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Title page for ETD etd-12082015-110505

Type of Document Dissertation
Author Vara, Brandon Anthony
URN etd-12082015-110505
Title Enantioselective Reaction Development using Chiral Bifunctional Brønsted Acid/Base Organocatalysis and Applications to Target Molecule Synthesis
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey N. Johnston Committee Chair
Craig Lindsley Committee Member
Gary Sulikowski Committee Member
R. Kip Guy Committee Member
  • organocatalysis
  • catalysis
  • Nutlin
  • organic
  • Fluorine
  • Carbon Dioxide
Date of Defense 2015-12-04
Availability unrestricted
The Nutlin class of cis-imidazoline small molecule therapeutics has been shown to inhibit the protein-protein interaction (PPI) between the tumor-suppressor protein p53 and MDM2. The more potent enantiomer of Nutlin-3, (–)-Nutlin-3 or Nutlin-3a, has long been used to probe the effects of this PPI in chemical and cancer cell biology, although obtaining the drug is often prohibitively expensive. An MDM2 homologue, MDMX, has recently exhibited similar disrupting effects on p53 and is overexpressed in a range of cancers, most commonly seen in pediatric retinoblastomas. Nutlin-3a also inhibits p53-MDMX complexation and has therefore been recognized as a potential chemotherapeutic.

A pair of chiral amidine-amide organocatalysts have been developed that effectively catalyze the addition of aryl nitromethanes to aryl aldimines (aza-Henry reaction) with high enantioselectivity (ee) and diastereoselectivity (dr) (up to 99% ee and >200:1 dr). This superior degree of selectivity has been extended to substituted arenes. These materials served as intermediates to the Nutlin cis-imidazolines, facilitating medicinal chemistry screening efforts for MDM2/MDMX-p53 inhibition (J. Org. Chem. 2014, 79, 6913-6938). A series of novel asymmetric Nutlin derivatives have been prepared in collaboration with Kip Guy at St. Jude Childrens’ Research Hospital, some of which show high nanomolar inhibition of MDM2- and MDMX-p53 measured by fluorescence polarization (FP).

Also reported is an extension of the enantioselective aza-Henry reaction using fluoronitroalkane pronucleophiles. β-Amino fluoronitroalkanes are constructed in good dr with high enantioselection (up to 96% ee) using a more Brønsted basic bis(amidine) organocatalyst. These products can be readily transformed into β-fluoroamines, a valued motif in drug discovery chemistry.

Details of the first example of an organocatalyzed, enantioselective carbon dioxide-capture-cyclization reaction are disclosed to assemble diverse iodocarbonates (J. Am. Chem. Soc. 2015, 137, 7302-7305). The coupling of homoallylic alcohols with CO2 under 1 atm of pressure reveals 6-membered iodocarbonates in up to 95% ee. These chiral carbonates can be further manipulated to access a variety of enantioenriched, oxygenated building blocks, many of which are challenging to construct using other asymmetric technologies.

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