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 annulation strategies for the synthesis of carbocyclic and heterocyclic systems. The Diels-Alder reaction serves as a model for the type of general annulation methods that we seek to develop. This classic reaction occupies a position of unique esteem among all ring-forming strategies due to its remarkable stereoselectivity, regioselectivity, and broad scope of application. Our research is concerned with the development of annulation methods which are inspired by the Diels-Alder reaction, but which apply to the synthesis of other ring systems.

Methods under study include processes involving the application of unusual highly unsaturated, conjugated molecules such as vinylketenes, conjugated enynes, and related species as building blocks for the construction of important classes of carbocyclic and heterocyclic compounds. The utility of these methods 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 and the azulene antiulcer drug egualen sodium. 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. Recently we reported the first syntheses of simple alkyl and aryl-substituted cyclopent[a]phenalenes, as well as a new method for the synthesis of substituted azulenes. 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 and Properties of 9-Alkyl- and 9-Arylcyclopenta[a]phenalenes", K. M. Shea, K. L. Lee, and R. L. Danheiser. Org. Lett. 2000, 2, 2353.

“Total Synthesis of (-)-Ascochlorin via a Cyclobutenone-Based Benzannulation Strategy”, G. B. Dudley, K. S. Takaki, D. D. Cha, and R. L. Danheiser. Org. Lett. 2000, 2, 3407.

"A Ring Expansion-Annulation Strategy for the Synthesis of Substituted Azulenes. Preparation and Suzuki Coupling Reactions of 1-Azulenyl Triflates", J. L. Kane, K. M. Shea, A. L. Crombie, and R. L. Danheiser. Org. Lett. 2001, 3, 1081.

"Synthesis of 2-Indanones via [4+1] Annulation Reactions of (Trialkylsilyl)arylketenes", A. M. Dalton, Y. J. Zhang, C. P. Davie, and R. L. Danheiser. Org. Lett. 2002, 4, 2465.

"Intramolecular [4+2] Cycloadditions of Iminoacetonitriles: A New Class of Azadienophiles for Hetero Diels-Alder Reactions", D. T. Amos, A. R. Renslo, and R. L. Danheiser. J. Am. Chem. Soc. 2003, 125, 4970.

"Ultrasonic Emulsification of Liquid, Near-Critical Carbon Dioxide-Water Biphasic Mixtures for Acceleration of a Hydrolysis Reaction", M. T. Timko, J. M. Diffendal, J. W. Tester, K. A. Smith, W. A. Peters, R. L. Danheiser, and J. I. Steinfeld. J. Phys. Chem. A 2003, 107, 5503.

"Copper-Mediated N-Alkynylation of Carbamates, Ureas and Sulfonamides. A General Method for the Synthesis of Ynamides" J. R. Dunetz and R. L. Danheiser. Org. Lett. 2003, 5, 4011.

"Ring Expansion-Annulation Strategy for the Synthesis of Substituted Azulenes and Oligoazulenes. 2. Synthesis of Azulenyl Halides, Sulfonates, and Azulenylmetal Compounds and Their Application in Transition-Metal-Mediated Coupling Reactions" A. L. Crombie, J. L. Kane, Jr., K. M. Shea, and R. L. Danheiser. J. Org. Chem. 2004, 69, 8652.

"A Practical Method for the Synthesis of 2-Alkynylpropenals", C. Thongsornkleeb and R. L. Danheiser, J. Org. Chem. 2005, 70, 2364.

"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.

“Improved Conversion and Selectivity of a Diels-Alder Cycloaddition by Use of Emulsions of Carbon Dioxide and Water”, M. T. Timko, A. J. Allen, R. L. Danheiser, J. I. Steinfeld, K. A. Smith, and J. W. Tester, Ind. Eng. Chem. Res. 2006, 45, 1594.

"[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.