This proposal focuses on the application of pericyclic reactions in new methodology for the synthesis of several important classes of carbocyclic and heterocyclic organic compounds. Part I describes the development of new strategies for the efficient synthesis of several classes of carbocyclic and heterocyclic compounds. Intramolecular [4 + 2] cycloaddition reactions of conjugated enynes will be investigated and employed in new routes to aromatic, dihydroaromatic, and seven-membered ring containing compounds. Heterocyclic variants of this process will be developed leading to five- and six-membered nitrogen and oxygen heterocycles. The application of this chemistry to the synthesis of pentacyclic polyketide marine natural products with protein tyrosine kinase inhibitory activity, the antitumor agent clavepictine A, and to the synthesis of quinolizidine and indolizidine alkaloids that are noncompetitive blockers for nicotinic receptor-channels will also be examined. Part II of the proposal describes the development of a tandem strategy in which a new ynamide-based benzannulation reaction is employed in conjunction with various heterocyclization processes to provide efficient access to polycyclic benzo-fused heteroaromatic systems including indoles, dihydroquinolines, and benzazocines. Applications of this chemistry to the synthesis of the antitumor agents ascochlorin and FR900482, the redox cofactor PQQ (methoxatin), and the alkaloid herbindole C are described. The new methods developed in this program will provide researchers with powerful new tools for the efficient chemical synthesis of several classes of organic compounds known to possess activity as pharmaceuticals. This research will thus benefit the development of new antimicrobial agents as well as drugs for the treatment of cancer, cardiovascular disease, and other disorders.

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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Hagan, Ann A
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Massachusetts Institute of Technology
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Willumstad, Thomas P; Boudreau, Paul D; Danheiser, Rick L (2015) Synthesis of Highly Substituted Quinolines via a Tandem Ynamide Benzannulation/Iodocyclization Strategy. J Org Chem 80:11794-805
Lam, Tin Yiu; Wang, Yu-Pu; Danheiser, Rick L (2013) Benzannulation via the reaction of ynamides and vinylketenes. application to the synthesis of highly substituted indoles. J Org Chem 78:9396-414
Willumstad, Thomas P; Haze, Olesya; Mak, Xiao Yin et al. (2013) Batch and flow photochemical benzannulations based on the reaction of ynamides and diazo ketones. Application to the synthesis of polycyclic aromatic and heteroaromatic compounds. J Org Chem 78:11450-69
Lan, Yu; Danheiser, Rick L; Houk, K N (2012) Why nature eschews the concerted [2 + 2 + 2] cycloaddition of a nonconjugated cyanodiyne. Computational study of a pyridine synthesis involving an ene-Diels-Alder-bimolecular hydrogen-transfer mechanism. J Org Chem 77:1533-8
Wang, Yu-Pu; Danheiser, Rick L (2011) Synthesis of 2-iodoynamides and regioselective [2+2] cycloadditions with ketene. Tetrahedron Lett 52:2111-2114
Benda, Konstantin; Knoth, Tanja; Danheiser, Rick L et al. (2011) A New Route to Silyl-substituted Cyclobutenones and Silylketenes. Tetrahedron Lett 52:46-48
Robinson, Julia M; Tlais, Sami F; Fong, Jennie et al. (2011) A [4 + 4] annulation strategy for the synthesis of eight-membered carbocycles based on intramolecular cycloadditions of conjugated enynes. Tetrahedron 67:9890-9898
Mak, Xiao Yin; Crombie, Aimee L; Danheiser, Rick L (2011) Synthesis of polycyclic benzofused nitrogen heterocycles via a tandem ynamide benzannulation/ring-closing metathesis strategy. Application in a formal total synthesis of (+)-FR900482. J Org Chem 76:1852-73
Robinson, Julia M; Sakai, Takeo; Okano, Katsuhiko et al. (2010) Formal [2 + 2 + 2] cycloaddition strategy based on an intramolecular propargylic ene reaction/Diels-Alder cycloaddition cascade. J Am Chem Soc 132:11039-41
Sakai, Takeo; Danheiser, Rick L (2010) Cyano Diels-Alder and cyano ene reactions. Applications in a formal [2 + 2 + 2] cycloaddition strategy for the synthesis of pyridines. J Am Chem Soc 132:13203-5

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