Studies Towards the Synthesis of Morphan Natural Products

Morphan rings are located at the core of a vast number of natural products and have been the synthetic targets of a great number of synthetic organic chemists. Previously our group reported the nitrenium ion mediated cyclofunctionalization of alkenes. In this dissertation, application of this cyclofunctionalization strategy towards the development of morphan rings in natural products will be discussed. Of central interest to our lab were two alkaloid families, madangamine and akuammiline. Both of them have a central morphan ring, which provided an unique opportunity to apply the cyclofunctionalization strategy in order to construct them. Madangamine alkaloids have a pentacyclic structure, which has evoked synthetic interests since the late 1990s. Chapter one includes a study on the synthesis of the diazatricyclic core of these alkaloids. The akuammiline family of alkaloids, exemplified by aspidophylline A and strictamine, has gained synthetic interest only in the last decade. Chapter two includes a study towards the synthesis of akuammiline alkaloids, development of the morphan ring core and an advanced indolenine intermediate leading to these alkaloids. The second part of this dissertation comprises a study of the development of inhibitors towards cystathionine-γ-lyase (CSE), one of the main H2S-producing enzymes in mammals. 2-Arylidene hydrazinecarbodithioates have been developed as novel inhibitors of CSE and shows selectivity against cystathionine-β-synthase, another prominent H2S-producing enzyme. The structurally unique nature of this inhibitor family, compared to other known amino-acid based inhibitors, has provided it as a valuable study for H2S-production.