Chemical synthesis of natural products inspired by their biogenesis is appealing due to the possibility to formulate biosynthetic hypotheses and invent the appropriate synthetic methodology to access synthetic targets. The proposed chemical synthesis studies should lead to the identification of novel, bioactive molecules and pharmacological tools. The overall goal of the project is to develop and refine biomimetic syntheses using copper-mediated enantioselective oxidation processes (Project 1), photochemical cycloaddition employing excited state intramolecular proton transfer (ESIPT) (Project 2), and asymmetric reactions of acylphloroglucinols (Project 3). Professor Porco and colleagues will apply these methodologies to the chemical synthesis of complex natural products including bisorbicillinol, sorbicillactone A, aglaiastatin, ponapensin, and myrtucommulones A and B. A collaboration in place with Professor Linda Doerrer (Boston University) will continue mechanistic investigations to understand the copper-mediated enantioselective oxygenase and oxidase processes. Likewise, a continuing collaboration with Professor Eric N. Jacobsen and coworkers (Harvard University) will seek to identify chiral thiourea photocatalysts for asymmetric photocycloadditions. Collaborations are also in place with biological collaborators including Dr. John A. Beutler (National Cancer Institute) and Professor Jerry Pelletier (McGill University) to evaluate compounds as anticancer agents and protein translation inhibitors.
The aims of the proposed project are to: 1) Synthesize the telomerase inhibitor (-) diazaphilonic acid, achieve the enantioselective syntheses of bisorbicillinol and bisvertilone using asymmetric oxidative dearomatization, achieve the enantioselective synthesis of the antileukemic agent sorbicillactone A, undertake mechanistic studies for copper-mediated oxidations using UV and Raman spectroscopy, and develop asymmetric oxidative dimerization of hydroxystyrene monomers to access 2,3-dihydrobenzofuran natural products. 2) Develop catalytic asymmetric photocycloaddition approaches to rocaglamide and related natural products employing chiral thioureas, achieve the syntheses of the aglain natural products ponapensin and foveoglin A and the rocaglates aglaiastatin and aglaroxin, and evaluate rocaglate and aglain compounds as protein translation inhibitors. 3) Develop asymmetric syntheses of the acylphloroglucinol natural products myrtucommulones A and B using chiral phase transfer catalysis and synthesize the natural product bullataketal A.

Public Health Relevance

This competing renewal application reflects the continuing interest of the Principal Investigator, John A. Porco, Jr., and colleagues in new chemical reaction development and synthesis of biorelevant molecules using approaches inspired by the biogenesis of complex natural products. The planned syntheses of complex natural products and derivatives are highly relevant to public health by facilitating identification of novel, bioactive molecules. The products of the proposed research ultimately should be useful as novel pharmacological tools and cytotoxic agents for treatment of various prevalent human malignancies, including human cancers.

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)
Program Officer
Lees, Robert G
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Boston University
Schools of Arts and Sciences
United States
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Kärkäs, Markus D; Porco Jr, John A; Stephenson, Corey R J (2016) Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis. Chem Rev 116:9683-747
Bhattacharya, Bidisha; Chatterjee, Sujoy; Devine, William G et al. (2016) Fine-tuning of macrophage activation using synthetic rocaglate derivatives. Sci Rep 6:24409
Boyce, Jonathan H; Eschenbrenner-Lux, Vincent; Porco Jr, John A (2016) Syntheses of (+)-30-epi-, (-)-6-epi-, (±)-6,30-epi-13,14-Didehydroxyisogarcinol and (±)-6,30-epi-Garcimultiflorone A Utilizing Highly Diastereoselective, Lewis Acid-Controlled Cyclizations. J Am Chem Soc 138:14789-14797
Gandin, Valentina; Masvidal, Laia; Hulea, Laura et al. (2016) nanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs. Genome Res 26:636-48
Chu, Jennifer; Cencic, Regina; Wang, Wenyu et al. (2016) Translation Inhibition by Rocaglates Is Independent of eIF4E Phosphorylation Status. Mol Cancer Ther 15:136-41
Chu, Jennifer; Galicia-Vázquez, Gabriela; Cencic, Regina et al. (2016) CRISPR-Mediated Drug-Target Validation Reveals Selective Pharmacological Inhibition of the RNA Helicase, eIF4A. Cell Rep 15:2340-7
Wang, Wenyu; Cencic, Regina; Whitesell, Luke et al. (2016) Synthesis of Aza-Rocaglates via ESIPT-Mediated (3+2) Photocycloaddition. Chemistry 22:12006-10
Qi, Chao; Xiong, Yuan; Eschenbrenner-Lux, Vincent et al. (2016) Asymmetric Syntheses of the Flavonoid Diels-Alder Natural Products Sanggenons C and O. J Am Chem Soc 138:798-801
Gervais, Anais; Lazarski, Kiel E; Porco Jr, John A (2015) Divergent Total Syntheses of Rhodomyrtosones A and B. J Org Chem 80:9584-91
Stone, Steven D; Lajkiewicz, Neil J; Whitesell, Luke et al. (2015) Biomimetic kinetic resolution: highly enantio- and diastereoselective transfer hydrogenation of aglain ketones to access flavagline natural products. J Am Chem Soc 137:525-30

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