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

Wilmot, Jeremy T.

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https://hdl.handle.net/2142/18298 Copy

Description

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.

Issue Date

2011-01-14T22:45:20Z

Director of Research (if dissertation) or Advisor (if thesis)

Gin, David Y.

Doctoral Committee Chair(s)

Gin, David Y.

Committee Member(s)

• Hergenrother, Paul J.
• Burke, Martin D.
• McCall, Benjamin J.

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(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.

Graduation Semester

2010-12

Permalink

http://hdl.handle.net/2142/18298

Copyright and License Information

Copyright 2010 Jeremy Todd Wilmot

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