Studies Directed Towards the Synthesis of Alstoscholarine and Inhibitors of Cystathionine Gamma Lyase
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The first chapter of this thesis describes the synthetic application of nitrenium ions towards the synthesis of the natural product alstoscholarines and a second mitochrondia activator of caspases (SMAC) mimetic. Alstoscholarine is a pentacyclic alkaloid with a azabicyclo[3.3.1]nonane system fused with both indole and a pyrrole ring systems. The core of the natural product, an azabicyclo[3.3.1]nonane system, was constructed by employing a PIFA-mediated oxamidation of an unsaturated hydroxamate. To complete the synthesis, conversion of a lactam to pyrrole was required, which had little precedent in the chemical literature. In order to complete the total synthesis of alstoscholarines efforts were redirected to achieve the aforementioned transformation. Application of nitrenium ion was also employed in the synthesis of an SMAC mimetic. Eschenmoser sulfide contraction is a problematic transformation with respect to secondary amides. Using ethyl bromopyruvate as a coupling partner, mild conditions have been identified for Eschenmoser sulfide contraction with secondary thioamides leading to the formation of β-enaminone α-oxoesters. Reductive annulation of these systems leds to the formation of pyrrolidine systems in a single step. The second part of this thesis details our effort towards the development of potent inhibitors of cystathionine gamma lyase, an enzyme responsible for endogenous H2S production. Upregulation of H2S is necessary to maintain the body homeostasis control and any imbalances associated with diseases. 2-Arylidene hydrazinecarbodithioates has been developed as potent selective inhibitors of CSE.
SubjectNatural Products, Eschenmoser sulfide contraction, PIFA, nitrenium ions, alstoscholarine, crisping A, CSE