Development of a modular synthesis of unsymmetrically substituted heterocycles with functional group tolerant N,O-chelated group 4 hydroamination precatalysts

The development of a synthetic approach to 2,5-unsymmetrically substituted piperazines from readily available terminal alkynes and amine substrates employing both intermolecular and intramolecular hydroamination methodologies developed in the Schafer group is reported in this thesis. The approach requires only three isolation/purification protocols. Firstly, regioselective intermolecular hydroamination in the presence of titanium bis(amidate) precatalyst is performed, followed by the one-pot addition of trimethylsilyl cyanide to the imine and subsequent displacement of the TMS group to obtain α-aminonitriles. Reduction of the α-aminonitriles is required to achieve the desired hydroamination precursors. The piperazine core is then completed by intramolecular diastereoselective hydroamination with the zirconium tethered bis(ureate) catalyst. The synthetic approach employed features two hydroamination reactions for the synthesis of these biologically active heterocycles. Synthesis of enantiopure piperazine was achieved via a chiral auxiliary-based approach; after the enantiopure aminonitrile was synthesized, subsequent reduction and enantiospecific intramolecular hydroamination with the zirconium tethered bis(ureate) catalyst were performed. The synthetic sequence thus developed illustrates the usefulness of inexpensive and low-toxicity group 4 amidate and ureate catalysts for the rapid synthesis of functionalized heterocycles suitable for further medicinal chemistry investigations. The screening of a series of novel unsymmetrically substituted piperazines for calcium channel blocking activity was performed. Potent N-type calcium channel blockers were discovered and a new trend in the development of piperazine medicinally relevant heterocycles was found. This contribution highlights a modular synthetic approach to the efficient preparation of previously unknown piperazines suitable for biological screening. In addition to 2,5-disubstituted piperazines, 2,5-disubstituted diazepanes were efficiently obtained on the basis of the developed strategy. Specific heterocyclic structural features in the 1H NMR spectra inspired us to propose a practical NMR-based method for revealing the relative stereochemical configuration of the synthesized heterocycles. Overall, this thesis covers different aspects of medicinal chemistry, green chemistry, synthetic chemistry and catalysis to provide conceptual and practical contributions to each of these branches of modern chemistry. Concepts and protocols developed in the course of this thesis can bring an important contribution to new approaches in drug discovery and our understanding of the application of hydroamination in synthetic chemistry.