Part I: Total Synthesis Of Aspeverin And Penicimutamide A. Part Ii: Total Chemical Synthesis Of All-L And All-D Kras(G12V) And The Further Exploration Of Isonitrile Mediated Peptide Ligations

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Part I: Fungi serve as a rich source of prenylated indole alkaloids, which exhibit important biological activities including antiproliferative, antibiotic, and antihelminthic properties. Their promise as therapeutics, coupled with their diverse and complex molecular architectures, have made prenylated indole alkaloids popular targets for synthetic chemists in order to probe their activities and develop new synthetic methods. Herein, we describe the first total synthesis of aspeverin, a unique bridged carbamate-containing prenylated indole alkaloid isolated from Aspergillus versicolor. We also describe the synthesis of a closely related congener, penicimutamide A, isolated from a mutant strain of Penicillium purpurogenum. These molecules belong to a recently described subclass of prenylated indoles thought to be degradation products of parent bicyclo[2.2.2]diazaoctane congeners. In this research, we showcase a highly diastereoselective Diels?Alder cycloaddition, followed by an electrophilic Rawal arylation – reductive indolization to forge the pentacyclic scaffold of these natural products. A novel sequence for installation of a geminal dimethyl group was also developed. This involved a carefully devised transannular carbamate cyclization followed by a ring-opening / alkylation sequence. Finally, the bridging carbamate common to both of these natural products was forged using a hypervalent iodine(III)-mediated oxidative cyclization. Part II: The KRas protein is a small GTP-binding protein important in cellular signaling, involved in growth, differentiation, motility, and survival. Oncogenic mutated Ras is involved in approximately 30% of all cancers. Despite the identification of this target in human cancers over 30 years ago, no small molecules targeting KRas have been successful in the clinic, and this target has long been considered “undruggable.” In an effort to develop novel therapeutics, this project seeks to complete a total synthesis of an all-D amino acid variant of the KRas protein. This synthetic protein enantiomer will be used as a tool for mirror-image yeast surface display studies to identify all-D residue peptide ligands for KRas. In this section, the synthesis of biotinylated variants of KRas(G12V) consisting of all-L and all-D amino acid residues is described. Moreover, we demonstrate that this enantiomeric pair of 166-residue proteins bind to nucleotide substrates as well as Ras-binding peptides with enantiospecificity. During our studies on the total synthesis of KRas, we further demonstrate the utility of isonitrile-mediated activation of C-terminal thiocarboxylic acids for peptide ligation. This method is advantageous, in that it does not rely on a cysteine disconnection and takes place under mild conditions in polar aprotic organic solvents. Beyond a synthesis of KRas, we also demonstrate that isonitrile-mediated ligation and native chemical ligation strategies can be combined and applied toward a novel synthesis of HIV-1 protease I66A.

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2017
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Aspeverin; Peptide Synthesis; Prenylated Indole Alkaloid; Ras; Total Synthesis
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Chemical Biology
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Doctor of Philosophy
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Government Document
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Attribution-NonCommercial-NoDerivatives 4.0 International
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dissertation or thesis
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