Doctor of Philosophy, Case Western Reserve University, 2013, Chemistry

Triterpenoids are a broad and structurally diverse class of natural products primarily derived from the plant kingdom. The triterpenoid family consists of nearly thirty thousand members with over two hundred unique carbocyclic skeletons. Consequently, triterpenoids are known to have a wide array of biological activities, including antifungal, anti-inflammatory, anti-cancer, as well as anti-viral and anti-bacterial properties. Considerable efforts in drug discovery have focused on the isolation and structural elucidation of novel triterpenoid molecules from the plant sources. Moreover, semisynthetic triterpenoids, created by further manipulation of the exterior functional groups, have been shown to enhance the potency of their natural precursors. In this regard, the increase in structural complexity of triterpenoid-like molecular libraries through alteration of the carbocyclic core skeleton of the parent natural product can be viewed as a promising tool to study the chemical biology and medicinal chemistry of this natural product family. This work represents a general synthetic strategy for remodeling of a triterpenoid skeleton based on the reactivity patterns of lanosterol, and application of the devised strategy to pentacyclic triterpenoid bryonolic acid. Lanosterol was chosen because of the unsaturated B/C ring fusion, which can undergo iterative allylic oxidation/oxidative cleavage to produce transannular polyketones. These polyketones, in turn, can form distinct molecular skeletons via regio- and stereoselective aldol addition and Norrish-Yang photocyclization. The main advantage of this approach is that instead of relying on reaction development and catalysis to impart stereochemical and regiochemical selectivity, the inherent complexity of the natural product-derived substrates drives stereoselective and regioselective reactions. The central finding described herein is that the subtle changes in the parent triterpenoid, which is subjected to the devised divers (open full item for complete abstract)

Committee: Gregory Tochtrop (Advisor); Anthony Pearson (Committee Chair); John Protasiewicz (Committee Member); Blanton Tolbert (Committee Member); John Letterio (Committee Member) Subjects: Chemistry; Organic Chemistry; Pharmaceuticals