Organocatalytic Kornblum-DeLaMare Reactions of Endoperoxides and Applications in Drug Discovery

Abstract

<p>Five industry-relevant animal experiments were completed to investigate amino acid supplementation in reduced protein diets and the impacts on meat-chicken performance, metabolism, and physiology. Specifically, the role of the non-<p>The incorporation of oxygen and nitrogen atoms into a molecular skeleton is highly important in organic synthesis as many bioactive compounds contain heteroatoms within their structure. Endoperoxides are versatile molecules that are present among natural and bioactive compounds and can be used to introduce oxygen atoms during syntheses. The aim of this thesis was to investigate the reactivity of 3,6-dihydro-1,2-dioxines under basic conditions to generate enantioenriched and potentially bioactive compounds.</p> <p>In Chapter 2, a library of 1,2-dioxines was generated from the addition of singlet oxygen to 1,3-butadienes via a photooxygenation process. The <i>meso</i>-endoperoxides <b>I</b> reacted with catalyst <b>II</b> via an organocatalytic enantioselective Kornblum-DeLaMare rearrangement affording hydroxyketone products<b>III</b> with er up to 98:2. The newly formed hydroxyketones <b>III</b> were employed in the synthesis of enantioenriched lactones <b>IV</b> (er up to 89:11). Unsymmetrical endoperoxides <b>V</b> were subjected to a kinetic resolution generating highly enantioenriched 1,2-dioxines <b>VII</b> (er up to 99:1).</p> <p>In Chapter 3, endoperoxides <b>VIII</b> were reacted with primary and secondary amines via a domino Kornblum-DeLaMare/aza-Michael reaction generating a library of 12 novel aminoketones <b>IX</b> in excellent yields (71–100%) that were selectively reduced using a combination of SnCl₄/NaBH₄ (dr up to 93:7). The stereochemistry of the diol series <b>X</b> was determined via a crystal structure and a conserved coupling pattern observed through all 1H NMR spectra. This novel reaction permitted the insertion of nitrogen atoms into structures already containing oxygen atoms and was then applied in targeted synthesis (Chapter 4).</p> <p>The novel domino reaction was successfully employed in Chapter 4 for the synthesis of (±)-HPA-12 (<b>XI</b>), an inhibitor of the CERT protein, in 4 steps from 1,2-dioxine <b>VIII</b> (34% overall yield). A library of 8 HPA-12 bioisosteres was generated by the addition of Nheterocyclic amines, the library was then biologically tested resulting in the discovery of hydrazide <b>XII</b>, found to be active against Gram-positive bacteria <i>Bacillus subtilis</i> (15.6 µg/mol) and <i>Staphylococcus aureus</i> (12–16 µg/mol).</p>