The Synthesis of Indolizidine and Quinolizidine Derivatives using the Electron-rich Dearomatization Agent {WTp(NO)(PMe3)}

Liebov, Benjamin, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Liebov, Benjamin, Arts & Sciences Graduate-lasg, University of Virginia

Chapter 1 introduces the reader to aromaticity and the activation of aromatic molecules through coordination to electron deficient and electron-rich metal fragments. Coordination of aromatics to electron-deficient metals in an η6 fashion activates them towards nucleophilic additions. Conversely, coordination to an electron-rich metal fragment through η2 (dihapto) coordination renders aromatic molecules dearomatized and makes them susceptible to electrophilic addition.
Chapter 2 gives an overview of alkaloid chemistry and the syntheses of several alkaloid analogs using electron-rich dearomatization techniques. Through dihapto-coordination, several inexpensive aromatics can be chemically transformed to alkaloid analogs. The chapter ends with the introduction of the synthetic challenges of converting pyrroles and pyridines to indolizidines and quinolizidines, respectively.
Chapter 3 focuses on the reactivity of pyrrole and its activation through electron-rich dearomatization. Upon coordination of 2-methylpyrrole to a tungsten(0) dearomatization agent followed by protonation, a dihapto-coordinated 2H-2-methylpyrrolium complex is isolated. After a Michael addition of MVK or EVK to the 2-methylpyrrolium complex, an intramolecular cyclization takes place to form an indolizidinium core.
Chapter 4 explores the formation and reactivity of a coordinated indolizidinium complex. The indolizidinium core has an α,β-unsaturated iminium where the alkene portion can be dihydroxylated or hydrogenated. Following hydride reduction of the hydrogenated indolizidinium complex, a fully saturated coordinated-indolizidine can be isolated. Subsequent oxidation leads to a dehydroindolizidine that can be dihydroxylated to form a dihydroxylated indolizidine.
Chapter 5 introduces the reader to the reactivity of pyridine and its activation when coordinated to a tungsten(0) dearomatization agent. A dihapto-coordinated 2-picolinium complex may be formed and a Michael addition with acrolein, MVK or EVK can occur at the nitrogen. Upon formation of the dearomatized 2,6-lutidinium complex a Michael addition with MVK followed by an aldol condensation leads to a cyclized quinolizidinium core.

PHD (Doctor of Philosophy)
Dearomatization, Alkaloids , Tungsten
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