Current investigations in our laboratory focus on the development of new synthetic methods and strategies, and their application in the total synthesis of natural products and biologically important compounds. A major thrust of our current research is the design and invention of new cycloaddition and annulation strategies for the synthesis of carbocyclic and heterocyclic compounds. Many of the methods under study involve the application of unusual molecules and highly reactive species as building blocks for the construction of important classes of organic compounds. We are particularly interested in the chemistry of highly unsaturated conjugated molecules (such as vinylketenes, iminoacetonitriles, conjugated enynes, and vinylallenes), and unusually strained molecules such as arynes, cycloalkynes, and cyclic allenes.
The utility of the methods under development is being tested and refined through their application in the total synthesis of biologically active natural products. Recent accomplishments include the total synthesis of the antitumor antibiotic ascochlorin, the azulene antiulcer drug egualen sodium, and neurotoxic alkaloids isolated from poison dart frogs. Considerable progress has also been made toward the first practical synthesis of glycinoeclepin A, the hatching stimulus agent of the soybean cyst nematode, a major agricultural pest. Other studies focus on the synthesis of unusual polycyclic aromatic systems with novel electronic and spectroscopic properties. Finally, another area of research in our lab focuses on the development of environmentally benign methods for organic synthesis. In this connection, for example, we are investigating the utility of supercritical water and carbon dioxide as reaction media for organic synthesis.
"Synthesis of Highly Substituted Indolines and Indoles via Intramolecular [4 + 2] Cycloaddition of Ynamides and Conjugated Enynes" J. R. Dunetz and R. L. Danheiser. J. Am. Chem. Soc. 2005, 127, 5776.
"Total Synthesis Quinolizidine Alkaloid (-)-217A. Application of Iminoacetonitrile Cycloadditions in Organic Synthesis", K. M. Maloney and R. L. Danheiser, Org. Lett. 2005, 7, 3115.
"Stereoselective Synthesis of Highly Substituted Cyclopentenones through [4 + 1] Annulations of Trialkylsilyl Vinyl Ketenes with ±-Benzotriazolyl Organolithium Compounds", C. P. Davie and R. L. Danheiser, Angew. Chem. Int. Ed. 2005, 44, 5867.
"The Reaction of (Trialkylsilyl)vinylketenes with Lithium Ynolates: A New Benzannulation Strategy", W. F. Austin, Y. Zhang, and R. L. Danheiser, Org. Lett. 2005, 7, 3905.
"Intramolecular [4+2] Cycloadditions of Benzynes with Conjugated Enynes, Arenynes, and Dienes", M. E. Hayes, H. Shinokubo, and R. L. Danheiser, Org. Lett. 2005, 7, 3917.
"Pictet-Spengler Reactions in Multiphasic Supercritical Carbon Dioxide/CO2-Expanded Liquid Media. In Situ Generation of Carbamates as a Strategy for Reactions of Amines in Supercritical Carbon Dioxide", J. R. Dunetz, R. P. Ciccolini, M. Fröling, S. M. Papp, A. J. Allen, A. B. Holmes, J. W. Tester, and R. L. Danheiser, Chem. Commun. 2005, 4465.
"Palladium Catalysed Aryl Amination Reactions in Supercritical Carbon Dioxide", C. J. Smith, M. W. S. Tsang, A. B. Holmes, R. L. Danheiser, and J. W. Tester, Org. Biomol. Chem. 2005, 3, 3767.
"Reaction Rates in Ultrasonic Emulsions of Dense Carbon Dioxide and Water", M. T. Timko, R. L. Danheiser, J. I. Steinfeld, J. W. Tester, and K. A. Smith, AIChE J. 2006, S2, 1127.
"[2 + 2] Cycloaddition of Ketenes with Ynamides. A General Method for the Synthesis of 3-Aminocyclobutenone Derivatives", A. L. Kohnen, X. Y. Mak, T. Y. Lam, J. R. Dunetz, and R. L. Danheiser, Tetrahedron 2006, 62, 3815.
“Synthesis of Terminal 1,3-Diynes via Sonogashira Coupling of Vinylidene Chloride Followed by Elimination. Preparation of 1,3-Decadiyne”, A. L. Kohnen and R. L. Danheiser, Organic Syntheses, 2007, 84, 77.
“Synthesis of Ynamides by N-Alkynylation of Amine Derivatives. Preparation of N-Allyl-N-(Methoxycarbonyl)-1,3-decadiynylamine”, A. L. Kohnen, J. R. Dunetz, and R. L. Danheiser, Organic Syntheses, 2007, 84, 88.
"A Benzannulation Strategy for the Synthesis of Phenols and Heteroaromatic Compounds Based on the Reaction of (Trialkylsilyl)vinylketenes with Lithium Ynolates", W. F. Austin, Y. Zhang, and R. L. Danheiser, Tetrahedron, 2008, 64, 915.
“Synthesis of Amides and Lactams in Supercritical Carbon Dioxide”, Mak, X. Y.; Ciccolini, R. P.; Robinson, J. M.; Tester, J. W.; Danheiser, R. L., J. Org. Chem. 2009, 74, 9381.
"Cyano Diels-Alder and Cyano Ene Reactions. Applications in a Formal [2 + 2 + 2] Cycloaddition Strategy for the Synthesis of Pyridines.", T. Sakai and R. L. Danheiser, J. Am. Chem. Soc. 2010, 132, 11039.
"Formal [2 + 2 + 2] Cycloaddition Strategy Based on an Intramolecular Propargylic Ene Reaction/Diels-Alder Cycloaddition Cascade", J. M. Robinson, T. Sakai, K. Okano, T. Kitawaki, and R. L. Danheiser, J. Am. Chem. Soc. 2010, 132, 13203.
"A New Route to Silyl-Substituted Cyclobutenones and Silyliketenes", K. Benda, T. Knoth, R. L. Danheiser, and E. Schaumann, Tetrahedron Lett. 2011, 52, 46.
"Synthesis of 2-Iodoynamides and Regioselective [2 + 2] Cycloadditions with Ketene", Y.-P. Wang and R. L. Danheiser, Tetrahedron Lett. 2011, ASAP.
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