Cycloaddition Reaction.

We report the development of a general route to the synthesis of [4.3.1], [3.3.1],
an especially [3.2.1] bicyclic compounds structurally related to vitisinol D, a natural
product. This allows for diastereoselective synthesis of bicyclic compounds with
five adjacent chiral centers. This route was employed in a preliminary SAR
investigation into the neuroprotectant effect of small molecules in an in vivo
experiment measuring the degree of restorative effect of synaptic transmission in
the neuromuscular junction of Drosophila melanogaster larvae under acute
oxidative stress. One of the compounds exhibited intriguing potential as a
neuroprotectant and outperformed resveratrol in restoring synaptic function under
oxidative stress. The hypothesis that bridged bicyclic compounds may hold promise as drug scaffolds due to their conformational rigidity and ability to orient
functional appendages in unique orientations is developed.
The second focus is a mechanistic investigation into a tetrabutylammoniumcatalyzed
cycloaddition as evidence of a novel ammonium-alkyne interaction. A
carbamate nitrogen adds to a non-conjugated carbon–carbon triple bond under the
action of an ammonium catalyst leading to a cyclic product. Studies in
homogeneous systems suggest that the ammonium agent facilitates cyclitive
nitrogen–carbon bond formation through a cation–π interaction with the alkyne
unit. Using Raman spectroscopy, this cation–π interaction is directly observed for
the first time. DFT modeling elucidated the mechanistic factors in this
cycloaddition.
A teaching experiment was developed based on this mechanistic investigation.
Control experiments were employed to demonstrate the testing of two alternative
mechanistic hypotheses. Cyclization reactions were performed with a soluble base
(sodium phenoxide) with and without tetrabutylammonium bromide under
homogeneous conditions. Students observed that ammonium salt accelerates the
reaction. They were encouraged to develop a testable hypothesis for the role of
the ammonium salt in the cyclization mechanism: typical phase transfer or other.
IR spectroscopy was used to directly observe a dose dependent shift of the alkyne
stretching mode due to a cation−π interaction. Undergraduates were able to
employ the scientific method on a contemporary system and see how data are
generated and interpreted to adjudicate between rival hypotheses in a way that
emulates authentic and current research in a lab setting.

The present thesis will be largely focused on identifying and understanding the scope and mechanistic details associated with the tetrabutylammonium fluoride (TBAF) mediated cyclization of alkynyl hydrazines and (O)-hydroxylamines. Also, the synthesis of 2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid (CMPF) and its analogs will be discussed along with an analysis of their effects on insulin secretion.
Chapter 1 will present the importance of developing isoxazoline and pyrazoline type heterocycles given that they are continually demonstrated to possess a variety of biological activities. Further, the scope of the reaction in terms of functional group tolerability, scalability and mild conditions will be shown. To expand the importance of this work, a route to access non-racemic heterocycles is also noted. With the heterocycles in hand, new methods were developed to generate more complex frameworks in the form of a novel one pot deprotection/functionalization reaction. Chapter 2 will focus on mechanistic investigations of the cyclization. From the initial discovery of the reaction, its actual mechanism was unknown and a main point of interest. What appeared unusual is that a nucleophilic attack occurs on an unactivated triple bond. Given the identity of the products, a reasonable proposal was a 5-endo-dig type cyclization. However, such a pathway would result in the generation of a vinyl anion intermediate which is well known to be of very high energy and it would seem unlikely to occur under mild conditions. Various trapping experiments were used to demonstrate that the vinyl anion forms and a 5-endo-dig-cyclization is the operative mechanism.
Chapter 3 analyzes the importance of the tetrabutylammonium fluoride reagent. During optimization studies, it became clear that this base is the ideal reagent to facilitate the cyclization although other bases can also enable the transformation at much slower rates. Addition of non-basic ammonium salt additives to bases such as KF and CsF had a dramatic effect on the rate of the reaction. To determine whether the observed rate differences were merely a phase transfer effect or something more, both empirical and Raman spectroscopy data were collected. Based on this, the first evidence for an ammonium-alkyne cation-pi type interaction was shown.
Chapter 4 will summarize the work on the synthesis of 2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid (CMPF) and its analogs in order to be used in various biological assays. The main goals were to determine a possible structure activity relationship between the substrates and insulin secretion in beta cells and also determine the fate of CMPF in vivo. Several 13C labeled analogs of CMPF were synthesized and successfully used to show for the first time that CMPF in metabolized in vivo in mice.