Date of Award
Doctor of Philosophy (PhD)
José S. Madalengoitia
Guanidines are ubiquitous in nature and have important applications in biological chemistry and industry, presenting themselves in biomacromolecules and organic materials respectively. The zwitterionic-1,3-diaza-Claisen rearrangement has allowed facile access to a variety of highly-substituted, complex guanidines, which would otherwise require a significant amount of time or resources to synthesize.
Previously, the intramolecular version of the 1,3-diaza-Claisen rearrangement has been used to generate tricyclic guanidines from bridged, bicyclic electron-deficient isothioureas. Extension of this methodology to simpler electron-deficient isothioureas has afforded stable zwitterionic intermediates, which have been isolated via silica gel column chromatography with common organic solvents. Heating the zwitterionic intermediates in an aromatic solvent gives the desired guanidines in good yields. A substrate scope examining isothiourea sterics and electronics has shown that the rearrangement can be accelerated by increasing the strength of the electron withdrawing group, stabilizing the alkene fragment, and employing additional substitution patterns. Mechanistic studies employing deuterium-labeled isothioureas have shown that a sigmatropic rearrangement mechanism and ionic rearrangement mechanisms are both possible. The mechanism is dependent on the substrate structure, and the presence of trace thiophilic metal or weak acid.
Diastereoselective rearrangements employing remote stereocontrol of an existing stereocenter are also possible. DFT-calculations are being examined to predict rearrangement activation energies based on the possible transition states. Finally, altering the electronics of the isothiourea has resulted in an unexpected Sommelet-Hauser [2,3]-sigmatropic rearrangement. This new result has expanded the scope of guanidines, producing guanidine scaffolds represented in various natural products.
Number of Pages
Luedtke, Matthew William, "Expansion Of The Intramolecular Zwitterionic-1,3-Diaza-Claisen Rearrangement Beyond Bridged-Bicyclic Electron-Deficient Isothioureas To Generate Substituted Cyclic Guanidines" (2019). Graduate College Dissertations and Theses. 1109.
Available for download on Monday, December 06, 2021