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

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2011

Author dc:creator

• Wilmot, Jeremy T.

Contributors dc:contributor

• Gin, David Y.
• Hergenrother, Paul J.
• Burke, Martin D.
• McCall, Benjamin J.

• 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

Statement dc:rights

• Copyright 2010 Jeremy Todd Wilmot

Language dc:language

en

Handle dc:identifier

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

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/18298