Biomimetic Synthesis of Complex Natural Products The goals of the proposed continuing research program are to develop novel synthetic methods and biomimetic approaches to important classes of bioactive agents, as well as to evaluate compounds in strategic biological collaborations. Approaches include catalytic, asymmetric photocycloadditions using chiral trifluoroethanol catalysis guided by excited state computational analysis, syntheses of bioactive natural products using oxidative dearomatization with bis(?-oxo)dicopper(III) complexes including efforts towards catalytic asymmetric oxidations, and reductive isomerization of ?-alkynyl enones to vinyl allenones and subsequent cycloadditions to access vinylallene-derived natural products. The Principal Investigator, Professor John Porco, and his colleagues will use these new methodologies to synthesize bioactive natural products including the antitumor agents aglaiastatin, sorbicillactone A, chloropestolide A, and the antivira agent humulone. In collaborative studies with investigators at Boston University, the National Cancer Institute (NCI), the Novartis Institutes for BioMedical Research, McGill University, and the Whitehead Institute, Porco and his colleagues will assay the biological activity of the produced compounds. This proposed effort is organized into three core projects with the following aims: """""""" Develop catalytic asymmetric photocycloadditions of 3-hydroxyflavones and achieve asymmetric syntheses of the aglains foveoglin A and perviridisin B and the rocaglates aglaiastatin and aglaroxin. """""""" Complete asymmetric syntheses of (-)-sorbicillactone A, bisvertinolone and isobisvertinol, sorbifuranones A and C, and humulone and variants. """""""" Complete asymmetric syntheses of the antitumor natural products iso-A82775C, pestalofones B and C, chloropestolide A, and chloropupukeananin. This work will carry forward a highly productive research program for Professor Porco and his coworkers. Through their continued collaborations with biological researchers to assess bioactive natural products and derivatives, this new project will lead to the translation of such compounds into evaluation in clinical setting.

Public Health Relevance

Biomimetic Synthesis of Complex Natural Products The goals of the proposed continuing research program are to develop novel synthetic methods and biomimetic approaches to access important classes of bioactive agents and to explore fundamental questions of compound mechanism of action in strategic biological collaborations. The relevance to public health of the planned studies entails identification of novel, biologically active agents for use as pharmacological therapies for both viral illnesses and human cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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Boston University
Schools of Arts and Sciences
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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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