The proposed research will seek to 1) develop a general method to perform catalytic asymmetric Nazarov cyclization and 2) achieve the total synthesis of two natural products, merrilactone A and tetrapetalone A using Nazarov cyclization as the key step. These natural products are neurotrophic and inhibit lipoxygenases, respectively. Synthesis of these structurally interesting compounds will allow us to explore unique chemical transformations and improve our ability to study the bioactivity of these molecules. The research will contribute potentially enantioselective strategies for the synthesis of these and other natural products with biologically significant behavior, enabling chemists to prepare and study pharmacological agents for medical applications. As an example of potential impact of these chemical methods, one specific aim of this application describes the synthesis of the neurotrophic agent merrilactone A. The ability to synthesize a molecule of this complexity and unusual bioactivity could eventually provide medical researchers with tools to combat neurodegenerative diseases, and methods to synthesize other molecules that will impact diseases important to public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079364-05
Application #
8029570
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2007-01-01
Project End
2012-08-31
Budget Start
2011-01-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$282,956
Indirect Cost
Name
University of Rochester
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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
Huang, Yu-Wen; Frontier, Alison J (2015) Enantioselective Nazarov Cyclization Catalyzed by a Cinchona Alkaloid Derivative. Tetrahedron Lett 56:3523-3526
Jacob, Steven D; Brooks, Joshua L; Frontier, Alison J (2014) No acid required: 4Ï€ and 6Ï€ electrocyclization reactions of dienyl diketones for the synthesis of cyclopentenones and 2H-Pyrans. J Org Chem 79:10296-302
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
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
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
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
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:
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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