Synthetic organic chemistry continues to play a dominant role in optimizing the therapeutic-activity of biologically active structures. Research in my group is directed toward the development of novel transition-metal-catalyzed carbon-carbon bond forming reactions applied to the carbocyclization of acyclic substrates. Our goal is to provide novel cyclization methodologies for organic synthesis that utilize common organic functional groups and proceed catalytic in metal. Our approach has been to address both mechanistic aspects of the cyclizations as well as simple synthetic applications of the new methods. During the tenure of this grant we will continue our investigations into catalytic metal-mediated carbocyclizations of trienes and tetraenes. The studies are designed to exploit the unique structure and reactivity of organometal intermediates to control the stereochemical and regiochemical course of carbon-carbon bond construction between two coordinated double bonds in the context of cyclization reactions. This competing renewal describes the continuing development of novel synthetic methodologies based upon catalytic transition-metal-mediated carbocyclizations. The proposed research is a blend of basic studies (e.g., substrates, trapping reagents, simple diastereoselectivity, 1,2- and 1,3- stereoinduction, enantioselective cyclization, new metal catalysts, etc.) on the catalytic metal-mediated carbocyclizations of trienes and tetraenes, and simple applications of the methodologies to the synthesis of biologically-active and/or medicinally-relevant ring systems. The proposed studies for the next four years are broken down into four parts. Part I is focussed on synthetic applications of the iron-catalyzed ene carbocyclizations of trienes and on the development of a complementary cobalt-catalyzed cyclization. Part 2 describes the continued development of palladium-catalyzed tetraene carbocyclizations. The proposed research in this section focuses on an application to the synthesis of prostanoids and on model studies relevant to the structural problems in the hydroazulenes and the central ring in the ionophore antibiotic Tetronasin (ICI 139603). Studies directed toward development of rhodium-catalyzed tetraene carbocyclizations is also described. Part 3 describes efforts to prepare enantiopure carbocyclic and heterocyclic ring systems in a stereocontrolled fashion through the use of recoverable chiral auxiliaries. Part 4 describes investigations into defining other new, but mechanistically related, carbocyclization reactions.
| Takacs, James M; Han, Jianxin (2004) Improving catalyst scope: use of multiple aniline substrates to optimize a palladium-catalyzed bisdiene cyclization. Org Lett 6:3099-102 |
| Takacs, James M; Schroeder, Scott D; Han, Jianxin et al. (2003) Controlling mode selectivity in palladium-catalyzed bisdiene carbocyclizations: optimizing for cyclization-trapping over cycloisomerization. Org Lett 5:3595-8 |
| Takacs, James M; Leonov, Alexei P (2003) Palladium-catalyzed bisdiene carbocyclizations: a facile [3 + 2] cycloaddition reaction mode. Org Lett 5:4317-20 |
| Takacs, James M; Xu, Zhenrong; Jiang, Xun-tian et al. (2002) Carbon nucleophiles in the Mitsunobu reaction. Mono- and dialkylation of bis(2,2,2-trifluoroethyl) malonates. Org Lett 4:3843-5 |
