I. Chemical-Scale Studies of Ligand-Gated Ion Channels, and II. Novel Methods for Phosphonate Synthesis

Citation

Kedrowski, Sean M. A. (2012) I. Chemical-Scale Studies of Ligand-Gated Ion Channels, and II. Novel Methods for Phosphonate Synthesis. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/RQ16-6C44. https://resolver.caltech.edu/CaltechTHESIS:10112011-135016656

Abstract

Section 1: Chemical-Scale Studies of Ligand-Gated Ion Channels : Ligand-gated ion channels are amazing molecular machines that respond to specific small-molecule agonists by opening a central pore to enable ions to flow through them. In the aggregate, they transduce chemical signals into electrical currents, and they have numerous critical physiological functions. The tools of pharmacology and unnatural amino acid (and hydroxy acid) mutagenesis enable us to study these receptors on an atomic level. Two such projects are presented here. First, the synthesis of a new 5-HT3 receptor agonist helps to map the receptor’s binding site. Second, mutant cycle analysis in the nicotinic acetylcholine receptor with the novel unnatural residue α-hydroxyserine (Sah) enables the identification of a crucial hydrogen bond whose formation is part of the pathway leading from acetylcholine binding to pore opening.

Section 2: Novel Methods for Phosphonate Synthesis : Phosphonates are a key functional group in both organic synthesis and biological chemistry. The Arbuzov reaction stands as dominant method available for synthesizing this important class of compounds. Two new methods for phosphonate synthesis are presented here. The first method enables room-temperature phosphonate synthesis from carboxylic acids, taking advantage of a novel Wolff-Kishner-type reductive deoxygenation of an intermediate acyl phosphonate. The second method enables phosphonate synthesis through the reductive coupling of ketones/aldehydes with dialkyl phosphites, mediated by a tosylhydrazone derivative. The latter method requires only mild heating (60 °C) and enables access to phosphonates containing azides, benzyl halides, and other functional groups poorly tolerated by the Arbuzov onditions.

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