The goal of the proposed research is develop new chemical methodologies to enable the synthesis of bioactive flavonoid and xanthone-derived natural products that could lead to novel, anti-cancer and anti-infective agents. Chemical methodologies that will be developed include novel [4+2] dehydrogenative cycloadditions for the synthesis of prenylflavonoid and related Diels-Alder natural products, enantioselective [4+2] cycloadditions of 2'-hydroxychalcones and dienes using chiral boron complexes, metal-catalyzed, asymmetric rearrangement of 3-alloxyflavones, vinylogous addition of siloxyfurans to 5-hydroxychromones to synthesize tetrahydroxanthones, and photocycloaddition of m-quinone methide (m-QM) intermediates to construct bicyclo[3.2.2] ring systems. Professor Porco and colleagues will apply these new methodologies to the chemical synthesis of bioactive natural product targets including kuwanons G and H, sangennol F, sangennon C, sorocenol B, secalonic acids A and D, microsphaerin B, and acremoxanthone A. Collaborations are in place to evaluate compounds in biological assays, including their efficacy as human gastrin-releasing peptide receptor (GRP-R) antagonists, as inhibitors of the E3 ubiquitin ligase gp78, and against geographic isolates of the malarial parasite P. falciparum.
The aims of the proposed project are to: Achieve total syntheses of the GRP-R antagonists kuwanons G and H and the asymmetric syntheses of sorocenol B, sanggenol F, and sanggenons A and C. Develop asymmetric syntheses of the tetrahydroxanthones blennolides A and B and accomplish total syntheses of the dimeric natural products secalonic acids A and D and microsphaerin B. Achieve syntheses of the anti-infective agents acremodinin A and acremoxanthone A. The proposed project will enable new research directions for Professor Porco and his collaborators involving the use of nanoparticles in organic reactions, asymmetric catalysis, and novel cycloaddition strategies that are not possible with current grant programs.

Public Health Relevance

The goal of the proposed research program is to develop new methodologies for the syntheses of complex, flavonoid and xanthone-derived natural products and to study their biological properties in collaborative efforts. The relevance to public health of the planned syntheses of complex natural products entails identification of novel, biologically active antitumor and anti-infective agents. Specifically, such agents will be useful as novel pharmacological therapies and as cytotoxic agents against both human cancers and malaria.

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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Boston University
Schools of Arts and Sciences
United States
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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
Qin, Tian; Iwata, Takayuki; Ransom, Tanya T et al. (2015) Syntheses of Dimeric Tetrahydroxanthones with Varied Linkages: Investigation of ""Shapeshifting"" Properties. J Am Chem Soc 137:15225-33
Qin, Tian; Skraba-Joiner, Sarah L; Khalil, Zeinab G et al. (2015) Atropselective syntheses of (-) and (+) rugulotrosin A utilizing point-to-axial chirality transfer. Nat Chem 7:234-40
Qi, Chao; Qin, Tian; Suzuki, Daisuke et al. (2014) Total synthesis and stereochemical assignment of (±)-sorbiterrin A. J Am Chem Soc 136:3374-7
Yeung, Charles S; Ziegler, Robert E; Porco Jr, John A et al. (2014) Thiourea-catalyzed enantioselective addition of indoles to pyrones: alkaloid cores with quaternary carbons. J Am Chem Soc 136:13614-7
Boyce, Jonathan H; Porco Jr, John A (2014) Asymmetric, stereodivergent synthesis of (-)-clusianone utilizing a biomimetic cationic cyclization. Angew Chem Int Ed Engl 53:7832-7
Qin, Tian; Porco Jr, John A (2014) Total syntheses of secalonic acids?A and D. Angew Chem Int Ed Engl 53:3107-10
Xiong, Yuan; Schaus, Scott E; Porco Jr, John A (2013) Metal-catalyzed cascade rearrangements of 3-alkynyl flavone ethers. Org Lett 15:1962-5
Qi, Chao; Cong, Huan; Cahill, Katharine J et al. (2013) Biomimetic dehydrogenative Diels-Alder cycloadditions: total syntheses of brosimones A and B. Angew Chem Int Ed Engl 52:8345-8
Little, Andrew; Porco Jr, John A (2012) Total syntheses of graphisin A and sydowinin B. Org Lett 14:2862-5

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