Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Doctor of Philosophy




Kerr, Michael A.


The work disclosed in this dissertation outlines novel reactions involving indoles and their applications towards the total synthesis of natural products, tronocarpine and dippinine B.

Showcased in Chapter 2 is a novel mode of activation for donor-acceptor cyclopropanes via an external hydrogen bond. The hydrogen bond increases the cyclopropane’s electrophilicity permitting indole nucleophiles to open the ring. The result is 3-postion functionalized indoles.

An external hydrogen-bond donor, HFIP (1,1,1,3,3,3-hexafluoroisopropanol), is used as a solvent to provide the medium necessary for favourable hydrogen-bond interaction with donor-acceptor cyclopropanes. Hydrogen bond activation of donor-acceptor cyclopropanes was successful in generating a multitude of functional indole products in high yields.

Chapter 3 outlines the application of single electron transfer agent, Mn(OAc)3, to isolate 1,2-annulated indoles in a one-pot procedure. The products generated in this novel methodology create molecular scaffolding that maps nicely onto natural products tronocarpine and dippinine B. The methodology accesses a variety of 1,2-substituted indoles that tolerated all substituents tested.

Chapter 4 explores the progress towards realizing the synthesis of the molecules tronocarpine, and dippinine B. These natural products are desired for their anti-microbial and anti-fungal properties. Paired with their challenging framework, this makes them intriguing targets for synthetic chemists. The focal point of the synthetic pathways in this chapter involves the Mn(OAc)3 radical methodology disclosed in Chapter 3.

Lastly, Chapter 5 reports a thermo-controlled, diastereoselective opening of oxime-ether tethered donor-acceptor cyclopropanes to generate bicyclic oxazines. The N-O heterocyclic products can be reductively cleaved to access substituted pyrrolidines with set stereochemistry from the controlled opening of the cyclopropane. This work reports high yields and diastereo-control generating cis/trans selective annulated products. Substituted pyrrolidines are highly sought for pharmaceuticals and natural product synthesis.

Summary for Lay Audience

Important as a component of many pharmaceuticals, indole is a biological molecule found throughout the natural world. These pharmaceuticals are important components of treatments for cancer, depression, Alzheimer’s disease, viral infection, hypertension, and more. Chemists strive to develop modifications of indole molecules in search of easier, cheaper routes to both established, and novel pharmaceutical products. The research in this thesis outlines two new methods for the synthesis of further functionalized indole products. Method one involves radicals to cyclize an additional ring to an indole precursor. The products produced map onto the structure of important natural products found in Malaysian plant Tabernaemontana corymbosa. Method two functionalizes indoles by reacting them with strained three-membered ring molecules called cyclopropanes. This method is the first disclosed that does not require metals or high pressure as part of the reaction medium. Using the new methods developed, work towards natural products that have antifungal and antimalarial properties was under taken. The final component of this thesis develops a strategy to isolate highly substituted five-membered rings that contain nitrogen; these molecules are called pyrrolidines. The pyrrolidine structure is also highly desired in pharmaceutical targets. To access pyrrolidines, again cyclopropanes are used, but under specific reaction temperatures selective isomers of the pyrrolidine are isolated.