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Complex botanical natural products: Synthesis of cephalotaxus esters and of the C19-diterpenoid skeleton of aconitum and delphinium alkaloids

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Title: Complex botanical natural products: Synthesis of cephalotaxus esters and of the C19-diterpenoid skeleton of aconitum and delphinium alkaloids
Author(s): Wilmot, Jeremy T.
Director of Research: Gin, David Y.
Doctoral Committee Chair(s): Gin, David Y.
Doctoral Committee Member(s): Hergenrother, Paul J.; Burke, Martin D.; McCall, Benjamin J.
Department / Program: Chemistry
Discipline: Chemistry
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): cephalotaxine cephalotaxus esters harringtonine homoharringtonine homodeoxyharringtonine anhydroharringtonine deoxyharringtonine total synthesis natural products aconitum delphinium C19-diterpenoids aconitine alkaloid radical N-acyl iminium iminium radical conjugate addition ion channel deoxyhomoharringtonine
Abstract: The Cephalotaxus esters are a class of alkaloids extracted from plants of the Cephalotaxus genus and have been shown to be potent inhibitors of P-388 murine leukemia cells. While direct acylation of cephalotaxine has been reported to be difficult, the construction and acylation of cephalotaxine using a β-lactone acyl chain surrogate in the synthesis of anhydroharringtonine, deoxyharringtonine, homodeoxyharringtonine, and homoharringtonine is described. The natural esters as well as several non-natural analogues were tested against various human cancer cell lines not previously challenged by these alkaloids. Variations in the structure of the ester chain were found to confer differing activity profiles against vincristine resistant HL-60/RV+. The Aconitum and Delphinium alkaloids comprise a family of compounds isolated from the Aconitum and Delphinium genera. Several compounds within this class show potent Na+ ion channel activity ranging from the ion channel activation of aconitine to the ion channel blocking of lappaconitine. The completed synthesis of the skeleton of the C19-diterpenoid alkaloids is described. Key steps include a Diels–Alder cycloaddition of a cyclopropene with a 2,5-dioxycyclopenta-1,3-diene, a second Diels–Alder cycloaddition with a 2,5-dihydroazepine 2π component, an intramolecular N-acyliminium cyclization, and a radical conjugate addition.
Issue Date: 2011-01-14
Rights Information: Copyright 2010 Jeremy Todd Wilmot
Date Available in IDEALS: 2011-01-14
Date Deposited: December 2

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