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

Master of Science, Miami University, 2010, Chemistry and Biochemistry

Many biologically active compounds contain multiple fused rings, and often the synthesis of these compounds can be quite complex. Efforts to produce these intricate molecular frameworks through cycloaddition reactions are advantageous, with the ability to produce fused ring structures in only one step. This thesis describes the work towards the synthesis of fused ring products through gold-catalyzed cycloadditions. The construction of various carbocycles was achieved through transannular, intermolecular, and intramolecular methods. Rapid assembly of the core structure of Cortistatin A, a potent antiangiogenesis natural product, was achieved through a transannular [4 + 3] cycloaddition from a macrocyclic precursor. Additionally, the [4 + 3] cycloaddition reaction was extended to the intermolecular variant using propargyl ester and diene precursors. Progress towards the application of intramolecular gold-catalyzed cycloadditions is also described. Where appropriate, investigation of the regioselectivity and stereochemistry of these reactions is analyzed, and mechanistic pathways are also discussed.

Committee: Benjamin W. Gung (Advisor); Richard T. Taylor (Committee Chair); C. Scott Hartley (Committee Member); Shouzhong Zou (Committee Member) Subjects: Organic Chemistry

Doctor of Philosophy, Miami University, 2010, Chemistry and Biochemistry

Unit I, Using allene RCM reactions, 12, 14 and 16 membered furan/allene macrocycles were synthesized. Selective epoxidation reactions and Platinum catalysis were unable to initiate a successful transannular [4+3] cycloaddition reaction from the 14 member macrocycle. However, a palladium catalyst system was then tested which produced the first reported example of a transannular [4+3] cycloaddition reaction in 37% yield. Gold catalysis showed a slight improvement on the product yield but competing rearrangement and [4+2] reactions were problematic. After changing the 3C component from an allene to a propargyl acetate, the reaction was optimized from 13 and 14 membered macrocycles using gold catalysis to generate [4+3] cycloadducts in high yield. The transannular [4+3] cycloaddition methodology was then applied to synthesizing the ABCD ring structure of Cortistatin A. Unit II, A short synthesis of S-(+)-Siphonodiol was completed utilizing a strategy which took advantage of the hidden symmetry of the molecule. Key steps in the synthesis were copper mediated alkyne coupling reactions. Unit III, Two new chiral N-Heterocyclic Carbene complexes were synthesized and the structures were confirmed using x-ray analysis. These complexes were found to be useful as catalysts and showed similar reactivity to Au(I)IPr in intramolecular cyclopropanation reactions from propargyl acetate/alkene substrates.

Committee: Benjamin Gung PhD (Advisor); Richard Taylor PhD (Committee Chair); James Hershberger PhD (Committee Member); David Tierney PhD (Committee Member); Gary Janssen PhD (Committee Member) Subjects: Chemistry

Doctor of Philosophy, Miami University, 2013, Chemistry and Biochemistry

Unit I, Two successful 13- and 15-membered macrocycles containing furan and α-chloroketone functional groups were synthesized. Macrocycles were subjected to solvent mixture (Et3N, CF3CH2OH, and Et2O), and an oxyallyl cation was presumably formed, which proceeded to react with the furan moiety to give transannular [4C+3C] cycloaddition products. In addition, the tricyclic ring system with an oxabicyclo-[3.2.1]octadiene and a fused 6-membered ring was produced efficiently using the readily available propargyl ester-furan substrate in the presence of a Au(I) complex. The reaction involves a tandem 3,3-rearrangement of the propargyl ester followed by an intramolecular [4C+3C] cycloaddition reaction. Unit II, With the use of benzonitrile-stabilized Au(I) catalyst [Au(IPr)(NCPh)]+SbF6-, a spectrum of reactivity is observed upon reactions of propargyl esters with cyclic vinyl ethers, ranging from exclusive [3C+2C] cycloaddition reactions to exclusive cyclopropanation depending on the structure of the vinyl ether. Some cyclopropanation products rearrange into the corresponding [3C+2C] cycloaddition products after treatment with fresh Au(I) complex at 80°C. Vinylcyclopropanes formed from dihydrofuran and dihydropyran resisted such rearrangement, even in the presence of fresh Au(I) catalyst at elevated temperature. A dual pathway is proposed for the Au(I) catalyzed reactions between propargyl esters and cyclic vinyl ethers. In addition these cycloaddition reactions were attempted with chiral NHC Au(I) complexes and novel chiral ADC Au(I) complexes. The ADC Au(I) catalyzed cycloaddition reaction led to the discovery of a cascade reaction consisting of first: [3C+2C] cycloaddition between propargyl ester and vinyl ether followed by cyclopropanation of the enol ester double bond, in the [3C+2C] cycloadduct, with propargyl ester. These cascade products were found to be resistant to rearrangement of the cyclopropyl ring in the presence of fresh Au(I) catalysts at elevated (open full item for complete abstract)

Committee: Benjamin Gung PhD (Advisor); Richard Taylor PhD (Committee Chair); Scott Hartley PhD (Committee Member); David Tierney PhD (Committee Member); Steven Keller PhD (Committee Member) Subjects: Chemistry; Organic Chemistry