Online

Tocher, Jordan Allen

Chemistry

2020

Ph. D.

Guanidines are found readily in many natural product scaffolds and biological systems. However, the chemical makeup of the guanidines is such that synthesis of guanidine-containing molecules remains challenging. In 2004, the Madalengoitia group first reported a zwitterionic 1,3-diaza Claisen rearrangement that affords complex guanidines. This was later expanded from the initial strained-bridged bicyclic systems to systems that encompassed more linear precursors, positively charged intermediates, and compounds with ring-expansion applications. Due to the historical precedent that introduction of a positive charge into a rearranging system can benefit the kinetics and thermodynamics of a reaction, experiments were designed in order to probe a cationic 1,3-diaza Claisen rearrangement. The work described herein utilizes the fact that ureas tethered to tertiary allylic amines can be dehydrated in the presence of triethylamine and a dehydrating sulfonyl chloride in order to in-situ generate carbodiimides. The intramolecular addition of the amine to the formed carbodiimide, followed by in situ protonation affords guanidines with a quaternary ammonium that undergo cationic 1,3-diaza-Claisen rearrangements to produce the targeted highly substituted cyclic guanidines. The reaction design has been studied with regards to the reaction conditions and the subsequent isolation and purification of the product guanidines. Additionally, the tolerance and scope of the rearrangement has been explored by making structural changes around the rearrangement center. Also, the hypothesized sigmatropic mechanism of the rearrangement has been studied using deuterium labeling strategies. In effect, the methods devised have given access to novel guanidines that would be difficult to synthesize through conventional pathways.