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- All Subjects: Organic Chemistry
- Creators: Biegasiewicz, Kyle
- Resource Type: Text
TRPM8 is the primary cold sensor in humans and is activated by ligands that feel cool such as menthol and icilin. It is implicated to be involved in a variety of cancers, nociception, obesity, addiction, and thermosensitivity. There are thought to be conserved regions of structural and functional importance to the channel which can be identified by looking at the evolution of TRPM8 over time. Along with this, looking at different isoforms of TRPM8 which are structurally very different but functionally similar can help isolate regions of functional interest as well. Between TRP channels, the transmembrane domain is well conserved and thought to be important for sensory physiology. To learn about these aspects of TRPM8, three evolutionary constructs, the last common primate, the last common mammalian, and the last common vertebrate ancestor TRPM8 were cloned and subjected to preliminary studies. In addition to the initial ancestral TRPM8 studies, fundamental studies were initiated in method development to evaluate the use of biological signaling sequences to attempt to force non-trafficking membrane protein isoforms and biophysical constructs to the plasma membrane. To increase readout for these and other studies, a cellular based fluorescence assay was initiated. Eventual completion of these efforts will lead to better understanding of the mechanism that underlie TRPM8 function and provide enhanced general methods for ion channel studies.
Beyond TRPM8 studies, an experiment was designed to probe mechanistic features of TRPV1 ligand activation. TRPV1 is also a thermosensitive channel in the TRP family, sensing heat and vanilloid ligands like capsaicin, commonly found in chili peppers. This channel is also involved in many proinflammatory interactions and associated with cancers, nociception, and addiction. Better understanding binding interactions can lead to attempts to create therapeutics.
This thesis is about how Fe catalysts can be degraded using photocatalysis and how Fe catalysts can degrade small molecules in conjunction with light. The goal of this paper is to look further into more sustainable methods of organic chemistry. Many current organic chemistry practices involve the use of precious metals. Iron is a more sustainable catalyst because it is abundant and inexpensive which is important for preserving the earth and making the organic chemistry more accessible. Along the same lines, light is a renewable energy source and has demonstrated its ability to aid in reactions. Overall, the goal of this paper is to explore the more sustainable alternatives to harsh and toxic organic chemistry practices through the use of Iron and light.
Amidinates and guanidinates are promising supporting ligands in organometallic and coordination chemistry, highly valued for their accessibility, tunability, and comparability with other popular anionic N-chelating hard donor ligands like β-diketiminates. By far the most powerful way to access these ligands involves direct metal-nucleophile insertion into N,N’- substituted carbodiimides. However, the majority of reported examples require the use of commercially accessible carbodiimide peptide coupling reagents with simple alkyl substituents leading to low variation in potential substituents. Presented here is the design, synthesis, and isolation of a novel N,N’-bis[3-(diphenylphosphino)propyl]carbodiimide via an Aza-Wittig reaction between two previously described air stable substrates. At room temperature, 3-(diphenylphosphanyl-borane)-propylisocyanate was added to N-(3-(diphenylphospino)propyl)-triphenylphosphinimine, leading to product formation in minutes. One-pot phosphine-borane deprotection, followed by simple filtration of the crude mixture through a small, basic silica plug using pentane and diethyl ether granted the corresponding carbodiimide in high purity and yield (over 70%), confirmed by 1H, 13C, and 31P NMR spectroscopy. In addition to accessing different central carbon substituents, modification of phosphine substituents should be easily accessible through minor variations in the synthesis. With these precursors, anionic amidinates and guanidinates capable of κ4 -N,N,P,P-coordination may be accessed. The ability of the labile phosphine arms to associate and dissociate may facilitate catalysis. Thus, this carbodiimide provides a tunable, reliable one step precursor to novel substituted amidinates and guanidinates for homogeneous transition metal catalysis.
Chemistry has always played a foundational role in the synthesis of pharmaceuticals. With the rapid growth of the global population, the health and medical needs have also rapidly increased. In order to provide drugs capable of mediating symptoms and curing diseases, organic chemistry provides drug derivatives utilizing a limited number of chemical building blocks and privileged structures. Of these limited building blocks, this project explores Late–stage C–H functionalization of (iso)quinolines using abundant metal catalysis in order to achieve site-selective molecular modification.