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


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.


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.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:phosphonates, hydrogen-bond
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Dougherty, Dennis A.
Thesis Committee:
  • Stoltz, Brian M. (chair)
  • Dougherty, Dennis A.
  • Clemons, William M.
  • Grubbs, Robert H.
Defense Date:25 August 2011
Record Number:CaltechTHESIS:10112011-135016656
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6710
Deposited By: Sean Kedrowski
Deposited On:06 Jan 2012 22:27
Last Modified:03 Oct 2019 23:53

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