Synthesis and applications of cyclopropylamines and cyclopropanols from a titanium-mediated cyclopropanation

Chapter I describes the application of the Kulinkovich reaction to the synthesis of novel bicyclic compounds from amino acids. A Ti(IV)-mediated intramolecular cyclopropanation was used to make [3.1.0] and [4.1.0] azabicycles. Some of these compounds bear structural similarity to neurotransmitters, while others possess the pyrrolizidine core found in alkaloids with a myriad of therapeutic applications. Azabicycles with functionalized side chains were made, and these compounds have potential applications in peptidomimetics. The utility of the azabicycles is extended with a ring-expanding reaction. In Chapter 2 the efforts to open the cyclopropylamine are explained. The cyclopropylamines proved resistant to many types of reactions. It was found, however, that the analogous cyclopropanols will undergo oxidative fragmentation. Chapter 3 details alternative syntheses of amides. The original conditions for aminolysis of amino acid-derived methyl esters were unsuitable for the desired applications, thus, dichlorodimethyl silane was used to convert unprotected amino acids to amides and bislithium aryl amides were used for the aminolysis of unactivated esters. The bislithium aminolysis was shown to work on allyl and benzyl esters and applied to the synthesis of apoptosis-inducing compounds. In Chapter 4, the synthesis of constrained analogs of neurotransmitters is reported. An intermolecular Kulinkovich reaction was used to make known and novel cyclopropylamines that are similar to histamine, tryptamine, mescaline and Ecstasy. These compounds were made in fewer steps than previous syntheses. Many of the known compounds are potent monoamine oxidase inhibitors and have potential in treating neurological disorders