Donor-Acceptor Cyclopropanes as Building Blocks for the Synthesis of Natural Product Scaffolds
The first chapter of this thesis provides an introduction to natural products and describes how they are a valuable source of bioactive compounds, which feature heavily in clinically used drugs. The recently reported bioactive natural product maoecrystal V was introduced followed by the chemistry of cyclopropanes, which were intended to be used in the synthesis of maoecrystal V. Synthetic strategies towards the synthesis of maoecrystal V were investigated in chapter 2. A retrosynthetic analysis of maoecrystal V was proposed, which featured a cyclopropane ring expansion. Using a model system, the key step, an intermolecular Diels-Alder cycloaddition was used to construct the [2.2.2]-bicyclooctane scaffold of maoecrystal V. Concurrently to this work, Baran and co-workers completed the synthesis of maoecrystal V and found that it possessed little to no bioactivity against a wide range of cancer cell lines. An introduction to spiroketals and the less common benzannulated spiroketals followed by the methodology to construct them are described in chapter 3. Based on some preliminary results from another study, attention was turned to utilising donor-acceptor cyclopropanes in the synthesis of benzannulated n,5-spiroketals (n = 6 or 5), which are found in numerous bioactive natural products. Chapter 4 details a new synthetic strategy to gain access to the benzannulated 6,5-spiroketals in a highly efficient manner, using donor-acceptor cyclopropanes. Vinyl cyclopropanes 312 were smoothly converted to the corresponding benzannulated 6,5-spiroketals by treatment with palladium(0). A series of benzannulated 6,5-spiroketals 313 with three or four stereocentres embedded were synthesized in good to excellent yields from simple, commercially available starting materials 321. The requirement of two chromatographic separations over six or seven steps and mild reaction conditions make this methodology attractive. Chapter 4 also presents a synthetic study towards berkelic acid, which has a benzannulated 6,5-spiroketal scaffold embedded. The successful construction of this model system indicates the practical value of this methodology and its potential in the total synthesis of natural products containing benzannulated 6,5-spiroketal moieties. In Chapter 5, the synthesis of benzannulated 5,5-spiroketals via vinyl and phenyl cyclopropanes is described. In the presence of Pd(0), different benzannulated 5,5-spiroketals were formed from vinyl cyclopropanes 353. While the phenyl cyclopropanes required Lewis acid catalysts to proceed. Various phenyl substituted benzannulated 5,5-spiroketals 372 were obtained from the corresponding 1,3-diketones or -keto esters 386.
Advisor: Hawkins, Bill; Tan, Eng Wui
Degree Name: Doctor of Philosophy
Degree Discipline: Chemistry
Publisher: University of Otago
Keywords: donor-acceptor cyclopropanes; maoecrystal V; benzannulated 6,5-spiroketals; berkelic acid; benzannulated 5,5-spiroketals
Research Type: Thesis