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PART I: Ring-Rearrangement Metathesis of Himbert Arene-Allene Cycloadducts for the Rapid, Modular Construction of Complex Molecular Scaffolds and PART II: Application of Zincke Aldehydes Toward the Synthesis of Gelsemine

  • Author(s): Lam, Jonathan Kevin
  • Advisor(s): Vanderwal, Christopher D
  • et al.

Developing new synthetic methods and strategies is an important area of research in organic chemistry. Especially useful are transformations that rapidly and rationally generate complex molecular architectures, with multiple new bonds and new stereocenters, from simple, achiral and modular precursors. This dissertation discusses the synthetic investigation and exploitation of two such reactions.

In PART I, the intramolecular Diels-Alder (IMDA) reaction of aromatic dienes and allene dienophiles, utilized in conjunction with ring-rearrangement metathesis (RRM) to prepare angularly-fused polycyclic lactams, is discussed. The mechanism of the IMDA reaction was investigated with the aid of computational molecular modeling. The reaction was determined to proceed through a concerted mechanism; however, competing radical pathways accounted for stereochemical infidelity and fragmentation observed for some substrates.

An improved, modular synthesis of the precursors was developed to directly couple aromatic amines with the allene fragment precursor, which allowed for the preparation of a small library of heterocyclic compounds. This two-step protocol generates topologically interesting structures, containing two or more new rings, and two new sp3 stereocenters. Computational modeling also guided the development of the unknown analogous reaction for allenyl ketone substrates, which yield carbocyclic products.

Unexpected stereoselectivity and reactivity observations were made in the alkene metathesis reaction, which could not be readily explained. Computational studies were able to elucidate a subtle yet fundamental relationship between reaction mechanism and length of alkene tether in these types of substrates.

In PART II, efforts toward the synthesis of the alkaloid natural product gelsemine are discussed. The synthetic strategy employs a Zincke aldehyde rearrangement/IMDA cascade previously developed by the Vanderwal lab. Using 4-phenylpyridine as a model system, the expected transformation successfully gives an advanced synthetic intermediate lacking only the oxindole substructure, and the key C3-O4 and C5-C16 bonds present in the target. Elaboration of this intermediate toward the target is detailed.

A number of protected 4-(2-aminophenyl)pyridine analogues were prepared to facilitate oxindole formation and circumvent later stage complications that arose in the model system. These compounds all either failed to undergo Zincke salt formation, pyridinium ring-opening, or subsequent rearrangement/IMDA, thus delineating the synthetic boundaries of this type of chemistry.

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