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Progress Toward a Scalable Synthesis of Azaspirene, An Angiogenesis Inhibitor and Synthesis of 2-Amino-benzimidazole Compounds Targeting Subdomain IIa of the Internal Ribosome Entry Site Inhibiting Translation of The Hepatitis C Virus
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Progress Toward a Scalable Synthesis of Azaspirene, An Angiogenesis Inhibitor and Synthesis of 2-Amino-benzimidazole Compounds Targeting Subdomain IIa of the Internal Ribosome Entry Site Inhibiting Translation of The Hepatitis C Virus
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Progress Toward a Scalable Synthesis of Azaspirene, An Angiogenesis Inhibitor and Synthesis of 2-Amino-benzimidazole Compounds Targeting Subdomain IIa of the Internal Ribosome Entry Site Inhibiting Translation of The Hepatitis C Virus
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Dissertation
Progress Toward a Scalable Synthesis of Azaspirene, An Angiogenesis Inhibitor and Synthesis of 2-Amino-benzimidazole Compounds Targeting Subdomain IIa of the Internal Ribosome Entry Site Inhibiting Translation of The Hepatitis C Virus
2014
Overview
Chemical studies toward the synthesis of an angiogenesis inhibitor azaspirene is described. There is a need for a concise and scalable asymmetric synthesis of azaspirene. The current strategy employed can lead to the production of small libraries of azaspirene derivatives and other members of the pseurotin family, where structure activity relationship (SAR) studies can be conducted in anticipation of creating innovative and more effective anti-cancer drugs. Amino acids as well as other optically active compounds make great raw materials for the synthesis of asymmetric products with deliberate stereocontrol. Numerous synthetic routes for the synthesis of azaspirene are presented with the latest strategy starting from optically active malic acid showing the most viability. Azaspirene has a highly oxygenated complex spirocyclic structure that poses abundant synthetic challenges which are addressed herein. D-Malic acid is made by the double inversion of D-aspartic acid and the stereocenter is preserved throughout the synthesis. Cyclization to the succinimide derivative forms the lactam present in azaspirene. An aldol reaction and subsequent DMP oxidation form the 1,3-diketone necessary for an asymmetric palladium-mediated -hydroxylation reaction. The chiral alcohol will be used as the oxygen in the β-oxygenated enone ring after Margaretha cyclization using a highly functionalized ester to add the diene tail of azaspirene. The benzyl group found in azaspirene will be added via a Grignard reaction at a late stage in the synthesis allowing for diversity. The synthesis of a small set of 2-amino-benzimidazole compounds that bind a RNA construct of the hepatitis C virus (HCV) internal ribosome entry site (IRES) with ligand affinity in the submicro-molar range is described. The binding interaction is demonstrated by a 2.2Å resolution crystal structure of a 2-amino-benzimidazole compound bound to the RNA construct published by the Bergdahl group with collaborators. The total synthesis and crystal structure were used to guide the production of novel compounds, and the results presented herein will influence the design and construction of novel inhibitors expected to increase potency against HCV.
