Date of Award

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Vyacheslav V. Samoshin

First Committee Member

Jianhua Ren

Second Committee Member

Andreas Franz

Third Committee Member

Liang Xue

Fourth Committee Member

Mamoun Alhamadsheh

Abstract

Natural products have been demonstrated to be of great significance to the pharmaceutical industry in the development of new drugs and medicine. Unfortunately, synthetic approaches to obtain these natural products often prove increasingly challenging due to the complexity of synthesizing the target drug in the proper stereochemistry. The availability of enantioselective reactions can play a pivotal role in overcoming this challenge, yielding access to optically pure intermediates and products. Chiral ligands based on a trans-1,2-diaminocyclohexane motif are often employed for this purpose and their complexes with transition metals have been demonstrated to act as efficient chiral catalysts in asymmetric reactions. In contrast, studies involving cis-1,2-diaminocyclohexane derivatives as chiral catalysts are strongly underrepresented.

We have designed and performed the synthesis of an axially chiral conformationally locked cis-1,2-diamine scaffold, conveniently designed for further derivatization into more complex structures. A key step in this synthesis was the chiral resolution of a racemic intermediate, realized through both chemical and enzymatic means in a comparative study. Utilizing the newly gained optically pure primary diamine scaffold, a library of chemically diverse secondary diamine ligands has been synthesized and characterized through NMR spectroscopy, mass spectrometry, and chiral HPLC. Assignment of the absolute configuration within the cis-1,2-diamine scaffold was realized through single-crystal X-ray crystallography experiments on one of the synthetic intermediates.

The synthesized ligands have been evaluated for their potential to function as chiral catalysts in the asymmetric Henry reaction and asymmetric transfer hydrogenation. As a function of both steric and electronic structural variation, a range of catalytic activities and enantioselectivities in the Henry reaction were observed. The ligands proved to be less suitable for asymmetric transfer hydrogenation with only a select number of ligands catalyzing the reaction, and a single example resulting in a decent enantioselectivity.

We additionally explored the possibility of incorporating a chemical switch into the scaffold, responsible for switching the axial chirality of the molecule. As a consequence of inverting the axial chirality, the configuration of the potential reaction product in asymmetric synthesis would also be inverted. To this extent, we performed the synthesis of a novel specifically designed crown ether, dicyclohexeno-18-crown-6, furnished with two π-bonds in the cyclohexane rings, allowing for additional modification into more advanced functionalized structures.

Pages

254

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