In order to enable the study of bioactive natural products with complex structures, chemists need to be able to synthesize them and any unnatural analogs of interest. However, there are many molecules with dense arrays of chiral centers that are still difficult to prepare with high efficiency and selectivity. Synthetic chemist are constantly searching for versatile, effective new methods for the creation of vicinal chiral centers and quaternary centers, especially in an enantiopure form. The development of efficient, stereoselective carbon-carbon bond-forming methods will enable chemists to more effectively prepare biologically interesting target molecules, and enable more detailed study of these compounds for applications as chemical therapies. The common theme throughout the aims of the research program is the Nazarov electrocyclization, which delivers cyclopentane rings containing adjacent stereocenters and/or quaternary carbon centers.
The aims of the grant seek to develop new variations of the cyclization for application to enantioselective synthesis, execute the cyclization in the demanding syntheses of bioactive target molecules that would be difficult to prepare using other strategies. Novel cyclization strategies will also be developed during the synthetic aims, as well as two desymmetrization sequences to obtain either a single enantiomer (from a prochiral precursor) or a single diastereoisomer (from the thermodynamically controlled cyclization of a chiral precursor). Specifically, we intend to study 1) the conjugate addition-initiated Nazarov electrocyclization, 2) enantioselective synthesis of tetrapetalone A and 3) enantioselective total synthesis of tubingensins A and B via a novel interrupted Nazarov cyclization. The public health challenges associated with AIDS, hepatitis C, and the recent emergence of dangerous new viruses like SARS and H1N1 influenza demand a drug pipeline full of compounds able to battle these rapidly mutating diseases. Natural products represent a valuable pool of potential antivirals, if chemical studies can be performed to understand and improve activity and potency. Human lipoxygenases (HLOs) are implicated in a number of disease processes, including cancer, heart disease, asthma, atherosclerosis and psoriasis. Identification of new HLO inhibitors with specificity and complementary modes of action is essential for continued progress in the treatment of these diseases.
The aims of this grant focus on the synthesis of a soybean lipoxygenase inhibitor, which is a good model for the study of HLO (tetrapetalone A) and two new small molecule agents with antiviral activity (tubingensins A and B). Successful synthesis will make these natural products available by chemical synthesis, paving the way for a thorough biological evaluation and study of structure/activity relationships. Ultimately, goals include the identification of new antiviral agents and a better understanding of the behavior of lipoxygenase inhibitors.

Public Health Relevance

Many bioactive natural products have complex structures that are difficult to prepare with high efficiency and selectivity. The new chemical methods that will be developed over the course of this project will strongly augment the synthetic toolbox available for the preparation of valuable compounds with pharmaceutical potential. Furthermore, achieving the advanced synthetic aims of the program research will allow us to build rare molecules with promising, but poorly understood biological activity for further assessment as agents for the treatment of cancer, inflammatory diseases and viral infections.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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University of Rochester
Schools of Arts and Sciences
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Huang, Yu-Wen; Frontier, Alison J (2015) Enantioselective Nazarov Cyclization Catalyzed by a Cinchona Alkaloid Derivative. Tetrahedron Lett 56:3523-3526
Carlsen, Peter; Jiang, Chao; Herrick, Ildiko R et al. (2015) Studies toward the AB ring system of the tetrapetalone natural products. Tetrahedron 71:5886-5896
Jacob, Steven D; Brooks, Joshua L; Frontier, Alison J (2014) No acid required: 4? and 6? electrocyclization reactions of dienyl diketones for the synthesis of cyclopentenones and 2H-Pyrans. J Org Chem 79:10296-302
Carlsen, Peter N; Mann, Tyler J; Hoveyda, Amir H et al. (2014) Synthesis of (±)-tetrapetalone A-Me aglycon. Angew Chem Int Ed Engl 53:9334-8
Vaidya, Tulaza; Cheng, Ryan; Carlsen, Peter N et al. (2014) Cationic cyclizations and rearrangements promoted by a heterogeneous gold catalyst. Org Lett 16:800-3
Callahan, K P; Minhajuddin, M; Corbett, C et al. (2014) Flavaglines target primitive leukemia cells and enhance anti-leukemia drug activity. Leukemia 28:1960-8
Spencer 3rd, William T; Vaidya, Tulaza; Frontier, Alison J (2013) Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates. European J Org Chem 2013:
Ciesielski, Jennifer; Lebœuf, David; Stern, Harry A et al. (2013) Gold (III) Chloride-Catalyzed 6-endo-trig Oxa-Michael Addition Reactions for Diastereoselective Synthesis of Fused Tetrahydropyranones. Adv Synth Catal 355:2077-2082
Leboeuf, David; Theiste, Eric; Gandon, Vincent et al. (2013) Efficient Nazarov cyclization/Wagner-Meerwein rearrangement terminated by a Cu(II)-promoted oxidation: synthesis of 4-alkylidene cyclopentenones. Chemistry 19:4842-8
Ciesielski, Jennifer; Gandon, Vincent; Frontier, Alison J (2013) Cascade cyclizations of acyclic and macrocyclic alkynones: studies toward the synthesis of phomactin A. J Org Chem 78:9541-52

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