Electronic Thesis and Dissertation Repository

Thesis Format



Master of Science




Pagenkopf, Brian L.


The formation of carbon-heteroatom bonds is pivotal in obtaining structural frameworks present in a variety of important natural products and bioactive molecules. In that regard, Lewis-acid promoted cycloadditions of strained carbocycles have proven to be powerful tools for the construction of heterocyclic frameworks. The Pagenkopf group was the first to discover the cycloaddition of donor-acceptor (DA) cyclopropanes with nitriles. Since the strain energy of cyclobutane is comparable to that of cyclopropane, our group has sought to extend to the comparatively unexplored homologous cyclobutane scaffold. Disclosed here is the first [4+2] cycloaddition of nitriles with DA cyclobutanes via Lewis-acid activation. This work describes the synthesis of tetrahydropyridine derivatives in moderate to good yields. A variety of electronically diverse cyclobutanes engaged in [4+2] cycloaddition with both aliphatic and aromatic nitriles. Reduction of the cycloadduct affords substituted piperidine exclusively as the cis-2,6-diastereomer in excellent yield, and the cycloadduct also undergoes clean dealkoxycarbonylation.

Summary for Lay Audience

The formation of chemical bonds is pivotal in obtaining key structural frameworks present in a variety of important natural products and bioactive molecules. Strain-activated carbon ring systems have proven to be powerful building blocks in the field of synthetic organic chemistry. These compounds are strain-activated because they possess chemical bond angles that deviate from the favorable 109.5° tetrahedron bond angle. In this thesis, we use small strain-activated carbocycles that are endowed with chemical groups, that is, donor and acceptor groups, to further enhance their chemical reactivity. The donor and acceptor groups are attached adjacent to one another, and they hence facilitate bond cleavage between them to give a ring opened intermediate. This ring-opened form can subsequently go through a plethora of interesting reactions. These small strained-activated molecules have received rising research interest because of their ability to easily react with various partners to give new compounds or structural frameworks not easily synthesized. The current work investigated new compounds obtained from the reaction of these strain-activated carbocycles. The chemistry disclosed herein is a flexible method for the synthesis of valuable nitrogen-containing structures, such as tetrahydropyridines. Mechanistic insights are provided, and the synthetic potential of products was demonstrated. We expect that this chemistry can prove to be a useful tool in applications such as target-oriented synthesis of natural products and pharmaceutically important molecules.