Investigation of N-sulfonyliminium Ion Triggered Cyclizations for the Synthesis of Piperidine Scaffolds
Date of Award
Honors College Thesis
Chemistry and Biochemistry
Matthew Donahue, Ph.D.
Chemistry and Biochemistry
In consideration of the on-going global pandemic, immediate access to Food and Drug Administration approved pharmaceutical medications and vaccines is a matter of utmost priority to our national healthcare system. One significant modality in managed care is the dispensation of prescription drugs for the prevention or treatment of illnesses and diseases. According to the Centers for Disease Control and Prevention, physicians order and provide over 2.9 billion prescriptions each year with analgesics, antihyperlipidemics, and dermatological agents being the most prescribed therapeutic classes. Within those classes exists a disparate variety of chemical structures that must be prepared on a metric ton scale to meet the continual societal demand.
The piperidine scaffold is very prevalent in many FDA approved drugs, making it an important pharmacophore and essential in the field of drug discovery. Piperidines are the building blocks for over 70 different types of commercial drugs, such as Ritalin and Evista. The complexity of these structures along with the economic costs of sourcing all the raw materials is a contributing factor to the increasing burden of prescription drug costs. Therefore, by developing new chemical reactions to access the piperidine scaffold, the economic and chemical challenges can be effectively managed to ensure healthcare demands are met. The overarching goal of this project is to develop a robust catalytic, asymmetric synthesis of piperidine rings from feedstock petrochemicals.
In an initial study of the N-sulfonyl iminium ion Pictet-Spengler cyclization with N-para-toluenesulfonyl homoveratrylamine and 3-phenylpropanal, a screen of metal triflates was examined. The hypothesis is that transition metal triflates are sufficiently Lewis acidic to activate relatively inert sulfonamide nitrogen atoms to condense with aldehydes and trigger the intramolecular cyclization forming piperidines. Initial results indicated that scandium (III), stannous (II) and copper (II) triflates gave the fastest conversion to the N-sulfonyl piperidine, while triflates such as lanthanum (III), sodium (I) and magnesium (II) gave little to no conversion under the allotted time. Further examinations were made to study the steric effects of the aldehyde carbon chain and hybridization, as well as the N-sulfonyl group substituent on cyclization conversion. A second acid catalyst screen was conducted of the N-sulfonyl iminium ion Aza Prins/Ritter reaction with N-sulfonyl homoallylic amine and 3-phenylpropanal to observe the difference between Bronsted acids and Lewis acids on cyclization conversion.
The fundamental investigation of chemical reactivity for the synthesis of nitrogen heterocycles from petroleum feedstocks has significant impact on societal healthcare needs. The control of reaction variables such as catalyst and ligand architectures in asymmetric transformations increases our understanding of interactions at the atomic level. Additional studies have focused on the use of chiral ligands, such as PyBOX ligands to induce asymmetry in the cyclization event. When screened against N-para-toluenesulfoyl homoveratrylamine with the successful metal triflates (scandium (III) and copper (II)) under various solvents, preliminary results showed no conversion towards the piperidine product. Future studies will focus on examining the kinetics of chiral ligand mechanisms and increasing the reactivity of iminium ions.
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Birkhoff, Kaitlyn, "Investigation of N-sulfonyliminium Ion Triggered Cyclizations for the Synthesis of Piperidine Scaffolds" (2021). Honors Theses. 817.