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Title page for ETD etd-06262014-154830

Type of Document Dissertation
Author O'Reilly, Matthew Charles
Author's Email Address matthew.c.oreilly@vanderbilt.edu
URN etd-06262014-154830
Title Application of Organocatalysis to the Synthesis of Chiral Morpholines, Piperazines, Aziridines, Azetidines, beta-fluoroamines, and gamma-fluoroamines; Discovery of Selective Phospholipase D Inhibitors with Optimized in vivo Properties
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Craig Lindsley Committee Chair
Brian Bachmann Committee Member
Gary Sulikowski Committee Member
H. Alex Brown Committee Member
  • piperazines
  • morpholines
  • Phospholipase D
  • organocatalysis
  • fluoroamines
  • aziridines
  • azetidines
Date of Defense 2014-06-17
Availability unrestricted
My doctoral research has focused on (i) using organocatalysis to prepare enantioenriched pharmaceutically relevant scaffolds and (ii) preparing isoenzyme selective inhibitors of phospholipase D.

(i) Methodologies for asymmetric chlorination and fluorination of aldehydes have recently been reported; the potential of such building blocks in organic synthesis, however, were yet be exploited. We sought to fully unveil the synthetic potential of enantioenriched chlorinated and fluorinated aldehydes or alcohols as chiral building blocks toward the synthesis of various pharmaceutically relevant scaffolds. Morpholines, piperazines, azetidines, and aziridines are biologically relevant scaffolds and are often used as important synthetic intermediates. These scaffolds, however, are often difficult to prepare in enantioenriched form. By utilizing organocatalysis to arrive at chiral β-chloro alcohols, I was able to generate all of these scaffolds through a novel and facile manifold of reactions in good overall yields and excellent enantiomeric excess. Importantly, these synthetic methods provide access to these enantioenriched scaffolds from achiral aldehydes, of which hundreds are commercially available. In a similar vein, we found that organocatalytic asymmetric fluorination methods provide access to fluoro-aldehydes from achiral aldehydes. Fluorination is a common method used to improve a compounds metabolic stability, bioavailability, ancillary pharmacology profile, protein-ligand interactions, and CNS exposure. Using organocatalysis to generate enantioenriched β-fluoro alcohols, I was able to utilize a general reaction pathway towards chiral fluorinated scaffolds of pharmaceutical relevance. Of note, the chiral fluorinated scaffolds would have previously been accessed through alternate chemistry that is frequently plagued with low yields, rearrangements, and dehydration products. Our method offers a considerable advantage compared to past literature precedent.

(ii) Phospholipase D (PLD)—an enzyme that catalyzes the hydrolysis of phosphatidyl choline to phosphatidic acid (PA)—has two mammalian isoforms that share 53% sequence homology. PA is a lipid second messenger involved in various signaling cascades. Aberrant PLD activity—and atypical PA concentrations—have been implicated in a number of human diseases. Until recently, there were no ways to chemically modulate either PLD isoenzyme selectively; therefore, it was difficult to distinguish between phenotypes driven by aberrant PLD1 or PLD2 activity. Prior to my work, a highly potent and selective PLD1 inhibitor was discovered in the Lindsley lab, but PLD2 inhibitors with enhanced selectivity profiles remained highly desirable. Therefore, we began a medicinal chemistry campaign to discover selective PLD2 inhibitors with improved physiochemical and DMPK properties. This effort produced compounds with enhanced potency and selectivity. Moreover, a key stereocenter was identified during the process that immensely increases PLD1 potency with IC50 amplifications of 200 to 590-fold. Modifications to incorporate a pyridyl group delivered the most selective PLD2 inhibitor, and the scaffold was found to have significantly improved in vivo properties compared to previous compounds. These lead compounds were screened in a wide range of in vitro anticancer and antiviral assays and were found to significantly affect pathogenic phenotypes. My compounds are now being applied to delineate the role of PLD2 function in various disease states.

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