The objectives of this proposed program are to develop ideas and reaction sequences to transform simple, commercially available compounds into structurally complex, biologically active natural products with high efficiency and to investigate the properties of these substances in biological contexts. The underlying theme of the chemical studies described in this application is the design and execution of cascades of reactions that rapidly form the topologically and stereochemically complex structures of two natural products: (1) the promising angiogenesis inhibitor Cortistatin A, and (2) the potent and selective anticancer compound Maoecrystal V. These natural products have genuine potential as chemotherapeutic agents for the treatment of human diseases and molecular architectures that inspire the development of concepts for the benefit of the field of organic synthesis. The new synthesis proposals are rooted in the idea that judicious sequences of fundamental, carbonyl-dependent reactions will enable rapid syntheses of these challenging target molecules. The synthesis pathways developed in this program will be leveraged to gain insights into the biomolecular target selectivities of these fascinating natural products. Lay language: Small molecule drugs for the treatment of human diseases and molecular probes for discovery-based research activities in cell biology are produced by the methods and concepts of chemical synthesis. The significance of this program comes from the powerful ideas and methods that it will develop for achieving short, efficient syntheses of two structurally complex, biologically active natural products and the discoveries of new biomolecular targets for attacking diseases in humans.
The conception and development of powerful strategies and reaction sequences to rapidly form the complex molecular structures of biologically active natural products is one of the frontier activities in the field of chemical synthesis. This program is developing innovative carbonyl-based cascades of cyclizations for use in syntheses of several natural products with properties that could improve human health.
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| Abrams, Dylan J; West, Julian G; Sorensen, Erik J (2017) Toward a mild dehydroformylation using base-metal catalysis. Chem Sci 8:1954-1959 |
| Forneris, Clarissa C; Ozturk, Seyma; Gibson, Marcus I et al. (2017) In Vitro Reconstitution of OxyA Enzymatic Activity Clarifies Late Steps in Vancomycin Biosynthesis. ACS Chem Biol 12:2248-2253 |
| Liu, Junjia; Bedell, T Aaron; West, Julian G et al. (2016) Design and Synthesis of Molecular Scaffolds with Anti-infective Activity. Tetrahedron 72:3579-3592 |
| Liu, Junjia; Marsini, Maurice A; Bedell, T Aaron et al. (2016) Diastereoselective syntheses of substituted cis-hydrindanones featuring sequential inter- and intramolecular Michael reactions. Tetrahedron 72:3713-3717 |
| West, Julian G; Bedell, T Aaron; Sorensen, Erik J (2016) The Uranyl Cation as a Visible-Light Photocatalyst for C(sp(3) )-H Fluorination. Angew Chem Int Ed Engl 55:8923-7 |
| Bedell, T Aaron; Hone, Graham A B; Bois, Justin Du et al. (2015) An expedient synthesis of maraviroc (UK-427,857) via C-H functionalization. Tetrahedron Lett 56:3620-3623 |
| West, Julian G; Huang, David; Sorensen, Erik J (2015) Acceptorless dehydrogenation of small molecules through cooperative base metal catalysis. Nat Commun 6:10093 |
| Siler, David A; Mighion, Jeffrey D; Sorensen, Erik J (2014) An enantiospecific synthesis of jiadifenolide. Angew Chem Int Ed Engl 53:5332-5 |
| Reber, Keith P; Tilley, S David; Carson, Cheryl A et al. (2013) Toward a synthesis of hirsutellone B by the concept of double cyclization. J Org Chem 78:9584-607 |
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