought to exist only within the cell cytoplasm. Herein is demonstrated the synthesis of a series of bosutinib probes for drug action studies to better understand the role of Src inhibition in the suppression of cancer cells.

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